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EPA-HQ-OPP-2002-0096-0001

Notice

Norflurazon and Fenbutatin-Oxide Tolerance Reassessment Decisions; Notice of Abailability

[ Federal Register: June 11, 2002 ( Volume 67, Number 112)] [ Notices] [ Page 39980­ 39981] From the Federal Register Online via GPO Access [ wais. access. gpo. gov] [ DOCID: fr11jn02­ 70] ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ENVIRONMENTAL PROTECTION AGENCY [ OPP­ 2002­ 0096; FRL­ 7181­ 6] Norflurazon and Fenbutatin­ Oxide Tolerance Reassessment Decisions; Notice of Availability AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ SUMMARY: This notice of tolerance reassessment for norflurazon and fenbutatin­ oxide starts the 30­ day public comment period during which the public is invited to submit comments on the Agency's Report of the Food Quality Protection Act ( FQPA) Tolerance Reassessment Progress and Risk Management Decision ( TRED) for Norflurazon'' and Report of the Food Quality Protection Act ( FQPA) Tolerance Reassessment Progress and Risk Management Decision ( TRED) for Fenbutatin­ oxide.'' The Agency is providing an opportunity, through this notice, for interested parties to comment on the Agency's tolerance reassessment decisions in accordance with procedures described in Unit I of this document. All comments will be carefully considered by the Agency. If any comment causes the Agency to revise its decision on tolerance reassessment for norflurazon and/ or fenbutatin­ oxide, the Agency will publish notice of its amendment in the Federal Register. DATES: Comments, identified by docket ID number OPP­ 2002­ 0096, must be received on or before July 11, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I under SUPPLEMENTARY INFORMATION. To ensure proper receipt by the EPA, it is imperative that you identify docket ID number OPP­ 2002­ 0096 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Beth Edwards, telephone number: ( 703) 305­ 5400; e­ mail address: edwards. beth@ epa. gov for norflurazon; and Lorilyn Montford, telephone number: ( 703) 308­ 8170; e­ mail address: montford. lorilyn@ epa. gov for fenbuuutatin­ oxide, Special Review and Reregistration Division ( 7508C) Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general. This action may, however, be of interest to persons who are or may be required to conduct testing of chemical substances under the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) or the Federal Food, Drug, and Cosmetic Act ( FFDCA); environmental, human health, and agricultural advocates; pesticides users; and the public interested in the use of pesticides. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select Laws and Regulations,'' Regulations and Proposed Rules,'' and then look up the entry for this document under the Federal Register­­ Environmental Documents.'' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. To access TRED documents electronically, go directly to the TREDs table on the EPA Office of Pesticide Programs Home Page, at http:// www. epa. gov/ pesticides/ reregistration/ status. htm. 2. In person. The Agency has established an official record for this action under docket ID number OPP­ 2002­ 0096. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, including printed and paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity [[ Page 39981]] Branch ( PIRIB), Rm. 119, Crystal Mall 2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305­ 5805. C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by the EPA, it is imperative that you identify docket ID number OPP­ 2002­ 0096 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW, Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, Rm. 119, Crystal Mall 2, 1921 Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305­ 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0/ 9.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP­ 2002­ 0096. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI That I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the appropriate person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burdens or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the notice or collection activity. 7. Make sure to submit your comments by the deadline in this document. 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. Background A. What Action is the Agency Taking? This notice constitutes and announces the availability of the norflurazon and fenbutatin­ oxide TREDs. These decisions have been developed as part of the public participation process that EPA and the U. S. Department of Agriculture ( USDA) are using to involve the public in the reassessment of pesticide tolerances under FFDCA. The EPA must review tolerances and tolerance exemptions that were in effect when FQPA was enacted in August 1996, to ensure that these existing pesticide residue limits for food and feed commodities meet the safety standard of the new law. In reviewing these tolerances, the Agency must consider, among other things, aggregate risks from non­ occupational sources of pesticide exposure, whether there is increased susceptibility to infants and children, and the cumulative effects of pesticides with a common mechanism of toxicity. The tolerances are considered reassessed once the safety finding has been made that aggregate risks are not of concern. A reregistration eligibility decision ( RED) was completed for norflurazon in June 1996 and fenbutatin­ oxide in September 1994, prior to FQPA enactment, and therefore needed an updated assessment to consider the provisions of the Act. FFDCA requires that the Agency, when considering whether to establish, modify, or revoke a tolerance, consider available information'' concerning the cumulative effects of a particular pesticide's residues and other substances that have a common mechanism of toxicity.'' At this time, norflurazon and fenbutatin­ oxide have not been identified as sharing a common mechanism of toxicity and are not scheduled for a cumulative risk assessment. Additionally, the tolerances for norflurazon ( 58) and fenbutatin­ oxide ( 42) are now considered reassessed as safe under section 408( q) of FFDCA. The reregistration program is being conducted under Congressionally­ mandated time frames, and the EPA recognizes both the need to make timely reregistration decisions and to involve the public. Therefore, the Agency is issuing these TREDs as final documents because no risk mitigation or changes to existing labeling are necessary. All comments received within 30 days of publication of this Federal Register notice will be carefully considered by the Agency. If any comment significantly impacts a TRED, the Agency will amend its decision by publishing a Federal Register notice. B. What is the Agency's Authority for Taking this Action? The legal authority for these TREDs falls under FIFRA, as amended in 1988 and 1996. Section 4( g)( 2)( A) of FIFRA directs that, after submission of all data concerning a pesticide active ingredient, the Administrator shall determine whether pesticides containing such active ingredient are eligible for reregistration,'' and either reregistering products or taking other appropriate regulatory action.'' List of Subjects Environmental protection, Pesticide Tolerances. Dated: May 31, 2002. Lois A Rossi, Director, Special Review and Reregistration Division, Office of Pesticide Programs. [ FR Doc. 02­ 14636 Filed 6­ 10­ 02; 8: 45 am] BILLING CODE 6560­ 50­ S

epa

2024-06-07T20:31:42.054013

regulations

EPA-HQ-OPP-2002-0104-0001

Notice

Industrial Economics Inc.; Transfer of Data

39978 Federal Register / Vol. 67, No. 112 / Tuesday, June 11, 2002 / Notices involving rates or services applicable to public property. Small Business Regulatory Enforcement Fairness Act Western has determined that this rule is exempt from Congressional notification requirements under 5 U. S. C. 801 because the action is a rulemaking of particular applicability relating to rates or services and involves matters of procedure. Availability of Information Comments, letters, memorandums, or other documents made or kept by Western in developing the proposed rate will be made available for inspection and copying at the Rocky Mountain Customer Service Region located at 5555 East Crossroads Boulevard, Loveland, CO 80538 8986. Submission to the Federal Energy Regulatory Commission The interim rate herein confirmed, approved, and placed into effect, together with supporting documents, will be submitted to FERC for confirmation and final approval. Order I confirm and approve on an interim basis, effective July 1, 2002, Rate Schedule L AS4 for Energy Imbalance Service for the Western Area Colorado Missouri control area for the Western Area Power Administration. The rate schedule shall remain in effect on an interim basis, pending FERC confirmation and approval of it or a substitute rate on a final basis through March 31, 2003. Dated: May 30, 2002. Spencer Abraham, Secretary. Rate Schedule L AS4, ( Supersedes L T3); Schedule 4 to OATT, July 1, 2002. Department of Energy Western Area Power Administration, Rocky Mountain Region, Western Area Colorado Missouri Control Area; Schedule of Rate for Energy Imbalance Service Effective The first day of the first full billing period beginning on or after July 1, 2002, through March 31, 2003. Available Within the Rocky Mountain Customer Service Region's Western Area Colorado Missouri control area ( WACM). Applicable To customers receiving Energy Imbalance Service from WACM. Character and Conditions of Service WACM provides Energy Imbalance Service when there is a difference between a customer's resources and obligations. Energy Imbalance is calculated as resources minus obligations ( adjusted for transmission and transformer losses) for any combination of scheduled transfers, transactions, or actual load integrated over each hour. Both Federal transmission customers and customers on others' transmission systems within WACM must either obtain this service from WACM or make alternative comparable arrangements to satisfy its Energy Imbalance Service obligation. Formula Rate All Energy Imbalance Service provided, both inside and outside the bandwidth, will be settled financially, accounted for hourly at the end of each month. The WACM shall establish a deviation band of ± 5 percent ( with a minimum of 2 MW) of the actual load to be applied hourly to any energy imbalance that occurs as a result of a customer's schedules and/ or meter data. Normally, there are four scenarios for Energy Imbalance Service, each of which receive a specific pricing calculation. They are: ( 1) Over delivery within the bandwidth; ( 2) under delivery within the bandwidth; ( 3) over delivery outside the bandwidth; and ( 4) under delivery outside the bandwidth. During periods of control area operating constraints, Western reserves the right to eliminate credits for over deliveries and parties over delivering may share in the cost to Western of the penalty. Within the Bandwidth The gross energy imbalance for each applicable entity within WACM shall be totaled and netted to determine an aggregate energy imbalance for WACM. The sign of the aggregate energy imbalance will determine whether sale or purchase pricing will be used ( surplus conditions use sale pricing and deficit conditions will use purchase pricing). Depending upon the sign of the aggregate energy imbalance for all entities within WACM, the pricing for charges and credits within the bandwidth will be: Weighted Average Sale or Purchase Price @ 100%. Outside the Bandwidth Each entity within WACM will be charged or credited independently for Energy Imbalance Service taken, dependent upon their over­ or underdelivery status. Under Delivery ( customer deficit) = Customer will be charged 150% of the weighted average real­ time purchase price. Over Delivery ( customer surplus) = Customer will be credited 50% of the weighted average real­ time sale price. Expansion of the bandwidth will be allowed during the following instances: The loss of a physical resource. Upon evidence of proven frequency bias contribution for control area needs. The transition ( start up/ shut down) period for large thermal resources. Pricing Defaults When no hourly data is available, the pricing defaults for sales and purchase pricing both within and outside the bandwidth will be applied in the following order: Weighted average real­ time sale or purchase pricing for the day ( on and off peak). Weighted average real­ time sale or purchase pricing for the month ( on and off peak). Weighted average real­ time sale or purchase pricing for the prior month ( on and off peak). Weighted average real­ time sale or purchase pricing for the month prior to the prior month ( and continuing until sale or purchase pricing located) ( on and off peak). Billing The billing determinants for the above formula rates are specified in the final rate order and in the associated service agreement. [ FR Doc. 02 14609 Filed 6 10 02; 8: 45 am] BILLING CODE 6450 01 P ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0104; FRL 7182 7] Industrial Economics Inc.; Transfer of Data AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: This notice announces that pesticide related information submitted to EPA's Office of Pesticide Programs ( OPP) pursuant to the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) and the Federal Food, Drug, and Cosmetic Act ( FFDCA), including VerDate May< 23> 2002 20: 10 Jun 10, 2002 Jkt 197001 PO 00000 Frm 00031 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 11JNN1. SGM pfrm12 PsN: 11JNN1 39979 Federal Register / Vol. 67, No. 112 / Tuesday, June 11, 2002 / Notices information that may have been claimed as Confidential Business Information ( CBI) by the submitter, will be transferred to Industrial Economics Inc. in accordance with 40 CFR 2.307( h)( 3) and 2.308( i)( 2). Industrial Economics Inc. has been awarded multiple contracts to perform work for OPP, and access to this information will enable Industrial Economics Inc. to fulfill the obligations of the contract. DATES: Industrial Economics Inc. will be given access to this information on or before June 17, 2002. FOR FURTHER INFORMATION CONTACT: By mail: Erik R. Johnson, FIFRA Security Officer, Information Resources and Services Division ( 7502C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 305 7248; email address: johnson. erik@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action applies to the public in general. As such, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up the entry for this document under the `` Federal Register Environmental Documents.'' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. II. Contractor Requirements Under contract number GS 10F 0224J, the contractor will perform the following: EPA's Office of Enforcement and Compliance Assurance ( OECA) is responsible for providing assistance to enforcement professionals from EPA and the States in determining: ( 1) A violator's economic benefit of noncompliance; ( 2) the violator's ability to pay for compliance, clean­ ups and civil penalties ( hereinafter referred to as `` ability to pay''); ( 3) the value of a supplemental environmental project ( SEP); and ( 4) the value of compliance. This assistance is largely provided through five current computer models: Ben, Abel, Indipay, Munipay and Project. Ben calculates a violator's economic savings from violating the law. Abel, Indipay, and Munipay evaluate claims of inability to pay from for­ profit entities, individuals and municipalities, respectively. Project calculates the net­ present, after­ tax value of a proposed supplemental environmental project. OECA also provides support in these areas through the use of expert financial consultants where the models are insufficient. OECA must keep its models up to date, provide educational programs to ensure proper application of the models, support negotiations, trials and hearings, and provide advice to our enforcement professionals as to issues that arise in using the models. Since there are very few corporate finance, municipal finance, or accounting experts within OECA, the contractor shall provide that expertise and update the models, develop new models as appropriate and educate enforcement staff on the models. The contractor shall also provide expert advice to enforcement personnel regarding financial issues that impact enforcement litigation, and when directed, support enforcement negotiations, and appear as expert witnesses in hearings and trials. However, EPA employees will make all policy decisions in regard to finance/ accounting issues. To the extent that the work under this contract requires access to proprietary or confidential business or financial data of other companies, and as long as, such data remains proprietary or confidential, the contractor shall protect such data from unauthorized use and disclosure. All files or other information identified as CBI shall be treated as confidential and kept in a secure area with access limited to only contractor personnel directly involved in the case or special project assignment. The contractor, subcontractor, and consultant personnel are bound by the requirements and sanctions contained in their contracts with EPA and in EPA's confidentiality regulations found at 40 CFR part 2, subpart B. The contractor, subcontractors, and consultant must adhere to EPAapproved security plans which describe procedures to protect CBI, and are required to sign non­ disclosure agreements before gaining access to CBI. All official data, findings, and results of investigations and studies completed by the contractor shall be available for EPA and Department of Justice internal use only. The contractor shall not release any part of such data without the written direction of the project officer. This contract involves no subcontractors. OPP has determined that the contracts described in this document involve work that is being conducted in connection with FIFRA, in that pesticide chemicals will be the subject of certain evaluations to be made under this contract. These evaluations may be used in subsequent regulatory decisions under FIFRA. Some of this information may be entitled to confidential treatment. The information has been submitted to EPA under sections 3, 4, 6, and 7 of FIFRA and under sections 408 and 409 of FFDCA. In accordance with the requirements of 40 CFR 2.307( h)( 3), the contract with Industrial Economics Inc., prohibits use of the information for any purpose not specified in these contracts; prohibits disclosure of the information to a third party without prior written approval from the Agency; and requires that each official and employee of the contractor sign an agreement to protect the information from unauthorized release and to handle it in accordance with the FIFRA Information Security Manual. In addition, Industrial Economics Inc. is required to submit for EPA approval a security plan under which any CBI will be secured and protected against unauthorized release or compromise. No information will be provided to Industrial Economics Inc. until the requirements in this document have been fully satisfied. Records of information provided to Industrial Economics Inc. will be maintained by EPA Project Officers for these contracts. All information supplied to Industrial Economics Inc. by EPA for use in connection with these contracts will be returned to EPA when Industrial Economics Inc. has completed its work. List of Subjects Environmental protection, Business and industry, Government contracts, Government property, Security measures. Dated: June 3, 2002. Linda Vlier Moos, Acting Director, Information Resources and Services Division, Office of Pesticide Programs. [ FR Doc. 02 14635 Filed 6 10 02; 8: 45 am] BILLING CODE 6560 50 S VerDate May< 23> 2002 20: 10 Jun 10, 2002 Jkt 197001 PO 00000 Frm 00032 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 11JNN1. SGM pfrm12 PsN: 11JNN1

epa

2024-06-07T20:31:42.058615

regulations

EPA-HQ-OPP-2002-0108-0001

Notice

Pesticide Products; Registration Applications.

43114 Federal Register / Vol. 67, No. 123 / Wednesday, June 26, 2002 / Notices ENVIRONMENTAL PROTECTION AGENCY [ FRL 7237 9] Request for Nominations to the National and Governmental Advisory Committees to the U. S. Representative to the North American Commission for Environmental Cooperation AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice of request for nominations. SUMMARY: The U. S. Environmental Protection Agency ( EPA) is inviting nominations of qualified candidates to be considered for appointment to fill vacancies on the National and Governmental Advisory Committees to the U. S. Representative to the North American Commission for Environmental Cooperation. Current vacancies on these committees are scheduled to be filled by October 1, 2002. ADDRESSES: Submit nominations to: Mark Joyce, Designated Federal Officer, Office of Cooperative Environmental Management, U. S. Environmental Protection Agency ( 1601A), 1200 Pennsylvania Avenue NW., Washington, DC 20004. FOR FURTHER INFORMATION CONTACT: Mark Joyce, Designated Federal Officer, U. S. Environmental Protection Agency ( 1601A), 1200 Pennsylvania Avenue NW., Washington, DC 20004; telephone 202 564 9802; fax 202 501 0661; email joyce. mark@ epa. gov. SUPPLEMENTARY INFORMATION: The National and Governmental Advisory Committees advise the Administrator of the EPA in the Administrator's capacity as the U. S. Representative to the Council of the North American Commission for Environmental Cooperation ( CEC). The Committees are authorized under Articles 17 and 18 of the North American Agreement on Environmental Cooperation ( NAAEC), North American Free Trade Agreement ( NAFTA) Implementation Act, P. L. 103 182 and as directed by Executive Order 12915, entitled `` Federal Implementation of the North American Agreement on Environmental Cooperation.'' The Committees are responsible for providing advice to the United States Representative on a wide range of strategic, scientific, technological, regulatory and economic issues related to implementation and further elaboration of the NAAEC. The National Advisory Committee consists of 12 representatives of environmental groups and non­ profit entities, business and industry, and educational institutions. The Governmental Advisory Committee consists of 12 representatives from state, local and tribal governments. Members are appointed by the Administrator of EPA for a two year term with the possibility of reappointment. The Committees usually meet 3 times annually and the average workload for Committee members is approximately 10 to 15 hours per month. Members serve on the Committees in a voluntary capacity, but EPA does provide reimbursement for travel expenses associated with official government business. The following criteria will be used to evaluate nominees: They have extensive professional knowledge of the subjects the Committees examine, including trade and the environment, the NAFTA, the NAAEC, and the CEC. They represent a sector or group that is involved in the issues the Committees evaluate. They have senior level experience that will fill a need on the Committees for their particular expertise. They have a demonstrated ability to work in a consensus building process with a wide range of representatives from diverse constituencies. Nominees will also be considered with regard to the mandates of the Federal Advisory Committee Act that require the Committees to maintain diversity across a broad range of constituencies, sectors, and groups. Nominations for membership must include a resume describing the professional and educational qualifications of the nominee and the nominee's current business address and daytime telephone number. Dated: June 12, 2002. Mark N. Joyce, Designated Federal Officer. [ FR Doc. 02 16141 Filed 6 25 02; 8: 45 am] BILLING CODE 6560 50 P ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0108; FRL 7182 9] Pesticide Products; Registration Applications AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: This notice announces receipt of an application to register a pesticide product containing a new active ingredient not included in any previously registered products pursuant to the provisions of section 3( c)( 4) of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA), as amended. DATES: Written comments, identified by the docket ID number OPP 2002 0108, must be received on or before July 26, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002 0108 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By Mail: Regulatory Action Leader, Susanne Cerrelli, Biopesticides and Pollution Prevention Division ( 7511C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 308 8077 and e­ mail address: cerrelli. susanne@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? You may be affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Categories NAICS codes Examples of potentially affected entities Industry 111 Crop production 112 Animal production 311 Food manufacturing 32532 Pesticide manufacturing This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in the table could also be affected. The North American Industrial Classification System ( NAICS) codes have been provided to assist you and others in determining whether or not this action might apply to certain entities. If you have questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. VerDate May< 23> 2002 19: 57 Jun 25, 2002 Jkt 197001 PO 00000 Frm 00027 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 26JNN1. SGM pfrm17 PsN: 26JNN1 43115 Federal Register / Vol. 67, No. 123 / Wednesday, June 26, 2002 / Notices B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up the entry for this document under the `` Federal Register Environmental Documents.'' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. 2. In person. The Agency has established an official record for this action under docket ID number OPP 2002 0108. The official record consists of the documents specifically referenced in this action, any public comments received during an applicable comment period, and other information related to this action, including any information claimed as confidential business information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002 0108 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP 2002 0108. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI that I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person identified under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the registration activity. 7. Make sure to submit your comments by the deadline in this notice. 8. To ensure proper receipt by EPA, be sure to identify the docket control number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. Registration Application EPA received an application as follows to register a pesticide product containing an active ingredient not included in any previously registered products pursuant to the provision of section 3( c)( 4) of FIFRA. Notice of receipt of this application does not imply a decision by the Agency on the application. Product Containing an Active Ingredient not Included in any Previously Registered Product File Symbol: 70127 E. Applicant: Novozymes Biologicals, Inc., 111 Kelser Mill Road, Salem, VA 24153. Product name: Novozymes Biofungicide Green ReleafTM 710­ 140. Active ingredient: Bacillus licheniformis Strain SB3086 at 0.14%. Proposed classification/ Use: None. A biological fungicide for use on ornamental turf, lawns, golf courses, turf farms and ornamental plants as a preventive or curative treatment for several fungal diseases. List of Subjects Environmental protection, Pesticides and pest. Dated: June 12, 2002. Janet L. Andersen, Director, Biopesticides and Pollution Prevention Division, Office of Pesticide Programs. [ FR Doc. 02 16107 Filed 6 25 02; 8: 45 am] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0102; FRL 7182 2] Issuance of Experimental Use Permits AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: EPA has granted experimental use permits ( EUPs) to the following pesticide applicants. An EUP permits use of a pesticide for experimental or research purposes only in accordance with the limitations in the permit. VerDate May< 23> 2002 19: 57 Jun 25, 2002 Jkt 197001 PO 00000 Frm 00028 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 26JNN1. SGM pfrm17 PsN: 26JNN1

epa

2024-06-07T20:31:42.064010

regulations

EPA-HQ-OPP-2002-0114-0001

Notice

Exposure Modeling Work Group; Notice of Public Meeting

39718 Federal Register / Vol. 67, No. 111 / Monday, June 10, 2002 / Notices Application for Registration of Pesticide­ Producing Establishments ( EPA Form 3540 8), the Notification of Registration of Pesticide­ Producing Establishments ( EPA Form 3540 8A), and the Pesticides Report for Pesticide­ Producing Establishments ( EPA Form 3540 16). Application for Registration of Pesticide­ Producing Establishments information, collected on EPA Form 3540 8, is a one­ time requirement for all pesticide­ producing establishments. The reporting of pesticide production information collected on the Pesticides Report for Pesticide­ Producing Establishments, EPA Form 3540 16, is required within 30 days of receipt of the Notification of Registration of Pesticide­ Producing Establishments ( EPA Form 3540 8A); and then annually thereafter, on or before March 1. The information is entered and stored in EPA's Office of Enforcement and Compliance Assurance ( OECA)/ Office of Compliance ( OC) Section Seven Tracking System ( SSTS), a computerized data processing and record­ keeping system. The Office of Compliance/ OECA collects the establishment and pesticide production information for compliance oversight and risk assessment. The information is used by EPA Regional pesticide enforcement and compliance staffs, OECA, and the Office of Pesticide Programs ( OPP) within the Office of Prevention, Pesticides and Toxic Substances ( OPPTS), as well as the U. S. Department of Agriculture ( USDA), the Food and Drug Administration ( FDA), other Federal agencies, States under Cooperative Enforcement Agreements, and the public. An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. The OMB control numbers for EPA's regulations are listed in 40 CFR part 9 and 48 CFR chapter 15. The Federal Register Notice required under 5 CFR 1320.8( d), soliciting comments on this collection of information was published on 11/ 26/ 2001 ( 66 FR 59017), and no comments were received. Burden Statement: The annual public reporting and record keeping burden for this collection of information is estimated to be an average of 18 minutes for a one time response for the Application for Registration of Pesticide­ Producing Establishments ( EPA Form 3540 8), and 1 hour and 26 minutes for the annual yearly response for the Pesticides Report for Pesticide­ Producing Establishments ( EPA Form 3540 16). There is no public burden associated with the Notification of Registration of Pesticide­ Producing Establishments ( EPA Form 3540 8A) because EPA completes this form. Burden means the total time, effort, or financial resources expended by persons to generate, maintain, retain, or disclose or provide information to or for a Federal agency. This includes the time needed to review instructions; develop, acquire, install, and utilize technology and systems for the purposes of collecting, validating, and verifying information, processing and maintaining information, and disclosing and providing information; adjust the existing ways to comply with any previously applicable instructions and requirements; train personnel to be able to respond to a collection of information; search data sources; complete and review the collection of information; and transmit or otherwise disclose the information. The burden associated with this ICR is described below: Respondents/ Affected Entities: Pesticide producing establishments. Estimated Number of Respondents: 12,412. Frequency of Response: One time and yearly. Estimated Total Annual Hour Burden: 17,959 hours. Estimated Total Annualized Cost Burden: $ 0. Send comments on the Agency's need for this information, the accuracy of the provided burden estimates, and any suggested methods for minimizing respondent burden, including through the use of automated collection techniques to the addresses listed above. Please refer to EPA ICR No. 0160.07 and OMB Control No. 2070 0078 in any correspondence. Dated: May 29, 2002. Oscar Morales, Director, Collection Strategies Division. [ FR Doc. 02 14486 Filed 6 7 02; 8: 45 am] BILLING CODE 6560 50 U ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0114; FRL 7183 4] Exposure Modeling Work Group; Notice of Public Meeting AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: The Exposure Modeling Work Group ( EMWG) will hold a 1 day meeting on June 18, 2002. This notice announces the location and time for the meeting and sets forth the tentative agenda topics. DATE: The meeting will be held on June 18, 2002, from 9 a. m. to 3 p. m. ADDRESSES: This meeting will be held at the George Washington Carver Center, Room 4223, 5601 Sunnyside Ave., Beltsville, MD. FOR FURTHER INFORMATION CONTACT: James N. Carleton, Environmental Fate and Effects Division ( 7507C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 305 5736; fax number: ( 703) 308 6309; e­ mail address: carleton. jim@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general. This action may, however, be of interest to Tribes with pesticide programs or pesticide interests. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov. To access this document, on the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up the entry for this document under the `` Federal Register Environmental Documents.'' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr. 2. In person. The Agency has established an official record for this action under docket ID number OPP 2002 0114. The official record consists of the documents specifically referenced in this action, any public comments received during an applicable comment period, and other information related to this action, including any information claimed as Confidential Business Information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which VerDate May< 23> 2002 20: 20 Jun 07, 2002 Jkt 197001 PO 00000 Frm 00048 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 10JNN1. SGM pfrm17 PsN: 10JNN1 39719 Federal Register / Vol. 67, No. 111 / Monday, June 10, 2002 / Notices includes printed, paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. II. Tentative Agenda: This unit provides tentative agenda topics for the 1 day meeting. 1. Welcome and introductions. 2. Old action items. 3. Discussion of purpose of EMWG. 4. Update on screening concentration in ground water ( SCI­ GROW). 5. Update on basin­ scale modeling. 6. Fate database structure. 7. Rice modeling and new Environmental Fate Effects Division Model. 8. Update on Watershed Regression for Pesticides ( WARP). 9. Overview of EFED's procedure for developing new scenarios. List of Subjects Environmental protection, Pesticides and pests. Dated: June 5, 2002. Elizabeth Leovey, Acting Director, Environmental Fate and Effects Division, Office of Pesticide Programs. [ FR Doc. 02 14618 Filed 6 6 02; 1: 50 pm] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0109; FRL 7183 3] Technical Briefing on the Draft Revised Organophosphate Pesticide Cumulative Risk Assessment; Notice of Public Meeting; Changes and Additions AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: EPA previously announced in the Federal Register of May 15, 2002 ( 67 FR 34707) ( FRL 6836 3), a public technical briefing on the revisions to the preliminary organophosphate pesticide cumulative risk assessment, followed the next day by a public meeting of the CARAT Workgroup on Cumulative Risk Assessment/ Public Participation Process. The location of the CARAT Cumulative Risk Assessment/ Public Participation Process Workgroup meeting on June 19, 2002, has been changed to be the same as that of the technical briefing. In addition, a meeting of the CARAT Workgroup on Transition has been added on June 20, 2002. All three meetings will be held in the same location. DATES: The technical briefing will be held on Tuesday, June 18, 2002, from 9 a. m. to 5 p. m. In addition, EPA and the U. S. Department of Agriculture will hold public meetings of two CARAT Workgroups: Cumulative Risk Assessment/ Public Participation Process Workgroup on Wednesday, June 19, 2002, from 9 a. m. to 4 p. m., and the Workgroup on Transition on Thursday, June 20, 2002, from 1 p. m. to 5 p. m. ADDRESSES: The technical briefing and both CARAT Workgroup meetings will be held at the Holiday Inn Select, 480 King St., Old Town Alexandria, VA. The telephone number for the hotel is ( 703) 549 6080. The hotel is located about 10 blocks from the King Street Metro Station. FOR FURTHER INFORMATION CONTACT: By mail: Karen Angulo, Special Review and Registration Division ( 7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: 703 308 8004; email address: angulo. karen@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action applies to the public in general. As such, the Agency has not attempted to specifically describe all the entities potentially affected by this action. The Agency believes that a wide range of stakeholders will be interested in technical briefings on organophosphate pesticides, including environmental, human health, and agricultural advocates, the chemical industry, pesticide users, and members of the public interested in the use of pesticides on food. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov. To access this document, on the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up the entry for this document under the `` Federal Register Environmental Documents.'' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr. To access information about organophosphate pesticides, you can also go directly to the Home Page for the Office of Pesticide Programs ( OPP) at http:// www. epa. gov/ pesticides/ op: In addition, information about the cumulative process and the preliminary organophosphate cumulative risk assessment documents are found at http:// www. epa. gov/ pesticides/ cumulative. 2. In person. The Agency has established an official record under docket ID number OPP 2002 0109. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. II. How Can I Request to Participate in this Meeting? This meeting is open to the public. Outside statements by observers are welcome. Verbal statements will be limited to 3 to 5 minutes, and it is preferred that only one person per organization present the statement. Any person who wishes to file a written statement may do so immediately before or after the meeting. These statements will become part of the public version of the official record and will be available for public inspection at the address listed in Unit I. List of Subjects Environmental protection, Chemicals, Pesticides and pests. VerDate May< 23> 2002 20: 20 Jun 07, 2002 Jkt 197001 PO 00000 Frm 00049 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 10JNN1. SGM pfrm17 PsN: 10JNN1

epa

2024-06-07T20:31:42.068608

regulations

EPA-HQ-OPP-2002-0126-0001

Notice

Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food

70073 Federal Register / Vol. 67, No. 224 / Wednesday, November 20, 2002 / Notices ADDRESSES: The meeting will be held at Doubletree Hotel, 300 Army Navy Drive, Arlington, VA FOR FURTHER INFORMATION CONTACT: Georgia McDuffie, Field and External Affairs Division ( 7506c), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460 0001; telephone number: ( 703) 605 0195; fax number: ( 703) 308 1850; email address: mcduffie. georgia@ epa. gov. or Philip H. Gray, SFIREG Executive Secretary, P. O. Box 1249, Hardwick, VT 05843 1249; telephone number: ( 802) 472 6956; fax ( 802) 472 6957; e­ mail address: aapco@ plainfield. bypass. com. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general, and may be of particular interest to `` those persons who are or may be required to conduct testing of chemical substances under the Federal Food, Drug and Cosmetic Act ( FFDCA), or the FIFRA''. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. Can I Get Copies of this Document and Other Related Information? 1. Docket. EPA has established an official public docket for this action under docket ID number OPP 2002 0306. The official public docket consists of the documents specifically referenced in this action, any public comments received, and other information related to this action. Although, a part of the official docket, the public docket does not include Confidential Business Information ( CBI) or other information whose disclosure is restricted by statute. The official public docket is the collection of materials that is available for public viewing at the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The docket telephone number is ( 703) 305 5805. 2. Electronic access. You may access this Federal Register document electronically through the EPA Internet under the `` Federal Register'' listings at http:// www. epa. gov/ fedrgstr/. An electronic version of the public docket is available through EPA's electronic public docket and comment system, EPA dockets. You may use EPA dockets at http:// www. epa. gov/ edocket/ to view public comments, access the index listing of the contents of the official public docket, and to access those documents in the public docket that are available electronically. Although, not all docket materials may be available electronically, you may still access any of the publicly available docket materials through the docket facility identified in Unit I. B. 1. Once in the system, select `` search,'' then key in the appropriate docket ID number. II. Tentative Agenda: 1. Committee Business Issues. 2. Regional Reports & Introduction of Issue Papers/ Action Items. 3. Comments to the Committee/ Open Discussion with EPA Senior Managers ( To be determined). 4. Worker Protection Standard ( WPS) Program Element Review Update. 5. Non­ English/ Multiple Language Labels. 6. Tribal Pesticide Program Council ( TPPC)/ Section 18s & other Tribal Issues. 7. Update on Current OPP & OECA Activities. 8. SFIREG Issue Paper Status Report. 9. Closed Session. 10. Pesticide Regulatory Education Program ( PREP) Briefing/ Issues. 11. Soybean Rust Pest/ Section 18s Requests. 12. Status ( SLA) Label Improvement Project Proposals i. e. Mosquito Products/ West Nile virus Issues 13. States Label Issue Tracking System ( SLITS) Update 14. Certification Training Assessment Group ( CTAG) Update & Discussion 15. Issue Papers/ Past & Present List of Subjects Environmental protection, Pesticide and pests. Dated: November 6, 2002. Jay Ellenberger, Associate Director, Field and External Affairs Division, Office of Pesticide Programs. [ FR Doc. 02 29171 Filed 11 19 02; 8: 45 a. m.] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0126; FRL 7184 7] Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: This notice announces the initial filing of a pesticide petition proposing the establishment of regulations for residues of a certain pesticide chemical in or on various food commodities. DATES: Comments, identified by docket ID number OPP 2002 0126, must be received on or before December 20, 2002. ADDRESSESS: Comments may be submitted electronically, by mail, or through hand delivery/ courier. Follow the detailed instructions as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002 0126 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By mail: Joanne I. Miller, Registration Division, Office of Pesticide Programs, ( 7505C) Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 305 6224; e­ mail address: miller. joanne@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? You may be affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Categories NAICS codes Examples of potentially affected entities Industry 111 Crop productionmption 112 Animal production 311 Food manufacturing 32532 Pesticide manufacturing VerDate 0ct< 31> 2002 16: 46 Nov 19, 2002 Jkt 200001 PO 00000 Frm 00031 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 20NON1. SGM 20NON1 70074 Federal Register / Vol. 67, No. 224 / Wednesday, November 20, 2002 / Notices This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in this unit could also be affected. The North American Industrial Classification System ( NAICS) codes have been provided to assist you and others in determining whether this action might apply to certain entities. To determine whether you or your business may be affected by this action, you should examine the applicability provisions in OPP 2002 0126. If you have questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Copies of this Document and Other Related Information? 1. Docket. EPA has established an official public docket for this action under docket identification ( ID) number OPP 2002 0126. The official public docket consists of the documents specifically referenced in this action, any public comments received, and other information related to this action. Although a part of the official docket, the public docket does not include Confidential Business Information ( CBI) or other information whose disclosure is restricted by statute. The official public docket is the collection of materials that is available for public viewing at the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The docket telephone number is ( 703) 305 5805. 2. Electronic access. You may access this Federal Register document electronically through the EPA Internet under the `` Federal Register'' listings at http:// www. epa. gov/ fedrgstr/. An electronic version of the public docket is available through EPA's electronic public docket and comment system, EPA Dockets. You may use EPA Dockets at http:// www. epa. gov/ edocket/ to submit or view public comments, access the index listing of the contents of the official public docket, and to access those documents in the public docket that are available electronically. Once in the system, select `` search,'' then key in the appropriate docket ID number. Certain types of information will not be placed in the EPA Dockets. Information claimed as CBI and other information whose disclosure is restricted by statute, which is not included in the official public docket, will not be available for public viewing in EPA's electronic public docket. EPA's policy is that copyrighted material will not be placed in EPA's electronic public docket but will be available only in printed, paper form in the official public docket. To the extent feasable, publicly available docket materials will be made available in EPA's electronic public docket. When a document is selected from the index list in EPA Dockets, the system will identify whether the document is available for viewing in EPA's electronic public docket. Although not all docket materials may be available electronically, you may still access any of the publicly available docket materials through the docket facility identified in Unit I. B. 1. EPA intends to work towards providing electronic access to all of the publicly available docket materials through EPA's electronic public docket. For public commenters, it is important to note that EPA's policy is that public comments, whether submitted electronically or in paper, will be made available for public viewing in EPA's electronic public docket as EPA receives them and without change, unless the comment contains copyrighted material, CBI, or other information whose disclosure is restricted by statute. When EPA identifies a comment containing copyrighted material, EPA will provide a reference to that material in the version of the comment that is placed in EPA's electronic public docket. The entire printed comment, including the copyrighted material, will be available in the public docket. Public comments submitted on computer disks that are mailed or delivered to the docket will be transferred to EPA's electronic public docket. Public comments that are mailed or delivered to the docket will be scanned and placed in EPA's electronic public docket. Where practical, physical objects will be photographed, and the photograph will be placed in EPA's electronic public docket along with a brief description written by the docket staff. C. How and to Whom Do I Submit Comments? You may submit comments electronically, by mail, or through hand delivery/ courier. To ensure proper receipt by EPA, identify the appropriate docket ID number in the subject line on the first page of your comment. Please ensure that your comments are submitted within the specified comment period. Comments received after the close of the comment period will be marked `` late.'' EPA is not required to consider these late comments. If you wish to submit CBI or information that is otherwise protected by statute, please follow the instructions in Unit I. D. Do not use EPA Dockets or e­ mail to submit CBI or information protected by statute. 1. Electronically. If you submit an electronic comment as prescribed in this unit, EPA recommends that you include your name, mailing address, and an email address or other contact information in the body of your comment. Also include this contact information on the outside of any disk or CD ROM you submit, and in any cover letter accompanying the disk or CD ROM. This ensures that you can be identified as the submitter of the comment and allows EPA to contact you in case EPA cannot read your comment due to technical difficulties or needs further information on the substance of your comment. EPA's policy is that EPA will not edit your comment, and any indentifying or contact information provided in the body of a comment will be included as part of the comment that is placed in the official public docket, and made available in EPA's electronic public docket. If EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may not be able to consider your comment, i. EPA Dockets. Your use of EPA's electronic public docket to submit comments to EPA electronically is EPA's preferred method for receiving comments. Go directly to EPA Dockets at http:// www. epa. gov/ edocket, and follow the online instructions for submitting comments. Once in the system, select `` search,'' and then key in docket ID number OPP 2002 0126. The system is an `` anonymous access'' system, which means EPA will not know your identity, e­ mail address, or other contact information unless you provide it in the body of your comment. ii. E­ mail. Comments may be sent by e­ mail to opp­ docket@ epa. gov, Attention: Docket ID Number OPP 2002 0126. In contrast to EPA's electronic public docket, EPA's email system is not an `` anonymous access'' system. If you send an e­ mail comment directly to the docket without going through EPA's electronic public docket, EPA's e­ mail system automatically captures your e­ mail address. E­ mail addresses that are automatically captured by EPA's e­ mail system are included as part of the comment that is placed in the official public docket, and made available in EPA's electronic public docket. iii. Disk or CD ROM. You may submit comments on a disk or CD ROM that VerDate 0ct< 31> 2002 16: 46 Nov 19, 2002 Jkt 200001 PO 00000 Frm 00032 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 20NON1. SGM 20NON1 70075 Federal Register / Vol. 67, No. 224 / Wednesday, November 20, 2002 / Notices you mail to the mailing address identified in Unit I. C. 2. These electronic submissions will be accepted in WordPerfect or ASCII file format. Avoid the use of special characters and any form of encryption. 2. By mail. Send your comments to: Public Information and Records Integrity Branch ( PIRIB) ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460 0001, Attention: Docket ID Number Opp 2002 0126. 3. By hand delivery or courier. Deliver your comments to: Public Information and Records Integrity Branch ( PIRIB), Office of Pesticide Programs ( OPP), Environmental Protection Agency, Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket ID Number OPP 2002 0126. Such deliveries are only accepted during the docket's normal hours of operation as identified in Unit I. B. 1. D. How Should I Submit CBI to the Agency? Do not submit information that you consider to be CBI electronically through EPA's electronic public docket or by e­ mail. You may claim information that you submit to EPA as CBI by marking any part or all of that information as CBI ( if you submit CBI on disk or CD ROM, mark the outside of the disk or CD ROM as CBI and then identify electronically within the disk or CD ROM the specific information that is CBI). Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public docket and EPA's electronic public docket. If you submit the copy that does not contain CBI on disk or CD ROM, mark the outside of the disk or CD ROM ckearly that it does not contain CBI. Information not marked as CBI will be included in the public docket and EPA's electronic public docket without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the notice or collection activity. 7. Make sure to submit your comments by the deadline in this document. 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. What Action is the Agency Taking? EPA has received a pesticide petition as follows proposing the establishment and/ or amendment of regulations for residues of a certain pesticide chemical in or on various food commodities under section 408 of the Federal Food, Drug, and Cosmetic Act ( FFDCA), 21 U. S. C. 346a. EPA has determined that this petition contains data or information regarding the elements set forth in section 408( d)( 2); however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition. List of Subjects Environmental protection, Pesticides and pests. Dated: October 27, 2002. Debra Edwards, Acting Director, Registration Division, Office of Pesticide Programs. Summary of Petition The petitioner summary of the pesticide petition is printed below as required by section 408( d)( 3) of the FFDCA. The summary of the petition was prepared by Nichino America Incorporated, and represents the view of Nichino America Incorporated. The petition summary announces the availability of a description of the analytical methods available to EPA for the detection and measurement of the pesticide chemical residues, or an explanation of why no such method is needed. Nichino America Incorporated PP 1F6428 EPA has received a pesticide petition ( 1F6428) from Nichino America Incorporated, 4550 New Linden Hill Road, Suite 501, Wilmington, DE 19808 proposing, pursuant to section 408( d) of the FFDCA, 21 U. S. C. 346a( d), to amend 40 CFR part 180, by establishing a tolerances for combined residues of pyraflufen­ ethyl ( ethyl 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetate) and its acid metabolite, E 1, ( 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetic acid) expressed as the ester equivalent in or on the raw agricultural commodities ( RACs) derived from cotton; undelinted seed at 0.05 parts per million ( ppm); and gin byproducts at 1.5 ppm; in or on the RAC potato at 0.02 ppm; in or on the RACs corn grain, corn stover, corn forage, soybean seed, soybean forage, and soybean hay at 0.01 ppm; wheat forage, wheat hay, wheat straw, and wheat grain at 0.01 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408( d)( 2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The qualitative nature of the residues of pyraflufenethyl ( ET 751) in cotton, potatoes, corn, soybeans, and wheat is adequately understood. The metabolism of pyraflufen­ ethyl has been studied in cotton, wheat, and potato. Metabolism in the plant involves ester hydrolysis, de­ methylation on the pyrazole ring and further degradation of the phenoyxyacetate moiety to bound polar metabolites. The nature of the residue is adequately understood and the residues of concern are the parent, pyraflufenethyl and the acid metabolite, E 1, only. 2. Analytical method. The enforcement analytical method utilizes gas chromatography/ mass spectrophotometry with selected ion monitoring for detecting and measuring levels of pyraflufen­ ethyl and the acid metabolite with a general limit of quantification ( LOQ) of 0.02 ppm ( combined E 1 and parent). This method allows detection of residues at or above the proposed tolerances. The method has undergone independent laboratory validation as required by PR Notices 88 5 and 96 1. 3. Magnitude of residues in crops i. Potato. No apparent residues of pyraflufen­ ethyl were observed in potato at or above 0.02 ppm ( the LOQ VerDate 0ct< 31> 2002 16: 46 Nov 19, 2002 Jkt 200001 PO 00000 Frm 00033 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 20NON1. SGM 20NON1 70076 Federal Register / Vol. 67, No. 224 / Wednesday, November 20, 2002 / Notices for the analytical method). The field studies, conducted at 3x the highest intended label use rate, in 16 trials in 11 states, clearly support the proposed tolerances of 0.02 ppm ( combined E 1 and parent). No detectable residues of parent or the acid metabolite were observed in any processed potato fraction at 5x the maximum proposed application rate and proposed preharvest interval ( PHI) in a field study, with the LOQ of 0.02 ppm ( combined E 1 and parent). The tolerance that is being proposed for the use of pyraflufen­ ethyl plus the acid metabolite on potato is 0.02 ppm. ii. Cotton. Twelve field residue trials were conducted in seven different states. Applications in the trials were 3x the proposed label directions for use and at the proposed PHI of 7 days. Analysis of the treated samples showed that the residues of pyraflufen­ ethyl ( ethyl 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetate) plus its acid metabolite, E 1, ( 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetic acid) expressed as the ester equivalent at the exaggerated rate, were below the proposed tolerance of 0.05 ppm in cotton seed at the proposed labeled PHI in all samples. No residues were seen in the processed fractions of meal, hull, and oil, when one trial was run in a typical cotton growing area. The application rate for this processing study was 15x the maximum proposed application rate and at the proposed PHI. This indicates that there is no concentration of pyraflufen­ ethyl ( ethyl 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetate) plus its acid metabolite, E 1, ( 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetic acid), expressed as the ester equivalent in any of the processed fractions. Low residues seen in the undelinted cottonseed were consistent with the magnitude of residue trials. Combined residues of pyraflufen­ ethyl ( ethyl 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetate) plus its acid metabolite, E 1 ( 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetic acid) in cotton gin byproducts from applications at 3x the proposed application rate ranged from 0.125 ppm to 1.314 ppm, and averaged 0.035 ppm from applications made at 1x the proposed application rate. The proposed tolerance of 0.05 ppm for pyraflufen­ ethyl ( ethyl 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ fluorophenoxyacetate) plus its acid metabolite, E 1, ( 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetic acid) in cotton seed and 1.5 ppm in cotton gin byproducts are supported by the field residue data. iii. Corn. Three exaggerated rate residue trials were conducted in three different states on different soil types. Applications in the trials were 5x to 10x the proposed label directions for use as a pre­ plant burndown herbicide. Analysis of the treated samples showed zero residues of pyraflufen­ ethyl ( ethyl 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetate) plus its acid metabolite, E 1, ( 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetic acid) expressed as the ester equivalent at the exaggerated rate. The LOQ for the parent and the metabolite was 0.005 ppm in each case. Since no residues were observed at exaggerated rates in RACs, no processing studies were conducted. iv. Soybean. Three exaggerated rate residue trials were conducted in three different states on different soil types. Applications in the trials were 5x to 10x the proposed label directions for use as a pre­ plant burndown herbicide. Analysis of the treated samples showed zero residues of pyraflufen­ ethyl ( ethyl 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetate) plus its acid metabolite, E­ 1, ( 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetic acid) expressed as the ester equivalent at the exaggerated rate. The LOQ for the parent and the metabolite was 0.005 ppm in each case. Since no residues were observed at exaggerated rates in RACs, no processing studies were conducted. v. Wheat. Three exaggerated rate residue trials were conducted in three different states on different soil types. Applications in the trials were 5x to 10x the proposed label directions for use as a pre­ plant burndown herbicide. Analysis of the treated samples showed zero residues of pyraflufen­ ethyl ( ethyl 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetate) plus its acid metabolite, E 1, ( 2­ chloro­ 5­( 4­ chloro­ 5­ difluoromethoxy­ 1­ methylpyrazol­ 3­ yl)­ 4­ fluorophenoxyacetic acid) expressed as the ester equivalent at the exaggerated rate. The LOQ for the parent and the metabolite was 0.005 ppm in each case. Since no residues were observed at exaggerated rates in RACs, no processing studies were conducted. 4. Magnitude of the residue in animals. i. Ruminants. The maximum dietary burden in beef and dairy cows results from a diet comprised of undelinted cottonseed, cotton meal, cotton hulls, cotton gin byproducts, potato culls, potato waste, and from grain ( seed), forage, hay, stover ( fodder), silage, meal, hulls, straw, aspirated grain fractions, and milled byproducts of corn, soybeans, and wheat for a total dietary burden that is significantly lower than levels that would require the proposal of tolerances in ruminants. This conclusion is based on exaggerated rate animal metabolism studies carried out on pyraflufen­ ethyl and its significant metabolites. Therefore, an exemption from tolerances in milk, meat, and meat by­ products under 40 CFR 180.6( a)( 3) and ( b) is proposed as it is not possible to establish with certainty whether finite residues will be incurred, but there is no reasonable expectation of finite residues. ii. Poultry. The maximum poultry dietary burden results from a diet comprised of cotton meal, corn grain, corn milled byproducts, soybean seed, soybean meal, soybean hulls, wheat grain, and wheat milled byproducts for a total dietary burden that is significantly lower than the levels that would require the proposal of tolerances in poultry. This conclusion is based on the exaggerated rate metabolism studies carried out on pyraflufen­ ethyl and its acid metabolite. Therefore, an exemption from tolerances in poultry meat, meat byproducts, fat, and eggs under 40 CFR 180.6( a)( 3) and ( b) is proposed as it is not possible to establish with certainty whether finite residues will be incurred, but there is no reasonable expectation of finite residues. B. Toxicological Profile 1. Acute toxicity. Pyraflufen­ ethyl technical is considered to be nontoxic ( toxicity category IV) to the rat by the oral route of exposure. In an acute oral toxicity study conducted in rats, the oral LD50 value for technical pyraflufen­ ethyl was determined to be > 5,000 milligrams/ kilograms body weight ( mg/ kg bwt). The results from the acute dermal toxicity study in rabbits indicate that pyraflufen­ ethyl is slightly toxic ( toxicity category III) to rabbits by the dermal route of exposure. The dermal LD50 value of technical pyraflufen­ ethyl was determined to be > 2,000 mg/ kg for both male and female rabbits. Pyraflufen­ ethyl technical is considered to be nontoxic ( toxicity category IV) to the rat by the respiratory route of exposure. Inhalation exposure of rats to pyraflufen­ ethyl technical resulted in an VerDate 0ct< 31> 2002 16: 46 Nov 19, 2002 Jkt 200001 PO 00000 Frm 00034 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 20NON1. SGM 20NON1 70077 Federal Register / Vol. 67, No. 224 / Wednesday, November 20, 2002 / Notices LC50 > 5.53 milligrams/ Liter ( mg/ L) ( analytical) for both males and females. Pyraflufen­ ethyl technical was shown to be non­ irritating to rabbit skin ( toxicity category IV). Pyraflufen­ ethyl technical was shown to be slightly irritating to rabbit eyes ( toxicity category III). Application of technical material to the rabbit eye resulted in iris and conjunctival irritation from 1 to 24 hours, which was clear by 72 hours. Based on the results of a dermal sensitization study, pyraflufen­ ethyl technical is not considered a sensitizer in guinea pigs. 2. Genotoxicity. Pyraflufen­ ethyl technical was not mutagenic in any of the following genotoxicity studies. Point mutations in bacteria in an Ames study with Salmonella typhimurium, and Escherichia coli; negative in chromosome aberrations in vitro human lymphocytes, and in the mouse micronucleus; negative for DNA repair in in vitro and in vivo rat liver hepatocyte assays and Bacillus subtillis. For mammalian gene mutation, in one in vitro mouse lymphoma mutation assay, no evidence of mutagenicity was seen in the absence of metabolic activation. With S9 activation at levels up to 200 i g/ Liter, equivocal results were seen. The study report provided no criteria for positive or negative responses. When this in vitro study was repeated, no positive or equivocal results in the presence of activation with S9 at levels of S9 up to 350 i g/ Liter were seen. These levels of activation were greater than those tested in the earlier study and both small and large colonies were counted. The overall weight of evidence indicates that pyraflufen­ ethyl is not genotoxic. 3. Reproductive and developmental toxicity. The developmental toxicity study in rats conducted with pyraflufenethyl technical showed no evidence of teratogenic effects in fetuses and no evidence of developmental toxicity. Thus, pyraflufen­ ethyl is neither a developmental toxicant nor a teratogen in the rat. Pyraflufen­ ethyl was administered by gavage during gestation and showed no adverse effects on dams or fetuses at dose levels of 0, 100, 300, up to and including a limit dose of 1,000 mg/ kg/ day. The maternal and developmental toxicity no observe adverse effects ( NOAELs) were both > 1,000 mg/ kg/ day. Results from a developmental toxicity study in rabbits conducted with pyrafluflen­ ethyl technical also indicated no evidence of teratogenicity or developmental toxicity. Thus, pyraflufen­ ethyl technical is neither a developmental toxicant nor a teratogen in the rabbit. Rabbits fed pyraflufen­ ethyl at 0, 20, 60, or 150 mg/ kg/ day, resulted in severe maternal toxicity, including lethality, from gastrointestinal irritation at doses of 60 and 150 mg/ kg/ day. The maternal NOAEL was 20 mg/ kg/ day. The NOAEL for the offspring was 60 mg/ kg/ day, based on increased post­ implantation loss observed at 150 mg/ kg/ day. Neither the rat nor the rabbit developmental study showed evidence of unique fetal susceptibility to pyraflufen­ ethyl. In a multigeneration rat reproduction study conducted at dietary concentrations of 0, 100, 1,000 and 10,000 ppm, pyraflufen­ ethyl had no effect on reproductive parameters, including mating indices, fertility index, gestation index, duration of gestation, numbers of implantation sites, numbers and morphology of epididymal sperm, and estrous cycle at any dose level. Reproductive performance was not affected by pyraflufen­ ethyl at the highest dose level of 10,000 ppm ( male 721 to 844 mg/ kg/ day and female 813 to 901 mg/ kg/ day). The pup NOAEL was 1,000 ppm, based on decreased body weight in the F1 and F2 male and female pups on day 17 at the 10,000 ppm dose level. Results from the reproduction study and the developmental toxicity studies conducted with pyraflufen­ ethyl technical show no increased sensitivity to developing offspring as compared to parental animals, because the NOAELs for growth and development of offspring were equal to or greater than the NOAELs for parental or maternal toxicity. 4. Subchronic toxicity. A short­ term ( 28 day) dermal study in rabbits was conducted with pyraflufen­ ethyl technical. Pyraflufen­ ethyl was administered dermally to rats for 28 days at dose levels of 0, 300, and 1000 mg/ kg day. Slight, transient erythema was observed during week 3 in 3 treated males. This finding was not doserelated was not considered to be adverse, and the relationship to the test material administration was unclear. The NOAEL was considered to be 1,000 mg/ kg/ day. A 90 day rat feeding study was conducted at dose levels of 0, 200, 1,000, 5,000, or 15,000 ppm pyraflufenethyl The NOAEL in this study was considered to be 1,000 ppm ( 85.6 mg/ kg/ day for males and 95.4 mg/ kg/ day for females), based on slightly increased phosphorous concentrations in females and hepatocytic hypertrophy in males at 5,000 ppm. In addition, the highest dose of 15,000 ppm resulted in erythocyte toxicity, mitochondrial changes in the hepatocytes and the presence of Kupffer cells. Also, at the high dose level increased kidney weights in males and increased absolute and relative spleen weights in both sexes were observed. In a 90 day oral toxicity study in dogs, pyraflufen­ ethyl was administered via capsule at dose levels of 0, 40, 200, and 1,000 mg/ kg/ day. No treatmentrelated findings were observed and the NOAEL was determined to be > 1,000 mg/ kg/ day. At the limit dose, no effects in body weight or organ weights, clinical chemistry, hematology, histopathology, and gross pathology were observed. To determine whether the test material was absorbed or not, plasma was collected 1 hour after administration of pyraflufen­ ethyl during week 13. The detection of 2 major degradation products, E 1 and E 9, confirmed the adsorption and gastrointestinal and systemic exposure to pyraflufen­ ethyl. 5. Chronic toxicity. A 1 year chronic dog study was conducted in Beagle dogs, with pyraflufen­ ethyl administered orally by gelatin capsule at doses of 0, 40, 200, and 1,000 mg/ kg/ day. There were no mortalities and no clinical signs of toxicity. No treatmentrelated effects were noted on body weights, food consumption, hematology and clinical chemistry parameters, urinalysis, ophthmoscopy, and organ weights. No macrosopic or microscopic lesions were noted. The NOAEL was > 1,000 mg/ kg/ day. In a 2 year chronic toxicity/ oncogenicity study, pyraflufen­ ethyl was administered to CD rats at dietary levels of 0, 80, 400, 2,000, or 10,000 ppm ( equivalent to 0, 3.4, 17.2, 86.7, and 468.1 mg/ kg/ day for males and 0, 4.4, 21.8, 111.5, and 578.5 mg/ kg/ day for females). Mortality was unaffected by treatment. Body weight gain was statistically significantly depressed for those rats fed 10,000 ppm at 1 year compared to the control. Treatmentrelated histopathology was seen in the kidney, liver, and bile duct at 10, 000 ppm. At 2,000 and 10,000 ppm, vacuoles within the mitochondria of centriacinar and periacinar hepatocytes were seen. Effects on urine volume, urine specific gravity, and kidney weights were seen at 2,000 ppm in males. The NOAEL was 17.2 mg/ kg/ day for males and 21.8 mg/ kg/ day for females. No evidence of carcinogenicity was observed. In a 78 week carcinogenicity study, mice were fed pyraflufen­ ethyl in the diet at levels of 0, 200, 1,000, or 5,000 ppm ( equivalent to 0, 21, 110, 547 mg/ kg/ day for males and 0. 20, 98, 524 mg/ kg/ day for females). An maximum tolerance dose ( MTD) was reached at 1,000 ppm, based on increased liver weight and liver histopathological changes ( including necrosis) seen at this VerDate 0ct< 31> 2002 16: 46 Nov 19, 2002 Jkt 200001 PO 00000 Frm 00035 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 20NON1. SGM 20NON1 70078 Federal Register / Vol. 67, No. 224 / Wednesday, November 20, 2002 / Notices feeding level. In the highest dose group, effects of pyraflufen­ ethyl on hematological parameters were observed. The incidence of hepatocellular adenoma was increased in animals receiving 5,000 ppm, compared to controls. This benign tumor was likely induced by the adaptive response to the hepatocellular degeneration and not as a result of any genotoxic potential of pyraflufen­ ethyl. In addition the response was observed only at a dose level that was in excess of an MTD. 6. Animal metabolism. The qualitative nature of the residues of pyraflufenethyl and its acid metabolite, E 1, in animals is adequately understood. Pyraflufen­ ethyl is rapidly absorbed, metabolized, and excreted to feces and urine, with greater than 90% of the administered dose excreted within 24 hours in rats. Based on metabolism studies with goats, hens, and rats, there is no reasonable expectation that measurable pyraflufen­ ethyl­ related residues will occur in meat, milk, poultry, or eggs from the proposed use. 7. Metabolite toxicology. No toxicologically significant metabolites were detected in plant or animal metabolism studies for cotton or potatoes. 8. Endocrine disruption. Chronic, lifespan, and multigenerational bioassays in mammals and acute and subchronic studies on aquatic organisms and wildlife did not reveal any endocrine effects for pyraflufen­ ethyl. Any endocrine related effects would have been detected in this comprehensive series of required tests. The probability of any such effect due to agricultural uses of pyraflufen­ ethyl is negligible. C. Aggregate Exposure 1. Dietary exposure. The potential dietary exposure to pyraflufen­ ethyl has been calculated from the proposed tolerances for use on cotton, and potato. While tolerances at the LOQ are proposed for corn, soybean, and wheat, it is concluded that there is no potential for residues in these crops and thus no dietary exposure. These very conservative chronic dietary exposure estimates used the tolerance value for all the raw agricultural commodities. In addition these estimates assume that 100% of the cotton and potato crops contain pyraflufen­ ethyl residues. i. Food. The chronic population adjusted dose ( cPAD) for the general population, based on residues at the tolerance levels and 100% of potato and cotton crops treated is expected to be approximately 0.000020 mg/ kg bwt/ day or < 0.1% of the reference dose ( RFD) ( 0.172 mg/ kg/ day). Of the standard subgroups analyzed by the dietary exposure evaluation model ( DEEM), the subgroup with the highest exposures are children ages 1 to 6 years, with a cPAD of 0.000041 mg/ kg/ day or less than 0.1% of the RfD mg/ kg/ day. With children ages 7 to 12 with exposures of 0.000027 mg/ kg/ day, the exposure is less than 0.1% of the RfD. ii. Drinking water. As a screening level assessment for aggregate exposure, EPA evaluates drinking water level of comparison ( DWLOC), which is the maximum concentration of a chemical in drinking water that would be acceptable in terms of total aggregate exposure to that chemical. Based on the chronic RFD of 0.172 mg/ kg/ day, based on the NOAEL of 17.2 mg/ kg/ day observed in the chronic rat feeding study and an uncertainty factor ( UF) of 100, and EPA's default factors for body weight and drinking water consumption, the DWLOCs have been calculated to assess the potential dietary exposure from residues of pyraflufenethyl and the acid metabolite, E 1, in water. For the adult population, the chronic DWLOC was 35,086 parts per billion ( ppb) for the U. S. population, and for children 10,172 ppb. Chronic drinking water exposure analyses were calculated using EPA screening models, screening concentration in ground water ( SCIGROW for ground water and generic expected environmental concentration ( GENEEC) for surface water). The calculated peak GENEEC value for the acid metabolite, E 1, the major degradation of pyraflufen­ ethyl which is formed within an hour of addition to a water solution or to soil, is 0.3321 ppb and the SCI­ GROW value is 0.00024 ppb. These values are very conservative estimates compared to the values derived from the parent. Nonetheless, for the U. S. adult population, the estimated exposures of the E 1 acid metabolite in surface water and ground water are approximately 0.00094% and 0.0000007%, respectively, of the DWLOC. For children, the estimated exposures of the acid metabolite in surface water and ground water are approximately 0.0033% and 0.000002%, respectively of the DWLOC. Therefore, the exposures to drinking water from the acid metabolite are negligible. Based on the dietary and drinking water assessments, aggregate exposure to residues of pyraflufen­ ethyl and the acid metabolite in food and water can be considered to be negligible. 2. Non­ dietary exposure. It is being proposed that pyraflufen­ ethyl be registered in the following non­ food sites: airports, commercial plants, fence lines, farmyards, and farm buildings; storage and lumber yards; barrier strips and firebreaks; equipment areas, nurseries and ornamental plantings; established ornamental turf; railroad, roadside, and utility rights­ of­ ways; dry ditches and ditch banks; fuel tank farms and pumping stations; other similar non­ crop areas. Exposure to pyraflufenethyl for the mixer/ loader/ groundboom/ aerial applicator was calculated using the Pesticides Handlers Exposure Database ( PHED). These PHED assessments were based on a 70 kg operator treating 80 acres per day using ground boom equipment on both cotton and potato fields; an operator treating 1,200 acres per day using aerial equipment on cotton fields; and an operator treating 350 acres per day using aerial equipment on potato fields ( EPA, 1999) at a maximum use rate of 0.009 pounds active ingredient per acre for potato and 0.0045 pounds active ingredient per acre for cotton. All workers were assumed to be wearing long pants and long­ sleeved shirts. Mixer­ loaders were assumed to be wearing gloves, while aerial and ground applicators and flaggers were not assumed to be wearing gloves. Margins of exposure ( MOE) for acute and shortterm exposure were calculated utilizing a dermal and inhalation NOAEL of 20 mg/ kg/ day, based on maternal toxicity seen in the rabbit teratology study at 60 mg/ kg/ day, and assuming 100% dermal absorption. MOEs for intermediate­ term exposure were calculated utilizing a dermal endpoint of 250 mg/ kg/ day, the systemic NOAEL from the 28 day dermal toxicity study in the rat with the 2.5% EC formulation. This was the highest dose level in the study and no systemic effects were seen at this dose level. For the acute inhalation endpoint we used 86 mg/ kg/ day, based on a NOAEL of 1,000 ppm or 85.6 mg/ kg/ day in males in the 90 day oral feeding study in the rat. The combined MOE ( inhalation plus dermal) for pyraflufenethyl was greater than 4,900 for acute and short­ term exposure, while the intermediate­ term total MOEs were all greater than 56,000. The results indicate that large margins of safety exist for the proposed uses of pyraflufen­ ethyl. D. Cumulative Effects Pyraflufen­ ethyl belongs to the protox inhibitor class of compounds, and chemically is a 3­ phenylpyrazole. The herbicidal activity of protox inhibitors is due to the inhibition of protoporphyrinogen IX oxidase. All relevant toxicological data has been provided to EPA. Chemicals with a similar mode of action, i. e., the protox inhibitors, have different chemical VerDate 0ct< 31> 2002 16: 46 Nov 19, 2002 Jkt 200001 PO 00000 Frm 00036 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 20NON1. SGM 20NON1 70079 Federal Register / Vol. 67, No. 224 / Wednesday, November 20, 2002 / Notices structures compared to pyraflufen­ ethyl. Although other protox inhibitors have a similar herbicidal mode of action, there is no information available to suggest that these compounds exhibit a similar toxicity profile in the mammalian system. We are aware of no information to indicate or suggest that pyraflufenethyl has any toxic effects on mammals that would be cumulative with those of any other chemical. Since pyraflufenethyl is relatively non­ toxic, cumulative effects of residues and other compounds are not anticipated. Therefore, for the purposes of this Food Quality Protection Act ( FQPA) document, there should be no consideration of cumulative risk that would require assessment. E. Safety Determination 1. U. S. population. Based on the chronic toxicity data, the RfD for pyraflufen­ ethyl is considered to be 0.172 mg/ kg/ day. This value is based on the NOAEL of 17.2 mg/ kg/ day observed in the chronic rat feeding study and a safety ( uncertainty) factor of 100, the worse case estimate of chronic dietary exposure of pyraflufen­ ethyl from cotton, potatoes, corn, or soybean will utilize less than 0.1% of the RfD for the general U. S. population. EPA generally has no concern for exposures below 100% of the RfD because the RfD represents the level at or below which daily aggregate dietary exposure over a lifetime will not pose appreciable risks to human health. The complete and reliable toxicity data and the conservative chronic exposure assumptions support the conclusion that there is a reasonable certainty of no harm from dietary ( food) exposure to pyraflufen­ ethyl and the acid metabolite residues. Moreover, as exposure to residues of pyraflufen­ ethyl and the acid metabolite via water is negligible, there is a reasonable certainty of no harm from aggregate exposure to pyraflufenethyl and the acid metabolite residues. 2. Infants and children. The conservative estimates, as described above, indicate that chronic dietary exposure of pyraflufen­ ethyl and the acid metabolite from cotton and potato will utilize less than 0.1% of the RfD for non­ nursing infants, less than 0.1% of the RfD for children ages 1 to 6; and less than 0.1% of the RfD for all populations examined. No developmental, reproductive, or fetotoxic effects were noted at the highest doses of pyraflufenethyl tested in guideline reproductive or developmental toxicity studies. Based on the current toxicological data requirements, the data base relative to prenatal and postnatal effects for children is complete, valid and reliable. Results from the teratology studies and the 2 generation reproduction study support NOAELs for fetal/ developmental effects or reproductive/ offspring effects, respectively, equivalent to the highest concentrations tested. As such, there is no increased sensitivity of infants and children to residues of pyraflufen­ ethyl. Therefore, an additional safety ( uncertainty) factor is not warranted, and the RfD of 0.172 mg/ kg/ day, which utilizes a 100 fold safety factor, is appropriate to assure a reasonable certainty of no harm to infants and children. F. International Tolerances There is no Codex maximum residue level established for residues of pyraflufen­ ethyl and the acid metabolite on any crops. [ FR Doc. 02 29330 Filed 11 19 02; 8: 45 am] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY [ FRL 7410 5] Notice of Availability of Enforcement and Compliance History Online Web Site for 60­ Day Comment Period AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice of information availability and request for comments. SUMMARY: The Office of Compliance ( OC), within EPA's Office of Enforcement and Compliance Assurance ( OECA), announces the availability of and invites comments on its new Web site, Enforcement and Compliance History Online ( ECHO), which contains searchable, facility­ level enforcement and compliance information. DATES: Comments must be submitted no later than January 21, 2003. ADDRESSES: The Web site is available at http:// www. epa. gov/ echo. Comments may be submitted to echo@ epa. gov as a Word or WordPerfect file or mailed to Rebecca Kane, Environmental Protection Agency, Office of Enforcement and Compliance Assurance, MC 2222A, 1200 Pennsylvania Avenue NW., Washington, DC 20460. Specific data errors should be submitted using the error correction process on the ECHO site. FOR FURTHER INFORMATION CONTACT: Rebecca Kane at kane. rebecca@ epa. gov or ( 202) 564 5960. SUPPLEMENTARY INFORMATION: I. ECHO Background EPA is committed to public access to environmental information and has worked to develop a format for providing Internet access to facilitylevel compliance and enforcement information contained in core EPA data systems. Though the data included within ECHO previously were available to the public primarily through Freedom of Information Act requests, the information was not available in a searchable Web format. This new egovernment initiative makes it much easier for the public to obtain these data records on the Internet. EPA has worked with State governments to develop the content of the site and ensure accurate data and has pilot tested Internet access. A Joint EPA­ State Enforcement and Compliance Public Access Workgroup developed the template for the type, sources, and amount of data to be included within ECHO. This workgroup, developed in partnership with the Environmental Council of the States ( ECOS), made its recommendations in June 2000. EPA has field tested the approach and the data through: the Sector Facility Indexing Project ( http:// www. epa. gov/ sfipmtn1/), which shows data for a limited number of industrial sectors, and a four­ State pilot in the Pacific Northwest ( http:// www. epa. gov/ idea/ region10). Public feedback and lessons learned from these projects contributed to the development of the ECHO site. To prepare for launch of ECHO, EPA and the States conducted a comprehensive data review to ensure high quality information. ECHO also includes on the site an online error reporting process that allows users to alert EPA and the States to possible errors. This notice announces a 60­ day comment period, which is being provided to give interested parties, particularly those responsible for facilities included within the database, the opportunity to review ECHO's content, design, and accuracy of data. II. ECHO Data ECHO provides integrated compliance and enforcement information for approximately 800,000 regulated facilities nationwide. The site allows users to find facility­ level inspection, violation, enforcement action, and penalty information for the past two years. Facilities regulated under the Clean Air Act ( CAA) Stationary Source Program, Clean Water Act ( CWA) National Pollutant Elimination Discharge System ( NPDES), and Resource Conservation and Recovery Act ( RCRA) are included. ECHO reports provide a snapshot of a facility's environmental record, showing dates and types of violations, as well as the State or Federal government's response. VerDate 0ct< 31> 2002 16: 46 Nov 19, 2002 Jkt 200001 PO 00000 Frm 00037 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 20NON1. SGM 20NON1

epa

2024-06-07T20:31:42.075083

regulations

EPA-HQ-OPP-2002-0138-0001

Notice

Carbaryl: Availability of Risk Assessments.

55233 Federal Register / Vol. 67, No. 167 / Wednesday, August 28, 2002 / Notices For more current information: http:// epa. gov/ air/ caaac/ mobile sources. html. Individuals or organizations wishing to provide comments to the Subcommittee should submit them to Ms. Hogan at the address above by September 30, 2002. The Mobile Sources Technical Review Subcommittee expects that public statements presented at its meetings will not be repetitive of previously submitted oral or written statements. SUPPLEMENTARY INFORMATION: During this meeting, the Subcommittee may also hear progress reports from some of its workgroups as well as updates and announcements on activities of general interest to attendees. Dated: August 21, 2002. Margo T. Oge, Director, Office of Transportation and Air Quality. [FR Doc. 02– 21947 Filed 8– 27– 02; 8: 45 am] BILLING CODE 6560– 50– P ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0138; FRL– 7194– 2] Carbaryl; Availability of Risk Assessment AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: This notice announces the availability of documents that were developed as part of EPA's process for making pesticide reregistration eligibility decisions and tolerance reassessments consistent with the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA). These documents are the human health and environmental fate and effects risk assessments and related documents for carbaryl. This notice also starts a 60– day public comment period for the risk assessments. Comments are to be limited to issues directly associated with carbaryl and raised by the risk assessment or other documents placed in the docket. By allowing access and opportunity for comment on the risk assessment, EPA is seeking to strengthen stakeholder involvement and help ensure that our decisions under FQPA are transparent and based on the best available information. The tolerance reassessment process will ensure that the United States continues to have the safest and most abundant food supply. The Agency cautions that the risk assessments for carbaryl are preliminary and that further refinements may be appropriate. Risk assessments reflect only the work and analysis conducted as of the time they were produced and it is appropriate that, as new information becomes available and/ or additional analyses are performed, the conclusions they contain may change. DATES: Comments, identified by the docket ID number OPP– 2002– 0138 carbaryl, must be received on or before October 28, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0138 for carbaryl in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Anthony Britten, Special Review and Reregistration Division (7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 308– 8179; email address: britten. anthony@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general. This action may, however, be of interest to a wide range of stakeholders, including environmental, human health, and agricultural advocates; the chemical industry; pesticide users; and members of the public interested in the use of pesticides. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. On the Home Page select `` Laws and Regulations, '' `` Regulations and Proposed Rules, '' and then look up the entry for this document under the `` Federal Register— Environmental Documents. '' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. In addition, copies of the risk assessment and certain related documents for carbaryl may also be accessed at http: www. epa. gov/ pesticides/ reregistration/ status. htm. 2. In person. The Agency has established an official record for this action under docket ID number OPP– 2002– 0138. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0138 for carbaryl in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described VerDate Aug< 23> 2002 14: 18 Aug 27, 2002 Jkt 197001 PO 00000 Frm 00040 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 28AUN1. SGM 28AUN1 55234 Federal Register / Vol. 67, No. 167 / Wednesday, August 28, 2002 / Notices above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0/ 9.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP– 2002– 0138. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI that I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the notice. 7. Make sure to submit your comments by the deadline in this document. 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. Background A. What Action is the Agency Taking? EPA is making available risk assessments that have been developed as part of the Agency's public participation process for making reregistration eligibility and tolerance reassessment decisions for the organophosphate and other pesticides consistent with FFDCA, as amended by FQPA. The Agency's human health and environmental fate and effects risk assessments and other related documents for carbaryl are available in the individual pesticide docket. As additional comments, reviews, and risk assessment modifications become available, these will also be docketed for carbaryl. The Agency cautions that the carbaryl risk assessments are preliminary and that further refinements may be appropriate. Risk assessment documents reflect only the work and analysis conducted as of the time they were produced and it is appropriate that, as new information becomes available and/ or additional analyses are performed, the conclusions they contain may change. EPA is providing an opportunity, through this notice, for interested parties to provide written comments and input to the Agency on the risk assessment for the pesticide specified in this notice. Such comments and input could address, for example, the availability of additional data to further refine the risk assessments, such as percent crop treated information or submission of residue data from food processing studies, or could address the Agency's risk assessment methodologies and assumptions as applied to this specific chemical. Comments should be limited to issues raised within the risk assessment and associated documents. EPA will provide other opportunities for public comment on other science issues associated with the pesticide tolerance reassessment program. Failure to comment on any such issues as part of this opportunity will in no way prejudice or limit a commenter's opportunity to participate fully in later notice and comment processes. All comments should be submitted by October 28, 2002 using the methods in Unit I. of the SUPPLEMENTARY INFORMATION. Comments will become part of the Agency record for carbaryl. List of Subjects Environmental protection, Chemicals, Pesticides and pests. Dated: August 15, 2002. Betty Shackleford, Acting Director, Special Review and Reregistration Division, Office of Pesticide Programs. [FR Doc. 02– 21586 Filed 8– 27– 02; 8: 45 am] BILLING CODE 6560– 50– S ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0205; FRL– 7193– 7] Pesticide Product; Registration Applications AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: This notice announces receipt of an application to register a pesticide product containing a new active ingredient not included in any previously registered product pursuant to the provisions of section 3( c)( 4) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), as amended. DATES: Written comments, identified by the docket ID number OPP– 2002– 0205, must be received on or before September 27, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0205 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By mail: Raderrio Wilkins, Biopesticides and Pollution Prevention Division (7511C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 308– 1259 and e­ mail address: wilkins. raderrio@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? You may be affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Categories NAICS codes Examples of potentially affected entities Industry 111 Crop production 112 Animal production VerDate Aug< 23> 2002 14: 18 Aug 27, 2002 Jkt 197001 PO 00000 Frm 00041 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 28AUN1. SGM 28AUN1

epa

2024-06-07T20:31:42.084326

regulations

EPA-HQ-OPP-2002-0138-0002

Supporting & Related Material

Carbaryl Summary Uses C Carbaryl (1­ naphthyl methylcarbamate) is a widely used broad­ spectrum insecticide. Approximately 3.9 million pounds (59 percent) of carbaryl is used in agriculture, and approximately 2.2 million pounds (34 percent) of carbaryl is used by homeowners in residential settings. The remaining uses (7 percent) are in the nursery, landscape and golf course industries. C Agricultural uses include fruit and nut trees, many types of fruits and vegetables, and grain crops. Homeowners use carbaryl for lawncare, gardening, and petcare. Other uses for carbaryl include greenhouses, sod farms, mosquito adulticide use, and a special local need use of carbaryl on oyster beds in Washington State. Health Effects C Carbaryl can cause cholinesterase inhibition in humans; that is, it can overstimulate the nervous system causing nausea, dizziness, confusion, and at high exposures, respiratory paralysis, and death. C Carbaryl has been classified as "likely to be carcinogenic to humans" based on vascular tumors in mice. Risks Dietary Risks from Food C Acute dietary risk estimates with Carbamate Market Basket Survey data are not of concern for the entire U. S. population, including infants and children. Chronic (cancer and noncancer) dietary risks are also not of concern. Dietary Risks from Drinking Water C Carbaryl is moderately mobile in the environment, and is non­ persistent. C Acute surface water risks, based on high­ end estimates from computer modeling, are of concern for all populations when combined with food exposures. Chronic (noncancer and cancer) risks from surface water are low and not of concern. C Groundwater risks, both acute and chronic (noncancer and cancer), are low and not of concern when combined with food exposures. Groundwater concentrations are also based on modeling predictions. Residential risks C For exposures to homeowner handlers, 8 out of 17 scenarios resulted in noncancer risks of concern. For carbaryl, dermal exposures generally determined the risk levels. Cancer risks for all 17 scenarios were not of concern. C For postapplication exposure to homeowners, only one scenario (lawncare) resulted in noncancer risks of concern for adults. For children 10­ 12, there are no risks of concern; however, postapplication exposures are of concern for toddlers for pet treatment and lawncare. Cancer postapplication risks are low for all scenarios and are not of concern. Aggregating Dietary and Residential Risk C Based on selected residential scenarios that are not of concern alone, only one scenario had aggregate risks of concern when combined with dietary (food and drinking water) exposures. Occupational Exposures C Out of 128 short­ and intermediate­ term handler exposure scenario combinations, only18 had noncancer risks of concern, even when considering the highest level of personal protection practicable (including engineering controls). Out of 5 long­ term exposure scenarios, 2 had noncancer risks of concern. C For occupational handler cancer risks, 8 of the 128 handler exposure scenario combinations resulted in risks of concern to private growers. For commercial applicators, 21 scenarios had cancer risks of concern. C Occupational postapplication risks (noncancer and cancer) are of concern at the current 12 hour REI for most scenarios. Ecological Risks C For nongranular carbaryl uses, acute risk to birds is low, but chronic risk to birds is of concern. There is concern for both acute and chronic risk to mammals. C For all granular uses, there is concern for acute risk to birds and small mammals. There is no concern for acute risk to larger mammals. C There is concern for acute risk to freshwater fish and all aquatic invertebrates, and concern for chronic risk to freshwater aquatic invertebrates. There is no concern for chronic risk to freshwater fish. How the Risk Picture May Change The registrant is completing a chemical­ specific biomonitoring study which will further quantify and charcaterize occupational and residential use risks, and a targeted surface water monitoring study to further characterize the presence of carbaryl in drinking water.

epa

2024-06-07T20:31:42.088044

regulations

EPA-HQ-OPP-2002-0138-0003

Supporting & Related Material

Overview of Carbaryl Risk Assessment Introduction This document summarizes EPA's human health and ecological risk findings and conclusions for the carbamate pesticide carbaryl, as presented fully in the revised documents, "Human Health Risk Assessment: Carbaryl" dated July 30, 2002 and "Environmental Fate and Ecological Risk Assessment for the Reregistration of Carbaryl" dated August 17, 2002. The purpose of this overview is to help the reader identify the key features and findings of these risk assessments and better understand EPA's conclusions. We developed this overview in response to comments and requests from the public which indicated that the risk assessments were difficult to understand, that they were too lengthy, and that it was not easy to compare the assessments for different chemicals due to differing formats. Carbaryl is a carbamate insecticide, and it has been determined that N­ methyl carbamates share a common mechanism of toxicity: the inhibition of cholinesterase. As required by the Food Quality Protection Act (FQPA), EPA will consider the cumulative risks from food, water and non­ occupational exposure resulting from all relevant uses of the group of N­ methyl carbamates. The risk estimates summarized in this document, however, are for carbaryl alone. Use Profile Carbaryl (1­ naphthyl methylcarbamate) is one of the most widely used broad­ spectrum insecticides in agriculture, professional turf management, professional ornamental production, and in residential pet, lawn, and garden markets. Based on sales information provided by the technical registrant Aventis in September 1998, it appears that approximately 34% of carbaryl is used by homeowners in residential settings, 59% is used in agriculture, and the remaining 7% is used in the nursery, landscape and golf course industries. According to Aventis, this information still reflects current trends. C Technical Registrants. The technical registrants are Aventis, which provided the primary data for reregistration, and Burlington Scientific Corporation. Aventis is now owned by Bayer CropScience, and is still corresponding with EPA as Aventis, which is the legally recorded name on EPA pesticide registrations. C Agricultural Uses. Carbaryl is used in agriculture to control pests on terrestrial food crops, including fruit and nut trees (e. g., apples, pears, almonds, walnuts, and citrus), many types of fruits and vegetables (e. g., cucumbers, tomatoes, lettuce, blackberries, and grapes), and grain crops (e. g., corn, rice, sorghum, and wheat). Use Profile... 2 Based on the Aventis sales data cited above, approximately 3.9 million pounds of active ingredient was sold to the agricultural market. Based on available usage information for the years 1987 through 1996, an annual estimate of carbaryl total domestic usage in agriculture averaged approximately 2.5 million pounds of active ingredient for over 1.5 million acres treated. Its largest agricultural markets (measured as the percentage of pounds active ingredient used annually) are pecans (12%), apples (9%), grapes (6%), oranges (5%), alfalfa (5%), and corn (4%). Most of this use was in Arkansas, California, Georgia, Illinois, Indiana, Michigan, Mississippi, Ohio, Oklahoma, and Texas. Crops with a high percentage of the total U. S. planted acres treated include Chinese cabbage (57%), asparagus (43%), cranberries (39%), Brussels sprouts (33%), apples (23%), and blueberries (22%). C Residential Uses. Carbaryl is used by homeowners for lawncare, gardening (vegetables and ornamentals), and petcare. Apart from petcare, there are no labels for indoor uses. Carbaryl accounted for approximately 9% of the total residential insecticide market and was ranked fourth on the list behind the pyrethroids, chlorpyrifos, and diazinon (the latter two are now being removed from residential markets, so changes in market share are expected). Dusts (65%) and liquid concentrates (25%) account for most carbaryl sales in the residential market of 2 million pounds per year. C Other uses. Carbaryl is used for ornamentals and turf, including production facilities, such as greenhouses and sod farms. It is used on golf courses and on residential sites treated by professional applicators (e. g., annuals, perennials, and shrubs). Carbaryl is also labeled for use as a mosquito adulticide, and EPA has assessed the risks from this use. Another carbaryl application examined in the risk assessment is a special local need use to control burrowing shrimp on oyster beds in Washington State. C Formulations. Carbaryl formulations include baits, dusts, aerosol sprays, ready­ to­ use pump sprayers, pet collars, pet dips and shampoos, flowable concentrates, emulsifiable concentrates, granulars, soluble concentrates, water dispersible granules, and wettable powders. C Methods of Application. Typical application methods in agriculture include groundboom, airblast, chemigation, and aerial. Carbaryl can also be applied using handheld equipment such as low and high pressure handwand sprayers, backpack sprayers, compressed air sprayers, and turfguns. Homeowners can apply carbaryl with equipment that includes trigger sprayers, hose end sprayers, ready­ to­ use dust packaging, belly grinders, push­ type spreaders, and outdoor foggers. C Application Rates. Carbaryl rates vary depending on the crop. For most of agriculture, maximum seasonal rates range from 1 to 16 pounds active ingredient per acre. Examples of high rate applications are tree nut crops and golf courses. Examples of low rate applications are certain field and row crops. Depending on the crop, the maximum number of carbaryl applications per season can range from 1 to 8. The maximum, single application rate for carbaryl is for California citrus only, specified on the label as up to 16 lb ai/ acre. 3 Human Health Risk Assessment Dietary Risk from Food Carbaryl risks from food consumption are summarized in Table 1 below. Risks less than 100% of the Population Adjusted Dose (PAD), either acute (aPAD) or chronic (cPAD), are not of concern to the Agency. The aPAD is the dose at which a person could be exposed on any given day and no adverse health effects would be expected. The cPAD is the dose at which an individual could be exposed over the course of a lifetime and no adverse health effects would be expected. For the cancer dietary assessment, risks less than 1 x 10 ­6 are not of concern to the Agency. Table 1. Summary of Dietary Exposure and Risk for Carbaryl (including Carbamate Market Basket Survey Data) Population Subgroup Acute (99.9 percentile) Chronic Cancer Exposure (mg/ kg/ day)* % aPAD Exposure (mg/ kg/ day) % cPAD Risk U. S. Population 0. 004580 46 0.000032 <1 2.8x 10 ­8 Infants (< 1 year old) 0.007272 73 0.000054 <1 NA Children 1­ 6 0. 007546 75 0.000057 <1 NA *mg/ kg/ day= milligrams per kilogram per day. The acute and chronic (noncancer) dietary food risks are not of concern to the Agency; risks are less than 100% of both the aPAD and cPAD. Cancer dietary risk is also not of concern to the Agency as the risk to the general population of 2.8 x 10 ­8 is less than 1 x 10 ­6 . Below is a more detailed discussion of the dietary (food) risk estimates in Table 1. Acute Dietary (Food) Risk Acute dietary (food) risk is calculated considering what is eaten in one day. In this instance, that includes the full range of consumption values as well as the range of residue values in food. C For carbaryl, EPA conducted a Tier 3/ 4 dietary risk assessment, which is currently the most highly refined assessment possible. Dietary exposure was determined considering the level of carbaryl residues on food commodities and their potential consumption by multiple subpopulations, including infants and children. Acute dietary risk was then calculated by comparing dietary exposure to the aPAD. C As shown in Table 1, risk estimates for all commodities are less than 100% of the aPAD for all subpopulations when considering the 99.9th percentile of exposure. The highest exposed Dietary Risk from Food... 4 subpopulation (children 1­ 6 years) is at 75% of the aPAD, and the general population is at 46% of the aPAD. C EPA calculated the aPAD and dietary risk levels for carbaryl using the following data: ­ For the acute dietary assessment, the acute No Observed Adverse Effect Level (NOAEL) is 1 mg/ kg/ day from a developmental neurotoxicity study in rats. Increased incidence of neurological (functional observational battery) changes were observed on the first day of dosing in maternal animals at a Lowest Observed Adverse Effect Level (LOAEL) of 10 mg/ kg/ day. ­ The uncertainty factor (UF) is 100 for acute dietary risk, based on a 10x for standard uncertainties in applying animal studies to humans (interspecies extrapolation) and a 10x for varying effects among individuals (intraspecies variability). ­ The acute reference dose (acute RfD) is 0.01 mg/ kg/ day, calculated by dividing the NOAEL (1 mg/ kg/ day) by the UF (100). ­ The 10x Food Quality Protection Act Safety Factor (FQPA SF) was removed (i. e., is 1x) for all population subgroups. The Agency determined that this safety factor is adequate to protect infants and children because there are no residual uncertainties in the exposure databases, the toxicology database is complete, and the endpoint and NOAELs/ LOAEL for risk assessment were well defined. In the toxicology database, no quantitative or qualitative evidence of increased susceptibility in rat or rabbit fetuses following in utero exposure in the standard developmental studies was observed. There was a low level of concern for evidence of susceptibility seen in the developmental neurotoxicity study, and there was evidence of increased susceptibility in offspring in the 2­ generation reproduction study. However, the Agency believes that the acute and chronic RfDs would be protective of these effects so the FQPA SF was reduced to 1x. ­ The aPAD is 0.01 mg/ kg/ day, calculated by dividing the acute RfD (0.01 mg/ kg/ day) by the FQPA SF. Since the FQPA SF is 1x, the aPAD and the acute RfD are identical. ­ The acute dietary exposure analysis is based on the Dietary Exposure Evaluation Model (DEEM™), that uses exposure and consumption data to calculate risk as a percentage of the PAD. The DEEM™ analysis evaluated individual food consumption as reported by respondents in the USDA 1989­ 1992 Continuing Surveys for Food Intake by Individual (CSFII). For acute dietary risk assessments, the entire distribution of consumption events for individuals is multiplied by a randomly selected distribution of residues (probabilistic analysis, referred to as "Monte Carlo" ) to obtain a distribution of exposures. ­ The CSFII also has data for the years 1994 through 1998. Although these data are not yet routinely used in individual chemical assessments, EPA has developed risk estimates for Dietary Risk from Food... 5 carbaryl using these data. The risk estimates are, in general, slightly higher than those using the 1989­ 1992 data, but still resulted in exposures less than 100% of the aPAD. ­ The anticipated pesticide residues on food are extensively refined for the acute dietary assessment and were derived from: (1) the Carbamate Market Basket Survey (CMBS), which was translated to similar commodities when feasible; (2) monitoring data from USDA's Pesticide Data Program (PDP); (3) FDA's Surveillance Monitoring Program; (4) the percentage of the crop treated (estimated maximum percentage); and (5) data from crop field trials where there were insufficient PDP or FDA monitoring data. Field trial data were used for the following commodities: garden beets, turnips, mustards, dried beans, almonds, pecans, walnuts, field corn grain, rice, flax seed, okra, olive, peanuts, pistachio, and sunflower. ­ The Carbamate Market Basket Survey (CMBS) is an industry­ sponsored, year long, national survey of carbamate residues on selected food commodities purchased at grocery stores. The CMBS collected up to 400 single­ serve samples for 8 different crops (apple, banana, broccoli, grape, lettuce, orange, peach and tomato). Residue data from a market basket survey are generally considered to provide a close approximation to residues potentially found at the "dinner plate." Survey data are generally considered the most appropriate data source for use in pesticide risk and exposure assessment. Information from the CMBS is being used in carbamate dietary risk assessments in conjunction with all other available field trial and monitoring data. It is acknowledged that the sample preparation protocol used by the CMBS introduces a degree of uncertainty into the reported survey results. The protocol (hand­ rubbing certain commodities during the rinsing process) created a potential for residue loss prior to analysis; however, the degree to which this step had an effect on residue levels cannot be quantified. The Agency believes these survey data are useful to the carbaryl dietary risk assessment, as they tend to support PDP monitoring data findings of detectable residues on commodities important to the diets of infants and children. EPA also conducted a separate assessment using solely the PDP/ FDA monitoring data and field trial data for a better understanding of the overall risks. Use of this data set provides higher risk estimates than those based on inclusion of the CMBS carbaryl data. For example, using only PDP/ FDA and field trial data, exposure for all infants (less than 1 year old) is 133% of the aPAD, and exposure for children 1 through 6 is 110% of the aPAD. Dietary Risk from Food... 6 Chronic Dietary (Food) Risk Chronic (noncancer) dietary risk from food is calculated by using the average consumption value for foods and average residue values on those foods over a 70­ year lifetime. As previously shown in Table 1, dietary exposure for all populations is less than 1% of the cPAD, and therefore not of concern to the Agency. C EPA calculated the cPAD and dietary risk levels for carbaryl using the following data: ­ EPA used the Lowest Observed Adverse Effect Level (LOAEL) of 3.1 mg/ kg/ day for the chronic dietary assessment based on a 1­ year chronic toxicity feeding study in dogs. Decreases in plasma and brain cholinesterase were observed in females at this dose. Because the LOAEL dose was the lowest dose tested, a NOAEL was not established. ­ The uncertainty factor (UF) is 300, based on a 10x for standard uncertainties in applying animal studies to humans (interspecies extrapolation) and a 10x for varying effects among individuals (intraspecies variability), as well as a 3x for the added uncertainty of using a LOAEL instead of a NOAEL. ­ The chronic reference dose (chronic RfD) is 0.01 mg/ kg/ day, calculated by dividing the LOAEL (3.1 mg/ kg/ day) by the UF (300). ­ The 10x Food Quality Protection Act safety factor (FQPA SF) was removed (i. e., is 1x) for all population subgroups, as discussed in the acute dietary section. The Agency determined that this safety factor was adequate to protect infants and children because there are no residual uncertainties in the exposure databases, the toxicology database is complete, and the endpoint and NOAELs/ LOAEL for risk assessment were well defined. ­ The cPAD is 0.01 mg/ kg/ day, calculated by dividing the chronic RfD (0.01 mg/ kg/ day) by the FQPA SF. Because the FQPA SF is 1x, the cPAD and the chronic RfD are identical. ­ The chronic dietary exposure analysis is based on the Dietary Exposure Evaluation Model (DEEM™), which incorporates exposure and consumption data to calculate risk as a percentage of the cPAD. The DEEM™ analysis evaluated individual food consumption as reported by respondents in the USDA 1989­ 1992 Continuing Surveys for Food Intake by Individual (CSFII). For chronic dietary risk assessments, a 3­ day average consumption for each subpopulation is combined with average residues in commodities to determine average exposures. Using the 1994­ 1998 CSFII data does not alter the results. ­ The anticipated pesticide residues on food are extensively refined for the chronic dietary assessment for food and derived from: (1) monitoring data from USDA's Pesticide Data Dietary Risk from Food... 7 Program (PDP); (2) FDA's Surveillance Monitoring Program; (3) the percentage of the crop treated (weighted average); and (4) data from crop field trials where there were insufficient PDP or FDA monitoring data. Field trial data were used for the following commodities: garden beets, turnips, mustards, dried beans, almonds, pecans, walnuts, field corn grain, rice, flax seed, okra, olive, peanuts, pistachio, and sunflower. CMBS data are not used for chronic dietary assessment because they reflect single­ serving residue values. Cancer Dietary (Food) Risk Cancer dietary risk from food is also calculated by using the average consumption values for food and average residue values for those foods over a 70­ year lifetime. The chronic exposure value is multiplied by a linear low­ dose response factor (Q1*), based on animal studies, to determine the lifetime cancer risk estimate. For cancer dietary exposure, risk estimates less than than 1 x 10 ­6 (1 in 1 million) are not of concern to the Agency. C Carbaryl is classified as "likely to be carcinogenic to humans," based on vascular tumors in mice (males). The unit risk, or Q1* value, is 8.75 x 10 ­4 (mg/ kg/ day) ­1 . C The maximum estimated lifetime cancer dietary (food) risk of 2.8 X 10 ­8 for the general US population is not of concern. Use of the 1994­ 1998 CSFII has no impact on the overall results. Dietary Risk from Drinking Water Drinking water exposure to pesticides can occur through surface and ground water contamination. EPA considers both acute (one day) and chronic (lifetime) drinking water risks and uses either modeling or actual monitoring data, if available and of sufficient quality, to estimate those risks. To determine the allowable carbaryl exposure from drinking water, or the Drinking Water Level of Comparison (DWLOC), EPA first looks at how much of the overall allowable dietary risk is contributed by food. For carbaryl, EPA calculated food risk including the results of the Carbamate Market Basket Survey. The DWLOC is the amount of allowable risk left for exposure through drinking water. The DWLOC is then compared to a drinking water estimated environmental concentration (drinking water EEC). If the DWLOC is higher than the drinking water EEC, then the risk is not of concern to the Agency. Below is a discussion of the drinking water EECs for carbaryl, followed by a comparison of the DWLOCs to the drinking water EECs to assess risks. Dietary Risk from Drinking Water... 8 Estimated Environmental Concentrations for Carbaryl C Carbaryl is fairly mobile, but is not likely to persist or accumulate in the environment. As such, it is difficult for monitoring studies to detect peak concentrations that can occur. EPA determined that currently available monitoring studies for carbaryl are limited in this regard, and did not use them to define peak values for carbaryl. Instead, EPA used computer modeling to estimate drinking water EECs from ground and surface water that could be expected from normal agricultural use. Modeling is designed to provide a high­ end estimate of exposure. C A primary degradate of carbaryl is 1­ naphthol. The Agency is not, however, concerned about levels of 1­ naphthol in drinking water for this assessment. Due to the limited persistence of 1­ naphthol, it is not expected to be found in significant concentrations resulting from carbaryl applications, and even if found, it is not a cholinesterase inhibitor nor is it expected to be carcinogenic. C Drinking water EECs for surface water were estimated using computer modeling with PRZM/ EXAMS software, scenarios using an Index Reservoir, and a Percent Crop Area factor. Drinking water EECs from modeling vary depending on different scenarios for geographic location, crop, and pesticide application rates. C Drinking water EECs for surface water were estimated using five crop scenarios: (1) Ohio Sweet Corn, (2) Ohio Field Corn, (3) Oregon Apples, (4) Minnesota Sugar Beets, and (5) Florida Citrus. These scenarios were selected to represent the range of crops and use rates likely to result in higher environmental concentrations. These scenarios were also modeled at different application rates: label maximum application rate, average application rate (based on EPA's data review), and reported maximum application rate (from DOANE survey data). C Drinking water EECs for groundwater were estimated using the SCI­ GROW computer model based on the upper­ end agricultural application rate for carbaryl use on citrus. SCI­ GROW provides a screening value to use in determining exposure and the potential risk to human health. Modeled Risk Estimates The DWLOCs and drinking water EECs for carbaryl are presented in Table 2. Drinking water EECs that are higher than DWLOCs are bolded. Dietary Risk from Drinking Water... 9 Table 2. DWLOCs for Combined Food and Drinking Water Exposure and Drinking Water EECs for Carbaryl at the Maximum Label Application Rate Population Subgroup Acute DWLOCs and Drinking Water EECs (ppb) for Surface Water Drinking Water EEC (ppb) for Ground Water DWLOC Drinking water EECs (Modeling) at Maximum Label Application Rates Florida Citrus Oregon Apples Ohio Sweet Corn Ohio Field Corn Sugar Beets U. S. Population 188 494 144 37 30 19 0.8 All Infants (< 1yr) 27 494 144 37 30 19 Children 1­ 6 27 494 144 37 30 19 Children 7­ 12 38 494 144 37 30 19 Chronic (noncancer) DWLOCs and Drinking Water EECs (ppb) for Surface Water U. S. Population 349 28 9 3 2 2 All Infants (< 1yr) 100 28 9 3 2 2 Children 1­ 6 99 28 9 3 2 2 Children 7­ 12 100 28 9 3 2 2 Cancer DWLOCs and Drinking Water EECs (ppb) for Surface Water U. S. Population 39 28 9 3 2 2 Acute Drinking Water Risk Estimates for Surface Water C For surface water, using the label maximum application rates for carbaryl in the model, acute drinking water EECs exceed the DWLOCs for infants (less than 1 year) and children (1 to 6 years) for combined food and drinking water exposure in four of the five scenarios, with modeled drinking water EECs for surface water ranging from 30 ppb for Ohio Field Corn to approximately 500 ppb for Florida Citrus. Only the EECs for Minnesota Sugar Beets (19 ppb) were less that than the DWLOCs for all population subgroups. C The Agency has also assessed drinking water concentrations based on average application rates (based on usage data) and reported maximum application rates (based DOANE survey data). These rates are generally lower than the maximum label application rate, resulting in less exposure and fewer risks of concern. Dietary Risk from Drinking Water... 10 C The highest carbaryl drinking water EEC for surface water (494 ppb), which is from the maximum label application rate on Florida citrus, is presented with the notation that the majority of drinking water in Florida (greater than 90%) is derived from ground water. Therefore, potential high surface water concentrations would not necessarily indicate widespread, high exposure. The aggregate risk assessment therefore uses for comparison the next highest drinking water EEC, Oregon apples at the label maximum application rate (144 ppb). Chronic Drinking Water Risk Estimates Surface Water C Chronic (noncancer) and cancer drinking water risk estimates from surface water are significantly less than the DWLOCs and are not of concern for combined food and drinking water exposures. Chronic (noncancer) drinking water EECs for surface water range from 0.7 to 28 ppb for both average and maximum rates, significantly less than the chronic DWLOCs for carbaryl. Cancer drinking water EECs are also significantly less than the cancer DWLOCs. Drinking Water Risk Estimates for Groundwater C The modeled drinking water EEC for groundwater is 0.8 ppb, and is significantly less than the acute and chronic (cancer and noncancer) DWLOCs for combined food and drinking water exposure. Monitoring Data C EPA lacks a targeted drinking water monitoring study for carbaryl to compare with the screening­ level modeling results presented above. Carbaryl is the second most widely detected insecticide in surface water, based on the USGS NAWQA database, with a significant portion apparently transported to streams. Out of 5220 surface water samples analyzed, about 21% (1082) had detections greater than the minimum detection limit. The maximum observed concentration for carbaryl in surface water from the non­ targeted USGS NAWQA study is 5.5 ppb. The maximum observed concentration from a California state surface water database is 8.4 ppb, cited in EPA's environmental risk assessment for carbaryl. Both differ significantly from the 494 ppb peak value from computer modeling. The registrant submitted interim results from an ongoing targeted monitoring study of carbaryl surface water concentrations. However, the interim data are not sufficient to serve as the basis for the drinking water EECs in this risk assessment. Another finding in the NAWQA data is that streams draining urban areas showed more frequent detections and higher concentrations than streams draining agricultural or mixed land use areas. EPA has limited tools for assessing the effects of pesticide use in urban and suburban settings on surface water and groundwater quality, and may need additional data to provide estimates of the distribution of possible exposures. 11 Residential Risks Use Summary C Residents can receive nondietary exposures to carbaryl by mixing, loading, or applying pesticides (residential handler exposure), or by re­ entering an area after treatment (residential post­ application exposure) by homeowners or commercial pest control applicators. Residential exposures are broadly defined to include all non­ dietary, nonoccupational exposures, including recreational activities like golfing, and any other exposures than can occur in the general population. C Carbaryl has a wide variety of residential uses, including lawns, gardens, ornamentals, and pets. Other than pet treatment, there are no registered indoor uses. Carbaryl is used on golf courses, and may be used in public areas, such as schools or parks. Although EPA is not aware of public health uses of carbaryl in state or local mosquito control programs, it is labeled as a mosquito adulticide, which EPA did consider in the risk assessment. There is also potential exposure from carbaryl used in Washington State to control burrowing shrimp in oyster beds. EPA also considered this special local need (FIFRA 24c) use on oyster beds in the risk assessment. C Both homeowners (and professional applicators) can apply carbaryl by many methods, including trigger sprayers, hose­ end sprayers, granular spreaders, ready­ to­ use dust packaging, low pressure handwand sprayers, backpack sprayers, and turfguns. C Residential handlers may be exposed to carbaryl residues via the dermal (skin) and inhalation routes. Post­ application exposures to carbaryl for adults are most likely through the skin, whereas children may also receive oral exposures from mouthing behaviors (i. e., hand­ tomouth object­ to­ mouth, and soil ingestion). Noncancer Toxicity Summary C To estimate noncancer residential risks, the Agency calculates the ratio of the NOAEL selected for risk assessment to the exposure. This margin of exposure (MOE= NOAEL/ exposure) is compared to a target MOE. The total target MOE is based on uncertainty factors (UFs) that are routinely applied to residential risk assessments: 10x to account for interspecies extrapolation and 10x to account for intraspecies variations, plus any additional safety factor retained due to concerns unique to the protection of infants and children under FQPA. An MOE less than 100 is generally of concern to the Agency. C For carbaryl, the 10x FQPA SF has been removed (i. e., is 1x), for reasons explained above in the acute dietary section. Therefore, the target MOE for short­ and intermediate­ term exposures is 100. For long­ term exposures, the target MOE is 300, because the lowest dose tested in the long­ term study was the LOAEL, and a 3x uncertainty factor was added to account for uncertainties from using a LOAEL in place of a NOAEL. The only residential long­ term assessment for residential use is the postapplication exposure of toddlers to pet collars. Residential Risk... 12 C The NOAELs and LOAELs used in the residential risk assessment are summarized below: ­ Short­ and intermediate­ term dermal risk assessments for carbaryl are based on a NOAEL of 20 mg/ kg/ day from a 28­ day dermal toxicity study in rats using technical grade carbaryl. Decreases in red blood cell cholinesterase in males and females, and decreases in brain cholinesterase in males, were observed at the systemic LOAEL of 50 mg/ kg/ day. ­ Short­ term inhalation and incidental, nondietary ingestion risk assessments for carbaryl are based on a NOAEL of 1 mg/ kg/ day from a developmental neurotoxicity study in rats. Increased incidence of neurological (functional observational battery) changes and cholinesterase inhibition (red blood cell, plasma, whole blood, and brain) were observed at the LOAEL of 10 mg/ kg/ day. Since an oral study was used for these risk assessments, a 100% absorption factor was applied to extrapolate for the inhalation assessments. ­ Intermediate­ term inhalation risk assessments for carbaryl are based on a NOAEL of 1 mg/ kg/ day from a subchronic neurotoxicity study in rats. Increased incidence of neurological function changes and cholinesterase inhibition (red blood cell, plasma, whole blood, and brain) were observed at the LOAEL of 10 mg/ kg/ day. Since an oral study was used for these risk assessments, a 100% absorption factor was applied to extrapolate for the inhalation assessments. ­ The long­ term (greater than 6 month) exposure assessment for pet collars is based on a 3.1 mg/ kg/ day LOAEL from a 1­ year chronic toxicity feeding study in dogs. Decreases in plasma and brain cholinesterase in females were observed at this dose. Because the LOAEL dose was the lowest dose tested, a NOAEL was not determined. Therefore, the target MOE is 300 (which includes a 3x uncertainty factor for use of a LOAEL in place of a NOAEL). Since an oral study was used for these risk assessments, a 12.7% absorption factor was used to extrapolate for the dermal assessments. Noncancer Risks for Residential Handlers C EPA assessed only short­ term (1 to 30 day) exposures for residential handlers. Intermediate­ term exposures (30 days to several months) are unlikely because of the sporadic nature of applications by homeowners. C Maximum label application rates and use information specific to residential products served as the basis for the risk calculations. If additional information was available, such as average or typical rates, EPA used these values to allow for a more informed risk management decision. In most cases, these rates differed from maximum application rates by about a factor of two. C Exposure values in this assessment were based on three carbaryl­ specific residential handler studies. EPA also used two other sources of surrogate information: a study from the Outdoor Residential Risk... 13 Residential Exposure Task Force, of which Aventis is a member, and the Pesticide Handlers Exposure Database (PHED). C EPA assessed 17 major residential handler exposure scenarios, based on anticipated use patterns and current labeling for carbaryl, as well as the types of equipment and techniques used by homeowners to apply carbaryl. Most of the 17 scenarios include more than one site/ area/ rate combination. Table 3 presents the scenarios EPA considered and their associated risk estimates. Of these scenarios, 8 are of concern (MOEs are less 100), and these scenarios and MOEs are shown in bold. In all cases, dermal exposure is the primary contributor to risk. Table 3. Carbaryl Noncancer MOEs for Combined Short­ term Residential Handler Dermal and Inhalation Exposures # Scenario Descriptor Use Site Amount of Carbaryl Used (lb ai/ event) Combined Dermal and Inhalation MOEs 1 Garden: Ready­ to­ Use Trigger Sprayer Vegetables/ Ornamentals 0.012 to 0.00075 2100 to 33730 2 Garden/ Ornamental Dust Vegetables/ Ornamentals 0.4 to 0.079 21 to 85 0.079* 107 3 Garden: Hose­ End Sprayer General Use (2% soln) 2 21 Fire Ants 0.75 55 Other Uses: Perimeter Nuisance Pests, Vegetables, Vegetables/ Ornamentals, 0.26 to 0.012 158 to 3427 4 Garden: Low Pressure Handwand General Use (2% soln), Perimeter Nuisance Pests, Vegetables, Ornamentals, Fire Ant 0.19 to 0.012 193 to 3056 5 Trees/ Ornamentals: Low Pressure Handwand Ornamentals, Pome Fruits, Nuts/ Stone Fruits, Citrus 0.176 to 0.023 142 to 1084 6 Trees/ Ornamentals: Hose End Sprayer Ornamentals, Pome Fruits, Nuts/ Stone Fruits, Citrus 0.5* 72 0.176 to 0.023 204 to 1559 7 Garden: Backpack Sprayer General Use (2% soln), Perimeter Nuisance Pests, Vegetables, Vegetables/ Ornamentals, Fire Ants 0.19 to 0.012 1293 to 20468 8 Lawn Care: Hose End Sprayer Lawn (broadcast) 5 25 Lawn (spot) 0. 25 495 9 Dogs: Dusting Dog 0.0026 142 0.1 4 0.05 7 10 Dogs: Liquid Application Dog 0.001 14000000* 11 Granular & Baits Lawn Care: Belly Grinder Lawn (spot) 0.21 60 0.1 126 Residential Risk... # Scenario Descriptor Use Site Amount of Carbaryl Used (lb ai/ event) Combined Dermal and Inhalation MOEs 14 12 Granular & Baits Lawn Care: Push­ Type Spreader Lawn (broadcast) 4.2 to 2 477 to 1003 13 Granulars & Baits By Hand Ornamentals and Gardens 0. 21 15 14 Aerosol Various 0.08 65 15 Collars: Pet Dog 0.013 10800000* 16 Sprinkler Can (Source: Scenario 6) Ornamentals (2% solution) 0.1 359 17 Ornamental Paint On Ornamentals (2% solution) 0.02 297 *Average use rate based on exposure study data. ** These scenarios reflect dermal MOEs only, and are based on EPA's SOPs for Residential Exposure Assessment as opposed to monitoring data. Noncancer Risks for Residential Postapplication Exposures Several carbaryl­ specific studies were used in developing this assessment, including a turf transferable residue study conducted in California, Georgia, and Pennsylvania at approximately 8 lb ai/ acre. This study was conducted using the standard protocol from the Outdoor Residential Exposure Task Force. The Agricultural Reentry Task Force conducted several dislodgeable foliar residue studies with carbaryl. The olive pruning and cabbage weeding studies were used in the home garden risk assessments. EPA assessed the risks from postapplication exposure to carbaryl residues for the following populations: Adult Residential (homeowner); Youth­ aged children (10­ 12 years old); and Toddlers (3­ year olds). EPA considered short­ (1 to 30 days) and intermediate­ term (30 days to several months) exposures. The only long­ term exposure considered (greater than 6 months) is for pet collar uses. Adult Residential Postapplication C EPA assessed the following 5 scenarios for adult residential postapplication exposures: residential turf for lawncare and after mosquito control; recreational swimming and beach activity (following oyster bed treatments); golfing; home garden exposure to deciduous trees; and home garden exposure to fruiting vegetables. Within each scenario, ranges of exposure were evaluated for different application rates, duration of exposure, and postapplication activities (e. g., weeding, harvesting). Of the 5 scenarios, only 1 is of concern: short­ term risks from lawncare (i. e., heavy yardwork). C On the day of application, the short­ term MOE for lawncare is 43 at an application rate of 8 lb ai/ acre. After about 5 days, residues dissipate below the level of concern. At a lower application rate of 4 lb ai/ acre, the MOE on the day of application is 88, and it takes about 1 day for residues to dissipate below the level of concern. All the remaining MOEs are greater than 500, with most in the thousands to tens of thousands. Similarly, all intermediate­ term exposures for residential turf are greater than 400. Residential Risk... 15 Youth­ aged Children (10 to 12 year­ olds) C Children of this age can help with garden maintenance, and therefore are considered for postapplication activities related to fruiting vegetables and fruit trees (such as weeding and harvesting). The MOEs for these activities, both short and intermediate­ term, were all greater than 100 on the day of application, and therefore not of concern. The lowest MOEs are approximately 650 for high exposures from deciduous trees and 980 for high exposures from fruiting vegetables; the rest of the MOEs are significantly greater than 1000. Toddlers (3 year­ olds) C Toddlers were selected as a representative population for turf and companion animal risk assessments to provide the most conservative risk estimates. Exposures from turf were evaluated separately for lawncare uses and after mosquito control. Beach activity following oyster bed treatment was also evaluated. The assessment is based on combined risk estimates for several routes of exposure: dermal, hand­ to­ mouth, object­ to­ mouth, and soil ingestion. C Pet treatments result in short­ term risks of concern for toddlers, (MOE less than100) even 30 days after application, regardless of whether the formulation used was a dust, liquid or collar. Hand­ to­ mouth and dermal exposures are approximately equal contributors to the overall estimates for each product type. Intermediate­ term risk concerns for pet treatments are similar to the short­ term risk concerns. One use, pet collars, is assessed as a long­ term exposure, and is also of concern for toddlers (MOE= 43). Pet collars are assumed to be worn by pets all of the time so long­ term exposures to toddlers may occur. C Treated turf exposures (from products labeled for direct application to turf) also result in short­ term risks of concern for toddlers. The MOEs are less than 100 on the day of application for both rates considered, 4 lb ai/ acre (MOE= 11) and 8 lb ai/ acre (MOE= 5). These applications required 14 days and 18 days, respectively, to reach the target MOE. Intermediate­ term risks to toddlers improve, based on 30­ day average exposures and the dissipation rate for carbaryl, but the MOEs (91 and 45, respectively) are still of concern. Dermal and hand­ to­ mouth exposures are the key contributors, while soil ingestion and object­ to­ mouth exposures were a minor contributors to the total risk estimates. C Turf exposures following application of carbaryl as a mosquito adulticide are not of concern, regardless of how applications are made (i. e., by ground or air). Both short­ term (on the day of application) and intermediate­ term MOEs are equal to or greater than the target MOE of 100. The lowest MOEs are approximately 450 for aerial application and 850 for ground application, with the remaining MOEs ranging from the thousands to more than one hundred thousand. C Postapplication risks for toddlers playing on the beach after oyster bed treatment with carbaryl are not of concern to the Agency. Short­ term MOEs are greater than 100, even if the highest monitored sediment concentration value from any study available to the Agency was used as the basis for the calculations. The intermediate­ term results were similar. The lowest MOE is in the tens of thousands. Residential Risk... 16 Cancer Risks for Residential Handlers C Carbaryl is classified as "likely to be carcinogenic to humans," based on increased incidence of vascular tumors in mice. Cancer risks are calculated by multiplying the Lifetime Average Daily Dose (LADD), which represents dermal and inhalation exposure amortized over a lifetime, by the Q1* or unit risk, which is a quantitative dose response factor. The Q1* for carbaryl is 8.75 x 10 ­4 (mg/ kg/ day) ­1 . C For the 17 handler scenarios considered in EPA's residential handler assessment, cancer risks are not of concern to the Agency; the risks are equal to or less than 1x10 ­6 (most are in the 10 ­ 8 or 10 ­10 range) when evaluating a single application per year. C EPA also calculated, for each scenario, the maximum number of days of exposure per year that could occur with estimated risks still at or below the 1 x 10 ­6 risk level (i. e., not of concern). There are 5 scenarios where the maximum number of exposures at or below the 1 x 10 ­6 risk level is 5 days or fewer . Cancer Risks for Residential Postapplication Exposures C Postapplication cancer risks were calculated only for adults and considered the same scenarios used for assessing noncancer risks. C For all scenarios on turf, cancer risks are not of concern to the Agency; risks were in the 10 ­8 range or less on the day of application when evaluating a single reentry event per year during lawncare activities. Risks from home gardening, golfing, mosquito control, or oyster bed treatment, are also not of concern; they were in the 10 ­9 to 10 ­12 range when evaluating a single reentry event per year on the day of application. C The Agency calculated, for each scenario, the maximum number of days of exposure per year which could occur and risks would be at or below 1 x 10 ­6 (i. e., not of concern). Values range from 20 to over 365 days per year, while most exceed 365 days per year even on the day of application. Aggregating Risks from Food, Drinking Water and Residential Uses Aggregate risks for dietary exposures from food and drinking water were described earlier. This section describes the aggregate (combined) risk from food, drinking water and residential exposures. EPA generally does not calculate aggregate risks when dietary or residential risks are already of concern. In this case, however, EPA did generate an aggregate risk assessment to help inform risk management decisions. Aggregating Risks... 17 The purpose of the aggregate assessment is to identify risks that become a concern when combined with others. Therefore, residential risks already known to be of concern alone are not part of this aggregate assessment for carbaryl. Instead, EPA selected representative scenarios where residential risks alone are not already of concern. These scenarios include both postapplication and handler exposures. Postapplication exposures include: mosquito control; swimming/ beach activity (after oyster bed treatments); golfing; and garden harvest. The handler scenarios are mostly at the average application rate based on study data. The maximum application rates for these scenarios were not used because they are already of concern by themselves. The handler scenarios selected include: application of dusts to gardens and pets; hose end sprayer; liquid spray spot lawn treatments; and broadcast application of granulars to lawns. C After aggregating the dietary (food) and residential exposures not already of concern, EPA determined, for each assessed activity, the DWLOC (i. e., the allowable room left for drinking water exposure). C EPA compared the calculated DWLOCs to the chronic drinking water EECs from both surface water and ground water. For drinking water EECs from surface water, results from carbaryl use on Florida citrus and Oregon apples were used for comparison with the DWLOC because they are the two highest drinking water EECs for carbaryl. Short­ term Aggregate Risks C For those scenarios that are not residential risk concerns alone, all DWLOCs are greater than the chronic drinking water EECs (i. e., are not of concern), except for the DWLOC (19 ppb) for adults using garden dust use at the average application rate, which is less than the EEC (28 ppb) from carbaryl use on Florida citrus use. The DWLOC, however, is greater than the chronic drinking water EECs for ground water (EEC of 0.8 ppb), or for surface water from the Oregon apple use (9 ppb). Intermediate­ term Aggregate Risks C EPA did not calculate separate intermediate­ term aggregate risk estimates. The results would essentially be the same as the short­ term aggregate risk estimates because the hazard inputs are numerically identical. Intermediate­ term postapplication exposures, though, would be lower, because they represent a 30­ day average rather than the single­ day higher exposure estimate used for short­ term exposures. Cancer Aggregate Risks C Aggregate cancer risks are not of concern for any subpopulation regardless of the source of drinking water, even considering the high­ end drinking water EECs for Florida citrus. For the cancer risks, EPA used the same adult scenarios as the short­ term risk assessment. 18 Occupational Risk C The occupational risk assessment addresses on the job risks to pesticide workers who may be exposed to carbaryl when mixing, loading, or applying a pesticide (i. e., handlers), and when entering treated sites for routine tasks (postapplication). C Occupational noncancer risk is being measured using the same MOE approach, and the same NOAELs and LOAELs, as are used in the residential assessment (see the Toxicology Summary heading in the residential section). However, the occupational assessment does not consider a FQPA SF for sensitive populations (infants or children). Noncancer Risks for Occupational Handlers Use Scenarios C The Agency identified 28 major occupational exposure scenarios based on the equipment and techniques that could be used for carbaryl applications, and within these scenarios there are 128 different crop/ rate/ acres combinations. These scenarios represent short­ term (1 to 30 days) and intermediate­ term (30 days to several months) exposures. A few scenarios were also assessed for long­ term exposures (more than 180 days), mostly in the greenhouse and floriculture industry where long­ term exposures could be expected. All scenarios present the combined risk from dermal and inhalation exposures. C Occupational handler risk assessments were conducted considering eight levels of personal protection based on different combinations of the following: (1) baseline protection (typical work clothing or a long­ sleeved shirt and long pants, no respiratory protection and no chemical­ resistant gloves); (2) minimum personal protective equipment (baseline scenario with the use of chemicalresistant gloves and a dust/ mist respirator with a protection factor of 5); (3) maximum personal protective equipment (baseline scenario with the use of an additional layer of clothing (e. g., a pair of coveralls), chemical­ resistant gloves, and an air purifying respirator with a protection factor of 10); and (4) engineering controls (e. g., closed tractor cab or closed loading system for granulars or liquids). Current labels mostly specify single­ layer clothing, chemical­ resistant gloves, and no respirator. C The maximum application rates allowed by labels were used in the risk assessments. If additional information was available, such as average or typical rates, these values were used as well for a better understanding of the overall risks. C The unit exposure values (mg ai exposure/ lb ai handled) used in this assessment were predominantly based on the Pesticide Handlers Exposure Database (PHED). In addition to PHED, five exposure studies were used by the Agency to estimate exposures for: (1) professional dog groomers; (2) granular products using a backpack application device (two studies); (3) a ready­ to­ use trigger sprayer; and (4) professional lawncare operators using granular and liquid products. Occupational Risk... 19 Risk Summary Short­ term and Intermediate­ term risks. The risk assessment for short­ and intermediate­ term occupational exposures are similar because the toxicity endpoints (NOAELs) are numerically the same, and the target MOE of 100 is the same for both durations. C Out of the total of 128 crop/ rate/ area combinations assessed, 110 crop/ rate/ area combinations resulted in MOEs that meet or exceed the target MOE of 100 at some level of personal protective equipment (PPE) or engineering controls, but usually at a higher level than that specified on the current label. C The remaining crop/ rate/ acerage combinations resulted in MOEs that are less than the target MOE, even at the highest practical levels of PPE and engineering controls. Of these, 8 are aerial uses; 2 are wide area ground uses; 3 are granulars and baits applied by spoon, hand, or bellygrinder; 2 are for hand­ held devices; and 1 is for an animal groomer using a liquid application. Also, 2 crop/ rate/ area combinations for poultry use were assessed; however, Aventis has since submitted a letter to EPA requesting voluntary cancellation of the poultry use. C Table 4 below summarizes these remaining noncancer risks of concern for occupational handlers for short­ and intermediate­ term exposure durations that do not meet the target MOE, even after considering the highest level of PPE and engineering controls. Table 4. Noncancer Risks of Concern for Occupational Handlers, Short­ and IintermediateTerm Durations at Highest Level of PPE Practical Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary: Combined Dermal/ Inhalation MOEs Mixer/ Loaders 1f Dry Flowable: Wide area aerial 2 (rangeland/ forestry) 7500 58 3a Liquid: Aerial/ Chemigation 1.5­ 2 (wheat, max corn) 5 (stone fruit) 1200 350 57­ 76 78 3f Liquid: Wide area aerial 2 (Range/ Forestry) 1 (Mosquito adulticide) 7500 7500 9 18 3g Liquid: Wide area ground 1 (Mosquito adulticide) 3000 45 4a Wettable Powders: Aerial 1­ 2 (Wheat/ corn) 5 (stone fruit) 1200 350 40­ 80 55 4f Wettable Powders: Wide area aerial 2 (Range/ Forestry) 7500 6 Occupational Risk... Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary: Combined Dermal/ Inhalation MOEs 20 Applicators 5a Aerial: Agricultural uses, liquid sprays 2 (max corn) 1200 85 5b Aerial: Wide area uses, liquid sprays 2 (Range/ Forestry) 1 (Mosquito adulticide­ max rate) 7500 7500 14 27 5c Aerial: Agricultural uses, granular applications 2 (corn) 2 (corn) 1200 350 21 72 6b Airblast: Wide area uses, liquid sprays 1 (Mosquito adulticide ­ max rate) 3000 22 12 High pressure handwand 4 lb ai/ 100 gallons 1000 gallons 66 13 Animal groomer, liquid application 0. 01 lb ai/ dog 8 dogs 10 15 Granulars & baits applied by hand 9 (Ornamentals & gardens) 1 4 16 Granulars & baits applied by spoon 9 (Ornamentals & garderns) 1 75 Mixer/ Loader/ Applicators 17 Low pressure, high volume turfgun (ORETF Data) 8 (LCO Use on turf) 5 94 20 Granular, bellygrinder 9 (Turf) 1 27 Long­ term risks. Only a few occupational uses are expected to result in long­ term exposures. Of 5 scenarios assessed, 3 meet or exceed the target MOE of 300 at some level of personal protection. The two scenarios that fail to meet or exceed the target MOE are scenario 15: granulars & baits applied by hand; and scenario 16: granulars and baits applied by spoon. Both were assessed at the maximum application rate of 9 lb ai/ acre. Noncancer Risks for Occupational Postapplication Exposures C For postapplication exposures, EPA calculates the minimum length of time required following an application before residues have dissipated to the level where the calculated MOE reaches the target MOE. EPA uses this information to determine restricted entry intervals (REIs), the time period after which workers are allowed to reenter a treated area. For carbaryl, the current label specifies a 12 hour REI. C At the current REI, short­ term MOEs are of concern (i. e., less than 100) for all but the lowest exposure scenarios in some crops. Table 6 summarizes the crop groups that result in risks of concern during short­, intermediate­ and long­ term postapplication exposures, and at different levels of exposure depending on the activity and contact with treated surfaces. Occupational Risk... 21 Table 6. Noncancer Risks of Concern for Occupational Postapplication Exposures Low Exposure (e. g., irrigation) Medium Exposure (e. g., scouting) High Exposure (e. g., hand harvesting) Short­ term Exposure Duration (1 to 30 days) Crop and # of days to reach target MOE Cut Flowers ­ 7 Evergreen Fruit Trees ­ 6 Brassica ­6 Crop and # of days to reach target MOE Cut Flowers ­ 9 Evergreen Fruit Trees ­ 17 Brassica ­ 9 Bunch/ Bundle Group ­ 6 Low/ Medium Field/ Row Crops ­3 Tall Field/ Row Crops ­ 4 Sugarcane ­ 3 Root vegetables ­ 4 Curbit Vegetables ­ 4 Leafy Vegetables ­ 4 Stem/ stalk Vegetables ­ 1 Vine/ Trellis Group ­ 2 Crop and # of days to reach target MOE Cut Flowers ­ 12 Evergreen Fruit Trees (No high exposure) Brassica ­ 11 Bunch/ Bundle Group ­ 8 Low/ Medium Field/ Row Crops ­ 5 Tall Field/ Row Crops ­ 11 Sugarcane ­ 7 Root vegetables ­ 7 Curbit Vegetables ­ 7 Leafy Vegetables ­ 7 Stem/ stalk Vegetables ­ 5 Vine/ Trellis Group ­ 11 Low Berry ­ 4 Fruiting Vegetable ­ 2 Deciduous Fruit Trees ­ 8 Nut Trees ­ 11 Turf/ Sod ­ 14 Intermediateterm Exposure Duration (30 days to several months) None Crop (calculated MOE) Evergreen Fruit Trees (MOE= 59) Crop (calculated MOE) Cut Flowers (MOE= 57) Evergreen Fruit Trees (No high exposure) Brassica (MOE= 79) Tall Field/ Row Crops (MOE= 97) Turf/ Sod (MOE= 46) Vine/ Trellis (MOE= 79) Long­ Term Exposure Duration (greater than six months) None None Crop (calculated MOE) Cut flower industry (MOE= 69). Cancer Risks for Occupational Handlers Occupational cancer risks equal to or less than 1 x 10 ­6 (1 in 1 million) are not of concern to the Agency. The Agency also carefully examines uses with estimated risks in the 10 ­6 to 10 ­4 range to seek cost­ effective ways of reducing risks. If carcinogenic risks are in this range for occupational handlers, increased levels of personal protective equipment (PPE) or engineering controls are added to the extent practical. The Agency considered two distinct populations for the carbaryl cancer risk assessment: private growers, at 10 applications per year, and commercial applicators at 30 applications per year. Occupational Risk... 22 Private growers (10 applications per year). C Of the 128 scenario combinations considered for private growers, all scenarios have risks less than 1 x 10 ­6 at some level of PPE or engineering controls, except for 8 scenarios that have risks between 1 x10 ­4 and 10 ­6 . Of these 8 scenarios, only 1 needed a higher level of PPE than specified on the current label to have risks in this range. Commercial applicators (30 applications per year) C Of the128 scenario combinations considered for commercial applicators, all have risks less than 1 x 10 ­ 6 at some level of PPE or engineering controls, except for 21 scenarios that have risks between 1 x 10 ­4 and 10 ­6 . Of these 21 scenarios, only 1 needed a higher level of PPE than specified on the current label to have risks in this range. Cancer Risks for Occupational Postapplication Exposures Based on a 10 ­6 risk concern, the current REI appears adequate to address cancer risks for many crop/ activity combinations. But for higher exposure situations, longer duration REIs are necessary for risks to cease to be of concern (< 10 ­6 ). In all cases, REIs based on cancer risks are less restrictive or similar (i. e., within a day or two of application for commercial farmworkers) than those based on the noncancer effects of carbaryl. In no cases do cancer risks indicate more restrictive REIs than for noncancer risks calculated for the corresponding exposure scenario. Private growers (10 applications per year). C All scenarios have risks in the 10 ­6 range, except for one scenario (very high exposure for tall field/ row crops), which was in the 10 ­5 range. All risks in the 10 ­6 range take up to approximately 5 days to fall below 1 x 10 ­6 . The risk in the 10 ­5 range takes 23 days to fall below 1 x 10 ­6 . Commercial farmworkers (30 applications per year). C All scenarios had cancer risks in the10 ­6 range or less on the day of application at the current REI, except for two very high exposure activities (hand harvesting). All risks in the 10 ­6 range take approximately 8 days to fall below 1 x 10 ­6 . The two very high exposure activities, for tall field/ row crops and vine/ trellis crop groups, have risks in the 10 ­5 range on the day of application, and take 31 and 13 days, respectively, to fall below 1 x 10 ­6 . Human and Domestic Animal Incidents C The Agency evaluated reports of human carbaryl poisonings and adverse reactions associated with its use from the following sources: OPP Incident Data System (IDS); Poison Control Centers' Toxic Exposure Surveillance System; California Department of Pesticide Regulation; the National Pesticide Telecommunications Network, now the National Pesticide Information Center (NPIC); open literature; and an unpublished study submitted by the registrant. Human and Domestic Animal Incidents... 23 C The data from IDS indicated that a majority of incidents associated with carbaryl exposure involved dermal reactions. A number of other cases involved asthmatics and people who experienced hives and other allergic type reactions. According to California data, about half of the cases involved skin and eye effects in handlers. About a quarter of the skin reactions were due to workers who were exposed to residues on crops. Reports from the literature are very limited but tend to support the finding that carbaryl has irritant properties. C The Poison Control Center cases involving nonoccupational adult exposure and exposures of older children showed an increased risk in five of the six measures used for comparing carbaryl incidents to all other pesticides. The carbaryl cases were almost twice as likely to require serious health care (hospitalization or treatment in a critical care unit) and were two and a half times more likely to experience major medical outcome (life­ threatening effects or significant residual disability) than other pesticides. This pattern of increased risk was not seen among occupational reports or in young children, which may mean that careless handling by non­ professionals is a particular hazard. In addition, five case report studies suggested that carbaryl may be a cause of chronic neurological or psychological problems. C The incident reports on domestic animals in IDS were evaluated. Based on limited data, there is some evidence that young kittens may be susceptible to adverse reactions to carbaryl. Ecological Risk Assessment To estimate potential ecological risk, EPA integrates the results of exposure and ecotoxicity using the quotient method. Risk quotients (RQs) are calculated by dividing acute and chronic exposure estimates by ecotoxicity values for various wildlife species. RQs are then compared to levels of concern (LOCs); the higher the RQ, the greater the potential risk. Environmental Fate Information C Carbaryl dissipates in the environment by abiotic and microbially mediated degradation. The major degradation product is 1­ naphthol, which is further degraded to CO2. Carbaryl is stable to hydrolysis in acidic conditions, but hydrolyzes in neutral (half­ life= 12 days) and alkaline environments (pH 9 half­ life= 3.2 hours). Under aerobic conditions the compound degrades rapidly by microbial metabolism, with half­ lives of 4 to 5 days in soil and aquatic environments. In anaerobic environments metabolism is much slower, with half­ lives on the order of 2 to 3 months. Carbaryl is moderately mobile in the environment. Open literature information suggests that its major degradate, 1­ naphthol, is less persistent and less mobile than carbaryl. Ecological Risk... 24 Nontarget Terrestrial Animal Risk Risks to Birds C The acute LOC for birds is 0.5 and the chronic LOC is 1.0. C Nongranular uses of carbaryl are not expected to pose an acute risk to birds. Of the scenarios assessed, none exceed the LOC for birds in any weight class. Most nongranular uses of carbaryl do pose a chronic risk for birds. C Granular uses of carbaryl pose an acute risk for 20 gram birds (highest RQ is 4.76). For 180 gram birds, uses that exceed the LOC are for trees/ ornamentals, turf grass, and tick control. For 1000 gram birds, no granular uses exceed the LOC. Risks to Mammals C The acute LOC for mammals is 0.5 and the chronic LOC is 1.0. C Nongranular uses, at the maximum label application rate, pose acute risks above the LOC for mammals (highest RQ is 12). At rates below the maximum label rate (i. e., the maximum reported application rate and the average application rate), most uses exceed the LOC for 15 gram mammals feeding on short grass (highest RQ is 11). Practically all nongranular uses pose chronic risks that exceed the LOC (highest RQ is 48). C Granular uses, at maximum label rates, pose acute risks that exceed the LOC for 15 gram and 35 gram mammals (highest RQs are 21.1 and 9.04 respectively), indicating that all granular carbaryl uses pose an acute risk to the smaller mammalian species. For 1000 gram mammals, no acute risks exceed the LOC. Nontarget Aquatic Animal Risk C The acute LOC for aquatic animals is 0.5 and the chronic LOC is 1.0. C EPA examined risks to aquatic animals for estimated environment concentrations in surface water based on five crop scenarios for carbaryl: apples, field corn, sweet corn, citrus and sugar beets. C Acute risks for freshwater fish exceed the LOC for use on citrus (highest RQ is 1.1). No scenario exceeded the chronic risk LOC. C Acute risks for estuarine/ marine fish do not exceed the LOC for any scenario. Data are not available to assess chronic risks. C Acute risks for aquatic invertebrates, both freshwater and estuarine/ marine, exceed the LOC for all scenarios. The acute RQs range from 0.8 to 161. Chronic risks for freshwater aquatic Ecological Risk... 25 invertebrates exceed the chronic LOC. The chronic RQs range from 1.7 to 91. No data are available to assess chronic risks to estuarine/ marine invertebrates. Risks to Honeybees C Carbaryl is highly toxic to honey bees. It is one of the pesticides more often implicated in bee mortality incidents, ranking second and third respectively, in two separate bee kill surveys undertaken in 1997 by the Washington State Department of Agriculture and the American Beekeeping Federation. Nontarget Plant Risk C For terrestrial plants, the carbaryl label indicates that carbaryl may cause injury to tender foliage if applied when foliage is wet or during high humidity, and carbaryl may also harm Boston ivy, Virginia creeper, or maidenhair fern. A few reported incidents cite injury to vegetable crops (potatoes, tomatoes, cabbage and broccoli). However, not all guideline data are available to fully assess carbaryl risk to terrestrial plants. C For aquatic plants, based on the single core green alga study available, the acute risk LOC is not exceeded for any of the five scenarios modeled, even at maximum label rates. However, not all guideline data are available to fully assess carbaryl risk to aquatic plants. Risks to Endangered Species C Acute endangered species LOCs for terrestrial animals (birds and mammals) is 0.1; for aquatic animals (freshwater or marine/ estuarine fish and invertebrates) it is 0.05. ° Granular uses exceed the endangered species LOC for 20­ gram birds, and they also exceed the LOC for 180­ gram birds for most agricultural uses of carbaryl. For 1000­ gram birds, RQs exceed the endangered species LOC for the trees and ornamentals, turf grass, and tick control uses. Nongranular uses of carbaryl do not exceed the avian endangered species LOC based on acute exposure. C The endangered species LOC for mammals is met or exceeded for all uses at three application rates: maximum label, average (based on usage data), and maximum reported (based on DOANE survey). ° All carbaryl uses, even at less than maximum label rates, exceed the endangered species LOC for both freshwater and marine/ estuarine aquatic invertebrates. At less than maximum label rates, the endangered species LOC is exceeded for freshwater fish only, based on the high­ end citrus use scenario, and not exceeded for estuarine/ marine fish for any of the five use scenarios modeled. Ecological Risk... 26 Ecological Incident Data C Carbaryl does not rank high in the list of pesticides responsible for bird or mammal mortality, based on information available in the USEPA Ecological Incident Information System. Three bird kill incidents, classified as "probable," involved blackbirds, ducks, starlings, and grackles in Virginia, New Jersey, and South Carolina. Only two incidents involved small mammals (grey and ground squirrels, mole, and rabbit) in South Carolina and Virginia. Numerous bee kill incidents have been recorded for carbaryl in several states including North Carolina, South Dakota and Washington. Additionally, several incidents on vegetable crops, including damage to potatoes, tomatoes, cabbage, and broccoli were classified as "probable." Summary of Pending Data Aventis has completed and is in the process of submitting (in August 2002) a residential postapplication biomonitoring study for lawn, and either a vegetable garden or ornamental flowers. Aventis will also submit (in October 2002) a biomonitoring study of field workers during harvesting and hand thinning operations in apples and cherries. Also, Aventis is a member of the Residential Exposure Joint Venture (REJV), which is a group of companies conducting a survey of homeowners to ascertain how consumer pesticide products are used (e. g., rate, frequency, pests, etc.). Aventis recently submitted an analysis of this data for carbaryl, which could be used to refine the exposure estimates in this assessment by refining the amounts of carbaryl used per homeowner application. In September 2002, Aventis will submit the final results of their surface water monitoring study for drinking water.

epa

2024-06-07T20:31:42.091603

regulations

EPA-HQ-OPP-2002-0138-0004

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Office of Prevention, Pesticides and Toxic Substances July 30, 2002 SUBJECT: Carbaryl: Revised HED Risk Assessment ­ Public Comment Period, Error Correction Comments Incorporated, DP Barcode: D284580, PC Code: 056801 FROM: Jeffrey L. Dawson, Chemist/ Risk Assessor Reregistration Branch 1 Health Effects Division (7509C) THRU: Whang Phang, PhD, Branch Senior Scientist Reregistration Branch 1 Health Effects Division (7509C) TO: Anthony Britten, Chemical Review Manager Reregistration Branch 3 Special Review & Reregistration Division (7508C) Attached is HED's risk assessment of the insecticide carbaryl for purposes of issuing a Reregistration Eligibility Decision (RED) Document for this active ingredient. This document is based on several disciplinary science chapters which include: Toxicology ­ D282980; Dietary Exposure D281419 Product and Residue Chemistry ­ D283328; Occupational and Residential Exposure D281418 and Estimated Environmental Concentrations ­ D240841. This chapter reflects recent changes in the hazard component based on the submission of additional toxicology studies (reproductive and three 21­ day dermal toxicity studies); changes in endpoint selection; revision of the Q1* for cancer risk assessment; and a reduction in the FQPA SF from 10 to 1. Modifications to the occupational and residential assessment includes changes in the calculations for pet uses; the use of recently submitted ARTF transfer coefficients for greenhouse crops; and changes to the updated duration policy for delineating short­ and intermediate­ term exposures. Also, mosquito adulticide and carbaryl use on oyster beds in Washington state have been quantitatively addressed. Modifications to the dietary risk assessment include: the use of updated processing factors; deletion of some use patterns; and the use of additional residue data. This document also addresses error correction comments raised by Aventis Crop Sciences included in the document Human Health Risk Assessment and Supporting Documents Phase 1 Error Correction (July 12, 2002) that were submitted on the previous version of this assessment (D281420, Dated June 7, 2002). Reviewers: RARC (6/ 6/ 01 Report), Revision (6/ 7/ 02) Reviewed By Paula Deschamp HUMAN HEALTH RISK ASSESSMENT Carbaryl U. S. Environmental Protection Agency Office of Pesticide Programs Health Effects Division (7509C) Jeffrey L. Dawson, Chemist/ Risk Assessor Date: July 30, 2002 HUMAN HEALTH RISK ASSESSMENT Carbaryl Risk Assessment Team: Risk Assessor: Jeffrey L. Dawson, Dietary Risk: Felecia Fort Product and Residue Chemistry: Felecia Fort Occupational and Residential Exposure: Jeffrey L. Dawson Epidemiology: Jerome Blondell, MPH, PhD Monica Spann, MPH Virginia Dobozy, VMD, MPH Toxicology: Virginia Dobozy, VMD, MPH Drinking Water Estimates: R. David Jones, Ph. D. E. Laurence Libelo, Ph. D. Table of Contents 1. 0 EXECUTIVE SUMMARY...................................................... 5 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION ..................... 17 2. 1 Chemical Structure and Identification....................................... 17 2. 2 Physical Properties of Carbaryl ............................................ 18 3. 0 HAZARD CHARACTERIZATION .............................................. 19 3.1 Hazard Profile ......................................................... 19 3. 2 FQPA Considerations ................................................... 22 3.2.1 Determination of Susceptibility ...................................... 22 3.2.2 Degree of Concern Analysis and Residual Uncertainties .................. 23 3.3 Dose Response Assessment ............................................... 24 3.4 Endocrine Disruption .................................................... 26 4.0 NON­ OCCUPATIONAL RISK ASSESSMENT AND CHARACTERIZATION ........... 27 4. 1 Summary of Registered Uses.............................................. 27 4.2 Dietary Risk Assessment ................................................. 31 4.2.1 Residue Profile ................................................... 32 4.2.2 Acute Dietary Risk Assessment ...................................... 34 4.2.3 Chronic Dietary Risk Assessment .................................... 37 4.2.4 Cancer Dietary Risk Assessment ..................................... 38 4.2.5 Characterization/ Uncertainties of the Dietary Risk Estimates .............. 38 4. 3 Estimated Environmental Concentrations In Water ............................ 39 4.3.1 Environmental Fate Characteristics ................................... 39 4.3.2 Monitoring Data .................................................. 40 4.3.3 Modeling EECs .................................................. 41 4. 4 Residential Risk Assessment .............................................. 43 4.4.1 Home Uses ...................................................... 44 4.4.2 Residential Handler Risk Assessment ................................. 44 4.4.2.1 Residential Handler Noncancer Risks ........................... 47 4.4.2.2 Residential Handler Cancer Risks .............................. 51 4.4.3 Residential Postapplication Risk Assessment ........................... 54 4.4.3.1 Residential Postapplication Exposure and Noncancer Risks .......... 59 4.4.3.2 Residential Postapplication Exposure and Risks For Cancer ......... 65 4.4.4 Residential Risk Characterization .................................... 66 4.4.5 Exposure from the Use of Tobacco ................................... 69 4.4.6 Other Residential Exposures ........................................ 69 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION ............. 70 5. 1 Calculation of Aggregate Risks and DWLOCs ................................ 70 5. 2 Acute Dietary Aggregate Risks and DWLOCs ................................ 73 5. 3 Chronic Dietary Aggregate Risks and DWLOCs .............................. 73 5. 4 Short­ term Aggregate Risks and DWLOCs................................... 74 5. 5 Intermediate­ term Aggregate Risks and DWLOCs............................. 75 5. 6 Aggregate Cancer Risks and DWLOCs...................................... 76 5. 7 Summary of Aggregate Risks ............................................. 77 6. 0 CUMULATIVE RISK......................................................... 78 7.0 OCCUPATIONAL RISK ASSESSMENT ......................................... 79 7. 1 Occupational Handler Risk Assessment ..................................... 79 7.1.1 Occupational Handler Non­ Cancer Risks .............................. 84 7.1.2 Occupational Handler Cancer Risks .................................. 88 7.2 Postapplication Exposures and Risks ....................................... 92 7.2.1 Occupational Postapplication Noncancer Risks ......................... 95 7.2.2 Occupational Postapplication Exposure and Risk Estimates for Cancer ....... 98 7. 3 Occupational Risk Characterization ....................................... 101 8.0 HUMAN AND DOMESTIC ANIMAL INCIDENT DATA REVIEW .................. 104 9.0 DATA NEEDS .............................................................. 105 APPENDIX 1: Toxicology Profile APPENDIX 2: Incident Review 5 1.0 EXECUTIVE SUMMARY The Health Effects Division (HED) of EPA's Office of Pesticide Programs has evaluated the carbaryl database and conducted a human health risk assessment for the reregistration of the chemical. Carbaryl is a list A reregistration chemical. Carbaryl is also subject to court specified deadlines resulting from a Natural Resources Defense Council (NRDC) petition of the Agency. This assessment incorporates error corrections and begins phase 3 of the public participation process. Use Patterns: Carbaryl [1­ napthyl methylcarbamate] is one of the most widely used broadspectrum insecticides in agriculture, professional turf management, professional ornamental production, and in the residential pet, lawn and garden markets. Carbaryl formulations include baits, dusts, pet collars, flowable concentrates, emulsifiable concentrates, granulars, soluble concentrates, and wettable powders. Carbaryl is used in agriculture to control pests on terrestrial food crops including fruit and nut trees (e. g., apples, pears, almonds, walnuts, and citrus), many types of fruit and vegetables (e. g., cucumbers, tomatoes, lettuce, blackberries, and grapes), and grain crops (e. g., corn, rice, sorghum, and wheat). Carbaryl is also used for direct animal treatments to control pests on companion animals such as dogs and cats. There are other uses for ornamentals and turf, including production facilities such as greenhouses, golf courses, and residential sites that can be treated by professional applicators (e. g., annuals, perennials, shrubs). Carbaryl can also be used by homeowners on lawns, for home and garden uses, and on companion animals. There are no labels for indoor uses within a residence. In agriculture, groundboom, airblast, and aerial applications are typical. Other applications can also be made using handheld equipment such as low pressure handwand sprayers, backpack sprayers, and turfguns. Homeowners can also use other types of application equipment including trigger sprayers, hose­ end sprayers, and ready­ to­ use dust packaging. Information on uses and application rates used in the risk assessment was provided by the registrant, Aventis Crop Science, at a SMART meeting on September 21, 1998 and from a review of current labels. The Agency's Biological and Economic Analysis Division has also concurred with the use patterns which serve as the basis for this assessment. Carbaryl also has more specialized uses that can lead to exposures in the general population such as an adulticide for mosquito control and for Ghost and Mud shrimp control in oyster beds in Washington State. These use patterns were also considered in this assessment. Hazard Characterization: Carbaryl is a carbamate insecticide where the mode of toxic action is through cholinesterase inhibition (ChEI). In most of the toxicology studies in which ChEI activity was measured, it was the endpoint used for setting the No Observed Adverse Effect Level (NOAEL) for risk assessment, the dose at which no adverse effects were observed. There was one exception; for chronic duration exposures, a NOAEL could not be defined in the toxicology study deemed most appropriate (i. e., chronic dog toxicity) so a Lowest Observed Adverse Effect Level (LOAEL), the dose at which the first adverse 6 effects were observed, was used for risk assessment purposes. Carbaryl is relatively acutely toxic by the oral route (Toxicity Category II) but has relatively low acute toxicity by the dermal and inhalation routes. It is not a dermal or eye irritant or a dermal sensitizer; however, there are reports of dermal irritation and dermal manifestations of an allergic response in humans exposed to carbaryl. The Agency is required by the Food Quality Protection Act to consider the special sensitivities of various susceptible populations such as infants and children. Current Agency policy retains the factor using criteria based on exposure and toxicity considerations. For carbaryl, a traditional factor of 3 was applied only to chronic duration exposures to account for the lack of a NOAEL in the selected chronic dog toxicity study (i. e., the use of a LOAEL). The Agency decided that the special FQPA Safety Factor should be reduced to 1 and that this was adequate to protect susceptible populations because there are no residual uncertainties in the exposure databases, the toxicology database is complete, and the endpoint and NOAELs for risk assessment were well defined. Dietary exposures were calculated using FDA and PDP monitoring data, a carbamate market basket survey, and percent crop treated information. Residential exposures were calculated using a number of carbaryl­ specific studies. In the toxicology database, no quantitative or qualitative evidence of increased susceptibility in rat or rabbit fetuses following in utero exposure in the standard developmental studies was observed. There was a low level of concern for evidence of susceptibility seen in the developmental neurotoxicity study, and there was evidence of increased susceptibility in offspring in the 2­ generation reproduction study. However, the Agency believes that the acute and chronic RfDs would be protective of these effects so the special FQPA safety factor was reduced to 1. Carbaryl has been classified as a Group C possible human carcinogen based on an increased incidence of hemangiosarcomas and combined hemangiomas/ hemangiosarcomas in CD­ 1 mice at 100 ppm and above (15 and 18 mg/ kg/ day for males and females, respectively). Mechanistic metabolism studies and a study in heterozygous p53­ deficient mice were considered inadequate to demonstrate a mode of action for the vascular tumors. Therefore, a linear low dose extrapolation approach was used for risk assessment; the Q1* is 8.75 x 10 ­4 (mg/ kg/ day) ­1 based on the mouse vascular tumors according to the February 2002 Cancer Assessment Review Committee (CARC) report. Also, CARC concluded that there is a concern for mutagenicity because carbaryl has been observed to be clastogenic in vitro. However, this concern is lessened because of a lack of effects observed in vivo (i. e., micronuclei induction and chromosome aberration studies were negative). Endpoints for acute and chronic dietary exposure risk assessments were selected by the HED Hazard Identification Assessment Review Committee (HIARC). The toxicity endpoints selected for risk assessment are neurotoxic effects associated with the inhibition of ChEI. The dose level used for the acute dietary risk assessment was a NOAEL which was defined in a developmental neurotoxicity study conducted with rats (1 mg/ kg/ day). The dose level used for the chronic dietary risk assessment was a LOAEL which was defined in a chronic dog feeding study (3.1 mg/ kg/ day). Because a NOAEL could not be defined in the chronic study, an additional factor of 3x was added to the customary 100x factor (i. e., 10x for extrapolation from animal studies to humans and 10x for intraspecies variation between the test animals and humans) to account for the uncertainty associated with a lack of a NOAEL. The acute and chronic reference doses (RfD) were 0.01 mg/ kg/ day (i. e., dose/ 100 for acute and dose/ 300 for chronic). The Population Adjusted Dose (PAD) is a modification of the acute or chronic RfD to 7 accommodate the FQPA safety factor and is calculated by dividing the RfD by the FQPA safety factor. The PADs are the values used for the acute and chronic dietary risk calculations. The Special FQPA Safety Factor was reduced to 1 as described above. Therefore, the aPAD and cPAD (i. e., PAD values for acute and chronic dietary exposures, respectively) are both 0.01 mg/ kg/ day. There are many potential ways people can be exposed to carbaryl in occupational and residential settings. The Agency considers exposures for those involved in the application of carbaryl (i. e., handlers) and those who can come into contact with carbaryl residues after application (i. e., reentry or postapplication). Both cancer and non­ cancer risk assessments were conducted for residential handlers and for people in the general population who might be exposed postapplication from lawn, garden, or pet uses of carbaryl or from more specialized uses such as mosquito adulticide applications and uses on oyster beds in Washington state. Similarly, both handler and postapplication risks were calculated for those people who could be exposed as part of their jobs such as a grower treating their crop or someone harvesting fruit. Endpoints for occupational and residential exposures from various routes (i. e., dermal, inhalation, and incidental oral) and differing durations (i. e., short­ term, intermediate­ term, and chronic) were selected by the HIARC. Based on current policy, short­ term exposure was defined as 1 to 30 days, intermediate­ term exposures as 30 days to several months, and chronic exposures as several months to a lifetime. [Note: Not all routes and durations are applicable to each population.] The toxicity endpoints selected for these carbaryl risk assessments are again based on neurotoxic effects associated with the inhibition of ChEI. The short­ and intermediate­ term dermal risk assessments for carbaryl are based on NOAEL of 20 mg/ kg/ day defined in a dermal toxicity study in rats using technical material where decreases in red blood cell cholinesterase in males and females and brain cholinesterase in males were observed. The short­ term inhalation and nondietary ingestion risk assessments for carbaryl are based on a NOAEL of 1 mg/ kg/ day which was defined in a developmental neurotoxicity study in rats where alterations in FOB measurements and cholinesterase inhibition (plasma, whole blood, and brain) were observed. The intermediate­ term inhalation and nondietary ingestion risk assessments are based on a NOAEL of 1 mg/ kg/ day that was defined in a subchronic neurotoxicity study in rats. The chronic risk assessments, regardless of how exposures occur (e. g., skin or inhaled) are based on a LOAEL of 3.1 mg/ kg/ day that was defined in a 1 year dog feeding study. In some assessments, a dermal absorption factor is required. A rat dermal absorption study using radiolabeled 14 C carbaryl was used to define a factor of 12.7 percent; this value was used to calculate the oral equivalent dermal dose for noncancer chronic duration exposures and for the calculation of cancer risks. No inhalation toxicity studies were available for risk assessment purposes so a route­ to­ route extrapolation was used to address risks from inhalation exposures. No inhalation absorption study was conducted; therefore, a 100 percent inhalation absorption factor has been used to convert all inhalation exposures to an oral equivalent inhalation dose. Dietary Risk Estimates: Potential dietary exposure to carbaryl occurs through food and water. Tolerances for residues of carbaryl are currently expressed in terms of carbaryl and its hydrolysis product, 1­ naphthol (calculated as carbaryl) for most raw agricultural commodities. However, HED is recommending that carbaryl per se be regulated in plants. In livestock commodities, carbaryl; 5,6­ dihydro­ 5,6­ dihydroxy carbaryl; and 1 At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. The primary concern was rubbing sampled commodities during the rinsing process except for broccoli and tomato because this created a potential for residue loss from the mechanical action associated with rubbing. A separate assessment was also completed using other sources of high quality residue data (e. g., PDP) for comparative purposes to more completely inform the risk management process. 8 5­ methoxy­ 6­ hydroxy carbaryl and all residues which can be hydrolyzed to carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, or 5­ methoxy­ 6­ hydroxy carbaryl under acidic conditions should be included in the tolerance expression and risk assessment for all endpoints of dietary concern. Once the tolerances for plants are revised, they will be compatible with Codex MRLs except for livestock commodities. A Tier 3/ 4 dietary risk assessment, which is the most highly refined assessment possible at this time, was conducted. Both acute and chronic dietary risk assessments were conducted. Dietary exposure was determined, considering the level of carbaryl residue on food commodities and their potential consumption by multiple subpopulations. Dietary risk was then calculated by comparing dietary exposure to the acute or chronic PADs. Data on anticipated carbaryl residues were determined based mainly on USDA Pesticide Data Program (PDP) and Food and Drug Administration (FDA) monitoring data. Field trial data were used for certain commodities. In addition, separate acute assessments were conducted incorporating the results of the Carbamate Market Basket Survey (CMBS). 1 The percentage of the crop treated (estimated maximum percentage and weighted average percentage for the acute and chronic analyses, respectively) was also considered. Food consumption data were from 2 of USDA's Continuing Surveys of Food Intakes by Individuals (CSFII) which ranged from 1989 to 1992 and from 1994 to 1998. The 1994 to 1998 data were included based on comments from the registrant, Aventis Crop Science, for comparative purposes (1989 to 1992 are normally used for risk assessment). In these surveys, 3­ day mean consumption and single­ day consumption information were recorded for 22 demographic and socio­ economic subpopulations, including infants, children, and nursing women. Dietary risk assessments were conducted using the Dietary Exposure Evaluation Model (DEEM™), which incorporates exposure and consumption data to calculate risk as a percentage of the PAD. Values greater than 100 percent of the PAD exceed HED's level of concern. Estimated acute dietary exposure for carbaryl at the 99.9 th percentile using the 1989 to 1992 CFSII data exceeds HED's level of concern for some population subgroups when CMBS data are not used and are not of concern when the CMBS are incorporated. The results of the acute dietary assessment when CMBS data have not been used indicate risks are greater than 100 percent of the aPAD for all infants (< 1 year old) and children (1­ 6 years old) at the 99.9 th percentile of exposure (133 % and 110% of aPAD, respectively). When CMBS data were incorporated, the highest exposed subpopulation was children (1­ 6 years old) at 75 percent of the aPAD. A sensitivity analysis was completed by the Agency (not using the CMBS) to evaluate the impacts of eliminating apples or peaches from the analysis and eliminating commodities with no detectable residues. Eliminating peaches appears to have the most impact as all infants in this analysis consume 72 percent of the aPAD but children (1­ 6 years old) still consume just over 100 percent of the aPAD (i. e., 102 percent). One comment from Aventis Crop Science was that 1994 to 1998 CFSII food consumption data should be used rather than 1989 to 1992 data. Results for most subpopulations were actually slightly worse (i. e., generally, 5 to 10 percent 9 more of the aPAD was consumed) if the 1994 to 1998 CFSII data were used. Estimated chronic dietary risks for all population subgroups are not of concern. Estimated chronic dietary exposures for all population subgroups consumed <1 percent of the cPAD. The CMBS data were not used in this analysis because risks are low and CMBS is single serving data. The cancer dietary exposure assessment was conducted using the Q 1* approach (i. e., linear, low dose extrapolation). Dietary exposure is determined from consumption and residue data, as was done for the acute and chronic dietary assessments. The food exposure is then multiplied by the Q 1* (8.75 x 10 ­4 ) (mg/ kg/ day) ­1 for carbaryl to determine the increased risk of cancer from consuming carbaryl residues in food over a lifetime (70 years). Risks estimates above 1 x 10 ­6 are of concern. Results indicate a maximum lifetime risk of 2.8 X 10 ­8 for the general US population. Concentrations in Water: Monitoring data for carbaryl residues in ground and surface water are available, but they are of limited utility in developing estimated environmental concentrations (EECs) for the aggregate dietary (food and water) risk assessment. Therefore, computer modeling was used to estimate surface (PRZM 3.12 and EXAMS 2.97.7) and ground (SCI­ GROW) water concentrations expected from normal agricultural use. These model estimates were compared to drinking water levels of concern (DWLOCs), the theoretical concentration of pesticide in drinking water that would be an acceptable upper limit in light of the aggregate exposure to that pesticide from other sources (food and residential use). The maximum calculated acute and chronic surface water EECs (494 ppb and 28 ppb, respectively) resulted from use on citrus in Florida. In Florida, the majority of drinking water is derived from groundwater (> 90%) so high surface water concentrations do not necessarily indicate high exposure. As a result, both Florida and the results for Oregon apples (the next highest EECs) have been considered in the aggregate assessment (144 and 9 ppb for acute and chronic, respectively). Groundwater EECs for the acute and chronic assessments were both 0.8 ppb as calculated with SCI­ GROW. Use of Consumer Products (Residential Handlers): The noncancer risks of short­ term dermal and inhalation exposure to residential handlers were calculated using Margins of Exposure (MOEs) in which the doses were selected from the 21­ day dermal toxicology study using technical material and the developmental neurotoxicity study, respectively. The target (acceptable) MOE for residential short­ term risk assessments is 100 based on the customary 100x uncertainty factor (i. e., 10x for inter­ and 10x for intra­ species) and the FQPA Safety Factor of 1. Calculated MOEs that equal or exceed the target MOE of 100 are not of concern. Combined (dermal and inhalation) risks were calculated for 17 scenarios (i. e., 52 site/ area/ rate combinations within those scenarios) considered representative of the residential uses, application rates and application equipment on carbaryl labels. For residential handlers, MOEs associated with most (40 of 52 considered) are 10 generally not of concern because they exceed the Agency's target MOEs for noncancer risk assessments (i. e., MOE = 100). The scenarios of concern involve the use of dusts (in gardens and on pets) and for some liquid sprays on gardens. The risk of cancer in residential handlers was calculated considering one application of carbaryl per year for 50 years. The annual frequency for use was reported to be 1 to 2 times per year (60 th percentile) and 5 times per year (84 th percentile) by the registrant, the Aventis Crop Science, at the SMART meeting held with the Agency. Risks were calculated by multiplying the Lifetime Average Daily Dose (LADD), which represents dermal and inhalation exposure amortized over a lifetime, by the Q1*. The risk considered acceptable is 1 x 10 ­6 , which means that an individual receiving a lifetime exposure to a pesticide increases their chance of developing cancer by one in a million. Based on a single day of exposure, cancer risks for most scenarios are in the 10 ­8 to 10 ­10 range although there is one scenario where the risk exceeds 1x10 ­6 (dusting dogs) even for a single day of use. Cancer risks have also been calculated using another approach where the number of days per year of exposure required to exceed a risk of 1x10 ­6 has been defined. There are 5 scenarios where the allowable days per year of exposure is less than or equal to 5 which should be considered in conjunction with the use/ usage data from Aventis Crop Science that indicates 5 uses per year is the 84 th percentile. In all cases, cancer risk estimates require less restrictive risk mitigation measures than do the corresponding results for noncancer concerns (i. e., noncancer risks appear to be driving the need for risk mitigation). Residential Postapplication Exposures: HED considered a number of residential postapplication exposure scenarios for toddlers, youthaged children and adults. Short­ term and intermediate­ term risks from declining residues were calculated for multiple scenarios, including exposures to treated lawns (toddlers and adults), golf courses (adults), gardens (adults and youth­ aged children) and pets (toddlers). Exposures from more limited uses such as a mosquito adulticide and for use in oyster beds were also considered. Short­ and intermediate­ term dermal risks were calculated using the NOAEL from the 21­ day dermal toxicity study (i. e., 20 mg/ kg/ day). Risks from short­ and intermediate­ term nondietary ingestion (e. g., mouthing behaviors) were calculated using NOAELs from the developmental neurotoxicity study in rats and the subchronic neurotoxicity study in rats where the NOAELs both happen to be 1 mg/ kg/ day. The target MOE is also 100 for all scenarios considered. MOEs were calculated over the amount of time it took residues to dissipate or out to a 30 day interval whichever applied depending upon the data. Short­ term MOEs were calculated based on the residue concentrations for each day while intermediate­ term risks were calculated using a 30 day average. The Agency has short­ term risk concerns for exposures to adults doing heavy yardwork, for toddlers playing on treated lawns, and for toddlers that have contact with treated pets. Activities associated with home gardening (e. g., harvesting) and golfing for adults, home gardening for youth­ aged children or any age or activity considered in the adulticide mosquito control or oyster assessment do not have risk concerns even on the day of application (i. e., MOEs $ 100 on the day of application). For adults, the MOEs for heavy yardwork do not meet or exceed risk targets (i. e., MOE $ 100) up to 5 days after application. For toddlers, the Agency has concerns for pet treatments and also for lawn uses. In fact, pet uses never reach acceptable levels even 30 days after application and not until 18 days at the maximum application rate considered on turf. Toddler MOEs from pet and turf uses represent total exposures from multiple pathways. For the pet uses, dermal and 11 hand­ to­ mouth exposures essentially both equally contribute to the overall estimate. For the turf uses, dermal and hand­ to­ mouth exposures are also the key contributors to the overall estimates. The Agency does not have intermediate­ term risk concerns for adults and youth­ aged children for any of the uses considered including lawncare, home gardens, golfing, and any aspect of adulticide mosquito control or uses in oyster beds. In contrast, the Agency does have intermediate­ term risk concerns for all toddler exposure scenarios considered (i. e., pet treatments and lawncare uses). As with the short­ term MOEs, pet and turf uses represent total exposures where the significant contributions to overall exposures are again made equally from the dermal and hand­ to­ mouth exposure pathways. Ingestion of carbaryl granules is also a potential source of exposure because children can eat them if they are found in treated lawns or gardens. This scenario is considered episodic by the Agency and is generally not recommended as a basis for risk management decisions. For illustrative purposes, if one considers a 2 percent formulation and the density of soil (0.67 mL/ gram, many granulars are claybased), only 0.005 mL of formulation would need to be ingested to have a risk concern (i. e., 7.5 mg * 1g/ 1000mg * 0.67 mL/ gram). [Note: This volume is orders of magnitude less than a teaspoon of granular formulation (i. e., 0.1% of a teaspoon where a tsp. = 5 mL).] Use in Tobacco: In addition to the routine residential risk assessment, HED calculated the risks of carbaryl exposure in tobacco because a pyrolysis study was submitted by the registrant that quantified residues of carbaryl at a level of 44.58 ppm in tobacco smoke (side­ stream and main­ stream combined). Since this is a composited sample of main­ stream and side­ stream smoke, it greatly exaggerates the actual exposure to the smoker, whose primary route of exposure is via main­ stream smoke. HED further assumed that 100 percent inhaled is absorbed (i. e., that none of the residue is exhaled along with the smoke). The MOE for consuming 15 cigarettes per day is 104 even with the conservative basis of the assessment. Aggregate Risks and DWLOCs: The Food Quality Protection Act requires that the Agency consider exposures from different sources (i. e., food water, and residential) that results in an aggregate risk for each chemical. Aggregate risks are calculated by considering food or food and residential (depends upon the specific scenario), subtracting these from the allowable exposure limit, and, if the exposure limit has not been exceeded, then calculating Drinking Water Levels of Concern (DWLOCs) to compare to surface or groundwater Estimated Environmental Concentrations (EECs). In many residential scenarios, MOEs exceed the Agency's risk targets making the calculation of DWLOCs and aggregate risks for those scenarios inappropriate because the allowable exposure limits have already been exceeded. Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment (133 % of aPAD). However, the risk picture could substantively change if residential risks are refined based on updated use information from the carbaryl use survey yet to be submitted to the Agency, and the Agency uses the CMBS data even with the caveats associated with that study. Keeping this in mind, the Agency completed DWLOC 12 and aggregate risk calculations for illustrative purposes using a number of representative exposure scenarios where the residential and dietary risk estimates did not already exceed the Agency's level of concern. For example, an acute assessment with CMBS data and short­ term assessments where residential handler risks weren't already of concern were completed. The acute aggregate assessment indicates that even with the use of the CMBS, aggregate risks when surface water is the source of drinking water, are still of concern for all infants, children (1 to 6 years old) and children (7 to 12 years old) regardless of whether or not Florida citrus or Oregon apple EECs are used. If Florida citrus surface water EECs are solely considered, aggregate risks are of concern for all subpopulations. [Note: For characterization of the EECs, surface water EECs for Florida citrus exceed exposure limits alone without even considering corresponding food intakes for all populations. Additionally, the surface water EECs for Oregon apples alone also exceed exposure limits, even without including food intakes, for infants and children.] Acute aggregate risks for all subpopulations are not of concern if groundwater is the source of drinking water. Chronic aggregate risks were not of concern for any subpopulation regardless of the source of drinking water, even considering the Florida surface water EECs. In the short­ term assessment, the Agency selected representative scenarios where residential risks alone were not of concern including mosquito control, oyster harvesting, golfing, garden harvest, and several handler scenarios (handlers all at average rates, max rate scenarios were of concern for residential exposures alone). If surface water EECs based on Oregon apples or groundwater EECs from SciGrow are considered, aggregate risks are not of concern for the selected scenarios. If EECs from Florida citrus are considered, aggregate risks are not of concern for the selected scenarios except for application of dusts to gardens. Separate intermediate­ term aggregate risk and DWLOC calculations were not completed for carbaryl because the short­ term aggregate risk estimates essentially present the same results since the hazard inputs are numerically identical. The only major differences would be the postapplication results where, instead of a single day exposure estimate, the exposures represent a 30 day average (i. e., risks would be accordingly lower since an average rather than a single high end day was considered). Aggregate cancer risks were not of concern for any subpopulation regardless of the source of drinking water, even considering the Florida surface water EECs. Cumulative Risks: Carbaryl is a member of the carbamate class of pesticides. This class also includes the aldicarb, methomyl and oxamyl among others. HED did not perform a cumulative risk assessment as part of this reregistration review for carbaryl because HED has not yet initiated a review to determine if there are any other chemical substances that have a mechanism of toxicity common with that of carbaryl. For purposes of this reregistration decision, EPA has assumed that carbaryl does not have a common mechanism of toxicity with other substances. 13 Occupational Handlers: There is significant potential for exposure to carbaryl users in a variety of agricultural and commercial settings. Tasks associated with occupational carbaryl use include mixing, loading and applying the chemical or guiding aerial applications (flaggers). All these activities are collectively referred to as handler tasks. A total of 28 scenarios were considered representative of the range of handler activities, crops or acres treated and equipment used. The risks from short­ and intermediateterm dermal exposures and short­ and intermediate­ term inhalation exposures in these scenarios were calculated and then added together to obtain overall risk estimates at varying levels of personal protection. The target MOEs were 100 for short­ term and intermediate­ term exposures. [Note: Does not include FQPA Safety Factors as they are not applicable to occupational exposures.] Risks from longterm (chronic) exposures were also calculated for a limited number of scenarios in the ornamental/ greenhouse industry. The short­ and intermediate­ term risk assessments were conducted, as described above. The long­ term risk assessment for carbaryl was based on a 1 year dog feeding study where effects (ChEI) were observed at 3.1 mg/ kg/ day (LOAEL). The target MOE was 300 (customary 100x plus 3x for use of LOAEL). Risks were calculated assuming one of eight possible levels of personal protection equipment, ranging from a baseline of typical work clothing (long­ sleeved shirt and long pants, no respiratory protection and no chemical­ resistant gloves) to engineering controls, such as a closed cab or closed loading system. Current carbaryl labels typically require that handlers wear long pants, long­ sleeved shirts, and gloves but do not require respirators. For most scenarios, the noncancer risks for this personal protection ensemble do not meet Agency risk requirements and additional levels of personal protection are required to achieve Agency risk targets. In fact, in many cases engineering controls such as closed loading systems or closed cab tractors are needed. The Agency does have risk concerns over the use of carbaryl in some agricultural and other occupational settings regardless of the level of personal protection used (i. e., MOEs at any level of personal protection are <targets). As would be expected, these scenarios with the highest associated risk also have high daily chemical use amounts based on application rates or high acreages treated or the exposures for the scenarios in question are relatively high. Generally, the areas that appear to be problematic include: large acreage aerial and chemigation applications in agriculture or for wide area treatments such as mosquito control; airblast applications at higher rates; pet grooming; and the use of certain handheld equipment for applications to turf or gardens (e. g., bellygrinder). This general trend was essentially the same for exposures of any duration. Several data gaps were also identified in many different use areas that include: dust use for animal grooming and in agriculture; various specialized hand equipment application methods (e. g., powered backpack, power hand fogger, and tree injection); and nursery operations such as seedling dips. The risk of cancer for occupational handlers was calculated for two populations, private growers (10 applications per year) and commercial applicators (30 applications per year), using the same 28 scenarios. According to Agency policy, acceptable cancer risks for occupational exposure to pesticides can vary from 1x10 ­4 to 1x10 ­6 , depending on the course of action taken by the Agency as outlined in the 2 The Agency has defined a range of acceptable cancer risks based on a policy memorandum dated August 14, 1996, by Office of Pesticide Programs Director Dan Barolo. This memo refers to a predetermined quantified "level of concern" for occupational carcinogenic risk. Occupational carcinogenic risks that are 1 x 10 ­6 or lower require no risk management action. For those chemicals subject to reregistration, the Agency is to carefully examine uses with estimated risks in the 10 ­6 to 10 ­4 range to seek ways of cost­ effectively reducing risks. If carcinogenic risks are in this range for occupational handlers, increased levels of personal protection are warranted as is commonly applied with noncancer risk estimates (e. g., additional PPE or engineering controls). Carcinogenic risks that remain above 1.0 x 10 ­4 at the highest level of mitigation appropriate for that scenario remain a concern. 14 the subject policy 2 . Risks for corresponding scenarios based on cancer concerns were generally less than the corresponding noncancer results across all scenarios. In fact, in all but one scenario, cancer risks were <1x10 ­4 at current carbaryl label requirements of single layer clothing, gloves, and no respirator for both private growers and commercial applicators (i. e., mixing/ loading wettable powders for wide area aerial applications). Higher levels of personal protection reduce this risk to <1x10 ­4 in both populations. If a 1x10 ­6 risk level is specified as a concern, results are similar in that risks for a majority of scenarios are <1x10 ­6 at current label requirements. In fact, only 8 of the 128 scenarios considered for private applicators have cancer risks >1x10 ­6 (and less than 1x10 ­4 ) even with the most protective ensembles of protective clothing or engineering controls. For commercial applicators, results indicate that risks for about half of the scenarios considered are <1x10 ­6 at current label requirements and that only 21 of the 128 scenarios considered have cancer risks >1x10 ­6 (and less than 1x10 ­4 ) even with the most protective ensembles of either protective clothing or engineering controls. Occupational Postapplication (Reentry Workers): Workers can be exposed to carbaryl residues when entering previously treated areas to perform certain activities, such as harvesting. Current label requirements specify 12 hour Restricted Entry Intervals (REIs) while Pre­ Harvest Intervals (PHIs) are less than 7 days for most crops with some as long as 28 days. Non­ cancer risks from short­ and intermediate­ term dermal postapplication exposure were calculated for 18 representative crop groupings using the MOE approach. The risks from long­ term dermal exposures were calculated for only a limited number of scenarios in the greenhouse and floriculture industries. For each scenario, the risk on the day of application was calculated, along with the time required to reach the target MOE, allowing for dissipation of the carbaryl residues. For all but the lowest exposure scenarios in some crops, MOEs do not meet or exceed target MOEs until several days after application. If short­ term risks are considered, MOEs meet or exceed target MOEs generally in the range of 3 to 5 days after application for lower to medium exposure activities and from 8 to 12 days after application in most higher exposure scenarios. If intermediate­ term risks are considered, MOEs are not of concern based on a 30 day average exposures except for higher level exposures such as harvesting in some crops. Chronic exposures are of concern for the cut flower industry but not for other general greenhouse and nursery production activities based on the most recent data. Cancer risks were calculated for private growers and professional farmworkers with the only difference being the annual frequency of exposure days. Cancer risks for private growers and commercial farmworkers are generally in the 10 ­8 to 10 ­6 range on the day of application. If a 1x10 ­4 cancer risk is the target, the current REI would be adequate for all scenarios considered in the 15 assessment. If a 1x10 ­6 cancer risk is used, then durations longer than the current REI should be considered for some cases which are not considered low to medium exposures. It should be noted that the cancer risk calculations are less restrictive than noncancer risk estimates for the same scenarios in all cases. Many mechanized or partially mechanized processes are possibly associated with the use of carbaryl that may limit or eliminate exposures (e. g., combines for grain harvest). Human and Domestic Animal Incidents: HED evaluated reports of human carbaryl poisonings and adverse reactions associated with its use from the following sources: OPP Incident Data System (IDS); Poison Control Centers' Toxic Exposure Surveillance System; California Department of Pesticide Regulation; the National Pesticide Telecommunications Network (NPTN); open literature; and an unpublished study submitted by the registrant. The data from IDS indicated that a majority of cases from carbaryl exposure involved dermal reactions. A number of other cases involved asthmatics and people who experienced hives and other allergic type reactions. It is noted that the dermal sensitization study in the guinea pig was negative. Reports of allergic­ type reactions in humans could be evidence of a difference in species sensitivity or could be attributable to inert ingredients in the marketed formulations. It is recommended that labels for products should advise that carbaryl can cause sensitizing effects in some people. According to California data, about half of the cases involved skin and eye effects in handlers. About a quarter of the skin reactions were due to workers that were exposed to residues on crops. Reports from the literature are very limited but tend to support the finding that carbaryl has irritant properties. The Poison Control Center cases involving non­ occupational adults and older children showed an increased risk in five of the six measures used for comparing carbaryl incidents to all other pesticides. The carbaryl cases were almost twice as likely to require serious health care (hospitalization or treatment in a critical care unit) and were two and a half times more likely to experience major medical outcome (life­ threatening effects or significant residual disability) than other pesticides. This pattern of increased risk was not seen among occupational reports or in young children. This may mean that careless handling by non­ professionals is a particular hazard. Five case report studies suggested that carbaryl may be a cause of chronic neurological or psychological problems. Some of these effects appear to be consistent with those reported from organophosphate poisoning. However, unlike organophosphates, no controlled studies have been undertaken. If such effects occur as a result of over­ exposure to carbaryl, they appear to be relatively rare. The effects reported among the five case reports are too inconsistent to draw any conclusions, but do suggest the need for further study. The epidemiologic study submitted by the registrant compared mortality rates in plant workers exposed to carbaryl to the general population. HED concluded that the sample of workers was too small and the period of follow­ up too short to permit definitive conclusions. The incident reports on domestic animals in IDS were evaluated. Based on limited data, there is some evidence that young kittens may be susceptible to adverse reactions to carbaryl. It is recommended that all labels for carbaryl products used on cats contain the age restriction stated in PR Notice 96­ 6 (should not be used in kittens less than 12 weeks of age). 16 Issues For Consideration: There are population­ based monitoring studies in the published literature or available from various governmental agencies in which carbaryl metabolites are measured in body fluids or environmental media. For example, the Agency's Office of Research and Development, along with other Agencies, has funded a project entitled Pesticide Exposure in Children Living in Agricultural Areas along the United States­ Mexico Border Yuma County, Arizona. Preliminary results of this study indicate that carbaryl residues were identified in the dust of 20 percent of the 152 houses sampled and in approximately 24 percent in 25 samples collected in 6 schools in the same region. With regard to this specific example, current Agency policy is not to use house dust estimates to calculate risks because of a lack of an appropriate exposure model. Also, in a 1995 study conducted by the Centers For Disease Control (Hill et al) entitled Pesticide Residues In Urine Of Adults Living In The United States: Reference Range Concentrations, 1000 adults were monitored via urine collection. One of the analytes measured in that study (1­ naphthol) is a potential metabolite of carbaryl as well as of napthalene and napropamide which may be a confounding factor. This metabolite (1­ naphthol) was identified in 86 percent of the 1000 adults monitored. Data from this study were not used quantitatively in the risk assessment for carbaryl because of the uncertainties associated with them, such as the exact contribution of each possible compound to the overall levels and no linked exposure information. HED instead considered them a qualitative indicator that exposures in the general population are likely to occur. As more data become available, the Agency will consider the information in an effort to refine the assessment. It should also be noted that Aventis Crop Science has completed and is in the process of submitting to the Agency a biomonitoring study of individuals in residences following the application by a member of the household to the lawn and either the vegetable garden or ornamental flowers. A biomonitoring study of field workers during harvesting and hand thinning operations in apples and cherries will also be submitted to the Agency. Based on personal communication with Aventis Crop Science scientists, preliminary results from the residential biomonitoring study indicate that the highest percentiles of the distribution of the younger children in the homes were similar to those predicted in the Agency's turf risk assessment for toddlers that are intended to represent the higher percentiles of the exposure distribution. Preliminary field worker results also appear to not be significantly different from Agency estimates. The database for carbaryl contains good quality studies which are sufficient for conducting a risk assessment for the reregistration of the chemical. However, certain key information, which would help refine the risk assessment, is missing. The one toxicology data gap includes a 90­ day inhalation study in the rat. The elimination of poultry from the acute and chronic dietary risk assessment significantly reduced the risks. For residential postapplication risk assessments, there are no data on the amount of residues transferrable from treated pets to humans. Additional residue data on turf would also help refine the hand­ to­ mouth and object­ to­ mouth toddler exposures. For the occupational handler risk assessments, several handler scenarios lack high quality data. For postapplication workers, additional residue dissipation data along with data from practices not well represented in Agency Policy 003 (Transfer Coefficients) are needed to refine the assessment (e. g., partially mechanized practices that could involve contact). 17 O O N H CH 3 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION The product chemistry chapter was prepared by Felicia Fort of the Health Effects Division (November 14, 2000 ­ DP Barcode 240989). All information below is excerpted from that chapter unless specifically noted. Section 2.1: Chemical Structure and Identification presents the nomenclature and structures associated with carbaryl and its metabolites. Section 2.2: Physical Properties of Carbaryl presents information about the properties of carbaryl. 2.1 Chemical Structure and Identification Chemical Name: 1­ naphthyl methylcarbamate Empirical Formula: C12H11NO2 Molecular Weight: 201.2 CAS Registry No.: 63­ 25­ 2 Chemical ID No.: 056801 Structures of carbaryl and major metabolites are shown below in Figure 1. Figure 1. Structures of Carbaryl and Major Metabolites Name Structure Carbaryl 1­ Naphthyl N­ methylcarbamate 5,6­ dihydro­ 5,6­ dihydroxy carbaryl Figure 1. Structures of Carbaryl and Major Metabolites Name Structure 3 From the EPA Technology Transfer Network, Office of Air Quality Planning and Standards, Air Toxics Website (www. epa. gov/ ttn/ atw) 18 OH 5­ methoxy­ 6­ hydroxy carbaryl 1­ Naphthol 2.2 Physical Properties of Carbaryl Physical state: white to light tan solid Melting point: 142 0 C Solubility: water (40 ppm at 25 C), dimethyl formamide ( 45 g/ 100 mL); acetone, cyclohexanone, and isophorone ( 25 g/ 100 mL); methylethyl ketone ( 20 g/ 100 mL); dichloromethane ( 15 g/ 100 mL); ethanol and ethyl acetate ( 10 g/ 100 mL); mixed aromatic solvents and xylene ( 3 g/ 100 mL); and kerosene ( 1 g/ 100 mL). Vapor pressure: 0.000041 mm Hg at 26 0 C 3 Specific gravity: 1.23 at 20 0 C Octanol/ water partition coefficient (Kow): 217 19 3.0 HAZARD CHARACTERIZATION The hazard component of the risk assessment is presented in this section. Section 3.1: Hazard Profile presents a discussion of the available toxicity data for carbaryl. Section 3.2: FQPA Considerations discusses the susceptibility of sensitive populations such as children and the uncertainties associated with that analysis. Section 3.3: Dose Response Assessment describes which data were selected for risk assessment purposes. Section 3.4: Endocrine Disruption describes issues related to EDSTAC and the screening process for possible chemicals of concern. 3.1 Hazard Profile The updated Toxicology Chapter of the RED was prepared by Dr. Virginia Dobozy (D282980). The toxicology data base is of good quality and is essentially complete. A 90­ day inhalation study with cholinesterase measurements is required. The database provides sufficient information for selecting toxicity endpoints for risk assessment and therefore, supports a reregistration eligibility decision for the currently registered uses. Carbaryl is a carbamate insecticide. Its primary mode of toxic action is through cholinesterase inhibition (ChEI) after single or multiple exposures. In most of the toxicology studies in which ChEI was measured, it was the endpoint used to set the Lowest Observed Adverse Effect Level (LOAEL). The acute toxicity studies showed that carbaryl was relatively toxic with acute oral dosing (Tox. Category II); but the acute dermal and inhalation toxicities were low (Tox. Categories III and IV, respectively). Carbaryl was not a dermal or eye irritant and was not a dermal sensitizer in animal studies (Table 1). However, human incidents of dermal irritation and dermal manifestations of an allergic response have been reported (see section 7.4 below for more information). Table 1: Acute Toxicity of Carbaryl Guideline No. Study Type MRIDs # Results Toxicity Category 81­ 1 Acute Oral ­ rat (99% a. i.) 00148500 LD50 for males = 302.6 mg/ kg; for females = 311.5 mg/ kg; combined = 307.0 mg/ kg II 81­ 2 Acute Dermal ­rabbit (99% a. i.) 00148501 LD50 > 2000 mg/ kg III 81­ 3 Acute Inhalation ­ rat (99% a. i.) 00148502 LC50 > 3.4 mg/ L IV 81­ 4 Primary Eye Irritation rabbit (99% a. i.) 00148503 not a primary eye irritant IV 81­ 5 Primary Skin Irritation rabbit (99% a. i.) 00148504 not a primary skin irritant IV Table 1: Acute Toxicity of Carbaryl Guideline No. Study Type MRIDs # Results Toxicity Category 20 81­ 6 Dermal Sensitization guinea pig (99% a. i.) 00148505 negative NA 81­ 7 Acute Delayed Neurotoxicity (Hen) * negative at 2000 mg/ kg (approximate LD50) NA 81­ 8 Acute Neurotoxicity rat 43845201­ 43845204 systemic LOAEL = 10 mg/ kg for males and females based on significant inhibition of RBC, plasma, whole blood and brain cholinesterase; NOAEL < 10 mg/ kg a. i. = active ingredient * Carpenter, C. P., Weil, C. S., Palm, P. E., Woodside, N. W., Nair, J. H. and Smyth, H. F. Mammalian Toxicity of 1­ napthyl­ Nmethyl carbamate (Sevin Insecticide). J. Agric. Food Chem. 9( 1): 30­ 39, 1961. The neurotoxicity data showed that carbaryl was not a delayed neurotoxicant in the hen. In the acute neurotoxicity study in the rat after a single dose of 10 mg/ kg carbaryl, ChEI was observed in plasma, whole blood, red blood cells (RBC) and brain. At the next higher dose (50 mg/ kg), clinical signs typical of carbamate toxicity were observed. In the subchronic neurotoxicity study after 90 days of administration, clinical signs of toxicity were seen at the same dose (10 mg/ kg/ day) as plasma, whole blood, RBC and brain ChEI. There was no evidence of structural neuropathology in these studies. No subchronic studies in the rat or dog are available, except for the subchronic neurotoxicity study in rats and 4­ week dermal toxicity studies in rats (one with technical chemical and two with formulations). One of the dermal toxicity studies was useful for risk assessment. In this study, the systemic NOAEL was 20 mg/ kg/ day based on decreased RBC ChEI in males and females and brain ChEI in males at 50 mg/ kg/ day. The chronic toxicity data showed that, in dogs, decreases in plasma, RBC and brain ChEI were observed at 10 mg/ kg/ day; clinical signs of toxicity were also observed in both sexes at 31 mg/ kg/ day. Brain and plasma ChEI were decreased in female dogs at 3.1 mg/ kg/ day. In the mouse, clinical signs of toxicity were not typical of ChEI, but there was ChEI (plasma, RBC and brain) at 146 mg/ kg/ day. In the chronic toxicity study in rats, carbaryl at the highest dose (350 mg/ kg/ day in males and 485 mg/ kg/ day in females) caused a variety of toxic effects in the liver, kidneys and urinary bladder. It also induced an increase in the incidence of thyroid follicular cell hypertrophy and degeneration of sciatic nerves and skeletal muscle. RBC ChEI was decreased in males at 60 mg/ kg/ day and in females at 79 mg/ kg/ day. The lowest LOAEL in the chronic studies was in the chronic dog study, i. e., 3.1 mg/ kg/ day, which was the lowest dose in females. In a follow­ up 5­ week study in dogs to clarify the NOAEL for ChEI, plasma ChEI was decreased in males at 3.83 mg/ kg/ day; no effects were observed at 1.43 mg/ kg/ day. 21 In a prenatal developmental toxicity study in the rat, maternal toxicity was observed at the same dose (10 mg/ kg/ day) as developmental toxicity; the NOAEL was 4 mg/ kg/ day. Developmental effects included decreased fetal body weight and increased incomplete ossification of multiple bones. In a prenatal developmental toxicity study in the rabbit, the maternal and developmental LOAELs were 50 mg/ kg/ day and 150 mg/ kg/ day, respectively. The respective NOAELs were 5 mg/ kg/ day and 50 mg/ kg/ day. The only evidence of developmental toxicity was a decrease in fetal body weight. These studies showed no evidence of a qualitative or quantitative increased susceptibility. In the reproduction study, there was evidence of a quantitative offspring susceptibility. The LOAEL for parental systemic toxicity was 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption. The NOAEL was 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females). The LOAEL for offspring toxicity was 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival. The NOAEL was 75 ppm (4.67­ 5.79 mg/ kg/ day for males and 5.56­ 6.41 mg/ kg/ day for females). In the developmental neurotoxicity study, there was evidence of qualitative susceptibility. Clinical signs of toxicity and plasma and brain ChEI were seen in maternal animals at the same dose (10 mg/ kg/ day) as changes in brain morphometric measurements (decreases in cerebellar measurements in females on Day 11 post­ partum) were observed in offspring; however, brain measurements were not conducted at the next lower dose. The Health Effects Division's (HED) Cancer Assessment Review Committee (CARC)( 11/ 7/ 01) classified carbaryl as Likely to be carcinogenic in humans based on an increased incidence of hemangiosarcomas in male mice at all doses tested (100, 1000 and 8000 ppm). The Q1*, based on the CD­ 1 mouse dietary study with ¾ Interspecies Scaling Factor, is 8.75 x 10 ­4 (mg/ kg/ day) ­1 in human equivalents. In addition to the required carcinogenicity studies in mice and rats, the registrant submitted a special study in genetically modified mice. Carbaryl was administered to heterozygous p53­ deficient (knockout) male mice in the diet at concentrations of up to 4000 ppm (716.6 mg/ kg/ day) for six months. There was no evidence of neoplastic or preneoplastic changes in the vascular tissues of any organ. A model validation study demonstrated that vascular tumors occur in heterozygous p53 deficient mice within six months of administration of a known genotoxic carcinogen (urethane). A recent review of the data from the submitted studies and the published literature show that carbaryl is clastogenic in vitro. The wide variety of induced aberrations (both simple and complex) was consistent between the submitted micronucleus study and the open literature. However, there are inconsistencies relative to the requirement for S9 activation. Nevertheless, the two in vivo studies for micronuclei induction or chromosome aberrations were negative. Similarly, the 6­ month p53 knockout transgenic mouse bioassay was negative. Carbaryl was also negative for DNA binding in the livers of mice treated with 8000 ppm for 2 weeks. Metabolism studies identified epoxide intermediates of carbaryl which were found to be conjugated to glucuronide, rapidly metabolized and excreted as any endogenous epoxide would be. Overall, these findings indicate that carbaryl produces epoxides and its DNA reactivity is manifested as chromosomal aberrations in cultured mammalian cells. Other in vitro 22 studies indicate carbaryl's effects on karyokinesis and cytokinesis, as well as stress genes associated with oxidative damage. Based on these considerations, the CARC concluded that there is a concern for mutagenicity, which is somewhat lessened because of the lack of an effect in in vivo mutagenicity studies. The metabolism data in the rat indicated that radiolabeled carbaryl was readily absorbed with oral dosing, distributed to various organs, metabolized and formed conjugated metabolites with compounds such glucuronic acid. A total of 20 components was found, and 2 major metabolites were identified, naphthyl sulfate and naphthyl glucuronide. Much of the radioactivity was eliminated within 24 hours after dosing (86% in urine and 11% in feces). Seven days post dosing, negligible amounts of the administered dose were found in tissues. Several special metabolism studies were conducted to explore a mechanism for the increase in tumor incidence in mice. The results appear to show that high doses of carbaryl treatment (1154 mg/ kg) led to a "phenobarbital" type of induction of liver xenobioticmetabolizing enzymes and interaction of carbaryl with chromatin protein in mice. A dermal absorption study indicated that 12.7% of a carbaryl formulation (43.9% a. i.) was absorbed. The toxicology profile for carbaryl is presented in Appendix 1. 3.2 FQPA Considerations The HIARC (February 19, 2002 meeting) concluded that there is a concern for pre­ and/ or postnatal toxicity resulting from exposure to carbaryl. 3.2.1 Determination of Susceptibility There was no evidence of quantitative or qualitative susceptibility following in utero exposures in developmental studies in the rat and rabbit. In the reproduction study, there was evidence of quantitative susceptibility of offsprings. The LOAEL for parental systemic toxicity was based on decreased body weight, weight gain, and feed consumption; the NOAEL was 27 mg/ kg/ day in males and 30 mg/ kg/ day in females. In the offspring the LOAEL was based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival; the NOAEL was 5 mg/ kg/ day in males and 6 mg/ kg/ day in females. No adverse effects were observed in the reproductive parameters. In the developmental neurotoxicity study, there was evidence of qualitative susceptibility. For maternal toxicity, the LOAEL was based on decreased body weight gain, alterations in Functional Observational Battery measurements and inhibition of plasma, whole blood and brain cholinesterase activity; the NOAEL was 1 mg/ kg/ day. For developmental neurotoxicity, the LOAEL was based on the morphometric changes seen in the brain of the offsprings; the NOAEL was 1 mg/ kg/ day. 23 3.2.2 Degree of Concern Analysis and Residual Uncertainties The HIARC concluded that there is no residual concern in the two­ generation reproduction study because the dose­ response effects in pups are well­ characterized and the NOAEL for the offspring effects is above that which was used for establishing the chronic Reference Dose (RfD) for chronic dietary risk assessment. The HIARC selected the LOAEL of 3.1 mg/ kg/ day established in the chronic toxicity study in dogs for establishing the chronic RfD. Since a LOAEL was used, an additional uncertainty factor of 3X was applied (i. e, lack of a NOAEL) to the LOAEL. Although a NOAEL was not established in this study, the HIARC determined that a 3X was adequate (as opposed to a higher value) because: 1) cholinesterase inhibition in females was not accompanied by clinical signs; 2) no inhibition was seen for any cholinesterase compartment in males at this dose; 3) the magnitude of inhibition of plasma cholinesterase inhibition (12­ 23% decrease) was comparable to the magnitude of inhibition (22%) seen in the 5­ week study in dogs indicating no cumulative effects following long­ term exposure; 4) the study was well­ conducted and there are sufficient data from subchronic and chronic duration studies in the other species which support cholinesterase inhibition as the critical effect. In addition, based on the cholinesterase inhibition data, the dog appears to be more sensitive than the rat in long­ term studies. Furthermore, use of the LOAEL of 3 mg/ kg/ day from the 1­ year dog study with an uncertainty factor of 300 results in a NOAEL of 1 mg/ kg/ day. This extrapolated NOAEL is identical to that of the offspring NOAEL of 1.0 mg/ kg/ day established in the developmental neurotoxicity study. Thus, the NOAEL of 1 mg/ kg/ day used for establishing the chronic RfD is below the NOAEL of 5 mg/ kg/ day for offspring toxicity, and the chronic RfD would be protective of the effects of concern for infants and children following chronic dietary exposures. With regard to the developmental neurotoxicity study, the HIARC concluded that there was a low level of concern based on the following residual uncertainties: ° The first uncertainty was the lack of a demonstrated effect level since morphometric measurements of brains in the offsprings were not performed at the mid­ dose (1 mg/ kg/ day). However, this concern was negated since even at the high dose of 10 mg/ kg/ day, the morphometric changes were minimal and therefore, it is unlikely that adverse effects would be seen at 1 mg/ kg/ day, which is 10% of the LOAEL. 24 ° The second uncertainty was the lack of comparative data in adults and offspring for cholinesterase inhibition. This concern was negated since no FOB alterations were seen in pups. Other studies in the data base have shown that when FOB alterations were seen in adult animals, they are usually accompanied with cholinesterase inhibition. Also, the results of the National Institute for Environmental Health Sciences study (discussed above) showed no difference in cholinesterase inhibition in pups and adults. There was a dose­ related decrease in cholinesterase activity in the brain and blood of dams at gestation day 19 and fetuses taken at this time also showed a very similar level of fetal brain cholinesterase. The HIARC concluded that the NOAEL of 1 mg/ kg/ day selected for establishing the acute RfD would address the low level of concern for the residual concerns and would be protective of the effects of concern for infants and children following a single oral exposure. 3.3 Dose Response Assessment The HIARC evaluated the toxicology data base of carbaryl, reassessed the Reference Dose (RfD) established in 1994 and selected the toxicological endpoints for acute dietary, as well as occupational and residential exposure risk assessments at a meeting on July 7, 1998. Re­ evaluations of the FQPA Safety Factor recommendation were done on April 28 and November 15, 1999, after the submission of prenatal developmental toxicity studies in the rat and rabbit, respectively. A re­ evaluation of the endpoints for risk assessment was conducted on March 1, 2001, February 19, 2002 and April 25, 2002. Table 2 contains a summary of the hazard doses and endpoints selected for use in the various human health risk assessments. Endpoints were selected for a broad spectrum of risk assessments, including acute and chronic dietary, short­, intermediate­ and long­ term dermal and inhalation exposures and short­ and intermediate­ term incidental exposure. For the chronic dietary and the long­ term dermal and inhalation exposure endpoints, a LOAEL was selected, which necessitated an additional 3x uncertainty factor. A common toxicological endpoint exists for the dermal, inhalation and incidental oral routes. Therefore, the Margins of Exposure (MOEs) can be combined for occupational and residential risk assessments. For acute, short­ , intermediate­ and long­ term aggregate risk assessments, the oral, dermal and inhalation routes can be combined because of the common toxicity endpoint (ChEI). Table 2. Summary of Toxicological Dose and Endpoints for Carbaryl for Use in Human Risk Assessment Exposure Scenario Dose (mg/ kg/ day) & Total UF Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Dietary & Nondietary Ingestion Risk Assessments Acute Dietary general population including infants and children NOAEL = 1 UF = 100 1 Developmental Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes on the first day of dosing in maternal animals Acute RfD and aPAD = 0.01 mg/ kg/ day Table 2. Summary of Toxicological Dose and Endpoints for Carbaryl for Use in Human Risk Assessment Exposure Scenario Dose (mg/ kg/ day) & Total UF Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment 25 Chronic Dietary all populations LOAEL= 3.1 UF = 300 1 Chronic toxicity ­ dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females. Chronic RfD and cPAD = 0.01 mg/ kg/ day [Note: A NOAEL could not be defined in this study. Therefore, an additional factor of 3 has been applied to account for the data deficiency.] Short­ term Incidental Oral (1 ­ 30 Days) [Residential Only] NOAEL= 1 Res. UF = 100 1 Developmental Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes and decreases in RBC, whole blood, plasma and brain cholinesterase Intermediate­ Term Incidental Oral (1 ­ several months) [Residential Only] NOAEL= 1 Res. UF = 100 1 Subchronic Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase. Non­ Dietary Risk Assessments Short­ Term Dermal (1 ­ 30 days) NOAEL= 20 Res. UF = 100 Occ. UF = 100 1 4­ week dermal toxicity with technical ­ rat systemic LOAEL = 50 mg/ kg/ day based on statistically significant decreases in RBC cholinesterase in males and females and brain cholinesterase in males. Intermediate­ term Dermal (30 days ­ several months) NOAEL= 20 Res. UF = 100 Occ. UF = 100 1 4­ week dermal toxicity with technical ­ rat systemic LOAEL = 50 mg/ kg/ day based on statistically significant decreases in RBC cholinesterase in males and females and brain cholinesterase in males. Long­ Term Dermal (Several months to a lifetime) LOAEL= 3.1 Res. UF = 300 Occ. UF = 300 1 Chronic toxicity ­ dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females. [Note: A NOAEL could not be defined in this study. Therefore, an additional factor of 3 has been applied to account for the data deficiency. Also, this study is not route­ specific as it was conducted via oral administration. Route­ to­ route extrapolation is required using an adsorption factor of 12.7 percent which is based on a rat dermal absorption study.] Short­ Term Inhalation (1 ­ 30 days) NOAEL= 1 Res. UF = 100 Occ. UF = 100 1 Developmental Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes and statistically significant decreases in RBC, whole blood, plasma and brain cholinesterase [Note: This study is not route­ specific as it was conducted via oral administration. Route­ to­ route extrapolation is required using an adsorption factor of 100 percent.] Table 2. Summary of Toxicological Dose and Endpoints for Carbaryl for Use in Human Risk Assessment Exposure Scenario Dose (mg/ kg/ day) & Total UF Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment 26 Intermediate­ Term Inhalation (30 days ­ several months) NOAEL= 1 Res. UF = 100 Occ. UF = 100 1 Subchronic Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase. [Note: This study is not route­ specific as it was conducted via oral administration. Route­ to­ route extrapolation is required using an adsorption factor of 100 percent.] Long­ Term Inhalation (Several months to a lifetime) [Occupational only] LOAEL= 3.1 Occ. UF = 300 1 Chronic toxicity ­ dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females. [Note: A NOAEL could not be defined in this study. Therefore, an additional factor of 3 has been applied to account for the data deficiency. Also, this study is not route­ specific as it was conducted via oral administration. Route­ to­ route extrapolation is required using an adsorption factor of 100 percent.] Cancer Classification: C Q1* = 8.75 x 10 ­4 (mg/ kg/ day) ­1 3.4 Endocrine Disruption EPA is required under the Federal Food Drug and Cosmetic Act, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there were scientific bases for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, carbaryl may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption. 27 4.0 NON­ OCCUPATIONAL RISK ASSESSMENT AND CHARACTERIZATION This section of the risk assessment addresses exposures to individuals in the general population that are not exposed as part of their employment. These exposures can occur through the diet and/ or they can occur because people have contact with carbaryl residues while using consumer products containing carbaryl or by being in areas that have been previously treated. Section 4.1: Summary of Registered Uses below summarizes available products and also describes the uses of those products. Products intended for commercial sales (e. g., in agriculture) and consumer products are included as each type of product can contribute to non­ occupational exposures through the diet, via residential use, or through commercial use in areas frequented by the general population such as golf courses. Section 4.2: Dietary Risk Assessment describes the residue and consumption data used in the dietary risk assessment, the risks associated with various populations of interest through the diet, and characterization of those risks. Section 4.3: Water Risk Assessment describes how water concentrations were determined, calculation of risks, and characterization of those risks. Section 4.4: Residential Risk Assessment describes how risks were calculated for people who use consumer products containing carbaryl and for those who are exposed as a result of being in areas that have been previously treated. 4.1 Summary of Registered Uses All products (e. g., manufacturing and various end­ use formulations) and the associated use patterns for carbaryl are described below. A brief overview of the types of equipment and application rates is also provided. The information in this section summarizes all use patterns of carbaryl as both commercial products and products intended for sale to homeowners can both contribute to exposures in the general population through the diet, drinking water, direct use (i. e., for homeowners only in this aspect of the risk assessment) and as a result of people frequenting areas that have been previously treated by either homeowners (e. g., lawns or gardens) or other public places that could have been commercially treated (e. g., golf courses). The need to have a thorough understanding of the use patterns for consumer products is self explanatory. Understanding the use of commercial products is key for the development of the dietary and drinking water assessments. It is also critical for evaluating some residential postapplication exposures such as for golfers. Carbaryl (1­ naphthyl N­ methyl­ carbamate) is a broad­ spectrum carbamate insecticide marketed in a variety of end­ use products for both occupational and homeowner use. End­ use product names include Adios, Bugmaster, Carbamec, Carbamine, Crunch, Denapon, Dicarbam, Hexavin, Karbaspray, Nac, Rayvon, Septene, Sevin, Tercyl, Tornado, Thinsec, and Tricarnam. Use sites include but are not limited to the following: fruit and nut trees; vegetable crops; field and forage crops; grapes; forestry; lawns and other turf such as golf courses; ornamental trees, shrubbery, annuals, and perennials; wide area treatment targets such as residential mosquito adulticide uses and oyster beds; poultry production facilities; and companion animals (e. g., dogs and cats). Table 3 summarizes all (homeowner and occupational products) currently available technical and manufacturing products along with their corresponding EPA registration numbers. 28 Table 3: Technical and Manufacturing Carbaryl Products Formulation EPA Reg. No. (% active ingredient) Technical 34704­ 707 (99%); 45735­ 24 (99%); 264­ 324 (99%),­ 325 (97.5%); 19713­ 75 (99%) Manufacturing Product 264­ 328 (80%); 264­ 325 (97.5%) 769­ 971 (80%); 5481­ 190 (46%) 19713­ 369 (50 %); 432­ 982 (97.5%); 73049­ 238 (1%) Based on a review (2/ 27/ 01) of the Office of Pesticide Programs – Reference Files System (REFS), there are over 300 active product labels (i. e., includes both homeowner and occupational products). Carbaryl formulations include dusts, emulsifiable concentrates, soluble concentrates, water dispersible granulars, flowable concentrates, wettable powders, granulars, baits, pet dips and pet shampoos, aerosol sprays, ready­ to­ use pump sprayers, and pet collars (i. e., treated articles). Table 4 summarizes the approximate number of Section 3­ registered products in each formulation category and the range of percent active ingredient. A complete listing of all the registration numbers under each category can be found in the Occupational/ Residential Exposure Assessment chapter (D281418). This chapter also includes in the Appendices, the Qualitative Usage Analysis For Carbaryl and the RED Use Profile Report prepared by the Agency's Biological and Economic Analysis Division. Many of the products described can be used in a variety of settings ranging from agriculture and commercial facilities to residential areas. Table 4: Carbaryl End­ Use Product Formulations Formulation Type Number of Products Range of Percent Active Ingredient Emulsifiable Concentrates & Flowable Concentrates 57 0.3 ­ 80 Wettable Powders & Soluble Granules 36 0.5 ­ 95 Dusts 130 0.3 ­ 80 Granular 45 1.43 ­ 15 Bait 55 1.3 ­ 13 Dips, Shampoos 2 0. 5 ­ 60 Pet collars (treated articles) 2 8. 5 ­ 16 Ready to Use Pump Sprayers & Aerosol Cans 6 0. 12 ­ 1 29 Equipment used to apply carbaryl in residential settings includes dust shaker cans, garden hoseend sprayers, trigger sprayers, low pressure handwands, belly grinders, push­ type spreaders, aerosol cans, and pet collars. In an occupational setting, carbaryl can be applied by airblast, aerial application, chemigation, groundboom, power duster, low and high pressure handwand, backpack, compressed air sprayer, fogger, hand­ held duster, hose­ end sprayer, duster cans, and aerosol can. Depending on the crop, the maximum number of carbaryl applications per season can range from 1 to 8. A variety of application rates are available on the carbaryl labels, ranging from 1 lb ai/ acre for curcurbits to 16 lb ai/ acre for a foliar treatment of citrus in California. Some products are marketed in a single marketplace while others are sold for use in various settings. Based on sales information provided by Aventis CropScience at the SMART meeting with EPA on September 24, 1998, it appears that approximately 34 percent of carbaryl use is by homeowners in residential settings, 59 percent is used in agriculture, and the remaining 7 percent is used in the nursery, landscape and golf course industries. The application parameters for major crop groups or application targets were defined by the physical nature of the use site, the physical nature of the formulation, the equipment needed for application and the application rate. Selected crop groupings and application targets along with corresponding typical (if available) and maximum application rates that are used in the risk assessment are presented in Table 5 below. Table5: Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft 2 (units may vary) lb ai/ A/ acre (units may vary) max. apps/ season lb ai/ season Average Rates Alfalfa, clover, trefoil 1. 5 1/ cutting 1. 5/ cutting 1. 1 Asparagus 2 4 ­ postharvest 3 ­ broadcast 2 ­ postharvest 6 ­ broadcast 10 ­ postharvest 0.9 0. 023 ­0. 094 Beans (fresh & dried), cowpeas, peas 1.5 4 6 0. 9 0.012­ 0.047 Beets, carrot, horseradish, radish, parsnip 2 ­ foliar 2.2 ­ soil broadcast 6 ­ foliar 4 ­ soil 6 0. 8 0.012­ 0.047 Blueberries 2 ­ foliar 0.5 lb/ 1000 ft 2 ­ soil 5 10 1. 7 0.012­ 0.047 Cole Crops (broccoli, brussel sprouts, cabbage, cauliflower, chinese cabbage, collards, kale, kohlrabi, mustard greens) 2 ­ foliar 2.2 ­ soil broadcast 4 6 0.8 0. 012­ 0.047 Caneberries 2 ­ foliar 2.2 ­ soil broadcast 5 4 10 Not specified 1.7 0. 012­ 0.047 Celery, Dandelion 2 ­ foliar 2.2 ­ soil broadcast 4 6 1.0 0. 012­ 0.047 Citrus 16 (foliar in CA only) 10 (foliar in FL only) 7.5 ­ foliar 1 lb/ 100 gal. 1 Not specified 8 Not specified 20 Not specified 20 Not specified 2.7 to 3.4 (lemons & oranges) 0.023­ 0.176 Corn (field and pop) 2 4 8 1.0 0. 012­ 0.047 Table5: Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft 2 (units may vary) lb ai/ A/ acre (units may vary) max. apps/ season lb ai/ season Average Rates 30 Corn (sweet) 2 ­ foliar 2.2 ­ soil broadcast 8 4 16 Not specified 1.3 0. 012­ 0.047 Cranberry 2 5 10 2.0 0. 012­ 0.047 Cucurbits (cucumber, melon, pumpkin, squash) 1 6 6 1.1 0. 012­ 0.047 Fruiting Vegetable (tomato, eggplant, pepper) 2 7 8 1.0 0. 012­ 0.047 Grapes 2 5 10 1.4 0. 012­ 0.047 Grasses Grown For Seed 1.5 2 3 0. 8 (based on hay) Leafy Vegetable (head and leaf lettuce, endive, mustard green) 2 ­ foliar 2.2 ­ soil broadcast 5 4 6 Not specified 1.1 0. 012­ 0.047 Nuts (almond, chestnut, pecan, pistachio, walnut, etc.), foliar or dormant/ delayed 5 4 15 2.5 (pecans) 0.047­ 0.12 Nuts (almond, chestnut, pecan, walnut), foliar in CA 1 lb ai/ 100 gal Not specified Not specified Not specified 0.047­ 0.12 Ornamental 2.2 or 2% solution ­ ­ 1. 5 0.023 Oyster beds (SLN only) 10 Not specified Not specified ­ Peanut 2 5 8 0.8 0. 012­ 0.047 Pome fruit 3 8 15 1. 2 (based on apples) 0.012­ 0.07 Potatoes & Tubers (turnips) 2 6 6 0.8 Rangeland pastures 1 1 1 0.9 Rice 1.5 2 4 1. 1 Right of Way 1. 5 3 0. 4 Sorghum 2 4 6 1.1 Stone fruit (apricot, cherry, nectarine, peach, plum/ prune), foliar or dormant/ delayed 3 4 ­ CA only 3 foliar & 1 dormant/ delayed 14 1.1 0. 047­ 0.12 Stone fruit (apricot, cherry, nectarine, peach, plum/ prune), foliar 1 lb ai/ 100 gal Not specified Not specified Not specified 0.047­ 0.12 Strawberries 2 5 10 1.4 0. 012­ 0.047 Sugar beets 1. 5 to 2 2 to 4 4 1.3 0. 012­ 0.047 Sweet Potatoes 2 foliar 8 lb/ 100 gal drip 8 foliar Not specified 8 foliar 1.2 1.6 foliar Not specified 0.012­ 0.047 Sunflower 1. 5 2 3 0.7 0. 012­ 0.047 Tobacco 2 4 8 1.1 Tree farm 1 ­ 2 0. 7 Turf/ golf 8­ liquids 9­ granulars ­ 0. 8/ 1000sf 2 to 4 0. 047 to 0.25 (lawns) [maximum levels for different products] Wheat, flax 1.5 2 3 0. 8 Ants 2% sol ­ ­ ­ 2% sol Mosquito Control 2 ­ ­ ­ Outdoor Banding 2% sol ­ ­ ­ 2% sol Table5: Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft 2 (units may vary) lb ai/ A/ acre (units may vary) max. apps/ season lb ai/ season Average Rates 4 At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. The primary concern was rubbing sampled commodities during the rinsing process except for broccoli and tomato because this created a potential for residue loss from the mechanical action associated with rubbing. A separate assessment was also completed using other sources of high quality residue data (e. g., PDP) for comparative purposes to more completely inform the risk management process. 31 Domestic Animals (e. g., cats/ dogs) Dust 0.2 lb ai/ dog Sha. 0.01 lb ai/ dog ­ ­ ­ Dust 0.2 lb ai/ dog Sha. 0.01 lb ai/ dog Domestic Animals (e. g., cats/ dogs) 1.3 oz/ dog collar ­ ­ ­ 1.3 oz/ dog collar Note: In many cases an application rate per area (e. g., 1000 ft 2 ) is provided but a 1 to 2 % ai w/ v solution can be used to make similar applications where volume outputs are difficult to regulate (i. e., handheld equipment where area treated is difficult to define). 4.2 Dietary Risk Assessment The Product and Residue Chemistry Chapters (D283328; May 30, 2002) and the Dietary Exposure Analysis (D281419; April 28, 2002) were prepared by Felecia Fort. Potential exposure to residues of carbaryl in the diet occurs through food and water. Carbaryl is used late in the season at maximal seasonal rates of 6­ 12 lb ai/ acre. [Note: There is also a section 3 registration that allows use on citrus up to 16 lb ai/ acre only in the state of California.] Post harvest intervals (PHIs) range from 1­ 29 days but most are one week or less. The qualitative nature of carbaryl residues in plants and animals is adequately understood. The carbaryl residue to be regulated in plants is carbaryl per se. The residues of concern in meat and milk are the free and conjugated forms of carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, and 5­ methoxy­ 6­ hydroxy carbaryl. Adequate Pesticide Data Program (PDP) and Food and Drug Administration (FDA) monitoring residue data are available for the vast majority (> 80%) of commodities. Detectable residues were found in 31 of 42 crops. In field trials, residues were less than the Limit of Quantitation (LOQ) in 5 crops but were quantifiable in all other raw agricultural commodities (RACs). The dietary exposure assessment is a Tier 3/ 4 assessment, which is the most highly refined assessment that can be conducted at this time. HED has provided anticipated residues (ARs) for carbaryl based on USDA PDP and FDA monitoring data, along with field trial data, for many commodities. In addition, separate acute assessments were conducted incorporating the results of the Carbamate Market Basket Survey (CMBS) 4 . 32 Carbaryl and its degradate 1­ naphthol are fairly mobile but are not likely to persist or accumulate in the environment. Available non­ targeted monitoring studies were of limited utility in developing estimated environmental concentrations (EECs) of carbaryl in water. Therefore, screening models were utilized in assessing carbaryl residues in drinking water (see Section 4.3 below for more details). Section 4.2.1: Residue Profile provides information on the residue data used to complete the dietary risk assessments. Section 4.2.2: Acute Dietary Risk Assessment presents the acute assessment with and without the CMBS data. Section 4.2.3: Chronic Dietary Risk Assessment presents the results for this duration of exposure. Section 4.2.4: Cancer Dietary Risk Assessment presents cancer risks. Section 4.2.5 Characterization/ Uncertainties of the Risk Estimates provides information that should be considered along with the numerical results of this assessment. 4.2.1 Residue Profile Tolerances for residues of carbaryl are currently expressed in terms of carbaryl (1­ naphthyl Nmethylcarbamate including its hydrolysis product 1­ naphthol, calculated as carbaryl, for most raw crop commodities (RACs) [40 CFR §180.169( a)]. The established tolerances for residues in/ on pineapples, pome fruits, avocados, and fresh dill are expressed in terms of carbaryl per se [40 CFR §180.169( d) and (e)]. Tolerances for residues in livestock commodities are expressed as carbaryl, including its metabolites 1­ naphthol (naphthyl sulfate), 5,6­ dihydrodihydroxy carbaryl, and 5,6­ dihydrodihydroxy naphthol, calculated as carbaryl [40 CFR §180.169( b) and (c)]. A tolerance for residues in pineapple bran is expressed in terms of carbaryl per se [40 CFR §186.550]. The HED Metabolism Committee concluded that the carbaryl residue to be regulated in plants is carbaryl per se (DP Barcode D221979, S. Hummel, 2/ 8/ 96). The Committee also concluded that carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, 5­ methoxy­ 6­ hydroxy carbaryl and all residues which can be hydrolyzed to carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl and 5­ methoxy­ 6­ hydroxy carbaryl under acidic conditions should be included in the tolerance expression and risk assessment for all endpoints of dietary concern for livestock commodities only. (C. Olinger, D255855, 6/ 21/ 99). An interim tolerance of 0.5 ppm has been established for carbaryl and its 1­ naphthol metabolite in eggs [40 CFR §180.319]. Tolerances of 2 ppm and 10 ppm have been established for residues of carbaryl in pineapples and bananas, respectively. The registrant intends to support the tolerances for residues of carbaryl in/ on these commodities as import tolerances. Currently, the Codex MRLs and U. S. tolerances are not compatible because the U. S. tolerance expression includes metabolites. Once the U. S. tolerance definition is amended, it will be compatible with the definition for Codex MRLs. The Metabolism Committee has also recommended that the tolerance expression for livestock commodities include the free and conjugated forms of carbaryl; 5,6­ dihydro­ 5,6­ dihydroxy carbaryl; and 5­ methoxy­ 6­ hydroxy carbaryl. The Codex MRLs and U. S. tolerances cannot be made compatible for livestock commodities with respect to the tolerance definition. The reregistration requirements for plant and livestock metabolism are fulfilled. Acceptable metabolism studies depicting the qualitative nature of residues in lettuce, radish, soybeans, ruminants and poultry have been submitted and evaluated. For the purpose of reregistration, adequate magnitude of the residue data are available on the following crops: alfalfa, almond, asparagus, beans (dried and succulent), blueberry, broccoli, cabbage, celery, cherry, citrus fruits, clover, corn (sweet and field), 33 cucurbits (cantaloupes, cucumbers and squash), cranberry, flax, grape, head and leaf lettuce, mustard greens, okra, peanut, peas (dried and succulent), pecan, pepper, pistachio, pome fruits, potato, prickly pear cactus, raspberry, rice, sorghum, soybean, spinach, stone fruits, strawberry, sunflower, sweet potato, tobacco, tomato, walnut. Geographical representation is adequate and a sufficient number of trials reflecting representative formulation classes were conducted. Carbaryl residues were <LOQ in/ on sweet potato, sugar beets, corn grain, flax seed, and peanuts. Quantifiable residues were detected in all other RACs. For a given crop, residue levels were quite variable overall, probably owing to climactic variations, but were generally consistent within any specific field trial location. There are data gaps which are listed in Section 8.0: Data Needs/ Label Requirements. Adequate PDP monitoring data were available for the commodities potatoes, carrots, sweet potato, celery, spinach, lettuce (head), broccoli, succulent peas (processed) , succulent beans, soybean, tomatoes, cantaloupe, winter squash, orange, orange juice, apple, apple juice, pear, peach, wheat, sweet corn, banana, grape, grape juice and milk. FDA monitoring data were used for the commodities, lettuce (leaf), cabbage, eggplant, succulent peas (fresh), non­ bell pepper, bell pepper, cucumber, watermelon, summer squash, cherries, raspberry, blueberry, asparagus, cranberries, pineapple, and strawberry. Monitoring data were translated to similar crops when possible, generally according to the HED SOP 99.3 "Translation of Monitoring Data". Monitoring data from the years 1994 through 1998 (PDP) and the years 1992 through 1998 (FDA) were considered. Field trial data were used for the commodities, garden beets, turnips, mustards, dried beans, almonds, pecans, walnuts, field corn grain, rice, flax seed, okra, olive, peanuts, pistachio, sugar beets, dried peas, and sunflower. HED conducts dietary risk assessments using the Dietary Exposure Evaluation Model (DEEM™), which incorporates consumption data generated in USDA's Continuing Surveys of Food Intakes by Individuals (CSFII), 1989­ 1992. In this assessment, CFSII data from 1994 to 1998 were also considered along with the earlier data for comparative purposes. Routinely, the 1989 to 1992 data are used for risk assessments; however, the Aventis Crop Science commented that the 1994 to 1998 data should also be considered. The Agency completed the analysis using both sets of consumption data in response to this comment. In these surveys, both 3­ day mean consumption and single­ day consumption information were recorded for 22 demographic and socio­ economic subpopulations including infants, children, and nursing women. For acute dietary risk assessments, the entire distribution of consumption events for individuals is multiplied by a randomly selected distribution of residues (probabilistic analysis, referred to as "Monte Carlo" ) to obtain a distribution of exposures in mg/ kg/ day. For chronic dietary risk assessments, the 3­ day average for each subpopulation is combined with average residues in commodities to determine average exposures (mg/ kg/ day). Anticipated residue estimates were prepared using USDA Pesticide Data Program (PDP) data, if available. Alternatively, FDA surveillance monitoring data from the years 1992­ 98 were used if sufficient samples were available. Data from crop field trials were used if there were insufficient PDP or FDA monitoring data. In addition, separate acute assessments were conducted incorporating the results of the CMBS as described above (i. e., rubbing fruit may reduce residues, use of other high quality data leads to a more informed risk management decision). The Biological and Economic Analysis Division (BEAD) provided information (F. Hernandez, 34 7/ 21/ 98) on the percent crop treated (% CT). For the chronic analysis, the weighted average %CT was incorporated; for the acute analysis, the estimated maximum %CT was used when appropriate. In acute analyses (except blended commodities) the adjustment for %CT is incorporated in the residue distribution files (RDFs) via addition of zero residue values corresponding to the % of crop not treated. For blended/ not furthered processed commodities where monitoring data are available, the entire distribution of monitoring data with no further adjustment for %CT were used. For blended/ processed commodities where monitoring data are available and for all blended commodities where field trial data were used, %CT is incorporated into a point estimate. For the chronic analyses, the %CT is listed as Adjustment Factor 2 in the DEEM analysis. One half the weighted average of the limits of detection was used in the dietary assessment for all treated non­ detectable residues. Detectable residues from composite monitoring data for non­ blended food forms were used to generate residue values in single units using the methods described in the H. Allender paper dated 5/ 26/ 99 "Statistical methods for Use of Composite Data in Acute Dietary Risk Assessment." The "decomposited" residues were then included in residue distribution files (RDF) for the probabilistic analysis. BEAD­ supplied percent crop treated data were incorporated into the anticipated residue or residue distribution file when appropriate. [Note: Single serving peach PDP data were used for non­ blended peach food forms instead of data that had been previously decomposited (Allender method).] A separate dietary assessment was conducted utilizing the CMBS results. The CMBS Task Force conducted a year long, national survey of carbamate residues on selected food commodities purchased at grocery stores. Residue data from a market basket survey are considered close approximations to residues potentially found at most `dinner plates'. These data are generally considered the most appropriate survey type for use in pesticide risk and exposure assessment. The CMBS collected up to 400 single­ serve samples of 8 different crops (apple, banana, broccoli, grape, lettuce, orange, peach and tomato). These data were used in the acute dietary analysis directly via RDFs incorporating %CT for all food forms which are considered to be partially or not blended. For blended commodities, the entire distribution of data with no further adjustment for % CT was used. If CMBS data were not available, then PDP or FDA monitoring or field trial data were used. CMBS data were translated to similar commodities when feasible; however, if PDP monitoring data were available for the processed commodity, then CMBS data were not translated (i. e., PDP orange juice data were used instead of CMBS data for oranges). The dietary risk assessments were completed with and without the results of the CMBS for comparative purposes, again as described above (i. e., rubbing fruit may reduce residues, use of other high quality data leads to a more informed risk management decision). Most of the carbaryl processing factors were obtained from processing studies submitted by the registrant. The rice processing factors were from a review by Thurston Morton (D216242, 9/ 17/ 98). 4.2.2 Acute Dietary Risk Assessment The following equations were used to calculate dietary exposure and non­ cancer risk for carbaryl. Dietary exposure (mg/ kg/ day) = consumption x residue 35 Dietary risk (% PAD) = dietary exposure (mg/ kg/ day) x 100 population adjusted dose (mg/ kg/ day) The population adjusted dose (PAD) is the adjusted RfD reflecting the retention or removal of the FQPA safety factor. For carbaryl, the FQPA safety factor has been reduced to 1x. The resulting acute PAD (aPAD) and chronic PAD (cPAD) are both 0.01 mg/ kg/ day. The doses and endpoints selected by the HIARC for these risk assessments are discussed in more detail in Section 3.3: Dose Response Assessment above. For this Tier 3/ 4 Assessment, estimated acute dietary exposure at the 99.9 th percentile of exposure exceeds HED's level of concern without incorporating the CMBS results for all infants and children (1­ 6 years) based on 1989 to 1992 CFSII data (Table 6). The highest exposed subpopulation incorporating all commodities using PDP and FDA monitoring data without CMBS data was all infants at 133 percent of the aPAD while children (1­ 6 years) were at 110 percent of the aPAD. The same general trend applied when the 1994 to 1998 CFSII data were considered but risks were actually higher for all subpopulations (infants at 134 percent of the aPAD and children (1 to 6 years old) at 138 percent of the aPAD). The Agency routinely uses the 1989 to 1992 CFSII data for risk assessments. However, Aventis Crop Science commented that 1994 to 1998 CFSII data should also be considered so the Agency used both for comparative purposes. Prior to the calculation of these risk estimates, residues in poultry were the key contributors to the risks for various populations. Since then, Aventis Crop Science has indicated that poultry uses will be deleted (i. e., poultry uses were not considered in this assessment). As such, it appears that consumption of apples and peaches are the critical contributors to acute dietary risks. A sensitivity analysis was conducted using 1989 to 1992 CFSII by eliminating these crops and crops where no detectable residues were found (Table 7). This analysis showed that risk estimates were not significantly affected by assuming zero in place of ½ LOD on samples reported as not detectable. Eliminating apples reduced exposures of children (1­ 6 years) to 82 percent of the aPAD but did not significantly impact the risks for all infants which were still at 118 percent of the aPAD. Eliminating peaches had the greatest impact. Risks to children (1­ 6 years) still exceeded 100 percent of the aPAD at 102 percent. Risks for all infants, however, were reduced to 72 percent of the aPAD. Table 6: Results of the Carbaryl Acute Dietary Analyses (Market Survey Data Not Included) Pop. Subgroup 99.9 th Percentile 99 th Percentile 95 th Percentile Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD All Commodities (1989­ 92 Consumption Data) Gen. Population 0. 005989 60 0.001381 14 0.000505 5 All Infants 0. 013251 133 0.003683 37 0.000864 9 Children 1 ­ 6 0. 010974 110 0.002552 26 0.001309 13 Children 7 ­ 12 0.008721 87 0.001644 16 0.000722 7 Females 13 ­ 50 0.004444 44 0.000918 9 0. 000318 3 Males 13­ 19 yrs 0. 003596 36 0.000899 9 0. 000428 4 Table 6: Results of the Carbaryl Acute Dietary Analyses (Market Survey Data Not Included) Pop. Subgroup 99.9 th Percentile 99 th Percentile 95 th Percentile Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD 36 Males 20+ yrs 0. 004223 42 0.000929 9 0. 000318 3 Seniors 55+ yrs 0.005789 58 0.001068 11 0.000307 3 All Commodities (1994­ 98 Consumption Data) Gen. Population 0. 006150 62 0.001467 15 0.000508 5 All Infants 0. 013420 134 0.004027 40 0.000922 9 Children 1 ­ 6 0. 013812 138 0.003282 33 0.001460 15 Children 7 ­ 12 0.007073 71 0.001473 15 0.000685 7 Females 13 ­ 50 0.004794 48 0.000997 10 0.000322 3 Males 13­ 19 yrs 0. 005181 52 0.000929 9 0. 000420 4 Males 20+ yrs 0. 003940 39 0.000922 9 0. 000336 3 Seniors 55+ yrs 0.005442 54 0.001003 10 0.000313 3 Table 7. Results of the Carbaryl Sensitivity Analyses. Acute ­ All Commodities at the 99.9th percentile of exposure (Market Basket Survey Data Not Included) Pop. Subgroup All commodities Eliminating Peaches Eliminating Apples Eliminating Commodities with No Detectable Residues Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Gen. Population 0. 005989 60 0.005451 55 0.004943 49 0.005870 59 All Infants 0. 013251 133 0.007188 72 0.011784 118 0.012965 130 Children 1 ­ 6 0. 010974 110 0.010164 102 0.008201 82 0.0010765 108 Children 7 ­ 12 0.008721 87 0.008243 82 0.006867 69 0.008555 86 Females 13 ­ 50 0.004444 44 0.004262 43 0.003890 39 0.004434 44 Males 13­ 19 yrs 0. 003596 36 0.003535 35 0.003014 30 0.003802 38 Males 20+ yrs 0. 004223 42 0.003949 39 0.003575 36 0.004178 42 Seniors 55+ yrs 0.005789 58 0.005456 55 0.005094 51 0.005703 57 When the CMBS data were included in the assessment, the acute risk picture for carbaryl significantly changed as risks for all population subgroups considered were less than 100 percent of the aPAD (Table 8). If 1989­ 1992 CFSII data are used, all infants and children (1­ 6 years) again had the highest associated risk levels at 73 percent and 75 percent of the aPAD, respectively. For 1994­ 1998 CFSII data, all infants and children (1­ 6 years) also have the highest risks at 81 and 93 percent of the 37 aPAD, respectively. At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. Hence, the use of these data in this assessment should be considered with associated caveats (e. g., rubbing fruit). Table 8. Results of the Carbaryl Acute Dietary Analyses (Market Basket Survey Data Included) Pop. Subgroup 99.9 th Percentile 99 th Percentile 95 th Percentile Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD All Commodities (1989­ 92 Consumption data) Gen. Population 0. 004580 46 0.001251 13 0.000465 5 All Infants 0. 007272 73 0.002875 29 0.000593 6 Children 1 ­ 6 0. 007546 75 0.002283 23 0.001242 12 Children 7 ­ 12 0.006126 61 0.001355 14 0.000682 7 Females 13 ­ 50 0.003672 37 0.000863 9 0. 000300 3 Males 13­ 19 yrs 0. 002735 27 0.000818 8 0. 000409 4 Males 20+ yrs 0. 003416 34 0.000842 8 0. 000298 3 Seniors 55+ yrs 0.004601 46 0.000921 9 0. 000277 3 All Commodities (1994­ 98 Consumption data) Gen. Population 0. 004759 48 0.001310 13 0.000468 5 All Infants 0. 008051 81 0.002624 26 0.000653 7 Children 1 ­ 6 0. 009274 93 0.002819 28 0.001352 14 Children 7 ­ 12 0.004831 48 0.001226 12 0.000646 6 Females 13 ­ 50 0.004194 42 0.000898 9 0. 000301 3 Males 13­ 19 yrs 0. 004430 44 0.000876 9 0. 000403 4 Males 20+ yrs 0. 003254 33 0.000840 8 0. 000313 3 Seniors 55+ yrs 0.004427 44 0.000836 8 0. 000281 3 4.2.3 Chronic Dietary Risk Assessment Chronic dietary risks were calculated using the same equations as described above for the acute dietary risk estimates with different inputs appropriate for this exposure duration. Chronic dietary risks are not of concern as risks were <1 percent of the cPAD for all population subgroups considered (Table 9). The Carbamate Market Basket Survey (CMBS) was not used in the calculation of chronic dietary risks because risks were low without considering it and it is not appropriate because it is for single serving data. 38 Table 9: Results of the Carbaryl Chronic and Cancer Dietary Analyses. Chronic Pop. Subgroup 1989­ 92 1994­ 1998 Exposure (mg/ kg/ day) % cPAD Exposure (mg/ kg/ day) % cPAD Gen. Population 0. 000032 <1 0.000035 <1 All Infants 0. 000054 <1 0.000059 <1 Children 1 ­ 6 years 0. 000057 <1 0.000074 <1 Children 7 ­ 12 years 0. 000036 <1 0.000034 <1 Females 13 ­ 50 years 0. 000026 <1 0.000028 <1 Males 13­ 19 years 0. 000022 <1 0.000026 <1 Males 20+ years 0. 000031 <1 0.000032 <1 Seniors 55+ 0.000031 <1 0.000030 <1 Cancer Gen. Population 0. 000032 2.8 x 10 ­8 0.000035 3.04 X 10 ­8 4.2.4 Cancer Dietary Risk Assessment The following equations were used to calculate dietary exposure and cancer risk using the Q1* approach for carbaryl (i. e., linear, low dose extrapolation). Cancer risks were only calculated for the general population. Dietary exposure (mg/ kg/ day) = consumption x residue Dietary cancer risk = average food exposure (mg/ kg/ day) x Q1* (mg/ kg/ day) ­1 Risk estimates above 1 x 10 ­6 are considered to be of concern. Results indicate a maximum lifetime risk of 2.8x10 ­8 for the general US population if the 1989 to 1992 CFSII data were used. If 1994 to 1998 CFSII data are considered, results are similar for the general U. S. population where cancer risks are 3.04x10 ­8 (Table 9). The Carbamate Market Basket Survey (CMBS) was not used in the calculation of chronic dietary risks. 4.2.5 Characterization/ Uncertainties of the Dietary Risk Estimates ° No detectable residues were found in/ on several commodities: carrots, chicory, flax seed, horseradish, parsnip, salsify, potato, celery, canned spinach, head lettuce, leaf lettuce, rhubarb, sugarbeets, Swiss chard, brussels sprouts, cabbage, kohlrabi, soybean, corn, banana, peanuts, meat, meat fat, and milk. Sensitivity analyses conducted by eliminating crops where no detectable residues were found showed that risk estimates were not significantly affected by assuming zero in place of ½ LOD on samples reported as not detectable. 39 ° The consumption database routinely used for dietary exposure analysis, CSFII 1989­ 1992, has a limited number of individuals for the age group infants less than one year old. The USDA has conducted the Supplemental Children's Survey (approximately 5000 children). For comparative purposes, based on comments from the registrant, the CSFII 1994­ 1998 data have also been used for risk calculations. The trends in the results essentially did not change significantly regardless of which data were used. Risks, in all cases, were slightly higher for all subpopulations using the 1994 to 1998 data. ° The latest cooking and processing factors that were available have been used in the assessment (e. g., processing grapes to raisins, cooking and washing factors for peas, and oil production for peanuts). ° The results of the Critical Exposure Contribution analysis showed that peaches and apples comprised a large percentage of the residues found in the upper percentile tails of the acute exposure distribution for both infants and children (i. e., they were the major risk contributors for children and infant exposure at the upper percentiles). ° Detectable residues from composite monitoring data for non­ blended food forms were used to generate residue values in single units using the Allender method. Though there is a statistical basis for using these data, some degree of uncertainty can be associated with this method. [Note: Peaches are a risk driver in this assessment and this analysis is based on single­ serving 2000 PDP data instead of data that have been decomposited.] 4.3 Estimated Environmental Concentrations In Water Dr. Laurence Libelo of the Environmental Fate and Effects Division (EFED) provided an analysis of the available monitoring data and a screening­ level assessment using simulation models to estimate the potential Estimated Environmental Concentrations (EECs) of carbaryl in ground and surface water (June 28, 2001). Section 4.3.1: Environmental Fate Characteristics provides a summary of the fate characteristics of carbaryl. Section 4.3.2: Monitoring Data provides a summary of the monitoring data that were considered in this assessment. Section 4.3.3: Modeling EECs presents the EECs used for comparison to the DWLOCs (Drinking Water Levels of Concern) calculated for the aggregate risk assessment (presented in Section 5 below). 4.3.1 Environmental Fate Characteristics Carbaryl is considered to be moderately mobile and not likely to persist or accumulate in the environment and its degradate, 1­ naphthol, appears to be less persistent and mobile than carbaryl itself. Under acidic conditions with limited microbial activity they may persist. Carbaryl dissipates in the environment by abiotic and microbially mediated degradation. The major degradation products are CO2 and 1­ naphthol, which is further degraded to CO2. Carbaryl is stable to hydrolysis in acidic conditions but hydrolyzes in neutral (t1/ 2 = 12 days) and alkaline 40 environments (pH= 9, t1/ 2 = 3.2 days). Carbaryl is degraded by photolysis in water (t1/ 2 = 21 days). Under aerobic conditions, the compound degrades rapidly by microbial metabolism, with half lives of 4 to 5 days in soil and aquatic environments. In anaerobic environments metabolism is much slower with ½ lives on the order of 2 to 3 months. Carbaryl is moderately mobile in the environment (Kf = 1.7 to 3.5). The major metabolite of carbaryl degradation by abiotic and microbially mediated processes is 1­ naphthol. This degradate represented up to 67 percent of the applied carbaryl in degradation studies. It is also formed in the environment by degradation of napthalene and other polyaromatic hydrocarbons. Only limited information is available for the environmental transport and fate of 1­ naphthol. While guideline studies were not specifically submitted for 1­ naphthol, open literature data suggest it is less persistent and less mobile than carbaryl. 4.3.2 Monitoring Data Monitoring data for groundwater and surface water are limited, and targeted data are not available. As reported in the U. S. E. P. A. Pesticides in Groundwater Database, carbaryl was detected in 0.4% of wells sampled. Carbaryl was detected in California (2 out of 1433 wells), Missouri (11 out of 325 wells), New York (69 out of 21027 wells) Rhode Island (13 out of 830 wells) and Virginia ( 11 out of 138 wells) (Jacoby et al., 1992). The maximum concentration detected was 610 µg/ L in NY, though typically the measured concentrations were significantly lower. The EPA STORET database contains 9389 records indicating that analysis was done for carbaryl. Of these, only 4 were reported concentrations above the detection limits. These analyses were all from one well in Cleveland, OK in 1988. The 4 reported concentrations were between 0.8 and 1 ppb. Carbaryl was detected at greater than the detection limit (0.003 : g/ L) in 1.1% of groundwater samples in the USGS NAWQA program. The maximum observed concentration was 0.021 : g/ L. Detections were mainly from three settings: wheat (5.8 % of well samples from wheat land use), orchards and vineyards (1.7 % of well samples from orchard and vineyard land use), and urban (1.8% of urban groundwater samples). A number of field studies have reported detectable carbaryl concentrations in surface waters. Because of limitation in the analytical methods used, there is some question as to the accuracy of carbaryl analysis. Poor analytical methods probably have resulted in lower detection rates and lower concentrations than actually present. Carbaryl was detected in surface water in 46% of the 36 NAWQA study units between 1991 and 1998. Carbaryl (along with carbofuran) was one of the two most widely detected insecticides. A significant portion of the total carbaryl applied was apparently transported to streams. Out of 5220 surface water samples analyzed, 1082 or about 21 percent were reported as having detections greater than the minimum detection limit (MDL). The maximum reported concentration was 5.5 ug/ L. For samples with positive detections the mean concentration was 0.11 : g/ L with a standard deviation of 0.43 : g/ L. In areas with high agricultural use, the load measured in surface waters was relatively 41 consistent 42 across the country at about 0.1 percent of the amount used in the basins. Streams draining urban areas showed more frequent detections and higher concentrations than streams draining agricultural or mixed land use areas. Aventis CropScience submitted interim results of an on­ going surface water monitoring study of carbaryl residues in surface water in areas with high agricultural and residential use. In this limited drinking water study, raw water was collected at 16 sites in agricultural areas and four in areas draining suburban areas. Samples at municipal water treatment facilities were collected for 8­ 12 months. When raw water showed positive detections for carbaryl, finished water samples collected at the same time were analyzed. In raw water samples from suburban sites, detectable residues in raw water ranged from 0.002 to 0.023 : g/ L. In samples from agricultural sites, 9 out of 15 water sources had some detectable level of carbaryl. The detections were generally at low levels with one of about 0.16 : g/ L and one of 0.031 : g/ L. The rest were below the level of quantitation (< 0.03 : g/ L). Samples from finished water were generally lower than raw water though it appears that raw and finished water sampling did not evaluate the same mass of water. The data do not give a good indication of the effectiveness of treatment because samples exiting and entering the treatment plant were different. In several cases, finished water had higher concentrations than raw water and finished water had detectable carbaryl when the raw did not. The highest concentration measured was in finished water (0.16 : g/ L). Raw water sampled at the same time had a much lower concentration (0.010 : g/ L). This illustrates that carbaryl contamination is transient, and that it is unlikely that any sampling would catch the actual peak concentration. That, and the limited number of sites sampled, limit the usefulness of this study. Non­ targeted monitoring, such as the NAWQA program has shown that much higher concentrations occur. This study, while useful, does not provide sufficient information to allow estimation of actual peak and mean concentrations that actually occur in all areas or of the effect of treatment. 4.3.3 Modeling EECs Because of the relatively limited persistence of the compound in the environment, it is highly unlikely that the non­ targeted monitoring studies which have been completed detected the maximum concentrations that occur. As a result, the non­ targeted monitoring data have been determined to be of limited utility in developing estimated environmental concentrations (EECs) for ecological and human health risk assessment. Therefore, computer modeling was used to estimate surface water and groundwater concentrations that could be expected from normal agricultural use (Table 10). The results of the modeling are supported by the available monitoring data. These results have been characterized as conservative, though not unreasonable estimates of possible concentrations in drinking water. Surface Water Modeling: Computer modeling with the EPA PRZM3.12 and EXAMS 2.97.7 programs were used to estimate the concentration of carbaryl in surface water. Index reservoir scenarios corrected for Percent Cropped Area (PCA) for representative crops were used. Three different application rates were used in modeling: the maximum allowed on the label for the specific crop, an "average" rate and the maximum rate reported to actually be used. EECs varied greatly depending on the geographic location, crop and application rate. The maximum calculated acute and chronic EECs 43 (494 ppb and 28 ppb, respectively) resulted from use on citrus in Florida. Modeling "average" and maximum resulting use rates gave EEC values generally 40­ 60% lower than maximum. The source of drinking water in relation to the EECs must be carefully considered when using these data. In this case, the results for Florida provided the highest estimates, however; in Florida the majority of drinking water is derived from groundwater (> 90%) so high surface water concentrations do not necessarily indicate high exposure. As a result, both Florida and the results for Oregon apples have been considered in the aggregate assessment (see Section 5.0 for more information). The EECs for Oregon apples are the next highest values for both the acute and chronic estimates. Ground Water Modeling: SCI­ GROW was used to calculate a groundwater screening exposure value to be used in determining the potential risk to human health. Carbaryl chemical properties are outside the range of values for which SCI­ GROW was developed (i. e., aerobic metabolism is faster and its partition coefficient is larger which equates to less leaching than the reference compounds ­ both factors indicate carbaryl degrades faster). SCI­ GROW estimates for groundwater EECs may not predict with complete accuracy, maximum levels because the concentrations calculated are 90 day averages. It is possible; therefore, that groundwater concentration peaks could not be identified. Groundwater levels are anticipated, however, to be more stable over time than surface water concentrations. Table 10: Carbaryl Drinking Water Estimated Environmental Concentrations (EECs) Crop Application Rate Descriptor Number of Applications per Year Pounds A. I. per application Water Acute (ppb) (1 in 10 year peak single day concentration) Water Chronic (ppb) (1 in 10 year annual average concentration) Source: Surface Water (PRZM/ EXAMs) Sweet Corn (OH) (PCA = 0.46) Maximum 1 8 2 37 3.2 Average 2 2 3. 4 45 2.2 Maximum 3 Reported 3 1 15 0.9 Source: Surface Water (PRZM/ EXAMs) Field Corn (OH) (PCA = 0.46) Maximum 1 4 2 30 2.1 Average 2 2 1 13 0.6 Maximum 3 Reported 2 1. 520 1 Source: Surface Water (PRZM/ EXAMs) Apples (OR) (PCA = 0.87) Maximum 1 5 2 144 9 Average 2 2 1. 2 12 0.7 Maximum 3 Reported 2 1. 625 1 Source: Surface Water (PRZM/ EXAMs) Sugar Beats (MN) (PCA = 0.87) Maximum 1 2 1. 519 2 Average 2 1 1. 5 12 1.1 Maximum 3 Reported 1 1. 2 9 0. 9 Source: Surface Water (PRZM/ EXAMs) Citrus (FL) (PCA = 0.87) Maximum 1 4 5 494 28 Average 2 2 3. 4 246 11 Table 10: Carbaryl Drinking Water Estimated Environmental Concentrations (EECs) Crop Application Rate Descriptor Number of Applications per Year Pounds A. I. per application Water Acute (ppb) (1 in 10 year peak single day concentration) Water Chronic (ppb) (1 in 10 year annual average concentration) 44 Maximum 3 Reported 3 4. 26 411 16 Source: Surface Water Monitoring 5.5 (Maximum Observed Concentration) Source: Groundwater (SCI­ GROW) Maximum 1 5 40. 8 0. 8 Source: Groundwater (NAWQA Monitoring Data) 0.02 0.02 1 Maximum application rate on label 2 Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD 3 Maximum rate of application reported in DOANES survey data 4.4 Residential Risk Assessment The residential risk assessment addresses exposures that individuals receive through their use of consumer products that contain carbaryl and those exposures one could receive from frequenting areas that have been previously treated with carbaryl such as a home lawn, a garden, or a golf course. Carbaryl can also be applied in wide area treatments such as on oyster beds or as a mosquito adulticide. These exposures have also been addressed in this assessment. The Occupational and Residential Exposure Assessment (D281418) was prepared by Jeff Dawson with the exception of the tobacco assessment completed by Dr. Virginia Dobozy. The document D281418 contains detailed descriptions of the data used, methods, and risks calculated for each scenario. Please refer to that document for more specific information. Section 4.4.1: Home Uses provides more specific information pertaining to how carbaryl consumer products are used in addition to the information presented above in Section 4.1: Summary of Registered Uses as it applied more directly to the residential risk assessment. Section 4.4.2: Residential Handler Risk Assessment describes the data, methods, and risk results (both cancer and noncancer) associated with the use of consumer products which contain carbaryl. Section 4.4.3: Residential Postapplication Risk Assessment describes the data, methods, and risk results associated with exposures to the general population including adults, infants, and youth­ aged children that occur from frequenting treated areas. Section 4.4.4: Residential Risk Characterization provides information pertaining to the quality of the assessment including data used, uncertainties with the methods, and any other information 45 that might be used to describe the quality of the results. Section 4.4.5: Risks Associated With Use In Tobacco describes how risks were calculated for smokers who may consume carbaryl treated tobacco in their cigarettes. Section 4.4.6: Other Residential Uses characterizes other potential sources of exposure outside of those quantitatively described in this assessment. 4.4.1 Home Uses Carbaryl is a widely­ used consumer product. Available products include liquids, wettable powders, and dusts for insect control on fruits, vegetables, ornamentals, and lawns. Products for flea control on pets are also available. Some of the equipment used in application includes dust shaker cans, garden hose end sprayers, trigger sprayers, low pressure handwands, belly grinders, push­ type spreaders, aerosol cans, and pet collars. In addition to the information presented in Section 4.1: Summary Of Registered Uses, Aventis Crop Science at the time of the September 24, 1998 SMART Meeting also presented the following information that is key to interpreting the residential risk assessment. Carbaryl accounted for approximately 9 percent of the total residential insecticide market and was ranked fourth on the list behind the pyrethroids, chlorpyrifos, and diazinon. In addition, the registrant also presented the following: ° According to the registrant, insect control on vegetables (~ 58% of users), annuals (~ 50% of users), lawns (~ 35% of users), trees/ shrubs (~ 34% of users) account for the majority of homeowner uses for carbaryl. Pet uses also accounted for ~13 percent of users. ° The annual frequency of use, for all crops/ targets, was reported to be at the 60 th percentile for 1 to 2 times per year and at the 84 th percentile for 5 times per year. ° Aphids, ants, fire ants, fleas, and slugs/ snails are predominant pests controlled by residential carbaryl users (~ 30 down to 15% of users, respectively). ° Most (75%) of vegetable gardens treated with carbaryl are <800 ft 2 but ~8 percent are between 800 and 1500 ft 2 , ~9 percent are between 1500 and 5000 ft 2 , and ~6 percent are greater than 5000 ft 2 . Tomatoes, peppers, cucumbers, beans, and fruit trees represent the most treated garden plants. ° Most (82%) of flower gardens treated with carbaryl are <500 ft 2 but ~10 percent are between 500 and 1200 ft 2 , and ~8 percent are greater than 1200 ft 2 . Roses, shrubs, and certain annuals represent the most treated flowering/ ornamental plants. ° Dusts (65%) and liquid concentrates (25%) account for most carbaryl sales in the residential annual market of 2 million pounds per year. 4.4.2 Residential Handler Risk Assessment The anticipated use patterns and current labeling indicate 17 major residential exposure scenarios, based on the types of equipment and techniques, in which homeowners can be exposed to 5 PHED is a generic database, which includes the results of over 100 exposure studies, developed by US EPA, Pest Management Regulatory Agency/ Health Canada and the California Department of Pesticide Regulation, in cooperation with the pesticide industry. 46 carbaryl during the application process. The quantitative exposure/ risk assessment developed for residential handlers is based on these scenarios. For most scenarios, multiple uses and application rates were considered for a total of 54 distinct combinations. The 17 major scenarios include: (1) Garden Uses: Ready­ to­ use Trigger Sprayer; (2) Garden Uses: Ornamental Duster; (3) Garden Uses: Hose­ end Sprayer; (4) Garden Uses: Low Pressure Handwand; (5) Tree/ ornamental Uses: Low Pressure Handwand; (6) Tree/ ornamental Uses: Hose­ end Sprayer; (7) Garden Uses: Backpack Sprayer; (8) Lawncare Liquid Uses: Hose­ end Sprayer; (9) Pet (Dog and Cat) Uses: Dusting; (10) Pet (Dog and Cat) Uses: Liquid Application; (11) Lawncare Granular and Bait Uses: Belly Grinder; (12) Lawncare Granular and Bait Uses: Push­ type Spreader; (13) Ornamental and Garden Uses: Granulars and Baits By Hand; (14) Various Pest Uses: Aerosol Cans; (15) Pet (Dog and Cat) Uses: Collars; (16) Garden and Ornamental Uses: Sprinkler Can; and (17) Garden and Ornamental Uses: Paint­ on. Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments, as described below. ° The unit exposure values used in this assessment were based on three carbaryl­ specific residential handler studies which quantified exposures during pet treatments with a dust; applications to gardens using a ready­ to­ use trigger sprayer, a dust, a hose­ end sprayer, and a low­ pressure handwand; and during applications to trees using a low­ pressure handwand and a hose­ end sprayer. Two other studies completed by the Outdoor Residential Exposure Task Force (ORETF) and the Pesticide Handlers Exposure Database (Version 1.1 August 1998) (PHED) 5 were also used as sources of surrogate information. [Note to Risk Managers: There is no data compensation issue associated with the use of the ORETF data in the carbaryl risk assessment because Aventis CropScience, the registrant for carbaryl, is a member of the ORETF]. Summaries of the five studies are included in the Occupational and Residential Risk Assessment (D281418). These studies are all considered to be of high quality. The quality of the data in PHED varies from scenarios that meet study guideline requirements to others where a limited number of poor quality data points are available. However, in all cases, the data used represent the best available for the scenario. The PHED unit exposure values range between geometric mean and median of available exposure data. When data from other studies were used, the 47 appropriate statistical measure of central tendency was used. Central tendency values, coupled with other inputs used by HED, are thought to result in conservative, deterministic estimates of risk. For pet collars only, a scenario from the SOPs For Residential Exposure Assessment not based on monitoring data was used to calculate exposures. The factors derived from the SOPs are generally thought to be conservative. ° Average body weight of adult handlers is assumed to be 70 kg because the toxicology endpoint values used for the risk assessments are appropriate for average adult body weight representing the general population. No specific effects were observed consistently in the toxicology studies to indicate an increased sensitivity of one gender over another. ° Homeowner handler assessments were completed based on individuals wearing shorts and shortsleeved shirts. ° Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product including mixing/ loading, if needed, as well as the application; ° Label maximum use rates and use information specific to residential products served as the basis for the risk calculations. If additional information, such as average or typical rates, were available, these values were used as well in order to allow risk managers to make a more informed risk management decision. Average application rates were available from the SMART meeting and BEAD's Quantitative Usage Analysis (QUA). These data indicate that in most cases, average application rates differ from maximum application rates by a factor of approximately two. The average application rates identified from the studies conducted by Aventis CropScience were also considered. ° The exposure duration (i. e., years per lifetime) values in the cancer risk assessment are consistent with those used for other chemicals (i. e., 50 years with home­ use chemicals and 70 year lifetime). Cancer risks were calculated assuming one exposure per year. In addition the number of days of exposure per year which could occur under the ceiling established by an acceptable risk level of 1x10 ­6 were also calculated. These estimates can then be compared to the annual use frequency of 1­ 2x (60 th percentile) and 5x (84 th percentile) presented at the SMART meeting. [Note: It is the understanding of the Agency that Aventis Crop Science is also submitting a use analysis based on the Residential Exposure Joint Venture (REJV) survey which could possibly refine these estimates. The Agency will consider these data as appropriate.] 48 ° Calculations were based on scenarios in the home that would reasonably be treated in a day (but would not necessarily take more than an hour or two) such as the size of a lawn, the size of a garden, the amount that can be applied with a piece of equipment, or the number of pets an individual might keep. Based on Agency Exposure SAC Policy 12: Recommended Revisions To The Standard Operating Procedures For Residential Exposure Assessment, the daily volumes handled and area treated, excerpted from the policy, used in each residential scenario include (along with corresponding inputs defined from carbaryl studies and the SMART meeting for a comparative analysis to allow for a more informed risk management decision): ° 1 container of each ready­ to­ use non­ pet product including garden dusts, trigger sprayers and aerosol cans (scenarios for 25% and 50% used of the total product volume were also presented for the trigger sprayer and garden dust scenarios to allow for a more informed risk management decision); ° ½ container of each ready­ to­ use pet product, including dusts and liquid shampoos; ° 1 pet collar; ° 100 gallons of finished spray output for hose­ end sprayers; ° 5 gallons when mixing/ loading/ applying liquids with a backpack sprayer or a low pressure handwand sprayer; value was also used for sprinkler can applications; ° 1 gallon of paint­ on solution for ornamental/ garden uses; ° 20,000 square feet to represent the surface area treated for broadcast applications to lawns; ° 1000 square feet as the treatment area for many spot applications in lawns, gardens, and ornamentals (this value used as appropriate when application rates were based on a square foot basis for spot­ type treatments); and ° 5 mounds per day treated for fire ant applications. ° For direct pet treatments, the Residential SOPs were used to define the amount of chemical that can be used to treat single animals, which was then used to calculate total human dose levels. The actual per animal application rates used were ½ of 6 oz. bottle for liquid shampoo (0.5%) and ½ of 4 lb. container for powders (10%). 4.4.2.1 Residential Handler Noncancer Risks Noncancer risks were calculated using the Margin of Exposure (MOE) approach, which is a ratio of the body burden (exposure) to the toxicological endpoint of concern. Short­ term dermal MOEs were calculated using a NOAEL of 20.0 mg/ kg/ day from the 21­ day dermal toxicity study in rats with technical material and short­ term inhalation MOEs were calculated using a NOAEL of 1 mg/ kg/ day from the oral developmental neurotoxicity study in rats. Body burden values were determined by first calculating daily exposures using application parameters (i. e., rate and area treated) along with unit exposure levels. Exposures were then normalized by body weight and adjusted for absorption factors (100 percent for both dermal and inhalation) as appropriate to calculate average daily dose levels (i. e., body burdens) as illustrated in equation below. 49 Daily Exposure (mg ai/ day) = Unit Exposure (mg ai/ lb ai) x Application Rate (lb ai/ A) x Daily Acres Treated (A/ day) Where: Daily Exposure = Amount deposited on the surface of the skin that is available for dermal absorption or amount that is inhaled, also referred to as potential dose (mg ai/ day); Unit Exposure = Normalized exposure value derived from August 1998 PHED Surrogate Exposure Table and various referenced exposure studies noted above (mg ai/ lb ai); Application Rate = Normalized application rate based on a logical unit treatment such as acres or gallons, maximum and typical values are generally used (lb ai/ A); and Daily Acres Treated = Normalized application area based on a logical unit treatment such as acres (A/ day) or gallons per day can be substituted (gal/ day). The dermal absorption factor of 100 percent based on an absorption study in rats was used for all dermal calculations since no route­ to­ route conversion was required. No specific inhalation absorption factor is available for carbaryl. Therefore, a factor of 100 percent was used for route­ to­ route calculations as is done with all pesticides. MOEs were calculated using the following formula. MOE = NOAEL (mg ai/ kg/ day) Average Daily Dose (mg ai/ kg/ day) Where: MOE = Margin of exposure, value used to represent risk or how close a chemical exposure is to being a concern (unitless); Average Daily Dose = The amount as absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/ kg body weight/ day); and NOAEL = No observed adverse effect level or dose level in a toxicity study where no observed adverse effects occurred in the study (mg pesticide active ingredient/ kg body weight/ day). A combined (dermal and inhalation) MOE was determined because common toxicity (cholinesterase inhibition) endpoints were used to calculate dermal and inhalation risks for each exposure duration. The following formula was used to calculate total MOE values by combining the route­ specific MOEs: MOE total = 1/(( 1/ MOE a) + (1/ MOE b) +.... (1/ MOE n)) Where: MOE a, MOE b, and MOE n represent MOEs for each exposure route of concern Short­ term risks for residential handlers (intermediate­ term scenarios are not thought to exist because of the sporadic nature of applications by homeowners) are presented in Table 11. For most scenarios (40 out of 52), risks are not of concern because MOEs exceed the required uncertainty factor of 100. As expected, the scenarios for which MOEs do not meet or exceed 100 have a relatively high unit exposure associated with them or the amount of chemical used over a day is relatively high (based on high application rates and/ or high amounts of area treated). The use of dusts in gardens and for pet 50 grooming along with some liquid sprays on ornamentals appear to be the most problematic scenarios. Unlike the occupational handler scenarios, the use of different levels of personal protective clothing and equipment is not considered for residential handlers because of a lack of availability, training, and maintenance. [Note: Scenarios where MOEs are of concern (i. e., <100) for are highlighted in the table.] TABLE 11 CARBARYL NONCANCER MOEs ATTRIBUTABLE TO COMBINED SHORT­ TERM HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS DERMAL MOEs INHALATION MOEs COMBINED MOEs APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 1 Garden: Ready­ to­ Use Trigger Sprayer (MRID 444598­ 01) Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 0.25 0.00075 34567.9 1393034.8 33730.9 Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 0.5 0.0015 17284.0 696517.4 16865.4 Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 1 0.003 8642.0 348258.7 8432.7 Average Study Use Rate 0.012 (lb ai/ 1000 ft2) 1 0.012 2160.5 87064.7 2108.2 2 Garden/ Ornamental Dust (MRID 444598­ 01) Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 0.25 0.1 94.6 804.6 84.6 Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 0.5 0.2 47.3 402.3 42.3 Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 1 0.4 23.6 201.1 21.2 Average Study Use Rate 0.079 (lb ai/ 1000 ft2) 1 0.079 119.7 1018.5 107.1 3 Garden: Hose­ End (MRID 444598­ 01) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 100 2 20.6 17500.0 20.6 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 216.7 184210.5 216.5 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 3431.4 2916666.7 3427.3 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 1790.3 1521739.1 1788.2 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 876.1 744680.9 875.1 Average Study Use Rate 0.26 (lb ai/ 1000 ft2) 1 0.26 158.4 134615.4 158.2 Fire Ant 0.0075 (lb ai/ gal spray) 100 0.75 54.9 46666.7 54.8 4 Garden: Low Pressure Handwand (MRID 444598­ 01) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 5 0.1 368.4 77777.8 366.7 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 193.9 40935.7 193.0 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 3070.2 648148.1 3055.7 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 1601.8 338164.3 1594.3 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 783.9 165484.6 780.2 Average Study Use Rate 0.083 (lb ai/ 1000 ft2) 1 0.083 443.9 93708.2 441.8 Fire Ant 0.0075 (lb ai/ gal spray) 5 0.0375 982.5 207407.4 977.8 TABLE 11 CARBARYL NONCANCER MOEs ATTRIBUTABLE TO COMBINED SHORT­ TERM HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS DERMAL MOEs INHALATION MOEs COMBINED MOEs APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 51 5 Trees/ Ornamentals: Low Pressure Handwand (MRID 445185­ 01) Ornamental 0.023 (lb ai/ 1000 ft2) 1 0.176 1087.0 468227.4 1084.4 Pome Fruit 0.07 (lb ai/ 1000 ft2) 1 0.07 357.1 153846.2 356.3 Nuts/ Stone Fruit 0.12 (lb ai/ 1000 ft2) 1 0.12 208.3 89743.6 207.9 Citrus 0.176 (lb ai/ 1000 ft2) 1 0.023 142.0 61188.8 141.7 Average Study Use Rate 0.0047 (lb ai/ gal, 17g ai/ 4 min at 2GPM) 5 0.024 1063.8 458265.1 1061.4 6 Trees/ Ornamentals: Hose End Sprayer (MRID 445185­ 01) Ornamental 0.023 (lb ai/ 1000 ft2) 1 0.176 1560.8 1217391.3 1558.8 Pome Fruit 0.07 (lb ai/ 1000 ft2) 1 0.07 512.8 400000.0 512.2 Nuts/ Stone Fruit 0.12 (lb ai/ 1000 ft2) 1 0.12 299.1 233333.3 298.8 Citrus 0.176 (lb ai/ 1000 ft2) 1 0.023 204.0 159090.9 203.7 Average Study Use Rate 0.005 (lb ai/ gal spray) 100 0.5 71.8 56000.0 71.7 7 Garden: Backpack Sprayer (PHED) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 5 0.1 2745.1 23333.3 2456.1 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 1444.8 12280.7 1292.7 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 22875.8 194444.4 20467.8 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 11935.2 101449.3 10678.9 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 5840.6 49645.4 5225.8 Average Study Use Rate 0.083 (lb ai/ 1000 ft2) 1 0.083 3307.3 28112.5 2959.2 Fire Ant 0.0075 (lb ai/ gal spray) 5 0.0375 7320.3 62222.2 6549.7 8 Lawn Care: Hose End Sprayer (MRID 449722­ 01/ ORETF OMA 004) Lawn (broadcast) 0.25 (lb ai/ 1000 ft2) 20 5 25.5 875.0 24.7 Lawn (spot) 0.25 (lb ai/ 1000 ft2) 1 0.25 509.1 17500.0 494.7 9 Dusting Dog (MRID 444399­ 01) Average Study Use Rate 0.0026 (lb ai/ dog) 1 0.0026 163.2 1076.9 141.7 Dog (10% & ½ of 2 lb) 0.1 (lb ai/ dog) 1 0.1 4.2 28.0 3.7 Dog (5% & ½ of 2 lb) 0.05 (lb ai/ dog) 1 0.05 8.5 56.0 7.4 10 Dogs: Liquid Application Dog (0.5% & ½ of 6 oz) 0.001 (lb ai/ dog) 1 0.001 14000000.0 No Data No Data 11 Granular & Baits Lawn Care: Belly Grinder Lawn (spot) 0.21 (lb ai/ 1000 ft2) 1 0.21 60.6 5376.3 59.9 Lawn (spot) 0.1 (lb ai/ 1000 ft2) 1 0.1 127.3 11290.3 125.9 12 Granular & Baits Lawn Care: Push­ Type Spreader (MRID 449722­ 01/ ORETF OMA 003) Lawn (broadcast) 0.21 (lb ai/ 1000 ft2) 20 4.2 490.2 18315.0 477.4 Lawn (broadcast) 0.1 (lb ai/ 1000 ft2) 20 2 1029.4 38461.5 1002.6 13 Granulars & Baits By Hand Ornamentals and Gardens 0.21 (lb ai/ 1000 ft2) 1 0.21 15.5 713.8 15.2 14 Aerosol Various 0.005 (0.5 % ai in soln./ 1 pt can) 16 0.08 79.5 364.6 65.3 15 Collar Dog 0.013 (16 % ai per 1.3 oz collar) 1 0.013 10769230.8 No Data No Data TABLE 11 CARBARYL NONCANCER MOEs ATTRIBUTABLE TO COMBINED SHORT­ TERM HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS DERMAL MOEs INHALATION MOEs COMBINED MOEs APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 52 16 Sprinkler Can (Source: Scenario 6) Ornamentals (2% Soln) 0.02 (2% soln used ad libitum) 5 0.1 359.0 280000.0 358.5 17 Ornamental Paint On Ornamentals (2% Soln) 0.02 (2% soln used ad libitum) 1 0.02 304.3 12323.9 297.0 4.4.2.2 Residential Handler Cancer Risks Cancer risks were calculated by comparing the Lifetime Average Daily Dose (LADD) to the Q1* (8.75 x 10 ­4 (mg/ kg/ day) ­1 ). The LADD was calculated using the equation below. LADD = ADD xTreatment frequency x Working duration 365 days/ year Lifetime Where: LADD = Lifetime Average Daily Dose or the amount as absorbed dose received from exposure to a pesticide in a given scenario amortized over a lifetime (mg pesticide active ingredient/ kg body weight/ day); ADD = Average Daily Dose or the amount as absorbed dose received from exposure to a pesticide in a given scenario on a daily basis (mg pesticide active ingredient/ kg body weight/ day) [Note: Represents inhalation and dermal exposure contributions, dermal component has been calculated with a 12.7 % absorption factor defined in a rat study.]; Treatment Frequency = The annual frequency of an application by an individual (days/ year); Working Duration = The amount of a lifetime that an individual spends engaged in a career involving pesticide exposure (years); Lifetime = The average life expectancy of an individual (years). Cancer risk was then calculated using the following equation: Risk = LADD x Q1* Where: Risk = Probability of excess cancer cases over a lifetime (unitless); Lifetime Average Daily Dose = The amount as absorbed dose received from exposure to a pesticide in a given scenario over a lifetime (mg pesticide active ingredient/ kg body weight/ day, also referred to as LADD); and Q1* = Quantitative dose response factor used for linear, low­ dose response cancer risk calculations (mg/ kg/ day) ­1 . 53 Table 12 presents the quantitative risks associated with each scenario considered in the assessment. For all but one scenario (i. e., treating dogs with ½ bottle of 10 percent dust ­ risk is 1.09x10 ­6 ), cancer risks are less than 1x10 ­6 (most are in the 10 ­8 or 10 ­10 range) when a single application per year is evaluated. The risk associated with dusting a dog should also be taken in context of the uncertainties associated with cancer risk assessment. In effect, this value is 1x10 ­6 . This table also includes the allowable number of days exposure per year. There are 5 scenarios where 5 days or less of exposure per year is allowable. These results should be considered in conjunction with the use and usage information supplied by the Aventis Crop Science that indicates the 50 th percentile annual frequency of use is between 1 and 2 uses per year and that 5 uses per year is at the 84 th percentile. As with the noncancer risks, the use of dusts in gardens and for pet grooming along with some liquid sprays on ornamentals appear to be the most problematic scenarios. [Note: The scenario where risks are still of concern (i. e., >1x10 ­6 ) is highlighted in the table.] Cancer risks appear to be less of concern compared to noncancer risks for all corresponding scenarios. TABLE 12: CARBARYL CANCER RISKS ATTRIBUTABLE TO COMBINED HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS CANCER RISK ALLOWED DAYS/ YR APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 1 Garden: Ready­ to­ Use Trigger Sprayer (MRID 444598­ 01) Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 0.25 0.00075 1.27e­ 10 >365 Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 0.5 0.0015 2.54e­ 10 >365 Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 1 0.003 5.08e­ 10 >365 Average Study Use Rate 0.012 (lb ai/ 1000 ft2) 1 0.012 2.03e­ 09 >365 2 Garden/ Ornamental Dust (MRID 444598­ 01) Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 0.25 0.1 4.81e­ 08 21 Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 0.5 0.2 9.62e­ 08 10 Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 1 0.4 1.92e­ 07 5 Average Study Use Rate 0.079 (lb ai/ 1000 ft2) 1 0.079 3.80e­ 08 26 3 Garden: Hose­ End (MRID 444598­ 01) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 100 2 2.11e­ 07 5 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 2.01e­ 08 50 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 1.27e­ 09 >365 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 2.43e­ 09 >365 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 4.97e­ 09 201 Average Study Use Rate 0.26 (lb ai/ 1000 ft2) 1 0.26 2.75e­ 08 36 Fire Ant 0.0075 (lb ai/ gal spray) 100 0.75 7.93e­ 08 13 4 Garden: Low Pressure Handwand (MRID 444598­ 01) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 5 0.1 1.18e­ 08 85 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 2.25e­ 08 45 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 1.42e­ 09 >365 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 2.72e­ 09 >365 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 5.56e­ 09 180 Average Study Use Rate 0.083 (lb ai/ 1000 ft2) 1 0.083 9.82e­ 09 102 Fire Ant 0.0075 (lb ai/ gal spray) 5 0.0375 4.44e­ 09 225 TABLE 12: CARBARYL CANCER RISKS ATTRIBUTABLE TO COMBINED HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS CANCER RISK ALLOWED DAYS/ YR APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 54 5 Trees/ Ornamentals: Low Pressure Handwand (MRID 445185­ 01) Ornamental 0.023 (lb ai/ 1000 ft2) 1 0.176 4.01e­ 09 250 Pome Fruit 0.07 (lb ai/ 1000 ft2) 1 0.07 1.22e­ 08 82 Nuts/ Stone Fruit 0.12 (lb ai/ 1000 ft2) 1 0.12 2.09e­ 08 48 Citrus 0.176 (lb ai/ 1000 ft2) 1 0.023 3.06e­ 08 33 Average Study Use Rate 0.0047 (lb ai/ gal, 17g ai/ 4 min at 2GPM) 5 0.47 4.09e­ 09 244 6 Trees/ Ornamentals: Hose End Sprayer (MRID 445185­ 01) Ornamental 0.023 (lb ai/ 1000 ft2) 1 0.176 2.79e­ 09 359 Pome Fruit 0.07 (lb ai/ 1000 ft2) 1 0.07 8.49e­ 09 118 Nuts/ Stone Fruit 0.12 (lb ai/ 1000 ft2) 1 0.12 1.45e­ 08 69 Citrus 0.176 (lb ai/ 1000 ft2) 1 0.023 2.13e­ 08 47 Average Study Use Rate 0.005 (lb ai/ gal spray) 100 0.025 6.06e­ 08 16 7 Garden: Backpack Sprayer (PHED) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 5 0.1 1.66e­ 09 >365 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 3.15e­ 09 317 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 1.99e­ 10 >365 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 3.81e­ 10 >365 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 7.79e­ 10 >365 Average Study Use Rate 0.083 (lb ai/ 1000 ft2) 1 0.083 1.38e­ 09 >365 Fire Ant 0.0075 (lb ai/ gal spray) 5 0.0375 6.22e­ 10 >365 8 Lawn Care: Hose End Sprayer (MRID 449722­ 01/ ORETF OMA 004) Lawn (broadcast) 0.25 (lb ai/ 1000 ft2) 20 5 1.73e­ 07 6 Lawn (spot) 0.25 (lb ai/ 1000 ft2) 1 0.25 8.64e­ 09 116 9 Dusting Dog (MRID 444399­ 01) Average Study Use Rate 0.0026 (lb ai/ dog) 1 0.0026 2.82e­ 08 35 Dog (10% & ½ of 2 lb) 0.1 (lb ai/ dog) 1 0.1 1.09e­ 06 1 Dog (5% & ½ of 2 lb) 0.05 (lb ai/ dog) 1 0.05 5.43e­ 07 2 10 Dogs: Liquid Application Dog (0.5% & ½ of 6 oz) 0.001 (lb ai/ dog) 1 0.001 3.11e­ 13 >365 11 Granular & Baits Lawn Care: Belly Grinder Lawn (spot) 0.21 (lb ai/ 1000 ft2) 1 0.21 7.21e­ 08 14 Lawn (spot) 0.1 (lb ai/ 1000 ft2) 1 0.1 3.43e­ 08 29 12 Granular & Baits Lawn Care: Push­ Type Spreader (MRID 449722­ 01/ ORETF OMA 003) Lawn (broadcast) 0.21 (lb ai/ 1000 ft2) 20 4.2 8.97e­ 09 112 Lawn (broadcast) 0.1 (lb ai/ 1000 ft2) 20 2 4.27e­ 09 234 13 Granulars & Baits By Hand Ornamentals and Gardens 0.21 (lb ai/ 1000 ft2) 1 0.21 2.83e­ 07 4 14 Aerosol Various 0.005 (0.5 % ai in soln./ 1 pt can) 16 0.08 5.94e­ 08 17 15 Collar Dog 0.013 (16 % ai per 1.3 oz collar) 1 0.013 4.04e­ 13 >365 16 Sprinkler Can (Source: Scenario 6) Ornamentals (2% Soln) 0.02 (2% soln used ad libitum) 5 0.1 1.21e­ 08 82 17 Ornamental Paint On Ornamentals (2% Soln) 0.02 (2% soln used ad libitum) 1 0.02 1.44e­ 08 69 55 4.4.3 Residential Postapplication Risk Assessment Carbaryl uses are extremely varied and include home gardens, ornamentals, turf (golf courses and lawns) and companion animals (e. g., on dogs and cats). Carbaryl also has more limited uses that were considered including as a mosquito adulticide in residential areas and for Ghost/ Mud shrimp control in Washington. As a result, a wide array of individuals of varying ages can potentially be exposed when they do activities in areas that have been previously treated or have contact with treated companion animals. The residential postapplication risk assessment addresses these types of exposures. The risks from exposure to carbaryl residues postapplication were determined for the following populations: 1) Residential (homeowner) Adults: The following postapplication scenarios were assessed: residential turf (lawncare), residential turf (after mosquito control), swimming/ beach activity (oyster bed treatments), golfing, home garden exposure to deciduous trees and home garden exposure to fruiting vegetables. Within each scenario, ranges of exposure were evaluated for different application rates, duration of exposure, and postapplication activities (e. g., weeding, harvesting). 2) Toddlers (3 year­ olds): Toddlers were selected as a representative population for turf and companion animal assessments. Exposures from turf were evaluated separately for lawncare uses and after mosquito control. Beach activity (oyster bed treatments) was also evaluated. Separate risk assessments were considered individually and as a total exposure for turf ­ dermal exposure and hand­ to­ mouth, object­ to­ mouth and soil ingestion. For pet uses and the beach play assessments, dermal and hand­ to­ mouth exposures were considered individually and as a total exposure. A separate assessment was done for toddlers who could potentially ingest carbaryl granules. [Note: Values for this population were used in the aggregate risk calculations for children (1 to 6 years old).] 3) Youth­ aged children (ages 10 to 12): children of this age could help with garden maintenance (deciduous trees and fruiting vegetables) and therefore were considered for activities related to fruiting vegetables and fruit trees. Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments, as described below. The assumptions and factors used in the risk calculations are consistent with current Agency policy for completing residential exposure assessments (i. e., SOPs For Residential Exposure Assessment and related documents). ° Several carbaryl­ specific studies were used in the development of this assessment including a turf transferable residue (TTR) study conducted in California, Georgia, and Pennsylvania at 8.17 lb ai/ acre (MRID 451143­ 01). This study was conducted using the standard ORETF protocol. The Georgia data were used for the assessment (all were similar). Residue transferability observed in this data was 1.20 percent. The Agricultural Reentry Task Force (ARTF) conducted several dislodgeable foliar residue (DFR) studies with carbaryl. The olive pruning (MRID 56 451751­ 02) and cabbage weeding (MRID 451917­ 01) studies were used in the home garden risk assessments. Aventis Crop Science is a member of the ARTF so there are no data compensation issues associated with the use of these data. All of these carbaryl­ specific studies should be considered high quality for risk assessment purposes. ° Two other studies completed by the Washington State Department of Ecology were used for completing the risk assessment for the oyster bed use. These studies provided water and sediment concentration data in Willapa Bay where these applications occur. ° Exposure frequency values used in cancer risk assessments for adults are the same as those used for residential handlers (1 time per year). However, the Agency does believe that there are higher frequency golfers (i. e., average golfers over all ages play 18 rounds year) based on a 1992 report (Golf Course Operations, Cost of Doing Business/ Profitability by the Center For Golf Course Management). The number of exposure days per year has also been calculated for all postapplication exposure scenarios. ° Several models and published data sources were also used to develop the risk assessment. These include papers related to: deposition from mosquito control by Dukes et al from Florida A& M University and transference of residues from treated pets by Boone et al from Mississippi State University. The Agency's Standard Operating Procedures For Residential Exposure Assessment were the primary guidance used for this assessment. Several other models and guidance documents were also used including the Agency's SWIMODEL (for swimmers in Willapa Bay after oyster bed treatments); AgDrift V2.0 (for risks from mosquito control), and the Risk Assessment Guidance For Superfund or RAGS (for dermal exposures during beach play and oyster harvest). Specific information from the mosquito control label and historical information for oyster bed applications were also used to complete the assessments (e. g., droplet spectra requirements to predict deposition from aerial treatments during mosquito control). ° The Agency calculates total exposures to individual chemicals when it is likely that behaviors could occur simultaneously that would lead to the overall dose for the exposed population of concern. The Agency has added together risk values (i. e., MOEs) for different kinds of exposures within the turf (dermal, hand­ to­ mouth, object­ to­ mouth, and soil ingestion) and pet scenarios (dermal and hand­ to­ mouth). These represent the standard set of exposures that are typically added together when chemicals are used on turf or on pets because it is logical they can co­ occur. ° Exposures to children playing on treated turf as well as adults on turf (lawncare and golfing) have been addressed using the latest Agency approaches for this scenario including: ° 5 percent of the application rate has been used to calculate the 0­ day residue levels used for defining risks from hand­ to­ mouth behaviors, measured TTR values are not used because of differences in transferability versus what would be expected during hand­ tomouth behaviors; 57 ° 20 percent of the application rate has been used to calculate the 0­ day residue levels used for defining risks from object­ to­ mouth behaviors, measured TTR values are not used because of differences in transferability versus what would be expected during hand­ tomouth behaviors, a higher percent transfer has been used for object­ to­ mouth behaviors because it involves a teething action believed to be more analogous to DFR/ leaf wash sample collection where 20 percent is also used; ° the measured TTR levels quantified in MRID 451143­ 01 have been used to complete the dermal exposure calculations as the 0­ day transferability was > 1 percent of the application rate for the short­ and intermediate­ term data sources, studies where transferability is less than 1 percent are not used for risk assessment purposes because the transfer coefficients used by the Agency for defining exposures are based on Jazzercize studies in which TTR values were measured by techniques where transferability is generally in the 1 to 5 percent range other than the ORETF roller method where transferability tends to be lower; ° short­ and intermediate­ term exposures have been calculated because play and mouthing behaviors are assumed to routinely occur daily and for extended periods such as over 30 days, carbaryl residues are also expected to be present based on residue dissipation data (i. e., slow dissipation rate); ° in cases where 0 day residues have been calculated based on application rates (i. e., hand object­ to­ mouth residues and for soil dissipation), dissipation over time measured in the TTR study (i. e., slope of decay curve) has been used to predict TTR and soil levels over time, carbaryl residues were detectable even at 14 days after application (i. e., final sampling interval) at all sites in the TTR studies used in this assessment, at 14 days average residues at the Georgia and Pennsylvania study sites were still orders of magnitude above the quantitation limit, this indicates that predicted residue levels for extended durations should be considered appropriate based on the empirical data (e. g., critical for consideration of intermediate­ term exposures); ° the transfer coefficients used, except golfing, are those presented at the 1999 Agency presentation before the FIFRA Science Advisory Panel that have been adopted in routine practice by the Agency; ° transfer coefficients have been adjusted for differences between short­ and intermediateterm exposures; ° adult golfers have been assessed using a transfer coefficient of 500 cm 2 /hour [Note: The Agency is currently developing a policy on golfer exposures and has used this value in other assessments]; ° 3 year old toddlers are expected to weigh 15 kg; ° hand­ to­ mouth exposures are based on a frequency of 20 events/ hour and a surface area per event of 20 cm 2 representing the palmar surfaces of three fingers; ° saliva extraction efficiency is 50 percent meaning that every time the hand goes in the mouth approximately ½ of the residues on the hand are removed; ° object­ to­ mouth exposures are based on a 25 cm 2 surface area; 58 ° exposure durations are expected to be 2 hours based on information in the Agency's Exposure Factors Handbook except for golfers where the exposure duration for an 18 hole round of golf is 4 hours based on a 1992 report (Golf Course Operations, Cost of Doing Business/ Profitability by the Center For Golf Course Management); ° soil residues are contained in the top centimeter and soil density is 0.67 mL/ gram; ° dermal, hand­ and object­ to­ mouth, and soil ingestion are added together to represent an overall risk from exposure to turf while granular ingestion is considered to be a much more episodic behavior and is considered separately by the Agency; and ° children of various ages down to the very young (e. g., 4 or 5 years old) are currently playing golf, the Agency recognizes that age may impact exposures because of changes in behavior and skin surface area to body weight ratios but has not yet developed a quantitative approach for calculating their risks. ° Exposures to children and adults working in home gardens have been addressed using the latest Agency approaches for this scenario including: ° youth­ aged children are considered along with adults; ° 12 year old youth are expected to weigh 39.1 kg; ° exposure durations are expected to be 40 minutes; ° Pre­ Harvest Intervals (PHIs) are less than 7 days for most crops with some as long as 28 days; ° transfer coefficients for youth were calculated by adjusting the appropriate adult transfer coefficients by a 50% factor as has been done by the Agency since the inception of the SOPs For Residential Exposure Assessment; ° the updated transfer coefficients specified in Agency policy 003 described above in the occupational risk assessment have been used rather than those currently specified in the SOPs because they represent more refined estimates of exposure for the fruiting vegetable and deciduous tree crop groups, these crop groups have been used in the SOPs to represent home garden exposures; ° the combination of adjusting transfer coefficients for youth­ aged children and using appropriate body weights for the age group results in dose levels that are slightly lower than that of adults in the same activity (the TC reduction and body weight reduction is essentially a 1: 1 ratio); and ° the DFR data used for the assessments are the same as those used in the occupational risk assessment for the selected crop groups. ° Exposures to children after contact with treated pets have been addressed using the latest Agency approaches for this scenario including: ° only toddlers are considered because their exposures are thought to be highest (i. e., they are considered the highest exposed population by the Agency); 59 ° an equilibrium approach based on a single child "hug" of the treated animal is used to assess dermal exposure as described in the 1999 Agency SAP Overview document (i. e., the skin loads after a single contact with the treated animal and additional contacts don't proportionally add exposures), the surface area of the dermal hug is based on a toddler skin surface area and typical clothing; ° residue dissipation is 5 percent per day for the shampoo and dust products (based on data from J. Chambers at Mississippi State University on other pet use products); ° the transferability of residues from fur is 20 percent; ° the active lifetime of a collar is expected to be 120 days based on label statements which was used by the Agency, a daily emission term from the collar of 0.000290 mg/ cm 2 /gram ai/ day is also based on measured data from Mississippi State University for a pet collar; ° risks are based on an even loading of residues across the entire surface of a 30 lb dog which has been chosen as a representative animal, the animal surface area was calculated using (12.3* Body Weight (g) 0.65 ) from the Agency's 1993 Wildlife Exposure Factors Handbook (i. e., dog surface area of 5986 cm 2 ); ° the daily frequency of hand­ to­ mouth contact with dogs is 40 events per day, in each event, the palmar surface of the hands (i. e., 20cm 2 /event) is placed in the mouth of the child contributing to nondietary ingestion exposure; and ° the Agency is currently in the process of considering revisions in its methodologies for completing risk assessments for pet products, some of the key inputs that are potentially subject to modification include the amount of residues which are transferable from pet fur, defining the number of hand­ to­ mouth events, and evaluating the emission term for collars. ° There are many likely studies focused on carbaryl in the published literature or available from various governmental Agencies because it is so widely used. For example, the Agency's Office of Research and Development along with other Agencies have funded a project entitled Pesticide Exposure in Children Living in Agricultural Areas along the United States­ Mexico Border Yuma County, Arizona. Preliminary results of this study indicate that carbaryl residues were identified in the dust of 20 percent of the 152 houses sampled and in approximately 24 percent in 25 samples collected in 6 schools in the same region. At this point, the Agency has not identified any data from the literature or other sources that would alter the conclusions of this risk assessment. As more data become available, the Agency will consider the information in efforts to refine the assessment (i. e., use additional information to alter numeric risk estimates or to characterize existing estimates if warranted). With regard to this specific example, current Agency policy is not to use house dust estimates to calculate risks because of a lack of an appropriate exposure model. Also, in a 1995 study conducted by the Centers For Disease Control (Hill et al) entitled Pesticide Residues In Urine Of Adults Living In The United States: Reference Range Concentrations, 1000 adults were monitored via urine collection. One of the analytes measured in that study (1­ naphthol) is a potential metabolite of carbaryl as well as of naphthalene and napropamide. This metabolite was identified in 86 percent of the 1000 adults monitored where the mean value was 17 ppb and the 99 th percentile was 290 ppb. These values were not used quantitatively in the risk assessment for carbaryl because of the uncertainties associated with them such as the exact contribution of each possible compound to the overall 60 levels and no linked exposure information. The investigators also reported results for (2­ naphthol) which is also a metabolite of naphthalene and indicated a common source of exposure because 1­ naphthol and 2­ naphthol levels were similar based on a Pearson correlation of 0.64 (P= 0.0001). The mean for 2­ naphthol is 7.2 ppb and the 99 th percentile was 54 ppb. The Agency instead considers them a qualitative indicator that exposures in the general population are likely to occur. ° Aventis Crop Science has completed and is in the process of submitting to the Agency a biomonitoring study of individuals in residences following the application by a member of the household to the lawn and either the vegetable garden or ornamental flowers. A biomonitoring study of field workers during harvesting and hand thinning operations in apples and cherries will also be submitted to the Agency. Based on personal communication with Aventis Crop Science scientists, preliminary results from the residential biomonitoring study indicate that the highest percentiles of the distribution of the younger children in the homes were similar to those predicted in the Agency's turf risk assessment for toddlers that are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission. ° Aventis Crop Science is also a member of the Residential Exposure Joint Venture which is a group of companies conducting a survey of homeowners to ascertain how consumer pesticide products are used (e. g., rate, frequency, pests, etc.). Also, based on discussions with Aventis Crop Science, an analysis of these data is expected to be submitted which could be used to refine the exposure estimates in this assessment because the amounts of carbaryl used per homeowner application could be refined. Preliminary discussions concerning this survey also indicate Agency estimates are in the range of those observed in the survey. 4.4.3.1 Residential Postapplication Exposure and Noncancer Risks Two different types of noncancer risk calculations were required based on expected exposure durations, i. e., short­ term ( 30 days) and intermediate­ term (30 days up to several months). Intermediate­ term risks were calculated in a postapplication situation, when they were not for residential handlers, because residue dissipation data demonstrated that carbaryl residues persist over that time and it is clear that the behaviors considered as the basis for this assessment can occur routinely over extended periods of time thus creating a potential window for exposures (e. g., children playing outside on the grass is expected to be a routine activity). Noncancer risks were calculated using the MOE approach, as described under Section 4.4.2. The toxicological endpoint of concern and target MOE for short­ term and intermediate­ term dermal exposures is the same as that used for the short­ term dermal exposure for residential handlers (i. e., NOAEL of 20 mg/ kg from the 21­ day dermal toxicity study in the rat and a target MOE of 100). The endpoints of concern and target MOE for short­ term and intermediate­ term nondietary ingestion exposure were defined in the rat developmental neurotoxicity study and subchronic neurotoxicity studies, respectively (i. e., NOAEL of 1 mg/ kg/ day defined in both studies with a target MOE of 100). Several different types of calculations were used in this assessment to reflect the varying age 61 groups, behaviors, data, and activities that were considered. In essence, all can be summarized by saying that a source of some sort (e. g., DFR on leaves) comes in contact with a person as they are doing an activity (e. g., harvesting garden plants). Exposures were then calculated by multiplying the source concentration by some factor (e. g., transfer coefficient for fruit harvesting) and the duration. All of the calculations are explained in detail in the Occupational and Residential Exposure Chapter (281418). Two of the key algorithms are presented below for informational purposes. These represent the predominant types of exposures considered in the postapplication assessment (i. e., dermal and hand­ tomouth Dermal exposures were calculated by considering the potential sources of exposure in the environment, which represent the DFRs on garden plants, TTRs on lawns, and transferable residues on treated pets using the following equation. It should also be noted that there are distinct transfer coefficients for different activities (e. g., fruit harvest versus lawncare). DE( t) (mg/ day) = (TR( t) (µg/ cm 2 ) x TC (cm 2 /hr) x Hr/ Day)/ 1000 (µg/ mg) Where: DE( t) = Daily exposure or amount deposited on the surface of the skin at time (t) attributable for activity in a previously treated area, also referred to as potential dose (mg ai/ day); TR( t) = Transferable residues that can either be dislodgeable foliar or turf transferable residue at time (t) where the longest duration is dictated by the decay time observed in the studies (µg/ cm 2 ); TC = Transfer Coefficient (cm 2 /hour); and Hr/ day = Exposure duration meant to represent a typical workday (hours). [Note: For pets, the TC and Hr/ day terms are replaced with a onetime "hug" scenario.] Likewise, nondietary ingestion from hand­ to­ mouth behaviors also consider the environmental concentrations and the mouthing behaviors of children. The following equation describes how these exposures have been calculated. Where: D = dose from hand­ to­ mouth activity (mg/ day); TR = Transferable Residue where dissipation is based on TTR study and the 0­ day value is based on the 5% initial transferability factor (µg/ cm 2 ); SE = saliva extraction factor (%); SA = surface area of the hands (cm 2 ); Freq = frequency of hand­ to­ mouth events (events/ hour); and Hr = exposure duration (hours). 6 Maximum rates of 4 to 8 lb ai/ acre are specified for different pests. There is one carbaryl label with a turf application rate of 11 lb ai/ acre; however, based on the information from the registrant at the SMART meeting and the TTR study (MRID 45334301), the maximum rate is more likely to be 8 lbs ai/ acre. In addition, risks exceed HED's level of concern at 8 lbs ai/ acre. 62 The (TR( t)) input may represent levels on a single day after application in the case of short­ term risk calculations. For intermediate­ term calculations, 30­ day average concentrations were calculated based on the applicability of the toxicology data (i. e., intermediate­ term endpoint is applied to exposures >30 days). Adult Short­ term MOEs only for lawncare (i. e., heavy yardwork) exceed the Agency's level of concern on the day of application (i. e., 43 to 88). For this activity, it takes 1 and 5 days, respectively at the 4 and 8 lb ai/ acre application rates, 6 for residues to dissipate to a point where short­ term MOEs are $ 100. In all other scenarios considered, short­ term MOEs are $ 100 on the day of application. These other scenarios include vegetable gardening, golfing, tending fruit trees. More localized exposures that occur after mosquito control or from exposures associated with oyster bed treatments are also included. Intermediate­ term MOEs were calculated using 30 day average exposures and the dissipation rate for carbaryl. In all cases, intermediate­ term MOEs are $ 100. Table 13 presents the postapplication MOE values calculated for adults after lawn and home garden applications of carbaryl. Table 13: Summary of Carbaryl Noncancer Postapplication Residential MOEs For Adults Scenario Descriptor Results Short­ term MOE on Day 0 Days Short­ term MOE UF Intermediateterm MOE Residential Turf (Lawncare) Max Rate at 4 lb ai/ A 88 1 842 Max Rate at 8 lb ai/ A 43 5 412 Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 3700­ 231268 0 35463­ 2216454 Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 7031­ 439409 0 67380­ 4211262 Golfing Max Rate at 4 lb ai/ A 1274 0 12297 Max Rate at 8 lb ai/ A 624 0 6021 Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 53654­ 3353387 0 517764­ 32360224 Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 101943­ 6371435 0 983751­ 61484426 Table 13: Summary of Carbaryl Noncancer Postapplication Residential MOEs For Adults Scenario Descriptor Results Short­ term MOE on Day 0 Days Short­ term MOE UF Intermediateterm MOE 63 Home Garden (Deciduous Tree) Very Low Exposure (propping) 17373 0 53139 Low Exposure (irrigation, scout, weed) 1737 0 5314 High Exposure (harvest, prune, train, tie, thin) 579 0 1771 Home Garden (Fruiting Vegetable) Low Exposure (irrigation, scout, thin, weed) 1758 0 9468 Medium Exposure (irrigation, scout) 1256 0 6763 High Exposure (harvest, prune, stake, tie) 879 0 4734 Oyster Beds Oyster Harvest 967137 0 2680745 Swimming 293651 0 No Data Youth­ aged children (10 to 12 years old) were only considered in the home garden scenarios per Agency guidance. Short­ term MOEs for these children were similar to those calculated for adults in that they were $ 100 for all of the gardening scenarios considered. Intermediate­ term MOEs were calculated using 30 day average exposures and the dissipation rate for carbaryl. In all cases, intermediate­ term MOEs are $ 100. Table 14 below summarizes the postapplication MOE values calculated for youth home garden applications of carbaryl. Table 14: Summary of Carbaryl Noncancer Postapplication Residential MOEs For Youth­ Aged Children Scenario Descriptor Results Short­ term MOE on Day 0 Days Short­ term MOE UF Intermediateterm MOE Home Garden (Deciduous Tree) Very Low Exposure (propping) 19408 0 59364 Low Exposure (irrigation, scout, weed) 1941 0 5936 High Exposure (harvest, prune, train, tie, thin) 647 0 1979 Table 14: Summary of Carbaryl Noncancer Postapplication Residential MOEs For Youth­ Aged Children Scenario Descriptor Results Short­ term MOE on Day 0 Days Short­ term MOE UF Intermediateterm MOE 64 Home Garden (Fruiting Vegetable) Low Exposure (irrigation, scout, thin, weed) 1964 0 10577 Medium Exposure (irrigation, scout) 1403 0 7555 High Exposure (harvest, prune, stake, tie) 982 0 5289 Toddler (3 year old) exposures were considered for a variety of scenarios as described above including play on treated turf, play with treated pets, after mosquito control, and after oyster bed treatments. Ingestion of granules, which is considered a highly episodic event by the Agency is also described below. The results from all scenarios considered are presented below in Table 15. Short­ term MOEs from exposure to treated turf (in products labeled for direct application to turf) were <100 on the day of application for both rates considered (i. e., 4 and 8 lb ai/ acre). In fact, shortterm MOEs from individual pathways were not $ 100 for any turf scenario considered on the day of application except for the soil ingestion component of the turf assessment which is a very minor contributor to overall exposures. As a reminder, dermal, hand­ to­ mouth, and object­ to­ mouth exposures pathways were considered along with soil ingestion. Total short­ term MOEs (all pathways) were $ 100 at the lower 4 lb ai/ acre application rate 14 days after application and 18 days at the higher 8 lb ai/ acre application rate. Dermal and hand­ to­ mouth exposures were the key contributors while soil ingestion was a minor contributor to the total MOE estimates. Intermediate­ term MOEs were calculated using 30 day average exposures and the dissipation rate for carbaryl. For both rates, intermediate­ term MOEs were <100. Exposures to toddlers were also considered after application of carbaryl as a mosquito adulticide. The risks are presented along with the turf use risks because the methods are similar except that mosquito control calculations also account for deposition from aerial and ground foggers. Regardless of how applications are made (i. e., by ground or air), both short­ term MOEs on the day of application and intermediate­ term MOEs were $ 100. The assessments for pet uses considered dermal and nondietary ingestion exposures and also calculated total MOEs. Short­ term MOEs for pet uses were <100 even 30 days after application regardless of whether the formulation used was a dust, liquid or collar. This trend was observed for each separate exposure pathway as well as the total MOE estimates. Hand­ to­ mouth and dermal exposures are approximately equal contributors to the overall estimates for each product type. The results are similar for the intermediate­ term MOEs for each scenario. There is one pet use which is also considered to be a chronic exposure by the Agency. Pet collars are assumed to be worn all of the time so chronic exposure can potentially occur. The chronic MOE for pet collars mirrors the short­ and intermediate­ term results. The assessments for beach play for toddlers after oyster bed treatment considered dermal and 65 nondietary ingestion exposures and also calculated total MOEs. Short­ term MOEs were >100 even if the highest monitored sediment concentration value from any study available to the Agency was used as the basis for the calculations. The intermediate­ term results were similar. Table 15: Summary of Carbaryl Noncancer Postapplication Residential Aggregate MOEs For Toddlers Scenario Descriptor Results Short­ term MOE on Day 0 Days For Short­ term MOE UF Intermediateterm MOE Chronic MOE Pet Treatments Liquids 2.0 +30 4 NA Dusts 0. 02 +30 0.04 NA Collars 18 +30 18 43 Residential Turf (High Activity) Max Rate at 4 lb ai/ A 11 14 91 NA Max Rate at 8 lb ai/ A 5 18 45 NA Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 448­ 27983 0 3826­ 239095 NA Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 851­ 53167 0 7269­ 454280 NA Oyster Beds Beach Play 29532 0 81859 NA Ingestion of carbaryl granules is also a potential source of exposure because children can eat them if they are found in treated lawns or gardens. This scenario is considered to be an episodic in nature. Therefore, acute dietary endpoints are always used. The concentration of carbaryl in granular products ranges generally from 2 to 10 percent. If this information is coupled with the body weight of a toddler (15 kg), the NOAEL of 1 mg/ kg/ day for short­ term assessments (which is also the same value used for the aPAD), and the uncertainty factor of 100 the amount of formulation that can be consumed at the uncertainty factor MOE level can be calculated. The Agency generally presents these results based on the number of carbaryl granules that can be ingested. However, the number of homeowner formulations is extensive and impossible to characterize in that much detail so a general weight estimate is presented. If a 2 percent formulation is ingested, 7.5 mg represents exposure at an MOE of 100 (i. e., 1.6 x 10 ­5 lb). If a 10 percent formulation is ingested, 1.5 mg represents exposure at an MOE of 100 (i. e., 3.3 x 10 ­6 lb). For illustrative purposes, if one considers a 2 percent formulation and the density of soil (0.67 mL/ gram, many granulars are clay based), only 0.005 mL of formulation would need to be ingested to have a risk concern (i. e., 7.5 mg * 1g/ 1000mg * 0.67 mL/ gram). Note that this volume is 66 orders of magnitude less than a teaspoon of granular formulation (i. e., 0.1% of a teaspoon where a tsp. = 5 mL). 4.4.3.2 Residential Postapplication Exposure and Risks For Cancer Postapplication cancer risks were calculated for adults only considering the same scenarios. Risks were calculated using a frequency of one exposure per year for 50 years. Cancer risks were calculated using a linear low­ dose extrapolation approach in which a LADD is calculated and then compared with a Q1* (8.75 x 10 ­4 (mg/ kg/ day) ­1 ), as described in Section 4.4.2.2. The number of days of exposure per year under a ceiling limit of cancer risks equal to 1x10 ­6 was also calculated. For all scenarios on turf, cancer risks are in the 10 ­8 range or less on the day of application when a single reentry event per year during lawncare activities is evaluated. For home gardening, golfing or from mosquito control, risks are slightly lower in the 10 ­9 to 10 ­12 range when a single reentry event per year is evaluated on the day of application. Table 16 below summarizes the postapplication risk values calculated for adults after applications of carbaryl. Risk managers should consider these values represent a single reentry day into a treated area over each year of a 50 year lifetime on the day of application and that the Agency lacks data to link the annual frequency of reentry activity to residential applications. As with the residential handler risks above, the Agency calculated the number of exposure days needed to reach a risk level of 1x10 ­6 for each scenario on the day of application, values range from 20 to over 365 days per year while most exceed 365 days per year. Table 16: Summary of Carbaryl Postapplication Residential Cancer Risks For Adults Scenario Descriptor Results Risk on Day 0 Allowed Days/ Year Residential Turf (Lawncare) Max Rate at 4 lb ai/ A 2.5 x 10 ­8 40 Max Rate at 8 lb ai/ A 5.1 x 10 ­8 20 Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 9.5 x 10 ­12 to 5.9 x 10 ­10 >365 Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 5.0 x 10 ­12 to 3.1 x 10 ­10 >365 Golfing Max Rate at 4 lb ai/ A 1.7 x 10 ­9 >365 Max Rate at 8 lb ai/ A 3.5 x 10 ­9 287 Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 6.5 x 10 ­13 to 4.1 x 10 ­11 >365 Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 3.4 x 10 ­13 to 2.1 x 10 ­11 >365 Table 16: Summary of Carbaryl Postapplication Residential Cancer Risks For Adults Scenario Descriptor Results Risk on Day 0 Allowed Days/ Year 67 Home Garden (Deciduous Tree) Very Low Exposure (propping) 2.5 x 10 ­10 >365 Low Exposure (irrigation, scout, weed) 2.5 x 10 ­9 >365 High Exposure (harvest, prune, train, tie, thin) 7.5 x 10 ­9 133 Home Garden (Fruiting Vegetable) Low Exposure (irrigation, scout, thin, weed) 2.5 x 10 ­9 >365 Medium Exposure (irrigation, scout) 3.5 x 10 ­9 289 High Exposure (harvest, prune, stake, tie) 4.9 x 10 ­9 202 Oyster Beds Oyster Harvest 4. 5 x 10 ­12 >365 Swimming 6.1 x 10 ­12 >365 4.4.4 Residential Risk Characterization Characterization of the residential risks is included below for both handlers and for postapplication exposures. Residential Handlers: The residential handler assessment for carbaryl is complex in that calculations were completed for 52 different equipment and application rate scenarios. Unlike the occupational assessments, only short­ term exposures were considered for handlers because homeowner use patterns are not believed by the Agency to lead to intermediate­ term exposures because of their sporadic nature. Cancer risks were also calculated using a linear, low­ dose extrapolation model (i. e., Q1*) for typical residential users (1 event/ year). Cancer risks were also considered by calculating the number of days exposure that would be required per year to achieve a cancer risk of 1x10 ­6 to illustrate risk levels from another perspective. All totaled, when each type of calculation is considered, 108 different crop/ application method calculations were completed for residential handlers. The data that were used in the in the carbaryl residential handler assessment represent the best data and approaches that are currently available. For most of the major use patterns, carbaryl­ specific data or data generated by the Outdoor Residential Exposure Task Force were used. These data generally are considered to be high quality by the Agency and the best source of information available for the scenarios where they were used. Carbaryl­ specific data were used to address the garden and 68 tree/ ornamental scenarios with several types of equipment and formulations including liquid trigger sprayers, dusts, and liquid sprays using low pressure handwand and hose­ end sprayers. Carbarylspecific data were also available for dusting dogs. The ORETF data for hose­ end sprayer applications to turf and granular applications to turf were also used to address those scenarios. In the remaining scenarios, the Pesticide Handlers Exposure Database (PHED) was used to develop the unit exposure values. The quality of the data included in PHED vary widely from scenarios that meet guideline requirements for studies to others where a limited number of poor quality datapoints are available. All data that have been used may not be of optimal quality but represent the best available data. The inputs for application rate and other use/ usage information (e. g., area treated and frequency of use) used by the Agency were supported by the available carbaryl labels and information supplied by the Aventis Crop Science at the September 24, 1998 SMART Meeting. It is also very clear that because carbaryl is such as widely used chemical that it is likely every potential exposure scenario has not been captured because of difference in use pattern. As more refined information becomes available on carbaryl use, the Agency will refine its assessment accordingly. In summary, with respect to residential handler risks, the Agency believes that the values presented in this assessment represent the highest quality results that could be produced given the exposure, use, and toxicology data that are available. However, there are certain elements where additional data are required. For example, it is difficult to ascertain where on a distribution certain input values may fall because the distributional data for exposure, application rates, acres treated and many other parameters are unrefined. Postapplication: Like the residential handler assessment discussed above, the postapplication residential assessment for carbaryl is also complex in that noncancer MOE calculations were required based on the recently selected endpoints along with cancer risk calculations using a linear, low­ dose extrapolation model. Carbaryl residues persist in the environment as indicated in the available DFR and TTR data for periods where intermediate­ term as well as short­ term noncancer risk estimates are required. Cancer risks were calculated only for adults per current Agency policy. The general population can be exposed through many different pathways that result from uses on lawns and turf, in gardens, on ornamental plants, and from treated pets. People can also be exposed from mosquito adulticide applications and uses in oyster beds. Carbaryl labels do not currently allow for indoor residential uses (e. g., crack and crevice). Settings where such exposures could occur would include around personal residences and in other areas frequented by the general public including parks, ball fields, and playgrounds. To represent the wide array of possible exposures, the Agency relies on the scenarios that have been defined in the SOPs For Residential Exposure Assessment and accompanying documents such as the overview presented to the FIFRA Science Advisory Panel. For turf uses, the Agency considered adults and toddlers (3 year olds) in the assessments. Adult activities included lawncare/ maintenance and also golfing. Toddler MOEs were calculated for playing on turf (using exposure data from the Jazzercize model) and also addressed nondietary ingestion (hand­/ object­ tomouth and soil ingestion). Exposures from tree and garden uses were evaluated by considering adults and youth­ aged children (10 to 12 years old) doing gardening activities such as weeding and harvesting for different crop groups. Transfer coefficients from the fruiting vegetable crop group and the 69 deciduous tree crop group were used, as described in the SOPs For Residential Exposure Assessment to represent exposures for these scenarios. MOEs from treated pets were evaluated for toddlers again for whom exposures may occur from dermal contact and hand­ to­ mouth behavior. Adulticide mosquito applications were considered by first defining how much residues are deposited on the ground after a mosquito control application then using the same methods approaches from the lawncare assessment to address adults doing heavy yardwork or golfing and also children playing on treated turf. The data that were used in the carbaryl residential postapplication assessment represent the best data and approaches that are currently available. To the extent possible, the Agency has attempted to use carbaryl­ specific data such as with the dislodgeable foliar residue (DFR) data used for the garden scenarios and the turf transferable residue (TTR) data used for the dermal component of the turf scenarios. When chemical­ specific data were unavailable, the Agency used the current approaches for residential assessment, many of which include recent upgrades to the SOPs. For example, for the toddler hand­ to­ mouth calculations, the TTR data were not used but a 5 percent transferability factor was applied to calculate residue levels appropriate for this exposure pathway. Another key approach to consider is the use of the dermal hug approach for pet products which was proposed at the September 1999 meeting of the FIFRA Science Advisory Panel. Oyster bed uses were evaluated based on guidance from Superfund and the Agency's SWIMODEL. There are also many embedded uncertainties that should be considered in the interpretation of this assessment such as those associated with the use of Jazzercize and with the nondietary ingestion calculations. Readers should consider these in the interpretation of the overall risk estimates. Readers should also consider the screening nature of the SOPs For Residential Exposure Assessment and how additional data could refine the results. Finally, the Agency believes that the values presented in this assessment represent the highest quality results that could be produced based on the currently available postapplication exposure data. Certainly risk managers and other interested parties should consider the quality of individual inputs when interpreting the results and make decisions accordingly. It is difficult to ascertain where on a distribution the values which have been calculated fall because the distributional data for exposure, residue dissipation and many other parameters are unrefined. The Agency does believe, however, that the risks represent conservative estimates of exposure because maximum application rates are used to define residue levels upon which the calculations are based. Additionally, estimates are thought to be conservative even when measures of central tendency (e. g., most transfer coefficients are thought to be central tendency) are used because values that would be considered to be in the lower percentile aspect of any input parameter have not been used in the calculations. There are many studies on carbaryl in the published literature or available from various governmental Agencies because it is so widely used that can be used to inform risk managers about the results of the risk assessment. For example, the Agency's Office of Research and Development, along with other Agencies, has funded a project entitled Pesticide Exposure in Children Living in Agricultural Areas along the United States­ Mexico Border Yuma County, Arizona. Preliminary results of this study indicate that carbaryl residues were identified in the dust of 20 percent of the 152 houses sampled and in approximately 24 percent in 25 samples collected in 6 schools in the same region. Also, in a 1995 study conducted by the Centers For Disease Control entitled Pesticide Residues In Urine Of Adults Living In 7 Hill RH et al (1995). Pesticide Residues in Urine of Adults Living in the United States: Reference Range Concentrations. Environmental Research 71: 99­ 108. 8 Pierce JP et al (1989). Tobacco Use in 1986 ­ Methods and Basic Tabulations from Adult Use of Tobacco Survey. U. S. Department of Health and Human Services Publication Number OM90­ 2004. Office on Smoking and Health, Rockville, Maryland. 70 The United States: Reference Range Concentrations, 7 1000 adults were monitored via urine collection. One of the analytes measured in that study (1­ naphthol) is a potential metabolite of carbaryl as well as of napthalene and napropamide. This metabolite was identified in 86 percent of the 1000 adults monitored where the mean value was 17 ppb and the 99th percentile was 290 ppb. These values were not used quantitatively in the risk assessment for carbaryl because of the associated uncertainties. However, the results from both studies indicate that carbaryl residues are present in areas frequented by the general population and that the scenarios which consider a broad range of exposures are reasonable. 4.4.5 Exposure from the Use of Tobacco Risks from carbaryl residues contained in tobacco products have been calculated based on a pyrolysis study in tobacco. In assessing exposure through use of tobacco, HED has assumed that the greatest exposure to carbaryl would come from cigarettes. Further, HED has assumed that the average U. S. smoker smokes 15 cigarettes per day. 8 Based on a pyrolysis study submitted by the registrant, residues of carbaryl total approximately 44.58 ppm in combined side­ stream and main­ stream tobacco smoke (Memorandum from Thurston Morton dated September 29, 1998, D230407). Since this is a composited sample of main­ stream and side­ stream smoke, it greatly exaggerates the actual exposure to the smoker, whose primary route of exposure is via main­ stream smoke. HED further assumes that 100 percent of that inhaled is absorbed (i. e., that none of the residue is exhaled along with the smoke). These assumptions result in an extreme overestimate of actual likely exposure. With the assumptions regarding residue levels and smoking frequency, and assuming an average body weight of 70 kg, HED estimated that exposure to carbaryl will not exceed 0.0096 mg/ kg/ day [44.58 : g/ g cigarette × 1 g/ cigarette × 15 cigarettes/ day × 1 mg/ 1000 : g ÷ 70 kg body weight = 0.0096 mg/ kg/ day]. The short­ term inhalation NOAEL is 1 mg/ kg/ day and is based on an developmental neurotoxicity study in the rat. Based on the inhalation NOAEL, the short­ term MOE for carbaryl exposure from the use of tobacco is estimated to be 104 even with the expectation that the calculated risks are an extreme overestimate. The residential target MOE is 100. The Agency has not examined intermediate­ or long­ term exposure to carbaryl via tobacco due to the severity and quantity of health effects associated with the use of tobacco products. 4.4.6 Other Residential Exposures This assessment for carbaryl reflects the Agency's current approaches for completing residential exposure assessments based on the guidance provided in the Draft: Series 875­ Occupational and Residential Exposure Test Guidelines, Group B­ Postapplication Exposure Monitoring Test Guidelines, the Draft: Standard Operating Procedures (SOPs) for Residential Exposure Assessment, and the 9 There are several aggregate risk guidance documents that address both deterministic and probabilistic risk assessment approaches. The major science policy papers are available at www. EPA. Gov/ pesticides. The two key documents used for this assessment are 1) Updated Interim Guidance For Incorporating Drinking Water Exposure Into Aggregate Risk Assessments (Stasikowski, 8/ 1/ 99) and 2) HED RARC Format and Risk Characterization Guidance (12/ 22/ 00). 71 Overview of Issues Related to the Standard Operating Procedures for Residential Exposure Assessment presented at the September 1999 meeting of the FIFRA Scientific Advisory Panel (SAP). The Agency is, however, currently in the process of revising its guidance for completing these types of assessments. Modifications to this assessment shall be incorporated as updated guidance becomes available. This will potentially include expanding the scope of the residential exposure assessments by developing guidance for characterizing exposures from other sources already not addressed such as from spray drift; residential residue track­ in; exposures to farmworker children; and exposures to children in schools. 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION Based on the requirements of FQPA, aggregate risk assessments consider combined exposure from food, water and residential uses. Different types of aggregate assessments are required depending upon the use patterns for a chemical, the types of toxic effects associated with it, and the anticipated durations of exposure. A series of aggregate calculations have been completed for carbaryl. Section 5.1: Calculation of Aggregate Risks and DWLOCs describes how these values have been determined. Section 5.2: Acute Dietary Aggregate Risks and DWLOCs presents the results for the acute dietary only assessment. Section 5.3: Chronic Dietary Aggregate Risks and DWLOCs presents the results for the chronic dietary only assessment. Section 5.4: Shortterm Aggregate Risks and DWLOCs presents the results for the short­ term assessment which includes dietary intake and residential exposures. Section 5.5: Intermediate­ term Aggregate Risks and DWLOCs presents the results for the intermediate­ term assessment which includes dietary intake and residential exposures. Section 5.6: Aggregate Cancer Risks and DWLOCs presents the results for the cancer assessment that includes dietary intake and residential exposures. Section 5.7: Summary of Aggregate Risks provides an overview of the aggregate risk assessment results. 5.1 Calculation of Aggregate Risks and DWLOCs The Agency has developed several guidance documents describing the mathematical approaches used in calculating aggregate risks, the theoretical basis for these calculations, and the interpretation of the Food Quality Protection Act that requires the Agency to complete these kinds of calculations. 9 The underlying approach, regardless of the calculation type, is the same. The overall risks associated with a specific chemical are determined by its hazard database and its associated uncertainty factors or negligible risks if the concern is cancer. These two elements, combined, are used to define limits for the amount of overall exposures an individual can receive from the chemical. Once these limits have been defined, contributions from different sources of exposure are added together to see if the aggregate limit is exceeded. The approach used by the Agency for these calculations is to add together estimates for dietary food intake and residential exposure (not used for acute assessment which is food and water 72 only) then subtract this from the exposure limit to see what portion of the limit is still available, if any. If there is room still left under the limit (i. e., dietary and residential exposures combined do not exceed the exposure limit), then drinking water exposures are considered by calculating DWLOCs (Drinking Water Levels of Concern). If there is no room left under the limit then the Agency knows the overall exposure limit has been exceeded even without considering drinking water intake and no further calculations are completed. DWLOCs represent the concentration of carbaryl residues in drinking water that cannot be exceeded for aggregate exposures to exceed the overall exposure limit. If appropriate, DWLOCs are calculated by defining what part of the exposure limit has not been taken up from dietary and residential exposures which in turn defines the maximum amount of exposure one can have from drinking water. This can be a very simple calculation such as subtracting acute food exposures from the aPAD or chronic food intake and residential LADD estimates from the Q1* in a cancer calculation. In some cases it can be more complex such as for the short­ term assessment that required using the 1/ MOE approach described above in Section 4.4.2.1: Residential Handler Noncancer Risks where water and dietary MOEs are added to the equation and compared to the target MOE. The equation was then solved for the water MOE which was in turn used to calculate the maximum drinking water exposure using the short­ term oral NOAEL. Maximum allowable drinking water exposure levels were then used to calculate concentrations in water based on standard daily consumption estimates and body weight factors for different subpopulations. Adults were assumed to intake 2 liters of water per day while small children and infants were assumed to intake 1 liter of water per day. Standard body weights were also used (i. e., 10 kg for small children, 60 kg for adult females, and 70 kg for other adult scenarios). The equation used to calculate the DWLOCs is presented below: DWLOC( µg/ L) = [water exposure (mg/ kg bw/ day) x body weight (kg)] [water consumption (L) x 10 ­3 mg/ µg] [Note: Water exposure, body weight, and consumption inputs are specific to certain exposure durations, toxicity concerns, and populations so they will vary from assessment to assessment.] Once the DWLOCs have been calculated they were then compared to the Estimated Environmental Concentrations (EECs) which were defined by the Environmental Fate and Effects Division (Section 4.3.3: Modeling EECs, Table 10). Drinking water sources can include surface water or groundwater. EEC values were calculated for both. For surface water, computer modeling with the EPA PRZM3.12 and EXAMS 2.97.7 programs were used to estimate the concentration of carbaryl in surface water. Index reservoir scenarios corrected for Percent Cropped Area (PCA) for representative crops were used. The maximum calculated acute and chronic EECs (494 ppb and 28 ppb, respectively) resulted from use on citrus in Florida. In this case, the results for Florida provided the highest estimates; however, in Florida the majority of drinking water is derived from groundwater (> 90%) so high surface water concentrations do not necessarily indicate high exposure. As a result, both Florida and the results for Oregon apples have been considered in the aggregate assessment. The EECs for Oregon apples are the next highest values for both the acute and chronic estimates (144 and 9 ppb, respectively). Carbaryl chemical properties are outside the range of values for which SCI­ GROW was developed (i. e., aerobic metabolism is faster and its partition coefficient is larger which equates to 73 less leaching than the reference compounds ­ both factors indicate carbaryl degrades faster than the reference chemicals). SCI­ GROW estimates for groundwater EECs may not predict with complete accuracy, maximum levels because the concentrations calculated are 90 day averages. It is possible; therefore, that groundwater concentration peaks could not be identified. Groundwater levels are anticipated, however, to be more stable than surface water concentrations. If the EEC is less than the corresponding DWLOC then the Agency has no concerns for aggregate risks for the scenario. If EECs exceed the DWLOC then aggregate risks are of concern. For carbaryl, there were many residential scenarios where the combined MOEs (i. e., combinations of inhalation, dermal and nondietary ingestion as appropriate) exceed the Agency's risk targets making the calculation of DWLOCs and aggregate risks for those scenarios inappropriate because exposure limits have already been exceeded. Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment. However, the risk picture could substantively change if residential risks are refined based on updated use information from the carbaryl survey yet to be submitted to the Agency and the Agency chooses to regulate using the results of the CMBS. Keeping this in mind, the Agency completed DWLOC and aggregate risk calculations for illustrative purposes using a number of representative exposure scenarios where the residential and dietary risk estimates did not already exceed the Agency's level of concern. For example, an acute assessment with CMBS results included and short­ term assessments where residential handler risks weren't already of concern were completed. The Agency also specifically selected some scenarios because they represent major residential uses (e. g., garden dusts) or specialized low exposure scenarios (e. g., mosquito control). The Agency approach for calculating aggregate risks using different sources of data to create different exposure scenarios for illustrative purposes is consistent with Agency­ wide guidance for exposure assessment and risk characterization (e. g., PDP and carbamate market basket survey, various water scenarios, and selected residential scenarios). The Agency takes this approach to allow for more informed risk management decisions that consider as much available data as possible along with the uncertainties associated with those data. For example, it is appropriate to present results based on both PDP and the carbamate market basket survey. PDP data are routinely used in Agency risk assessments and the market basket study is of sufficient quality for incorporation in the risk assessment. However, there are uncertainties associated with the use of each data source (e. g., rubbing of fruit prior to extraction in the carbamate market basket survey which may decrease residue levels as described above in Section 4.2). 74 5.2 Acute Dietary Aggregate Risks and DWLOCs The results of the acute aggregate risk assessment are presented below in Table 17. These calculations are based on the use of the Carbamate Market Basket Survey (CMBS). Even with the use of the CMBS, aggregate risks when surface water is the source of drinking water, are still of concern for all infants, children (1 to 6 years old) and children (7 to 12 years old) regardless of whether or not Florida citrus or Oregon apple EECs are used (i. e., surface water is not a major drinking water source in Florida). If Florida citrus data are solely considered, aggregate risks are of concern for all subpopulations. Aggregate risks for all subpopulations are not of concern if groundwater is the source of drinking water. [Note: Most DWLOCs exceed the corresponding EECs for groundwater by an order of magnitude or greater. This should be considered along with the caution that it is possible that SciGrow might underestimate groundwater concentrations for carbaryl.] Table 17: Acute DWLOC Calculations Based on Use of Carbamate Market Basket Survey Results Population Subgroup aPAD (mg/ kg/ day) Acute Food Exp. 99.9th% tile (mg/ kg/ day) Max. Acute Water Exposure (mg/ kg/ day) Acute DWLOC (ug/ L or ppb) EECs Surface Water (all PRZM/ EXMS) Ground Water (SciGrow) (ppb) FL Citrus (ppb) OR Apples (ppb) All Commodities Using 1989 ­ 1992 CFSII Consumption Data General Population 0. 010000 0.004623 0.005377 188 494 144 0.8 All Infants 0. 010000 0.007272 0.002728 27 494 144 0.8 Children (1­ 6 yrs) 0.010000 0.007344 0.002656 27 494 144 0.8 Children (7­ 12 yrs) 0.010000 0.006238 0.003762 38 494 144 0.8 Females (13­ 50 yrs) 0.010000 0.003546 0.006454 194 494 144 0.8 Males (13­ 19 yrs) 0.010000 0.002723 0.007277 255 494 144 0.8 Males (20+ yrs) 0.010000 0.003423 0.006577 230 494 144 0.8 Seniors (55+ yrs) 0.010000 0.004810 0.005190 182 494 144 0.8 All Commodities Using 1994­ 1998 CFSII Consumption Data General Population 0. 010000 0.004865 0.005135 180 494 144 0.8 All Infants 0. 010000 0.008091 0.001909 19 494 144 0.8 Children (1­ 6 yrs) 0.010000 0.009481 0.000519 5 494 144 0.8 Children (7­ 12 yrs) 0.010000 0.004921 0.005079 51 494 144 0.8 Females (13­ 50 yrs) 0.010000 0.004224 0.005776 173 494 144 0.8 Males (13­ 19 yrs) 0.010000 0.004515 0.005485 192 494 144 0.8 Males (20+ yrs) 0.010000 0.003359 0.006641 232 494 144 0.8 Seniors (55+ yrs) 0.010000 0.004649 0.005351 187 494 144 0.8 Note: For characterization purposes, the surface water EECs for Florida citrus exceed exposure limits alone, without even considering food intakes, for all populations. Additionally, the surface water EECs for Oregon apples exceed exposure limits alone, without even considering food intakes, for infants and children. 5.3 Chronic Dietary Aggregate Risks and DWLOCs The results of the chronic aggregate risk assessment are presented below in Table 18. Chronic aggregate risks were not of concern for any subpopulation regardless of the source of drinking water, even considering the Florida surface water EECs. There is one chronic residential exposure scenario associated with the use of pet collars where the MOEs for children are of concern. As such, exposure from pet collars was not included in the chronic DWLOC calculations because of the risk concerns for this scenario and to illustrate chronic, aggregate risks for all others who are not exposed to collars. 75 Table 18: Chronic DWLOC Calculations Population Subgroup cPAD (mg/ kg/ day) Chronic Food Exposure (mg/ kg/ day) Max. Chronic Water Exposure (mg/ kg/ day) Chronic DWLOC (ug/ L or ppb) EECs Surface Water (all PRZM/ EXMS) Ground Water (SciGrow) (ppb) FL Citrus (ppb) OR Apples (ppb) All Commodities Using 1989 ­ 1992 CFSII Consumption Data General Population 0. 010000 0.000032 0.009968 349 28 9 0. 8 All Infants 0. 010000 0.000054 0.009946 100 28 9 0. 8 Children (1­ 6 yrs) 0.010000 0.000057 0.009943 99 28 9 0. 8 Children (7­ 12 yrs) 0.010000 0.000036 0.009964 100 28 9 0. 8 Females (13­ 50 yrs) 0.010000 0.000026 0.009974 299 28 9 0. 8 Males (13­ 19 yrs) 0.010000 0.000022 0.009978 349 28 9 0. 8 Males (20+ yrs) 0.010000 0.000031 0.009969 349 28 9 0. 8 Seniors (55+ yrs) 0.010000 0.000031 0.009969 349 28 9 0. 8 All Commodities Using 1994­ 1998 CFSII Consumption Data General Population 0. 010000 0.000035 0.009965 349 28 9 0. 8 All Infants 0. 010000 0.000059 0.009941 99 28 9 0. 8 Children (1­ 6 yrs) 0.010000 0.000074 0.009926 99 28 9 0. 8 Children (7­ 12 yrs) 0.010000 0.000034 0.009966 100 28 9 0. 8 Females (13­ 50 yrs) 0.010000 0.000028 0.009972 299 28 9 0. 8 Males (13­ 19 yrs) 0.010000 0.000026 0.009974 349 28 9 0. 8 Males (20+ yrs) 0.010000 0.000032 0.009968 349 28 9 0. 8 Seniors (55+ yrs) 0.010000 0.000030 0.009970 349 28 9 0. 8 5.4 Short­ term Aggregate Risks and DWLOCs The results of the short­ term aggregate risk assessment are presented below in Table 19. The exposure scenarios which were considered in this assessment represent a broad range of carbaryl uses. The only scenarios for toddlers that were included were for the mosquito control and oyster bed uses. The Agency has risk concerns for all other scenarios that were addressed for toddlers based on residential exposures alone including uses on turf and uses on pets (see Section 4.4.3.1: Residential Postapplication Exposure and Noncancer Risks). In the residential assessment, youth (ages 10 to 12) were also considered in home garden scenarios. The risk estimates for these children are similar to that for adults so aggregate risks were calculated only for adults with the stipulation that the results represent both populations (i. e., risks are actually slightly worse for adults). For adults, the following postapplication exposures were considered: after mosquito control (doing heavy yardwork/ lawncare); golfing; gardening (highest exposure activity ­ tree fruit harvest); and oyster harvesting. Adults doing heavy lawncare tasks after normal applications to turf were of concern for residential exposure alone so they were not considered in the aggregate assessment. Additionally, several aggregate assessments for homeowner handlers (most at average application rates) were completed based on application of dusts (gardens and pets): hose­ end sprayer; liquid spray spot lawn treatments; and broadcast application of granulars to lawns. The handler scenarios are numbered and these correspond to the residential risk assessment scenario numbers. Risks for these handler scenarios at higher application rates (e. g., label maximums) were of concern for residential exposure alone so they were not considered in the aggregate assessment. All calculations for adults were completed for both women and men. Results were similar for both populations. If surface water EECs based on Oregon apples or groundwater EECs from Sci­ Grow are considered, aggregate risks are not of concern for the selected scenarios. If EECs from Florida citrus are considered, aggregate risks are not of concern for the selected scenarios except for application of dusts 76 to gardens at the average rate keeping in mind that surface water is not a major drinking water source in Florida. [Note: Most DWLOCs exceed the corresponding EECs for groundwater by orders of magnitude. This should be considered along with the caution that it is possible that Sci­ Grow might underestimate groundwater concentrations for carbaryl.] Table 19: Short­ term Aggregate Risk and DWLOC Calculations Using 1989­ 1992 CFSII Consumption Data Population Subgroup Target Agg. MOE Food MOE Nondietary Ing. MOE Dermal MOE Inhal. MOE Aggregat e MOE Water MOE Allowable Water Exposure (mg/ kg/ day) DWLOC (ug/ L or ppb) EECs Surface Water (all PRZM/ EXMS) Ground Water (SciGrow ) (ppb) FL Citrus (ppb) OR Apples (ppb) Postapplication Children Children (1­ 6 yrs) Aerial Mosquito Day 0 100 17544 562 2211 NA 437 130 0.007710 116 28 9 0.8 Children (1­ 6 yrs) Oyster Bed Day 0 100 17544 51681 68909 NA 11006 101 0.009909 149 28 9 0.8 Postapplication Adult Males Adult Male Aerial Mosquito Day 0­ Lawncare 100 32258 NA 3700 NA 3319 103 0.009699 340 28 9 0.8 Adult Male Golfing Day 0­ Max Rate 100 32258 NA 624 NA 612 120 0.008366 293 28 9 0.8 Adult Male Garden Day 0­ High Expo. 100 32258 NA 579 NA 569 121 0.008242 289 28 9 0.8 Adult Male Oyster Bed Use Day 0, Swim 100 32258 301815 10856944 NA 29065 100 0.009966 349 28 9 0.8 Adult Male Consumer Product Handlers Adult Male Scen. #2 Garden Dust Avg Rate 100 32258 NA 120 1019 107 1580 0.000633 22 28 9 0.8 Adult Male Scen #3 Gard. Hose End, Avg Rate 100 32258 NA 158 134615 157 274 0.003648 128 28 9 0.8 Adult Male Scen #8 Lawn Spot­ Liquids 100 32258 NA 509 17500 487 126 0.007948 278 28 9 0.8 Adult Male Scen #9 Dusting Dog Avg Rate 100 32258 NA 163 1077 141 343 0.002913 102 28 9 0.8 Adult Male/ Scen # 12 Lawn Broadcast Granular 100 32258 NA 490 18315 470 127 0.007874 276 28 9 0.8 Postapplication Adult Females Adult Female Aerial Mosquito Day 0­ Lawncare 100 38462 NA 3700 NA 3375 103 0.009704 291 28 9 0.8 Adult Female Golfing Day 0­ Max Rate 100 38462 NA 624 NA 614 119 0.008371 251 28 9 0.8 Adult Female Garden Day 0­ High Expo. 100 38462 NA 579 NA 570 121 0.008247 247 28 9 0.8 Adult Female Oyster Bed Use Day 0, Swim 100 38462 301815 10856944 NA 34007 100 0.009971 299 28 9 0.8 Adult Female Consumer Product Handlers Adult Female Scen. #2 Garden Dust Avg Rate 100 38462 NA 120 1019 107 1568 0.000638 19 28 9 0.8 Adult Female Scen #3 Gard. Hose End, Avg Rate 100 38462 NA 158 134615 158 274 0.003653 110 28 9 0.8 Adult Female Scen #8 Lawn Spot­ Liquids 100 38462 NA 509 17500 488 126 0.007953 239 28 9 0.8 Adult Female Scen #9 Dusting Dog Avg Rate 100 38462 NA 163 1077 141 343 0.002918 88 28 9 0.8 Adult Female/ Scen # 12 Lawn Broadcast Granular 100 38462 NA 490 18315 472 127 0.007879 236 28 9 0.8 5.5 Intermediate­ term Aggregate Risks and DWLOCs Separate intermediate­ term aggregate risk and DWLOC calculations were not completed for carbaryl because the short­ term aggregate risk estimates essentially present the same results since the hazard inputs are numerically identical. The only major differences would be the postapplication results 77 where, instead of a single day exposure estimate, the exposures represent a 30 day average. The DWLOCs were not of concern for the short­ term exposure scenarios and they would not be expected to be of concern for the intermediate­ term scenarios since the exposures would be lowered because an average was used instead of a single day, higher exposure estimate. 5.6 Aggregate Cancer Risks and DWLOCs The results of the aggregate cancer risk assessment are presented below in Table 20. The exposure scenarios which were considered in this assessment represent a broad range of carbaryl uses. The same scenarios for adults were considered as in the short­ term assessment described above in Section 5.4: Short­ term Aggregate Risks and DWLOCs. Aggregate cancer risks were not of concern for any subpopulation regardless of the source of drinking water, even considering the Florida surface water EECs. Table 20: Aggregate Cancer Risk and DWLOC Calculations Using 1989­ 1992 CFSII Consumption Data Population Subgroup Q1* (mg/ kg/ day) 1 Negligible Risk Level Target Maximum Exposure (mg/ kg/ day) Chronic Food Exposure (mg/ kg/ day) Residential Exposure LADD (mg/ kg/ day) Aggregate Cancer Risk (Food & Residential) Maximum Water Exposure (mg/ kg/ day) DWLOC (ug/ L or ppb) EECs Surface Water (all PRZM/ EXMS) Ground Water (SciGrow) (ppb) FL Citrus (ppb) OR Apples (ppb) Postapplication Adult Males Adult Male/ Aerial Mosquito Day 0­ Lawncare 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00000067 2.77E­ 008 0.001111 39 28 9 0.8 Adult Male/ Golfing Day 0­ Max Rate 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00000400 3.06E­ 008 0.001108 39 28 9 0.8 Adult Male/ Garden Day 0­ High Expo. 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00000857 3.46E­ 008 0.001103 39 28 9 0.8 Adult Male/ Oyster Bed Use Day 0, Swim 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00000001 2.71E­ 008 0.001112 39 28 9 0.8 Adult Male Consumer Product Handlers Adult Male/# 2 Garden Dust Avg Rate 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00004343 6.51E­ 008 0.001068 37 28 9 0.8 Adult Male/# 3 Garden Hose End, Avg Rate 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00003143 5.46E­ 008 0.001080 38 28 9 0.8 Adult Male/# 8 Lawn Spot Liquids 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00000987 3.58E­ 008 0.001102 39 28 9 0.8 Adult Male/# 9 Dusting Dog Avg Rate 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00003223 5.53E­ 008 0.001080 38 28 9 0.8 Adult Male/# 12 Lawn Broadcast Granular 8.75x10 ­4 1.0x10 ­­ 6 0.001143 0.000031 0.00001025 3.61E­ 008 0.001102 39 28 9 0.8 Postapplication Adult Females Adult Female/ Aerial Mosquito Day 0­ Lawncare 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00000067 2.33E­ 008 0.001116 34 28 9 0.8 Adult Female/ Golfing Day 0­ Max Rate 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00000400 2.63E­ 008 0.001113 33 28 9 0.8 Adult Female/ Garden Day 0­ High Expo. 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00000857 3.03E­ 008 0.001108 33 28 9 0.8 Adult Female/ Oyster Bed Use Day 0, Swim 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00000001 2.28E­ 008 0.001117 34 28 9 0.8 Adult Female Consumer Product Handlers Adult Female/# 2 Garden Dust Avg Rate 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00004343 6.08E­ 008 0.001073 32 28 9 0.8 Adult Female/# 3 Garden Hose End, Avg Rate 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00003143 5.03E­ 008 0.001085 33 28 9 0.8 Adult Female/# 8 Lawn Spot Liquids 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00000987 3.14E­ 008 0.001107 33 28 9 0.8 Adult Female/# 9 Dusting Dog 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00003223 5.10E­ 008 0.001085 33 28 9 0.8 Adult Female/# 12 Lawn Broadcast Granular 8.75x10 ­4 1.0x10 ­­ 6 0.001143 2.6E­ 005 0.00001025 3.17E­ 008 0.001107 33 28 9 0.8 78 5.7 Summary of Aggregate Risks In many residential scenarios, MOEs exceed the Agency's risk targets making the calculation of DWLOCs and aggregate risks for those scenarios inappropriate because exposure limits have already been exceeded. Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment. However, the risk picture could substantively change if residential risks are refined based on updated use information from the carbaryl use survey yet to be submitted to the Agency and the Agency regulates using the results of the CMBS. The Agency approach for calculating aggregate risks using different sources of data to create different exposure scenarios for illustrative purposes is consistent with Agency­ wide guidance for exposure assessment and risk characterization (e. g., PDP and carbamate market basket survey, various water scenarios, and selected residential scenarios). The Agency takes this approach to allow for more informed risk management decisions that consider as much available data as possible along with the uncertainties associated with those data. For example, it is appropriate to present results based on both PDP and the carbamate market basket survey. PDP data are routinely used in Agency risk assessments and the market basket study is of sufficient quality for incorporation in the risk assessment. However, there are uncertainties associated with the use of each data source (e. g., rubbing of fruit prior to extraction in the carbamate market basket survey). Keeping this in mind, the Agency completed DWLOC and aggregate risk calculations for illustrative purposes using a number of representative exposure scenarios where the residential and dietary risk estimates did not already exceed the Agency's level of concern. For example, an acute assessment with CMBS results included and short­ term assessments where residential handler risks weren't already of concern were completed. The highest EECs for surface water were from Florida citrus but most drinking water in Florida is from groundwater. Therefore, results from surface water in Florida and the next highest values (Oregon apples) were considered in the assessment. The acute aggregate assessment indicates that even with the use of the Carbamate Market Basket Survey (CMBS), aggregate risks when surface water is the source of drinking water, are still of concern for all infants, children (1 to 6 years old) and children (7 to 12 years old) regardless of whether or not Florida citrus or Oregon apple EECs are used (i. e., surface water is not a major drinking water source in Florida). If Florida citrus results are solely considered, aggregate risks are of concern for all subpopulations. Surface water EECs for Florida citrus exceed exposure limits, without even considering food intakes, for all populations. The surface water EECs for Oregon apples exceed exposure limits alone, without even considering food intakes, for infants and children. Acute aggregate risks for all subpopulations are not of concern if groundwater is the source of drinking water. Chronic aggregate risks were not of concern for any subpopulation regardless of the source of drinking water, even considering the Florida surface water EECs. In the short­ term assessment, the Agency selected representative scenarios where residential risks alone were not of concern including mosquito control, oyster harvesting, golfing, garden harvest, and several handler scenarios (all at average rates, max rate scenarios were of concern for residential exposures alone). If surface water EECs based on Oregon apples or groundwater EECs from SciGrow are considered, aggregate risks are not of concern for the selected scenarios. If EECs from Florida citrus are considered, aggregate risks are not of concern for the selected scenarios except for application of dusts to gardens. Separate intermediate­ term aggregate risk and DWLOC calculations were not completed for carbaryl because the short­ term aggregate risk estimates essentially presented the same results since the hazard inputs were numerically identical. The only major differences would be the postapplication results where, instead of a single day exposure 79 estimate, the exposures represented a 30 day average. Aggregate cancer risks were not of concern for any subpopulation regardless of the source of drinking water, even considering the Florida surface water EECs. 6.0 CUMULATIVE RISK The Food Quality Protection Act (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non­ occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low­ level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. Carbaryl is a member of the carbamate class of pesticides. This class also includes the aldicarb, methomyl and oxamyl among others. HED did not perform a cumulative risk assessment as part of this reregistration review for carbaryl because HED has not yet initiated a review to determine if there are any other chemical substances that have a mechanism of toxicity common with that of carbaryl. For purposes of this reregistration decision, EPA has assumed that carbaryl does not have a common mechanism of toxicity with other substances. The registrant must submit, upon EPA's request and according to a schedule determined by the Agency, such information as the Agency directs to be submitted in order to evaluate issues related to whether carbaryl shares a common mechanism of toxicity with any other substance and, if so, whether any tolerances for carbaryl need to be modified or revoked. If HED identifies other substances that share a common mechanism of toxicity with carbaryl, HED will perform aggregate exposure assessments on each chemical, and will begin to conduct a cumulative risk assessment once the final guidance HED will use for conducting cumulative risk assessments is available. HED has recently developed a framework that it proposes to use for conducting cumulative risk assessments on substances that have a common mechanism of toxicity. This guidance reflects recent revisions based on review and comment from earlier guidance issued on June 30, 2000 (65 FR 40644­ 40650) that is available from the OPP Website at: http:// www. epa. gov/ fedrgstr/ EPAPEST 2000/ June/ Day­ 30/ 6049. pdf. The recently revised guidance is entitled Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have A Common Mechanism Of Toxicity (January 14, 2002). In the guidance, it is stated that a cumulative risk assessment of substances that cause a common toxic effect by a common mechanism will not be conducted until an aggregate exposure assessment of each substance has been completed. Before undertaking a cumulative risk assessment, HED will follow procedures for identifying chemicals that have a common mechanism of toxicity as set forth in the "Guidance for Identifying Pesticide Chemicals and Other Substances that Have a Common Mechanism of Toxicity" (64 FR 5795­ 5796, February 5, 1999). HED will also address issues described in the document entitled 80 Consideration of the FQPA Safety Factor and Other Uncertainty Factors In Cumulative Risk Assessment of Chemicals Sharing a Common Mechanism of Toxicity (Draft: February 28, 2002). 7.0 OCCUPATIONAL RISK ASSESSMENT This section of the risk assessment addresses exposures to individuals who are exposed as part of their employment. These exposures can occur because people have contact with carbaryl residues while using commercial products containing carbaryl (i. e., handlers) or by being in areas that have been previously treated (postapplication workers). A thorough understanding of how carbaryl is used is critical to the development of a quality risk assessment. Because this information is also critical to the dietary and residential exposure assessments presented above, available use information has already been summarized. Please refer to Section 4.1: Summary of Registered Uses for information on how carbaryl is used. All calculations for occupationally exposed people are based on this information. Also, for more detailed information pertaining to the occupational risk calculations, please refer to the Occupational and Residential Exposure Assessment (D281418) prepared by Jeff Dawson. The document D281418 contains detailed descriptions of the data used, methods, and risks calculated for each scenario. Section 7.1: Occupational Handler Risk Assessment describes the data, methods, and risk results (both cancer and noncancer) associated with the use of commercial products which contain carbaryl. Section 7.2: Occupational Postapplication Risk Assessment describes the data, methods, and risk results associated with exposures to workers as they complete activities required for the production and maintenance of crops or other areas such as turf that might require the use of carbaryl. Section 7.3: Occupational Risk Characterization provides information pertaining to the quality of the assessment including data used, uncertainties with the methods, and any other information that might be used to describe the quality of the results. Section 7.4: Human and Domestic Animal Incident Data Review describes the analysis conducted by Agency epidemiologists. 7.1 Occupational Handler Risk Assessment The Agency completes occupational handler risk assessments using scenarios as the basis for the calculations as described in the U. S. EPA Guidelines For Exposure Assessment. For commercial pesticide products, the Agency categorizes handler exposures based on the kinds of formulations (e. g., liquids or various solids), the kinds of equipment used to make applications (e. g., groundboom, aerial, or airblast), the nature of the task (e. g., mixing/ loading, applying, or both combined), and the level of personal protection used. Identifying the duration of exposure is also a critical element in the development of a risk assessment to ensure that the proper hazard component is used. For carbaryl uses, the Agency identified 28 major occupational exposure scenarios based on the types of equipment and techniques that potentially can be used for carbaryl applications. Most of the scenarios were classified as having short­ term and intermediate­ term exposures (up to 30 days and 30 days to several months, respectively). A few other scenarios have also been addressed that are thought to have long­ term or chronic exposures (several months to every working day) associated with them in the greenhouse and floriculture industry. The quantitative exposure/ risk assessment developed for occupational handlers was based on the following scenarios. [Note: The numbers correspond to the tracking system included in D281418.] 81 Mixing/ Loading (1a) Dry Flowable for Aerial/ Chemigation in Agriculture; (1b) Dry Flowable for Airblast; (1c) Dry Flowable for Groundboom; (1d) Dry Flowable for High Pressure Handwand and Right of Way Sprayers; (1e) Dry Flowable for LCO Applications; (1f) Dry Flowable for Aerial Wide Area Uses; (2a) Granular for Aerial; (2b) Granular for Broadcast Spreader; (3a) Liquids for Aerial/ Chemigation; (3b) Liquids for Airblast; (3c) Liquids for Groundboom; (3d) Liquids for High Pressure Handwand and Right of Way Sprayers; (3e) Liquids for LCO Applications; (3f) Liquids for Aerial Wide Area Uses; (3g) Liquids for Ground Wide Area Uses; (4a) Wettable Powder for Aerial/ Chemigation; (4b) Wettable Powder for Airblast; (4c) Wettable Powder for Groundboom; (4d) Wettable Powder for High Pressure Handwand and Right of Way Sprayers; (4e) Wettable Powder for LCO Applications; (4f) Wettable Powder for Aerial Wide Area Uses; Applicator: (5a) Aerial/ Liquid Application; (5b) Aerial/ Liquid Wide Area Application; (5c) Aerial/ Granular Application; (6a) Airblast Application; (6b) Wide Area Ground Fogger (Airblast as surrogate); (7) Groundboom Application; (8) Solid Broadcast Spreader Application; (9) Aerosol Can Application; (10) Trigger Sprayer (RTU) Application; (11) Right­ of­ Way Sprayer Application; (12) High Pressure Handwand Application; (13) Veterinary Technician/ Animal Groomer Liquid Application; (14) Veterinary Technician/ Animal Groomer Dust Application; (15) Granulars/ Bait and Pellets Dispersed by Hand; (16) Granulars/ Bait and Pellets Dispersed with Spoon; 82 Mixer/ Loader/ Applicator: (17) Low Pressure/ High Volume Turfgun Application; (18a) Wettable powder, Low pressure handwand; (18b) Liquid: Low Pressure Handwand; (19) Backpack; (20) Granular Belly Grinder; (21) Push­ type Granular Spreader; (22) Handheld Fogger; (23) Powered Backpack; (24) Granular Backpack; (25) Tree Injection; (26) Drenching/ Dipping Seedlings For Propagation; (27) Sprinkler Can; Flaggers: (28a) Flagging For Liquid Sprays; and (28b) Flagging For Granular Applications. For each of these scenarios, risk calculations were completed based on eight levels of personal protection that were defined based on different combinations of the following: 1) baseline protection (typical work clothing or a long­ sleeved shirt and long pants, no respiratory protection and no chemical­ resistant gloves); 2) minimum personal protective equipment (baseline scenario with the use of chemical­ resistant gloves and a dust/ mist respirator with a protection factor of 5); 3) maximum personal protective equipment (baseline scenario with the use of an additional layer of clothing (e. g., a pair of coveralls), chemical­ resistant gloves, and an air purifying respirator with a protection factor of 10); 4) engineering controls (use of an appropriate engineering control such as a closed tractor cab or closed loading system for granulars or liquids). Current labels mostly require single layer clothing, chemical­ resistant gloves, and no respirator. Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments, as described below. The assumptions and factors used in the risk calculations are consistent with current Agency policy for completing occupational exposure assessments (e. g., PHED Surrogate Exposure Guide and Exposac Policy 9: Standard Values For Daily Acres Treated In Agriculture). [Note: PHED is a database that contains monitored field data used for assessments. See Section 4.4.2 Residential Handler Risk Assessment above for further information.] 83 ° Average body weight of an adult handler is 70 kg as described in the residential handler assessments (see Section 4.4.2). ° Several generic protection factors were used to calculate handler exposures. The protection factors used for clothing layers (i. e., 50%) and gloves (90%) have not been completely evaluated by the Agency. Additionally, protection factor was used to estimate exposures that involve engineering controls if required (98%). The values used for respiratory protection (i. e., PF 5 or PF 10) are based on the NIOSH Respirator Decision Logic. ° For cancer risk calculations, a value of 30 application events per year for all commercial applicator scenarios and 10 days per year to account for private growers was used. These values are supported by the data included in the University of California studies of seasonal labor in California and the recent Department of Labor National Agricultural Worker Survey (NAWS). The exposure duration values used by HED in the cancer risk assessment are consistent with those used for other chemicals (i. e., 35 working years and 70 year lifetime). ° In many scenarios, it is likely that a grower would mix, load, and apply chemicals all in one day because of limited labor, efficiency, or many other reasons. In most cases, mixing/ loading and application are considered separate job functions because of the available data and also it allows for more flexibility in the risk management phase (e. g., assigning requirements for specific types of protective equipment). ° Flagging during aerial applications has been addressed even though it may be limited in nature (10 to 15% of aerial application operations). Engineering controls (e. g., Global Positioning Satellite technology) are now predominantly used by pilots as indicated by the 1998 National Agricultural Aviation Association (NAAA) survey of their membership. ° The maximum application rates allowed by labels were used in the risk assessments. If additional information, such as average or typical rates, were available, these values were used as well in order to allow risk managers to make a more informed risk management decision. Average application rates were available from the SMART meeting and BEAD's QUA. ° The average occupational workday is assumed to be 8 hours. The daily areas to be treated were defined for each handler scenario (in appropriate units) by determining the amount that can be reasonably treated in a single day (e. g. acres, animals). The factors used for the carbaryl assessment are the same as those detailed in the HED Science Advisory Committee on Exposure Policy 9: Standard Values for Daily Acres Treated in Agriculture. The daily volumes handled and acres treated, excerpted from the policy, in each occupational scenario include: 10 The veterinary and fireant treatments are not included in the policy but represent values that have been used by HED in previous assessments. 84 ° Aerial applications: 1200 acres for large field crops and forest treatments, 350 acres for other field crops, and 7500 acres for mosquito control adulticide applications; ° Groundboom: 200 acres for large field crops (e. g., wheat and corn), 80 acres treated for other field crop groundboom applications, and 40 acres on golf course turf; ° Airblast: 40 acres treated for agricultural applications; ° 8 pet animals treated per day for veterinary and professional groomer uses 10 ; ° 1000 gallons of spray solution prepared when mixing/ loading liquids for high pressure handwand application or making the application; ° 40 gallons when mixing/ loading/ applying liquids with a backpack sprayer or a low pressure handwand sprayer; ° 10 mounds per day treated for fire ant applications. 10 ° For direct pet animal treatments, the Residential SOPs, were used to define the amount of chemical that can be used to treat a single animal, which in turn was used to calculate total human dose levels. The actual per animal application rates used were ½ of a 6 oz bottle for liquid shampoos (0.5%) and ½ of 4 lb container for animal powders (10%). ° Ultra low volume applications for uses, such as adulticide mosquito control, were considered using a large acreage estimate to aerial applicators. The mosquito adulticide uses were evaluated in the same manner as other chemicals used for that purpose (e. g., the same acreage estimates were used as for other chemicals like fenthion and naled). ° There were several scenarios which were identified for which no appropriate exposure data are known to exist. These include: animal grooming dust application; dust applications in agriculture; handheld fogging for mosquito and other pest treatments; power backpack application; tree injection; and drenching/ dipping seedlings (the mixing/ loading component only of this scenario has been addressed quantitatively). The unit exposure values (mg ai exposure/ lb ai handled) used in this assessment were predominantly based on PHED and summarized in the surrogate exposure guidance. In addition to PHED, five studies were used by the Agency. One used carbaryl to quantify exposures for professional dog groomers. Two were completed by Aventis Crop Science using other chemicals that quantified exposures to granular products using a backpack application device. One was submitted by Bayer (now in the process of acquiring Aventis Crop Science and with a signed PHED data waiver) that quantified exposures using a ready­ to­ use trigger sprayer. Lastly, an ORETF (Outdoor Residential Exposure Task Force, of which Aventis Crop Science is a member) study that quantified exposures of professional 11 Non­ ORETF data included in MRIDs 451672­ 01 and 452507­ 01 were from studies submitted by Aventis Crop Science. The propoxur trigger sprayer study has a signed PHED data waiver but has not been included into PHED. It also is the property of Bayer Crop Science which has recently acquired Aventis Crop Science. Some of the handler exposure data used in this assessment are from the ORETF, of which Aventis Crop Science, is a member. 85 lawncare operators using granular and liquid products. There are no data compensation issues with any of these data. 11 In all cases, what appears to be the best available data have been used to complete the calculations. 7.1.1 Occupational Handler Non­ Cancer Risks Noncancer risks were calculated using the MOE approach, as described under 4.4.2.1. The major differences are that personal protective devices are used and longer duration exposures (i. e., intermediate­ term and chronic) have been considered as appropriate. Risk estimates for short­ and intermediate­ term exposures are similar because all numerical inputs for both durations and the target MOEs were identical. A NOAEL from the 21­ day dermal toxicity study in rats using technical grade carbaryl was used to calculate results for both durations (i. e., 20 mg/ kg/ day). A NOAEL from the developmental neurotoxicity study in rats, that also observed at the same level in a subchronic neurotoxicity study in rats (i. e., 1 mg/ kg/ day), was used to calculate inhalation risks. The target MOE was 100 for all assessments. In the chronic assessments, a LOAEL (3.1. mg/ kg/ day) has been used from a 1 year dog feeding study for both dermal and inhalation exposures (with a dermal absorption factor of 12.7 percent applied). The target MOE for the chronic assessments is 300 because a LOAEL was used instead of a NOAEL. Short­/ Intermediate­ term Risks: In most scenarios, MOEs meet or exceed the required uncertainty factor of 100 at some level of personal protection. For the most part, current label requirements for personal protection (single layer clothing, gloves, and no respirator) appear to be generally inadequate for most scenarios except for operations where exposures are low and the amount of chemical used is also low. Table 21 summarizes the results for short­ term and intermediate­ term occupational handlers. [Note: Scenarios where MOEs are still of concern (i. e., <100) for any personal protection considered are highlighted and just the minimum required personal protective equipment (PPE) is highlighted if it exceeds current label requirements but target MOEs can be achieved at higher than label requirements for mitigation.] Table 21: Summary of Short­/ Intermediate­ Term Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE Mixer/ Loaders 1a Dry Flowable: Aerial/ Chemigation 1­ 2 (wheat/ corn) 2­ 5 (veg., stone fruit, 24C on oysters) 1200 350 363­ 726 498­ 1244 EC EC 1b Dry Flowable: Airblast 7.5­ 16 (various fruit & nut trees) 5 (nuts) 1.1­ 3 (pome & stone fruit, grapes) 40 40 40 1360­ 2902 101 143­ 391 EC SL/ GL/ PF5 Baseline Table 21: Summary of Short­/ Intermediate­ Term Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE 86 1c Dry Flowable: Groundboom 1.5­ 2 (wheat/ corn) 2 (strawberry/ veg) 8 (turf/ golf courses) 4 (turf/ golf courses) 200 80 40 40 2177­ 2902 107 2721 108 EC Baseline EC Baseline 1d Dry Flowable: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 430 Baseline 1e Dry Flowable: Low press./ High Vol. Turfgun 4 ­8 (LCO on turf) 5 430­ 860 Baseline 1f Dry Flowable: Wide area aerial 2 (rangeland/ forestry) 7500 58 MOE < 100 2a Granular: Aerial Application 2 (corn) 2 (corn) 1200 350 688 146 EC SL/ GL/ PF5 2b Granular: Solid broadcast spreader 1.5 (wheat/ corn) 2 (wheat/ corn) 2 (vegetables) 6 (turf/ golf courses) 9 (turf/ golf courses) 200 200 80 40 40 110 256 206 138 284 Baseline SL/ GL/ PF5 Baseline Baseline SL/ GL/ PF5 3a Liquid: Aerial/ Chemigation 1.5­ 2 (wheat, max corn) 1 (avg. corn) 5 (stone fruit) 2 (vegetables) 1200 1200 350 350 57­ 76 114 78 103 All MOEs < 100 EC MOE< 100 DL/ GL/ PF10 3b Liquid: Airblast Application 16 (Citrus­ 24C in California) 7.5 (Citrus) 5 (Nuts) 1.1­ 3 (Grapes, pome & stone fruit) 40 40 40 40 100 168 149 248­ 677 DL/ GL/ PF10 SL/ GL/ PF5 SL/ GL/ NR SL/ GL/ NR 3c Liquid: Groundboom 1.5 (wheat) 2 (corn) 2 (strawberries) 8 (turf/ golf courses) 4 (turf/ golf courses) 200 200 80 40 40 168 126 186 157 186 SL/ GL/ PF5 SL/ GL/ PF5 SL/ GL/ NR SL/ GL/ PF5 SL/ GL/ NR 3d Liquid: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 745 SL/ GL/ NR 3e Liquid: Low press./ High Vol. Turfgun 4 ­8 (LCO on turf) 5 745­ 1489 SL/ GL/ NR 3f Liquid: Wide area aerial 2 (Range/ Forestry) 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 7500 7500 7500 7500 9 248 121 18 MOE < 100 SL/ GL/ NR EC MOE < 100 3g Liquid: Wide area ground 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 3000 3000 3000 621 112 45 SL/ GL/ NR SL/ GL/ PF5 MOE < 100 4a Wettable Powders: Aerial 1­ 2 (Wheat/ corn) 5 (stone fruit) 2 (vegetables) 1200 350 350 40­ 80 55 137 All MOEs < 100 MOE < 100 EC 4b Wettable Powders: Airblast 16 (Citrus­ 24C in California) 1.1­ 7.5 (Citrus, nuts, grapes, pome & stone fruit) 40 40 150 320­ 2180 EC EC Table 21: Summary of Short­/ Intermediate­ Term Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE 87 4c Wettable Powders: Groundboom 1.5­ 2 (wheat/ corn) 2 (strawberries) 4­ 8 (turf/ golf courses) 200 80 40 240­ 320 599 299­ 599 EC EC EC 4d Wettable Powders: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 102 SL/ GL/ PF5 4e Wettable Powders: Low press./ High Vol. Turfgun 4 (LCO on turf) 8 (LCO on turf) 5 5 102 205 SL/ GL/ PF5 SL/ GL/ PF5 4f Wettable Powders: Wide area aerial 2 (Range/ Forestry) 7500 6 MOE< 100 Applicators 5a Aerial: Agricultural uses, liquid sprays 1­ 1.5 (wheat/ avg. corn) 2 (max corn) 5 (stone fruit) 2 (vegetables, 24C on oysters) 1200 1200 350 350 113­ 170 85 116 292 EC MOE< 100 EC EC 5b Aerial: Wide area uses, liquid sprays 2 (Range/ Forestry) 0.016­ 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 7500 7500 7500 14 181­ 1700 27 MOE< 100 EC MOE< 100 5c Aerial: Agricultural uses, granular applications 2 (corn) 2 (corn) 1200 350 21 72 MOE< 100 MOE< 100 6a Airblast: Agricultural uses 16 (Citrus 24C in California) 2­ 7.5 (Citrus, nuts, grapes, pome & max. stone fruit) 1.1 (avg. stone fruit) 40 40 40 105 224­ 841 123 EC EC SL/ GL/ PF5 6b Airblast: Wide area uses, liquid sprays 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 3000 3000 3000 113 150 22 SL/ GL/ PF5 EC MOE< 100 7 Groundboom 1.5­ 2 (Wheat, corn) 2 (Strawberries) 4­ 8 (Turf/ golf course) 200 80 40 122­ 162 304 152­ 304 Baseline Baseline Baseline 8 Solid broadcast spreader (granular) 1. 5­ 2 (Wheat, corn) 2 (Strawberries) 4­ 8 (Turf/ golf course) 200 80 40 103­ 138 258 115­ 172 Baseline Baseline Baseline 9 Aerosol Can 0. 01 lb ai/ can 2 cans 324 Baseline 10 Trigger pump sprayer 0. 01 lb ai/ can 1 can 8772 SL/ GL/ NR 11 Right of way sprayer 1. 5 lb ai/ 100 gallons 1000 gallons 199 SL/ GL/ NR 12 High pressure handwand 4 lb ai/ 100 gallons 1000 gallons 66 MOE< 100 13 Animal groomer, liquid application 0. 01 lb ai/ dog 8 dogs 9.7 MOE< 100 14 Animal groomer, dust application 0.2 lb ai/ dog 8 dogs 8750 Baseline (dermal exp only) 15 Granulars & baits applied by hand 9 (Ornamentals & gardens) 1 3.8 MOE< 100 16 Granulars & baits applied by spoon 9 (Ornamentals & garderns) 1 75.1 MOE< 100 Table 21: Summary of Short­/ Intermediate­ Term Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE 88 Mixerr/ Loader/ Applicators 17 Low pressure, high volume turfgun (ORETF Data) 8 (LCO Use on turf) 4 (LCO Use on turf) 5 5 94 104 MOE< 100 SL/ GL/ PF5 18a Wettable powder, low pressure handwand 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 8.3 135 MOE< 100 SL/ GL/ PF5 18b Liquids, low pressure handwand 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 127 1699 SL/ GL/ PF5 SL/ GL/ NR 19 Backpack sprayer 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 42 565 MOE< 100 Baseline 20 Granular, bellygrinder 9 (Turf) 1 27 MOE< 100 21 Granular, push­ type spreader 9 (Turf) 5 124 SL/ GL/ PF5 22 Handheld fogger No data No data No data No data 23 Power backpack No data No data No data No data 24 Granular, backpack 9 (Ornamentals) 1 1562 DL/ GL/ NR 25 Tree injection No data No data No data No data 26 Drench/ dipping forestry/ ornamentals 1.5 lb ai/ 100 gallons (Ornamental/ seedling dip) 100 gallons 199 SL/ GL/ NR 27 Sprinkler can 2% solution (Ornamentals) 10 gallons 226 Baseline Flaggers 28a Flagger: liquid sprays 2 (Corn) 2 (Vegetables) 1200 350 249 111 EC Baseline 28b Flagger: granular applications 2 (Corn) 2 (Vegetables) 1200 350 101 345 Baseline Baseline Baseline = Long pants, long­ sleeved shirts, no gloves SL = Single layer clothing with or without gloves (GL or NG) DL = Double layer clothing (i. e., coveralls over SL) with or without gloves (GL or NG) EC = Engineering controls NR = No respirator PF5 = Protection factor 5 respirator PF10 = Protection factor 10 respirator Current label = SL/ GL/ NR Min. Req. PPE = level of PPE where MOEs > 100, where current label is exceeded or no adequate PPE is found, results are bold. MOEs which never exceed 100 are for highest feasible type of mitigation (e. g., engineering control in most cases). 89 Chronic Risks: MOEs were calculated for only a limited number of exposure ornamental use scenarios where the Agency believes that this kind of exposure pattern may exist. These calculations were also completed at different levels of personal protection as illustrated in Table 22. For most scenarios (3 of 5), MOEs meet or exceed the required uncertainty factor of 300 at some level of personal protection. The granular hand application scenarios are problematic. The uncertainty factor of 300 is required for the chronic exposure scenarios because a LOAEL and not a NOAEL was used for risk assessment. Table 22: Summary of Chronic Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE Applicators 15 Granulars & baits applied by hand 9 (Ornamentals & gardens) 1 4.7 MOE< 300 16 Granulars & baits applied by spoon 9 (Ornamentals & garderns) 1 92.6 MOE< 300 Mixer/ Loader/ Applicators 18a Wettable powder, low pressure handwand 2% solution (ornamentals) 40 gallons 302 DL/ GL/ PF10 18b Liquids, low pressure handwand 2% solution (ornamentals) 40 gallons 3206 SL/ GL/ NR 19 Backpack sprayer 2% solution (ornamentals) 40 gallons 781 Baseline Baseline = Long pants, long­ sleeved shirts, no gloves SL = Single layer clothing with or without gloves (GL or NG) DL = Double layer clothing (i. e., coveralls over SL) with or without gloves (GL or NG) EC = Engineering controls NR = No respirator PF5 = Protection factor 5 respirator PF10 = Protection factor 10 respirator Current label = SL/ GL/ NR Min. Req. PPE = level of PPE where MOEs > 300, where current label is exceeded or no adequate PPE is found, results are bold. MOEs which never exceed 300 are for highest feasible type of mitigation (e. g., PPE in most cases). 7.1.2 Occupational Handler Cancer Risks Cancer risks were calculated by multiplying the LADD to the Q1* (8.75 x 10 ­4 (mg/ kg/ day) ­1 ), as described in 4.4.2.2. HED considered two distinct populations in the cancer risk assessment ­ private growers at 10 use events per year and commercial applicators with a use pattern of 30 days per year. The Agency has defined a range of acceptable cancer risks based on a policy memorandum dated August 14, 1996, by Office of Pesticide Programs Director Dan Barolo. This memo refers to a predetermined quantified "level of concern" for occupational carcinogenic risk. Risks that are 1 x 10 ­6 or lower require no risk management action. For those chemicals subject to reregistration, the Agency is to carefully examine uses with estimated risks in the 10 ­6 to 10 ­4 range to seek ways of cost­ effectively reducing risks. If carcinogenic risks are in this range for occupational handlers, increased levels of 90 personal protection are warranted as is commonly applied with noncancer risk estimates (e. g., additional PPE or engineering controls). Carcinogenic risks that remain above 1 x 10 ­4 at the highest level of mitigation appropriate for that scenario remain a concern. Cancer risks for private growers (i. e., 10 applications per year) were calculated for different exposure scenarios at different levels of personal protection. All scenarios for private growers have risks that are <1x10 ­4 at some level of personal protection specified in the Barolo memo. In fact, for all but one scenario (Scen 4f: Mixing/ loading Wettable Powders for wide area aerial applications) cancer risks are <1x10 ­4 at current label requirements for personal protection. If a 1x10 ­6 risk level is specified as a concern, results are similar in that risks for a majority of scenarios are <1x10 ­6 at current label requirements. In fact, only 8 of the 128 scenarios considered for private growers have cancer risks >1x10 ­6 (and less than 1x10 ­4 ) even when the most protective ensembles of either protective clothing or engineering controls are considered. As with the risks calculated for private growers, cancer risks for commercial applicators (i. e., 30 applications per year) were calculated for different exposure scenarios at different levels of personal protection. Again, risks for all but one scenario (Scen 4f: Mixing/ loading Wettable Powders for wide area aerial applications) are less than the 1x10 ­4 level specified in the Barolo memo at current label requirements for personal protection (i. e., risks for this scenario are < 1x10 ­4 if additional protective clothing or equipment is used). If a 1x10 ­6 risk level is specified as a concern for commercial applicators, results indicate that risks for about half of the scenarios considered are <1x10 ­6 at current label requirements and that only 21 of the 128 scenarios considered have cancer risks >1x10 ­6 (and less than 1x10 ­4 ) even when the most protective ensembles of either protective clothing or engineering controls are considered. In general, the cancer risk estimates would lead to less restrictive measures when compared to the noncancer results. Table 23 below provides a summary of the cancer risks that have been calculated for private growers and commercial applicators. Table 23: Summary of Occupational Handler Cancer Risks For Private Growers and Commercial Applicators Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary Private Growers Commercial Applicators Risk Min. Req. PPE Risk Min. Req. PPE Mixer/ Loaders 1a Dry Flowable: Aerial/ Chemigation 1­ 2 (wheat/ corn) 5 (stone fruit) 2 (vegetables, 24C on oysters) 1200 350 350 3.7 to 7.4x10 ­8 5.4x10 ­8 1.0x10 ­6 EC EC SL/ GL/ PF10 1.1 to 2.2x10 ­7 1.6x10 ­7 6.5x10 ­8 EC EC EC 1b Dry Flowable: Airblast 16 (Citrus, 24C in CA) 1.1­ 7.5 (grapes, various fruit & nut trees) 40 40 1.0x10­ 6 6.9x10 ­8 to 4.7x10 ­7 Baseline Baseline 5.9x10 ­8 1.4 to 9.3x10 ­7 EC DL/ GL/ PF10 1c Dry Flowable: Groundboom 2 (corn) 1.5 (wheat) 2 (strawberry/ veg) 8 (turf/ golf courses) 4 (turf/ golf courses) 200 200 80 40 40 4.7x10 ­7 6.3x10 ­7 2.5x10 ­7 5.0x10 ­7 2.5x10 ­7 Baseline Baseline Baseline Baseline Baseline 1.0x10 ­6 3.7x10 ­8 7.5x10 ­7 1.0x10 ­6 7.5x10 ­7 DL/ GL/ NR EC Baseline DL/ GL/ PF5 Baseline 1d Dry Flowable: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 6.3x10 ­8 Baseline 1.9x10 ­7 Baseline 1e Dry Flowable: Low press./ High Vol. Turfgun 4 ­8 (LCO on turf) 5 3.1 to 6.3x10 ­8 Baseline 9.4x10 ­8 to 1.9x10 ­7 Baseline 1f Dry Flowable: Wide area aerial 2 (rangeland/ forestry) 7500 4.6x10 ­7 EC 1.4x10 ­6 All < 1x10 ­6 Table 23: Summary of Occupational Handler Cancer Risks For Private Growers and Commercial Applicators Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary Private Growers Commercial Applicators Risk Min. Req. PPE Risk Min. Req. PPE 91 2a Granular: Aerial Application 2 (corn) 2 (corn) 1200 350 5.0x10 ­7 3.3x10 ­7 SL/ GL/ PF5 Baseline 9.5x10 ­7 9.9x10 ­7 DL/ GL/ PF5 Baseline 2b Granular: Solid broadcast spreader 1.5­ 2 (wheat/ corn) 2 (vegetables) 6­ 9 (turf/ golf courses) 200 80 40 1.4 to 1.9x10 ­7 7.6x10 ­8 1.1 to 1.7x10 ­7 Baseline Baseline Baseline 4.3 to 5.7x10 ­7 2.3x10 ­7 3.4 to 5.1x10 ­7 Baseline Baseline Baseline 3a Liquid: Aerial/ Chemigation 1 (avg. corn) 1.5 (wheat) 2 (corn) 5 (stone fruit) 2 (vegetables) 1200 1200 1200 350 350 9.7x10 ­7 9.9x10 ­7 8.5x10 ­7 9.5x10 ­7 4.9x10 ­7 SL/ GL/ PF5 DL/ GL/ PF5 SL/ GL/ NR SL/ GL/ PF5 SL/ GL/ NR 1.1x10 ­6 1.4x10 ­6 7.2x10 ­7 1.1x10 ­6 8.6x10 ­7 All < 1x10 ­6 All < 1x10 ­6 EC All < 1x10 ­6 DL/ GL/ PF5 3b Liquid: Airblast Application 16 (citrus, 24C in CA) 1.1­ 7.5 (grapes, various fruit & nut trees) 40 40 4.5x10 ­7 3.1x10 ­8 to 2.1x10 ­7 SL/ GL/ NR SL/ GL/ NR 1.0x10­ 6 9.3x10 ­8 to 6.4x10 ­7 SL/ GL/ PF5 SL/ GL/ NR 3c Liquid: Groundboom 1.5­ 2 (wheat/ corn) 2 (strawberries) 4­ 8 (turf/ golf courses) 200 80 40 2.1 to 2.8x10 ­7 1.1x10 ­7 1.1 to 2.3x10 ­7 SL/ GL/ NR SL/ GL/ NR SL/ GL/ NR 6.4 to 8.5x10 ­7 3.4x10 ­7 3.4 to 6.8x10 ­7 SL/ GL/ NR SL/ GL/ NR SL/ GL/ NR 3d Liquid: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 2.8x10 ­8 SL/ GL/ NR 8.5x10 ­8 SL/ GL/ NR 3e Liquid: Low press./ High Vol. Turfgun 4 ­8 (LCO on turf) 5 1.4 to 2.8x10 ­8 SL/ GL/ NR 4.2 to 8.5x10 ­8 SL/ GL/ NR 3f Liquid: Wide area aerial 2 (Range/ Forestry) 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 7500 7500 7500 7500 3.0x10 ­6 8.5x10 ­8 7.9x10 7 1.5x10 ­6 All < 1x10 ­6 SL/ GL/ NR SL/ GL/ NR All < 1x10 ­6 9.1x10 ­6 2.5x10 ­7 6.8x10 7 4.5x10 ­6 All < 1x10 ­6 SL/ GL/ NR EC All < 1x10 ­6 3g Liquid: Wide area ground 0.016 (Mosquito Adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 3000 3000 3000 3.4x10 ­8 3.2x10 7 6.0x10 ­7 SL/ GL/ NR SL/ GL/ NR EC 1.0x10 ­7 9.5x10 7 1.8x10 ­6 SL/ GL/ NR SL/ GL/ NR All < 1x10 ­6 4a Wettable Powders: Aerial 1.5 (Wheat) 2 (Corn ­ max) 1 (Corn ­ typ) 5 (stone fruit) 2 (vegetables) 1200 1200 1200 350 350 4.6x10 ­7 6.1x10 ­7 3.1x10 ­7 4.4x10 ­7 1.8x10 ­7 EC EC EC EC EC 1.4x10 ­6 1.8x10 ­6 9.2x10 ­7 1.3x10 ­6 5.3x10 ­7 All < 1x10 ­6 All < 1x10 ­6 EC All < 1x10 ­6 EC 4b Wettable Powders: Airblast 16 (Citrus­ 24C in California) 7.5 (Citrus) 5 (Nuts) 3 (Pome & stone fruit) 2 (Grapes) 1.1( Avg. stone fruit) 40 40 40 40 40 40 1.6x10 ­7 7.6x10 8 1.0x10 ­6 6.2x10 7 8.8x10 ­7 4.9x10 ­7 EC EC SL/ GL/ PF5 SL/ GL/ PF5 SL/ GL/ NR SL/ GL/ NR 4.9x10 ­7 2.3x10 7 1.5x10 ­7 9.2x10 8 1.0x10 ­6 5.7x10 ­7 EC EC EC EC DL/ GL/ PF5 DL/ GL/ PF5 4c Wettable Powders: Groundboom 1.5 (wheat) 2 (corn) 2 (strawberries) 8 (turf/ golf courses) 4 (turf/ golf courses) 200 200 80 40 40 7.6x10 ­8 1.0x10 7 8.3x10 ­7 8.1x10 ­8 8.3x10 7 EC EC SL/ GL/ PF5 EC SL/ GL/ PF5 2.3x10 ­7 3.1x10 7 1.2x10 ­7 2.4x10 ­7 1.2x10 7 EC EC EC EC EC 4d Wettable Powders: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 4.4x10 ­7 SL/ GL/ NR 5.2x10 ­7 DL/ GL/ PF5 4e Wettable Powders: Low press./ High Vol. Turfgun 4 (LCO on turf) 8 (LCO on turf) 5 5 2.2x10 ­7 4.4x10 ­7 SL/ GL/ NR SL/ GL/ NR 6.6x10 ­7 6.2x10 ­7 SL/ GL/ NR SL/ GL/ PF5 4f Wettable Powders: Wide area aerial 2 (Range/ Forestry) 7500 3.8x10 ­6 All < 1x10 ­6 1.1x10 ­5 All < 1x10 ­6 Table 23: Summary of Occupational Handler Cancer Risks For Private Growers and Commercial Applicators Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary Private Growers Commercial Applicators Risk Min. Req. PPE Risk Min. Req. PPE 92 Applicators 5a Aerial: Agricultural uses, liquid sprays 1­ 2 (wheat/ corn) 5 (stone fruit) 2 (vegetables, 24C on oysters) 1200 350 350 1.6 to 3.2x10 ­7 2.3x10 ­7 9.2x10 ­8 EC EC EC 4.7 to 9.5x10 ­7 6.9x10 ­7 2.8x10 ­7 EC EC EC 5b Aerial: Wide area uses, liquid sprays 2 (Range/ Forestry) 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 7500 7500 7500 7500 2.0x10 ­6 1.6x10 ­8 1.5x10 ­7 9.8x10 ­7 All < 1x10 ­6 EC EC EC 5.9x10 ­6 4.7x10 ­8 4.4x10 ­7 3.0x10 ­6 All < 1x10 ­6 EC EC All < 1x10 ­6 5c Aerial: Agricultural uses, granular applications 2 (corn) 2 (corn) 1200 350 6.2x10 ­7 1.8x10 ­7 EC EC 1.9x10 ­6 5.5x10 ­7 All < 1x10 ­6 EC 6a Airblast: Agricultural uses 16 (Citrus 24C in California) 7.5 (Citrus) 5 (Nuts) 3 (Pome & stone fruit) 2 (Grapes) 1.1 (Avg pome & stone fruit) 40 40 40 40 40 40 2.7x10 ­7 1.3x10 ­7 9.9x10 ­7 1.0x10 ­6 6.9x10 ­7 3.8x10 7 EC EC DL/ GL/ PF5 Baseline Baseline Baseline 8.2x10 ­7 3.9x10 ­7 2.6x10 ­7 1.5x10 ­7 1.0x10 ­7 7.9x10 ­7 EC EC EC EC EC SL/ GL/ NR 6b Airblast: Wide area fogger 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 3000 3000 3000 4.1x10 ­7 1.9x10 ­7 1.3x10 ­6 Baseline EC All < 1x10 ­6 8.6x10 ­7 5.8x10 ­7 3.9x10 ­6 SL/ GL/ NR EC All < 1x10 ­6 7 Groundboom 1.5­ 2 (Wheat/ corn) 2 (Strawberries) 8 (Turf/ golf course) 4 (Turf/ golf course) 200 80 40 40 1.3 to 1.7x10 ­7 6.9x10 ­8 1.4x10 ­7 6.9x10 ­8 Baseline Baseline Baseline Baseline 3.9 to 5.2x10 ­7 2.1x10 ­7 4.1x10 ­7 2.1x10 ­7 Baseline Baseline Baseline Baseline 8 Solid broadcast spreader (granular) 1.5­ 2 (Wheat/ corn) 2 (Strawberries) 4­ 8 (Turf/ golf course) 200 80 40 1.3 to 1.7x10 ­7 6.7x10 ­8 1.0 to 1.5x10 ­7 Baseline Baseline Baseline 3.8 to 5.0x10 ­7 2.0x10 ­7 3.0 to 4.5x10 ­7 Baseline Baseline Baseline 9 Aerosol Can 0.01 lb ai/ can 2 cans 8.7x10 ­8 Baseline 2.6x10 ­7 Baseline 10 Trigger pump sprayer 0.01 lb ai/ can 1 can 3.1x10 ­9 SL/ GL/ NR 9.4x10 ­9 SL/ GL/ NR 11 Right of way sprayer 1.5 lb ai/ 100 gallons 1000 gallons 4.3x10 ­7 Baseline 4.1x10 ­7 SL/ GL/ NR 12 High pressure handwand 4 lb ai/ 100 gallons 1000 gallons 6.6x10 ­7 SL/ GL/ PF5 1.1x10 ­6 All < 1x10 ­6 13 Animal groomer, liquid application 0.01 lb ai/ dog 8 dogs 3.1x10 ­6 All < 1x10 ­6 9.4x10 ­6 All < 1x10 ­6 14 Animal groomer, dust application 0.2 lb ai/ dog 8 dogs 3.5x10 ­9 Baseline 1.0x10 ­8 Baseline 15 Granulars & baits applied by hand 9 (Ornamentals & gardens) 1 8.0x10 ­6 All < 1x10 ­6 2.4x10 ­5 All < 1x10 ­6 16 Granulars & baits applied by spoon 9 (Ornamentals & garderns) 1 4.6x10 ­7 SL/ GL/ NR 1.2x10 ­6 All < 1x10 ­6 Mixerr/ Loader/ Applicators 17 Low pressure, high volume turfgun (ORETF Data) 8 (LCO Use on turf) 4 (LCO Use on turf) 5 5 3.1x10 ­7 6.1x10 ­7 SL/ GL/ NR SL/ GL/ NR 9.7x10 ­7 9.2x10 ­7 DL/ GL/ PF5 SL/ GL/ NR 18a Wettable powder, low pressure handwand 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 3.1x10 ­6 3.0x10 ­7 All < 1x10 ­6 SL/ GL/ NR 9.2x10 ­6 9.0x10 ­7 All < 1x10 ­6 SL/ GL/ NR Table 23: Summary of Occupational Handler Cancer Risks For Private Growers and Commercial Applicators Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary Private Growers Commercial Applicators Risk Min. Req. PPE Risk Min. Req. PPE 93 18b Liquids, low pressure handwand 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 2.1x10 ­7 1.2x10 ­8 SL/ GL/ PF5 SL/ GL/ NR 6.2x10 ­7 3.5x10 ­8 SL/ GL/ PF5 SL/ GL/ NR 19 Backpack sprayer 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 7.0x10 ­7 4.8x10 ­8 DL/ GL/ PF5 Baseline 2.2x10 ­6 1.4x10 ­7 All < 1x10 ­6 Baseline 20 Granular, bellygrinder 9 (Turf) 1 1.1x10 ­6 All < 1x10 ­6 3.4x10 ­6 All < 1x10 ­6 21 Granular, push­ type spreader 9 (Turf) 5 4.0x10 ­7 Baseline 8.2x10 ­7 SL/ GL/ NR 22 Handheld fogger No data No data No data No data No data No data 23 Power backpack No data No data No data No data No data No data 24 Granular, backpack 9 (Ornamentals) 1 1.9x10 ­8 DL/ GL/ NR 5.8x10 ­8 DL/ GL/ NR 25 Tree injection No data No data No data No data No data No data 26 Drench/ dipping forestry/ ornamentals 1.5 lb ai/ 100 gallons (Ornamental/ seedling dip) 100 gallons 1.1x10 ­7 SL/ GL/ NR 3.2x10 ­7 SL/ GL/ NR 27 Sprinkler can 2% solution (Ornamentals) 10 gallons 1.3x10 ­7 Baseline 4.0x10 ­7 Baseline Flaggers 28a Flagger: liquid sprays 2 (Corn) 2 (Vegetables) 1200 350 7.2x10 ­7 2.1x10 ­7 Baseline Baseline 3.5x10 ­7 6.3x10 ­7 EC Baseline 28b Flagger: granular applications 2 (Corn) 2 (Vegetables) 1200 350 2.1x10 ­7 6.1x10 ­8 Baseline Baseline 6.2x10 ­7 1.8x10 ­7 Baseline Baseline Baseline = Long pants, long­ sleeved shirts, no gloves SL = Single layer clothing with or without gloves (GL or NG) DL = Double layer clothing (i. e., coveralls over SL) with or without gloves (GL or NG) EC = Engineering controls NR = No respirator PF5 = Protection factor 5 respirator PF10 = Protection factor 10 respirator Current label = SL/ GL/ NR Min. Req. PPE = level of PPE where cancer risks > 1x10 ­6 , where current label is exceeded or no adequate PPE is found, results are bold. Risks which never exceed 1x10 ­6 are for highest feasible type of mitigation (e. g., engineering control in most cases). 7.2 Postapplication Exposures and Risks Workers can be exposed to carbaryl residues by entering previously treated areas to perform activities. Exposure varies with the specific tasks (i. e., transfer coefficient), the level of carbaryl residue in the environment (i. e., DFR or TTR depending upon crop), and the duration of the activity. Calculations were completed using the same approaches as already outlined above for the residential postapplication risk assessments (Section 4.4.3: Residential Postapplication Risks). An administrative approach, the Restricted Entry Interval (REI), is used by the Agency to manage risks for postapplication workers doing hand labor activities that require direct contact with treated plants. The REI is the amount of time required between application of a pesticide and engaging in a task or activity in a treated field that it takes for residues to dissipate to an appropriate level. Current labels for carbaryl specify REIs of 12 hours after application for all crop/ cultural practice combinations. In other cases (e. g., use of a combine or other mechanical harvesting) such as those 94 specified in the Agency's Worker Protection Standard (40CFR170) where no contact will occur, the Agency does not rely on the REI approach but adheres to the guidance included in §170.110.( c)( 3) that allows for entry if the criteria are met. The Agency also considers short­ term excursions for people for such activities as unclogging machinery as stipulated in the guidance included in §170.112.( c). The Agency encourages the use of viable engineering controls and other means to reduce exposures provided they are not overly burdensome for actual workers. Generally, it should also be noted that the use of personal protective equipment or other types of equipment to reduce exposures for postapplication workers is not considered a viable alternative for the regulatory process except in specialized situations (e. g., a rice scout will wear rubber boots in flooded paddies). As with the occupational handlers, a scenario­ driven approach is used to assess risks for reentry workers. The Agency's Policy 003.1 Science Advisory Council For Exposure Policy Regarding Agricultural Transfer Coefficients is used to define the scenarios. This policy presents various transfer coefficients which represent the range of activities associated with 18 distinct crop/ agronomic groupings based on different types of job tasks or activities needed to produce fruits, vegetables, grains, and other crops. In this scheme, carbaryl uses were identified in all of the crop groupings included in the policy. As such, all agronomic crop group/ transfer coefficients included in this policy were used to calculate postapplication risks for carbaryl. ° Low Berry (e. g., lowbush blueberries, cranberries, strawberries); ° Bunch/ bundle (e. g., bananas, hops, tobacco); ° Field/ row crops, low/ medium (e. g., alfalfa, barley, beans, cotton, peanuts, peas); ° Field/ row crops, tall (e. g., corn, sorghum, sunflowers); ° Cut flowers (e. g., floriculture crops); ° Sugarcane; ° Trees/ fruit, deciduous (e. g., apples, apricots, cherry, peaches, pears); ° Trees/ fruit, evergreen (e. g., avocados, Christmas trees, citrus); ° Trees/ nut (e. g., almonds, hazelnuts, macadamia, pecans, walnuts); ° Turf/ sod (e. g., golf courses, sod farms); ° Vegetable/ root (e. g., beets, carrots, onions, potatoes, turnips); ° Vegetable/ cucurbit (e. g., cantelope, cucumber, squash, watermelon); ° Vegetable/ fruiting (e. g., eggplant, pepper, tomato, okra); ° Vegetable/ head and stem brassica (e. g., broccoli, cauliflower, brussel sprouts, cauliflower); ° Vegetables/ leafy (e. g., collards, greens, lettuce, parsley, spinach, napa); ° Vegetables/ stem and stalk (e. g., artichoke, asparagus, pineapple); ° Vine/ trellis (e. g., blackberries, blueberries, grapes, kiwi, raspberries); and ° Nursery crops (e. g., container and B& B ornamentals). [Note: This assessment includes the latest transfer coefficients for nursery crops which have been recently submitted by ARTF and reviewed by the Agency. Additionally, the transfer coefficient for fruit tree hand thinning has been reduced from original policy estimates based on a reinterpretation by the Agency of the dataset upon which it was based.] 95 Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational postapplication risk assessments, as described below. The assumptions and factors used in the risk calculations are consistent with current Agency policy for completing occupational exposure assessments (e. g., Exposac Policy 3 and guidelines for handling DFR data). The assumptions and factors used in the risk calculations include: C Many assumptions and factors which are common to both handler and postapplication risk assessments are detailed in Section 7.1: Occupational Handler Risk Assessment (e. g., body weight). One major difference is that in the handler assessment, many different combinations of application rates and crop acres treated were considered but in the postapplication assessment, generally only maximum application rates were considered. C Four dislodgeable foliar residue (DFR) studies were submitted that meet current Agency guidelines for sampling techniques and data quality. These studies were conducted with carbaryl by the Agricultural Re­ entry Task Force (ARTF) using Iwata's DFR sampling method on tobacco (harvesting), olives (pruning), sunflowers (scouting), and cabbage (weeding). [Note: Aventis Crop Science is a member of the ARTF so there are no data compensation issues associated with the use of these data.] The percent of transferability averaged approximately 16 percent of the application rate for the crops. A turf transferrable residue (TTR) study was also completed by Aventis Crop Science using the ORETF roller method. The percent of transferability averaged approximately 1.1 percent for turf measurements at three different sites. HED used the values from these five studies for all postapplication crops and scenarios as the transferability is in the appropriate range for use in risk assessments. C Short­ term noncancer risks were calculated by comparing single day exposures based on the dissipation of carbaryl residues (i. e., single day risks were calculated based on daily DFR dissipation values over time). With the intermediate­ term postapplication risk calculations, 30­ day averages based on DFR dissipation and an appropriate duration for the endpoint were used to calculate postapplication risks. In the long­ term assessment, a 30 day average was used based on the likelihood that carbaryl could be sprayed at least once a month in the ornamental industry. The endpoints used are the same as those described above for the dermal component in the handler assessments (i. e., NOAEL of 20 mg/ kg/ day from 21­ day dermal rat toxicity study using technical material ­ target MOE = 100 and LOAEL of 3.1 mg/ kg/ day from a chronic dog feeding study with a dermal absorption factor defined in rats ­ target MOE = 300). C A standard pseudo­ first order kinetics analysis was used to analyze carbaryl residue dissipation over time as outlined in the Agency's draft Series 875 Postapplication Exposure Monitoring Guidelines. A more sophisticated curve­ fitting approach was not warranted because the correlation coefficients in the analysis were appropriate and the data have been used generically to extrapolate to a variety of other crops where decay rates and mechanisms may differ. C When the available DFR data were extrapolated to other crops, the data were adjusted for differences in application rate using a simple proportional approach. Carbaryl­ specific residue dissipation data were extrapolated to crops where no data were available. The tobacco DFR data were used to complete all assessments for the crop/ activity combinations included in the bunch/ bundle, sugarcane, and vine/ trellis agronomic crop groups. The olive DFR data were used to complete all assessments for the crop/ activity combinations included in all of the tree fruit and 96 nut crop groups. The sunflower DFR data were used to complete all assessments for the crop/ activity combinations in the tall field/ row crop group. No extrapolation was required in this assessment. The cabbage study was based on groundboom application, which is thought to be much more prevalent in the overall use pattern for carbaryl. The cabbage DFR data were used to complete all assessments for the crop/ activity combinations included in the berry, cut flower, low/ medium field and row, and all vegetable (i. e., stem/ stalk, brassica, leafy, fruiting, cucurbits, root) agronomic crop groups. The turf TTR data were used to complete all assessments for the crop/ activity combinations for the turf agronomic crop group. No extrapolation was required in this assessment. ° There were several scenarios for which no appropriate exposure data are known to exist. There are many kinds of potential exposure pathways that do not involve foliar contact that have not been addressed in this risk assessment. The scenarios include: transplanting many crops including in the ornamental and forestry industry; thinning some crops such as hops; some partially mechanized operations that also involve human contact (e. g., cotton harvesting where module builders and trampers are used); various operations with Christmas trees such as pruning or baling; and various operations with nut production such as sweeping for harvest. ° Aventis Crop Science is in the process of conducting a biomonitoring study with postapplication workers on key crops of concern (i. e., apples and cherries). The activities that were monitored included hand thinning of apples and hand harvest of both apples and cherries. Based on discussions with Aventis Crop Science, the preliminary results indicate that levels are similar to those predicted in the Agency's occupational postapplication risk assessment. 7.2.1 Occupational Postapplication Noncancer Risks Current label requirements specify 12 hour REIs. For all but the lowest exposure scenarios in some crops, short­ term MOEs are of concern (i. e., less than the required uncertainty factor of 100) at the current REI. Generally, short­ term MOEs meet or exceed the Agency uncertainty factor in the range of 3 to 5 days for lower to medium exposure activities and from 8 to 12 days after application in most higher exposure scenarios. Intermediate­ term MOEs are not of concern generally for low to medium level exposures but are of concern for higher level exposures such as harvesting in some crops. Chronic exposures are of concern for the cut flower industry but not for general greenhouse and nursery production activities. Table 24 below provides a summary of the noncancer risks that have been calculated for each crop group and each duration of exposure. The information presented includes the short­ term MOEs on the day of application, the day after application where the short­ term MOEs meet or exceed the target of 100, the intermediate­ term MOEs based on 30 day average exposures, and chronic MOEs also based on 30 day average exposures (only for a limited number of scenarios). Table 24: Summary of Carbaryl Noncancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor Very Low Low Medium High Very High Low Berry ST MOE Day 0 NA 184 NA 49 NA Days For ST MOE > UF NA 0 NA 4 NA Table 24: Summary of Carbaryl Noncancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor Very Low Low Medium High Very High 97 IT 30 Day Avg MOE NA 991 NA 264 NA Bunch/ Bundle ST MOE Day 0 NA 411 32 21 NA Days For ST MOE > UF NA 0 6 8 NA IT 30 Day Avg MOE NA 2365 182 118 NA Low /Med. Field/ Row Crops ST MOE Day 0 NA 982 65 39 NA Days For ST MOE > UF NA 0 3 5 NA IT 30 Day Avg MOE NA 5286 352 211 NA Tall Field/ Row Crops ST MOE Day 0 NA 245 61 25 <1 Days For ST MOE > UF NA 0 4 11 +30 IT 30 Day Avg MOE NA 970 242 97 6 Cut Flowers ST MOE Day 0 NA 30 18 11 NA Days For ST MOE > UF NA 7 9 12 NA IT 30 Day Avg MOE NA 159 99 57 NA Chronic MOE NA 194 121 69 NA Sugarcane ST MOE Day 0 NA NA 55 27 NA Days For ST MOE > UF NA NA 3 7 NA IT 30 Day Avg MOE NA NA 315 158 NA Decid. Fruit Trees ST MOE Day 0 1455 146 NA 49 NA Days For ST MOE > UF 0 0 NA 8 NA IT 30 Day Avg MOE 4450 445 NA 148 NA Evergreen Fruit Trees ST MOE Day 0 582 58 19 NA NA Days For ST MOE > UF 0 6 17 NA NA IT 30 Day Avg MOE 1780 178 59 NA NA Nut Trees ST MOE Day 0 NA 175 NA 35 NA Days For ST MOE > UF NA 0 NA 11 NA IT 30 Day Avg MOE NA 534 NA 107 NA Table 24: Summary of Carbaryl Noncancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor Very Low Low Medium High Very High 98 Turf/ Sod ST MOE Day 0 NA 312 NA 10 NA Days For ST MOE > UF NA 0 NA 14 NA IT 30 Day Avg MOE NA 1505 NA 46 NA Root Veg. ST MOE Day 0 NA 245 49 29 NA Days For ST MOE > UF NA 0 4 7 NA IT 30 Day Avg MOE NA 1322 264 159 NA Cucurbit Veg. ST MOE Day 0 NA 147 49 29 NA Days For ST MOE > UF NA 0 4 7 NA IT 30 Day Avg MOE NA 793 264 159 NA Fruiting Veg. ST MOE Day 0 NA 147 105 74 NA Days For ST MOE > UF NA 0 0 2 NA IT 30 Day Avg MOE NA 793 566 396 NA Brassica ST MOE Day 0 NA 37 18 15 NA Days For ST MOE > UF NA 6 9 11 NA IT 30 Day Avg MOE NA 198 99 79 NA Leafy Veg. ST MOE Day 0 NA 147 49 29 NA Days For ST MOE > UF NA 0 4 7 NA IT 30 Day Avg MOE NA 793 264 159 NA Stem/ stalk Veg. ST MOE Day 0 NA 137 82 41 NA Days For ST MOE > UF NA 0 1 5 NA IT 30 Day Avg MOE NA 788 473 236 NA Vine/ trellis ST MOE Day 0 NA 147 74 15 7 Days For ST MOE > UF NA 0 2 11 14 IT 30 Day Avg MOE NA 793 396 79 40 Nursery/ Ornamentals ST MOE Day 0 NA 669 421 184 NA Days For ST MOE > UF NA 0 0 0 NA IT 30 Day Avg MOE NA 3604 2266 991 NA Chronic MOE NA 4399 2765 1210 NA 99 7.2.2 Occupational Postapplication Exposure and Risk Estimates for Cancer Cancer risks for private growers (i. e., 10 exposures/ year) and commercial farmworkers (i. e., 30 exposures/ year) were calculated for different crop groups as described above and summarized in Table 25 below. Current label requirements specify 12 hour REIs. For all scenarios, cancer risks are <1x10 ­4 on the day of application (i. e., at the current REI). Likewise, cancer risks are <1x10 ­6 on the day of application for most crop/ activity scenarios with private growers and also for low to medium exposures for commercial farmworkers. In fact, risks for all scenarios were in the 10 ­6 range in all but two scenarios for commercial farmworkers participating in very high exposure activities (e. g., sweetcorn handharvesting) on the day of application. In these three cases, risks were in the 10 ­5 range on the day of application. For private growers, it takes approximately 5 days for risks to decline to <1x10 ­6 for crop/ activity combinations that exceed 1x10 ­6 on the day of application. For commercial farmworkers, it takes approximately 8 days for risks to reach the target level of concern of <1x10 ­6 . The 1996 Barolo memo which focused on cancer risk management should be considered in the interpretation of these results. Current label requirements appear to be adequate for all postapplication cancer risks if the 10 ­4 range is used for risk management. If the 10 ­6 risk range is considered, it also appears that the current REI appears adequate to address cancer risks for many crop/ activity combinations. However, for higher exposure situations, longer duration REIs are predicted. In all cases, REIs predicted based on cancer risks are less restrictive or similar (i. e., within a day or two for commercial farmworkers) than those predicted based on the noncancer effects of carbaryl. In no cases do cancer risks indicate more restrictive REIs than for noncancer risks calculated for the corresponding crop/ activity exposure scenario. Table 25: Summary of Carbaryl Cancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (From Policy 003) Very Low Low Medium High Very High Low Berry Private Grower Day 0 Risk NA 1.7 x 10 ­7 NA 6.2x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 NA 0 NA Com.. Farmworker Day 0 Risk NA 5.0 x 10 ­7 NA 1.9x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 NA 4 NA Bunch/ Bundle Private Grower Day 0 Risk NA 7.4 x 10 ­8 9.6x 10 ­7 1.5x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 0 2 NA Com.. Farmworker Day 0 Risk NA 2.2 x 10 ­7 2.9x 10 ­6 4.4x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 5 8 NA Low /Med. Field/ Row Crops Private Grower Day 0 Risk NA 3.1x 10 ­8 4.7x 10 ­7 7.8x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 9.3x 10 ­8 1.4x 10 ­6 2.3x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 2 5 NA Table 25: Summary of Carbaryl Cancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (From Policy 003) Very Low Low Medium High Very High 100 Tall Field/ Row Crops Private Grower Day 0 Risk NA 1.2 x 10 ­7 5.0 x 10 ­7 1.2 x 10 ­6 2.1 x 10 ­5 Private Grower Days < 1x10 ­6 NA0 0 223 Com.. Farmworker Day 0 Risk NA 3.7 x 10 ­7 1.5 x 10 ­6 3.7 x 10 ­6 8.5 x 10 ­5 Com.. Farmworker Days < 1x10 ­6 NA 0 3 10 31 Cut Flowers Private Grower Day 0 Risk NA 1.0 x 10 ­6 1.7 x 10 ­6 2.9 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 3 6 NA Com.. Farmworker Day 0 Risk NA 3.1 x 10 ­6 5.0 x 10 ­6 8.7 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 6 9 12 NA Sugarcane Private Grower Day 0 Risk NA NA 5.6 x 10 ­7 1.1 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA NA 0 1 NA Com.. Farmworker Day 0 Risk NA NA 1.7 x 10 ­6 3.3 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA NA 3 6 NA Decid. Fruit Trees Private Grower Day 0 Risk 2.1 x 10 ­8 2.1 x 10 ­7 NA 6.3 x 10 ­7 NA Private Grower Days < 1x10 ­6 0 0NA0NA Com.. Farmworker Day 0 Risk 6.3 x 10 ­8 6.3 x 10 ­7 NA 1.9 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 0 0NA6NA Evergreen Fruit Trees Private Grower Day 0 Risk 5.2 x 10 ­8 5.2 x 10 ­7 1.6 x 10 ­6 NA NA Private Grower Days < 1x10 ­6 0 0 5 NA NA Com.. Farmworker Day 0 Risk 1.6 x 10 ­7 1.6 x 10 ­6 4.7 x 10 ­6 NA NA Com.. Farmworker Days < 1x10 ­6 0 5 16 NA NA Nut Trees Private Grower Day 0 Risk NA 1.7 x 10 ­7 NA 8.7 x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 NA 0 NA Com.. Farmworker Day 0 Risk NA 5.7 x 10 ­7 NA 2.6 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 NA 10 NA Turf/ Sod Private Grower Day 0 Risk NA 8.1 x 10 ­8 NA 2.7 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 NA 2 NA Com.. Farmworker Day 0 Risk NA 2.4 x 10 ­7 NA 8.0 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 NA 4 NA Table 25: Summary of Carbaryl Cancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (From Policy 003) Very Low Low Medium High Very High 101 Root Veg. Private Grower Day 0 Risk NA 1.2 x 10 ­7 6.2 x 10 ­7 1.0 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 3.7 x 10 ­7 1.9 x 10 ­6 3.1 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 4 6 NA Cucurbit Veg. Private Grower Day 0 Risk NA 2.1 x 10 ­7 6.2 x 10 ­7 1.0 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 6.2 x 10 ­7 1.9 x 10 ­6 3.1 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 4 6 NA Fruiting Veg. Private Grower Day 0 Risk NA 2.1 x 10 ­7 2.9 x 10 ­7 4.1 x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 6.2 x 10 ­7 8.7 x 10 ­7 1.2 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 0 1 NA Brassica Private Grower Day 0 Risk NA 8.3 x 10 ­7 1.7 x 10 ­6 2.1 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 3 4 NA Com.. Farmworker Day 0 Risk NA 2.5 x 10 ­6 5.0 x 10 ­6 6.2 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 5 9 10 NA Leafy Veg. Private Grower Day 0 Risk NA 2.1 x 10 ­7 6.2 x 10 ­7 1.0 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 6.2 x 10 ­7 1.9 x 10 ­6 3.1 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 4 6 NA Stem/ stalk Veg. Private Grower Day 0 Risk NA 2.2 x 10 ­7 3.7 x 10 ­7 7.4 x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 6.7 x 10 ­7 1.1 x 10 ­6 2.2 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 1 4 NA Vine/ trellis Private Grower Day 0 Risk NA 2.1 x 10 ­7 4.1 x 10 ­7 2.1 x 10 ­6 4.1 x 10 ­6 Private Grower Days < 1x10 ­6 NA0 0 48 Com.. Farmworker Day 0 Risk NA 6.2 x 10 ­7 1.2 x 10 ­6 6.2 x 10 ­6 1.2 x 10 ­5 Com.. Farmworker Days < 1x10 ­6 NA 0 1 10 13 Table 25: Summary of Carbaryl Cancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (From Policy 003) Very Low Low Medium High Very High 102 Nursery/ Ornamentals Private Grower Day 0 Risk NA 4.5 x 10 ­8 7.2 x 10 ­8 1.7 x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 1.4 x 10 ­7 2.2 x 10 ­7 5.0 x 10 ­7 NA Com.. Farmworker Days < 1x10 ­6 NA 0 0 0 NA 7.3 Occupational Risk Characterization Characterization of the occupational risks is included below for both handlers and for postapplication exposures. Handlers: The occupational handler assessment for carbaryl is complex in that three different types of noncancer risk calculations were required based on the recently selected endpoints. The durations of exposure that were considered for noncancer toxicity were short­ term ( 30 days), intermediate­ term (30 days up to several months), and chronic (every working day). A complete array of calculations was completed for all identified exposure scenarios using the short­ and intermediateterm endpoints because the Agency believes that carbaryl uses fit the criteria for both of these durations. The only calculations that were completed using the chronic endpoint were limited and those associated with the greenhouse and floriculture industries where these kinds of exposures may occur. Cancer risks were also calculated using a linear, low­ dose extrapolation model (i. e., Q1*) for both private growers (i. e., 10 application days per year) and for those who may more actively use carbaryl such as a commercial applicator (i. e., 30 application days per year). Cancer calculations were completed as well for every scenario that has been identified for both private growers and commercial applicators. For all of the different types of endpoints selected (except chronic where a limited number of calculations were completed), the Agency identified exposures that fit into 28 different scenarios which are defined based on the equipment used to make applications or the type of formulation used. Within each of these categories, different application rates and acres treated values were considered to evaluate the broad range of applications that may occur with each kind of equipment (e. g., a groundboom may be used for turf or agriculture). All totaled, 128 different crop/ rate/ acres combinations were considered within the 28 scenarios for the short­ and intermediate­ term toxicity categories plus 4 chronic crop/ rate/ acre combinations. The overall result is that 4 sets of 128 calculations each (516 total calculations) were completed for occupational carbaryl handlers. Finally, it should be noted that each calculation was completed at different levels of personal protection to allow for a more informed risk management decision. Even given the scope of the calculations that have already been completed, it is likely that there are some uses of carbaryl that have not been quantitatively addressed in this document either through lack of exposure data or other information and because carbaryl is such a widely used chemical. These scenarios will be addressed by the Agency when they are identified as carbaryl progresses through the reregistration process. Readers are also encouraged to evaluate novel scenarios by considering the range of estimates already completed as it is likely that many uses could be quantitatively assessed by reviewing those calculations as a wide array of chemical use combinations and equipment types have already been considered. 103 The data that were used in the carbaryl occupational handler risk assessment represent the best data and approaches that are currently available. While some of the data which have been used may not be of optimal quality, they represent the best available data for the scenario in question. In many cases, the Pesticide Handlers Exposure Database (PHED) was used to develop the unit exposure values. The quality of the data included in PHED vary widely from scenarios that meet guideline requirements for studies to others where a limited number of poor quality datapoints are available. The results for each scenario should be reviewed in the context of the quality of these data. In addition to PHED, the Agency used a number of studies to define unit exposure values. Generally, the quality of these studies is excellent. Most, except for the trigger sprayer data, are very recent and based on the newest analytical requirements and monitoring techniques. PHED unit exposure values represent a central tendency of the data (i. e., geometric mean, median or arithmetic mean depending upon the distribution of the data). As such, the values based on the recent studies also are measures of central tendency (e. g., the geometric means were selected from each study for assessment purposes in most cases). Along with the unit exposure values used in the assessment, other inputs include application rates and daily acres treated values. Selected application rates represent a range for each major market in which carbaryl is used including agriculture, turf (lawncare, golf courses, etc.), ornamentals, and for wide area applications such as mosquito control. Many application rates also represent maximum amounts that are allowed by the label for certain settings. Where available, average use rates were also used to provide for a more informed risk management decision. The application rates that were selected for use in the risk assessment were defined based on labels, information provided by the Aventis Crop Science at the September 24, 1998 SMART Meeting for carbaryl, and based on various analyses of carbaryl use patterns completed by the Agency's Biological and Economic Analysis Division. The other key input for completing handler risk assessments used for defining how much chemical can be used in a day is how much can be treated in a day which is generally expressed as the number of acres treated per day. The values that were used for this parameter represent the latest Agency thinking on this issue. In fact, the Science Advisory Council For Exposure recently updated the policy for these inputs (July 2000 Exposure SAC Policy 9: Standard Values for Daily Acres Treated in Agriculture). These most recent values have been used for the calculations. In addition to the key sources of information considered above, there are many underlying factors that may impact the overall results of a risk assessment. For example, the protection factors used for adding additional levels of dermal and respiratory protection may impact the overall risk picture. The factors used in this assessment by the Agency are the ones that have been used for several years. Other such factors may include the fact that average application rates have been generally used to represent typical application rates to calculate ranges of risks when it is clear that the two values could differ greatly. The Agency has taken this approach because the data required to define typical application rates within each crop are generally unavailable. There are also exposure monitoring issues that should be considered. For example, in many cases the data included in PHED are based on the use of cotton gloves for hand exposure monitoring which are thought by many to overestimate exposure because they potentially retain residues more than human skin would over time (i. e., they may act like a sponge compared to the actual hand). A similar issue was noted with the carbaryl­ specific dog grooming study that used the handwash approach to monitor exposure after shampooing several dogs. These intangible elements of the risk assessment reflect many of the hidden uncertainties associated with exposure data. The overall impacts of these uncertainties is hard to quantify. The factor to again consider is that the Agency used the best available data to complete the risk assessment for carbaryl. In summary, the Agency believes that the risk values presented in this occupational assessment 104 represent the highest quality results that could be produced given the exposure, use, and toxicology data that are available. Certainly risk managers and other interested parties should consider the quality of individual inputs when interpreting the results and make decisions accordingly. It is difficult to ascertain where on a distribution the values which have been calculated fall because the distributional data for exposure, application rates, acres treated and many other parameters are unrefined. The Agency does believe, however, that the risks represent conservative estimates of exposure because maximum application rates are coupled with large acreage estimates to define risk estimates that likely fall in the upper percentiles of the actual exposure distributions. Additionally, risk estimates are thought to be conservative even when measures of central tendency are combined because values that would be considered to be in the lower percentile aspect of any input parameter have not been used in the calculations. Postapplication: Like the occupational handler risk assessment discussed above, the postapplication worker risk assessment for carbaryl is also complex in that three different types of noncancer risk calculations were required based on the recently selected endpoints along with cancer risk calculations using a linear, low­ dose extrapolation model. For all of the different types of endpoints selected (except chronic where a limited number of calculations were completed), the Agency identified exposures that fit into 18 different crop groups which are defined essentially based on the nature of the crop where a work activity would take place. Within each of these crop groups, ranges of transfer coefficients were considered to reflect differences in exposures that would be associated with the variety of cultural practices that are required to produce the crop/ product. All totaled, 54 different cultural practices were considered within the 18 crop groups for each toxicity category. The overall result is that 4 sets of 54 calculations each (216 plus a few chronic values) were completed for postapplication workers. Finally, it should be noted that each calculation was completed at different days after application to reflect residue dissipation over time in the environment and to allow for a more informed risk management decision. Even given the scope of the calculations that have already been completed, it is likely that there are some uses of carbaryl that have not been quantitatively addressed in this document either through lack of exposure data or other information and because carbaryl is such a widely used chemical. These scenarios will be addressed by the Agency when they are identified as carbaryl progresses through the reregistration process. Readers are also encouraged to evaluate novel scenarios by considering the range of estimates already completed as it is likely that many uses could be quantitatively assessed by reviewing existing calculations as a wide array of crop/ activity combinations have already been considered. The data that were used in the carbaryl postapplication worker risk assessment represent the best data and approaches that are currently available. The latest Agency transfer coefficient values have been used to complete this assessment including the recently submitted ARTF studies on greenhouse workers. Most of the values in the current Agency policy are based on the work of the Agricultural Reentry Task Force (ARTF) of which, Aventis Crop Science is a member. The current Agency policy is interim in nature but represents all of the data that have been submitted by the ARTF and evaluated by the Agency. The work of the ARTF is still ongoing so additional data may become available to refine the exposure estimates as more data are submitted to the Agency. Also, it is possible that there are exposure scenarios that have not been addressed by the Agency because the transfer coefficient model is not appropriate as there is little or no foliar contact associated with the activity. There are also potentially, partially mechanized activities that could lead to exposure where the Agency has no information. These will need to be carefully considered in the reregistration process. In addition to the exposure inputs for specific activities (i. e., transfer coefficients), the Agency used 4 carbaryl­ specific 105 DFR (Dislodgeable Foliar Residue) dissipation studies and a single TTR (Turf Transferable Residue) study to calculate risks for all postapplication workers in every region in the country. It is standard practice for the Agency to use these kinds of studies in this manner but it is likely that additional cropand region­ specific data could be used to further refine the risk assessment. Several other key pieces of data and information were considered in the development of the postapplication risk values including use and usage information and exposure frequency in the cancer risk assessment. For many agricultural crops, the maximum application rate is low (e. g., 1.5 to 2 lb ai/ acre) in many crops. As a result, postapplication risks were generally calculated at maximum rate levels because of the already inherent complexity of the assessment and because it is likely that results may not be extremely sensitive to changes in this value. In addition to the key sources of information considered above, there are many underlying factors that may impact the overall results of a risk assessment. For example, subtle differences between activities in similar crops within each of the 18 agronomic groups considered in the assessment may not be accurately reflected in the current transfer coefficient values. The use of 4 DFR studies to represent all crops and all regions within the country could lead to results that do not reflect actual use practices and conditions in some parts of the country. Additionally, the exposure frequency values that were used for private growers and professional farmworkers tend to be supported by available data but could be refined if data on work patterns and regional carbaryl use becomes available. As with the handler assessment above, the intangible elements reflect many of the hidden uncertainties associated with exposure data. The overall impacts of these uncertainties is hard to quantify. The factor to again consider is that the Agency used the best available data to complete the risk assessment for carbaryl. In summary, the Agency believes that the risk values presented in this postapplication assessment represent the highest quality results that could be produced given the exposure, use, and toxicology data that are available. Certainly risk managers and other interested parties should consider the quality of individual inputs when interpreting the results and make decisions accordingly. It is difficult to ascertain where on a distribution the values which have been calculated fall because the distributional data for exposure, residue dissipation and many other parameters are unrefined. The Agency does believe, however, that the risks represent conservative estimates of exposure because maximum application rates are used to define residue levels upon which the risk calculations are based. Additionally, risk estimates are thought to be conservative even when measures of central tendency (e. g., most transfer coefficients are thought to be central tendency) are used because values that would be considered to be in the lower percentile aspect of any input parameter have not been used in the calculations. 8.0 HUMAN AND DOMESTIC ANIMAL INCIDENT DATA REVIEW Data on incidents of adverse reactions in humans exposed to carbaryl were evaluated from several sources, including OPP's Incident Data System, Poison Control Centers, California Department of Pesticide Regulation, National Pesticide Telecommunications Network and the open literature. The data from the Incident Data System indicated that a majority of cases from carbaryl exposure involved dermal reactions. A number of cases involved asthmatics and people who experienced hives and other 106 allergic type reactions. According to California data, about half of the cases involved skin and eye effects in handlers. About a quarter of the skin reactions were due to workers that were exposed to residues on crops. Reports from the literature are very limited but tend to support the finding that carbaryl has irritant properties. The Poison Control Center cases involving non­ occupational adults and older children showed an increased risk in five of the six measures reported. These cases were almost twice as likely to require serious health care (hospitalization or treatment in a critical care unit) and were two and a half times more likely to experience major medical outcome (life­ threatening effects or significant residual disability) as compared to other pesticides. This pattern of increased risk was not seen among occupational reports or in young children. This may mean careless handling by non­ professionals is a particular hazard. Five case reports suggested that carbaryl may be a cause of chronic neurological or psychological problems. Some of these effects appear to be consistent with those reported from organophosphate poisoning. However, unlike organophosphates, no controlled studies have been undertaken. If such effects occur as a result of over­ exposure to carbaryl, they appear to be relatively rare. The effects reported among the five case reports are too inconsistent to draw any conclusions, but do suggest the need for further study. Carbaryl appears capable of causing dermal and allergic type reactions. Data support the need for personal protective equipment and eye protection for handlers for field workers who may have extensive exposure to carbaryl. Labels for products should advise that carbaryl can cause sensitizing effects in some people. Based on an evaluation of limited incident data on domestic animals in IDS, it is recommended that all labels for carbaryl products used on cats contain the age restriction stated in PR Notice 96­ 6 (should not be used in kittens less than 12 weeks of age). A detailed discussion of the incident data is presented in Appendix 2. 9.0 DATA NEEDS Toxicology data gaps ° 90­ day inhalation study in rats with cholinesterase measurements Product chemistry data gaps ° A review of the labels and supporting residue data indicate that several label amendments are required. Details are provided in the Product and Residue Chemistry Chapters (DP Barcode: D240989) dated November 14, 2000. ° The requirement for acceptable enforcement methods which determine residues of concern in plant and livestock commodities remains outstanding. ° The requirements for storage stability data are not satisfied for purposes of reregistration. 107 Additional data are required depicting the storage stability of carbaryl per se in an oilseed, processed commodities of an oily crop, and a dried fruit stored for up to 10 months. In addition, the registrant is relying on earlier magnitude of the residue studies that are not supported by the existing storage stability data; therefore, additional storage stability data are required. The required data must reflect storage intervals of 18 months for alfalfa commodities, 15 months for potatoes, 17 months for cottonseed, 22 months for wheat commodities, and 33 months for rangeland grass. In addition, if the registrant wishes to rely on the previously submitted sugar beet processing study, information pertaining to sample conditions and intervals for the study must be submitted. ° For the purpose of reregistration, the requirements for storage stability data for carbaryl residues in livestock commodities are partially satisfied. Additional information on the storage intervals prior to analysis for metabolite residues in the cattle feeding study is required. ° Separate tolerances on many commodities need to be reassigned concomitant with establishing tolerances for the appropriate crop group and subgroup. The recommended changes are summarized in Table C under "Tolerances Needed Under 40 CFR §180.169( a), crop group/ subgroup tolerances" of the Product and Residue Chemistry Chapters. ° The data submitted are not adequate to support the use of granular (G) formulations of carbaryl on leafy vegetables. Residues of carbaryl found in leaf lettuce were not consistent. Both samples of lettuce from the 10% G treatment had substantially higher residues (37.01 and 47.22 ppm) than one of the samples treated with the FlC (23.25 ppm). Additionally, all residues were significantly above the current tolerance of 10 ppm and all residue data submitted in support of the tolerance in lettuce (< 8.85 ppm). No explanation for the higher residues was given by the registrant. The registrant may elect to repeat the side by side trial on leaf lettuce again or submit a rationale for the results of the leaf lettuce study. ° Data are required depicting residues of carbaryl in/ on grass forage harvested immediately (0­ day) following the last of two applications of carbaryl (WP or FlC) at 1.5 lb ai/ A to pasture. A total of 12 field trials are required in areas throughout the U. S. ° Adequate data are available to reassess the tolerances for residues of carbaryl in/ on dried beans, cowpeas, lentils and peas with pods. These data support the establishment of crop subgroup tolerances for edible­ podded legume vegetables (6A), and for dried, shelled pea and bean except soybean (6C). However, additional residue data are required if the registrant seeks tolerances for residues in/ on succulent, shelled pea and bean commodities. A total of 12 tests, six tests each on a succulent, shelled cultivar of bean and garden pea, are required to support a tolerance for residues in/ on the succulent, shelled pea and bean crop subgroup (6B). The registrant is referred to OPPTS GLN 860.1500 for the number and distribution of tests required. 108 ° Adequate data are available to reassess the tolerance for wheat forage and straw. However, the Agency now considers wheat hay a significant RAC for feed purposes (OPPTS GLN 860.1000 Table 1.). A full set of 20 field trials as specified in OPPTS GLN 860.1500 are required depicting carbaryl residues in/ on wheat hay. When all the field trials are complete, PHIs and tolerances for hay based on the field trial data should be proposed. Data on wheat hay will be translatable to proso millet hay. ° Adequate residue data are available on olives provided that use directions for olives are amended to remove the statement allowing the use of summer oil as an adjuvant. Alternatively, two additional field trials are required supporting the use of a carbaryl­ summer oil tank mix. ° The registrant intends to support a tolerance for residues of carbaryl in/ on imported pineapples (Aventis Crop Science personal communication with C. Olinger, 9/ 24/ 98 SMART meeting). Residue data are required depicting residues in/ on pineapples following application of carbaryl at the maximum use rate and minimum PHI. Five trials must be submitted, three from Costa Rica and two from Mexico. ° Additional data are required depicting carbaryl residues in/ on cotton gin byproducts derived from cotton treated at the maximum labeled rate and harvested 28 days after the final application using commercial equipment (stripper and mechanical picker). At least three field trials representing each type of harvesting (stripper and picker) are required. ° The registrant does not intend to support carbaryl uses on avocados, barley, maple sap, oats, rye, and sweet sorghum; however, IR­ 4 has indicated (Correspondence from K. Dorschner, IR­ 4 Project, 9/ 15/ 94) that they may fulfill the residue data requirements for some of these commodities. These data have not been submitted. ° The reregistration requirements for magnitude of the residue in livestock commodities are not fulfilled. Additional data are required to support dermal and poultry house uses. Occupational/ Residential Exposure Data Gaps Residential Exposure ° For the postapplication risk assessments, there are no data on the amount of residues transferrable from treated pets to humans. Additional residue data on turf would help refine the hand­ to­ mouth and object­ to­ mouth toddler exposures. Occupational Exposure ° For the occupational handler risk assessments, several exposure data gaps were identified, including: dust use for animal grooming and in agriculture; various specialized hand equipment application methods (e. g., powered backpack, power hand fogger, and tree injection); and nursery operations such as seedling dips. 109 ° For occupational postapplication risk assessments, several data gaps exist, such as an incomplete dislodgeable foliar residue database and a lack of exposure data on partially mechanized cultural practices where there is a potential for exposure. ° There are also many kinds of mechanized activities that do not involve foliar contact that have not been addressed in this risk assessment. The scenarios include: transplanting many crops including in the ornamental and forestry industry; thinning some crops such as hops; some partially mechanized operations that also involve human contact (e. g., cotton harvesting where module builders and trampers are used); hand weeding some crops such as wheat; various operations with Christmas trees such as pruning or baling; and various operations with nut production such as sweeping for harvest. APPENDIX 1: Toxicology Profile Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90­ Day oral toxicity rodents N/ A 870.3150 90­ Day oral toxicity in nonrodents N/ A 870.3200 21/ 28­ Day dermal toxicity with technical carbaryl 45630601( 2002) acceptable/ nonguideline 0, 20, 50, 100 mg/ kg/ day systemic NOAEL = 20 mg/ kg/ day systemic LOAEL = 50 mg/ kg/ day based on decreased RBC cholinesterase in males and females and brain cholinesterase in males dermal NOAEL = 100 mg/ kg/ day dermal LOAEL not established 870.3200 21/ 28­ Day dermal toxicity with Sevin® XLR Plus (44.82% a. i.) 45630602 (2002) unacceptable/ nonguideline 0, 20, 50, 100 mcL/ kg/ day (0, 9.6, 24, 48 mg/ kg/ day) systemic NOAEL = 50 mcL/ kg/ day (24 mg/ kg/ day) systemic LOAEL = 100 mcL/ kg/ day (48 mg/ kg/ day) based on decreased body weight gain dermal NOAEL = 100 mcL/ kg/ day (48 mg/ kg/ day) dermal LOAEL not established 870.3200 21/ 28­ Day dermal toxicity with Sevin® 80S (80.07% a. i.) 45630603 (2002) unacceptable/ nonguideline 0, 20, 50, 100 mg/ kg/ day systemic NOAEL = 20 mg/ kg/ day systemic LOAEL = 50 mg/ kg/ day based on decreased RBC cholinesterase in males and females dermal NOAEL = 100 mg/ kg/ day dermal LOAEL not established 870.3250 90­ Day dermal toxicity N/ A 870.3465 90­ Day inhalation toxicity N/ A 870.3700a Prenatal developmental in rats 44732901 (1998) acceptable/ guideline 0, 1, 4, 30 mg/ kg/ day (oral gavage) Maternal NOAEL = 4 mg/ kg/ day LOAEL = 30 mg/ kg/ day based on clinical signs, decreased body weight gain (BWG) and food consumption Developmental NOAEL = 4 mg/ kg/ day LOAEL = 30 mg/ kg/ day based on decreased fetal body weight and incomplete ossification of multiple bones 870.3700b Prenatal developmental in rabbits 44904202 (1999) Acceptable/ guideline 0, 5, 50, 150 mg/ kg/ day (oral gavage) Maternal NOAEL = 5 mg/ kg/ day LOAEL = 50 mg/ kg/ day based on decreased BWG and plasma cholinesterase inhibition (ChEI) Developmental NOAEL = 50 mg/ kg/ day LOAEL = 150 mg/ kg/ day based on decreased fetal weight Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3800 Reproduction and fertility effects 45448101 (2001) acceptable/ guideline 0, 75, 300, 1500 ppm (4.67, 31.34, and 92.43 mg/ kg/ day for F0 males; 0, 5.56, 36.32, and 110.78 mg/ kg/ day for F0 females; 0, 5.79, 23.49, and 124.33 mg/ kg/ day for F1 males; and 0, 6.41, 26.91, and 135.54 mg/ kg/ day for F1 females averaged over the premating period) Parental NOAEL = 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) Parental LOAEL = 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption Reproductive toxicity NOAEL is $ 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) Reproductive toxicity LOAEL not be established Offspring NOAEL = 75 ppm (4.67­ 5.79 mg/ kg/ day for males and 5.56­ 6.41 mg/ kg/ day for females). Offspring LOAEL = 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival. 870.4100a Chronic toxicity in rodents N/ A 870.4100b Chronic toxicity in dogs 40166701 (1987) 0, 125, 400, 1250 ppm (0, 3.1, 10, 31.3 mg/ kg/ day) 42022801 (1991) 0, 20, 45, 125 ppm (5 weeks) (M: 0, 0.59, 1.43, 3.83; F: 0, 0,64, 1.54, 4.11 mg/ kg/ day) Together, the studies are Acceptable/ guideline MRID 40166701: NOAEL = not established in females LOAEL = 125 ppm based based on plasma and brain ChEI MRID 42022801: NOAEL = 45 ppm in males LOAEL = 125 ppm in males based on plasma ChEI 870.4200 Carcinogenicity in mice 42786901 (1993) Acceptable/ guideline 0, 100, 1000 or 8000 ppm (M: 0, 14.73, 145.99, 1248.93 mg/ kg/ day; F: 0, 18.11, 180.86, 1440.62) systemic LOAEL = 1000 ppm based on increased intracytoplasmic droplets in bladder in males and females, chronic progressive nephropathy in males; NOAEL = 100 ppm RBC ChEI LOAEL for males = 1000 ppm , for females = 8000 ppm; NOAEL = 100 ppm for males, 1000 ppm for females plasma ChEI for males and females LOAEL > 8000 ppm; NOAEL $ 8000 ppm brain ChEI for males and females LOAEL = 8000 ppm; NOAEL = 1000 ppm increase in vascular tumors in all treated males and in females at 8000 ppm increase in adenomas, multiple adenomas, carcinomas of kidney in males at 8000 ppm increase in hepatic neoplasms (adenomas, carcinomas, one hepatoblastoma) in females at 8000 ppm Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.4300 Chronic Toxicity/ Carcinogenicity in rats 42918801 (1993) Acceptable/ guideline 0, 250, 1500 & 7500 ppm (M: 0, 10, 60.2, 349.5 mg/ kg/ day; F: 0, 12.6, 78.6, 484.6 mg/ kg/ day) systemic LOAEL = 1500 ppm in females based on decreased BW and BWG; 7500 ppm in males based on increased clinical signs, decreased BW, BWG and food consumption, increase in cataracts, clinical pathology changes, organ weight changes, nonneoplastic changes; NOAEL = 250 ppm in females and 1500 ppm in males plasma ChEI LOAEL = 7500 ppm in males and females; NOAEL = 1500 ppm RBC ChEI LOAEL = 1500 ppm in males and females; NOEL = 250 ppm brain ChEI LOAEL = 7500 ppm in males and females; NOEL = 1500 ppm at 7500 ppm, increase in liver adenomas in females, increase in benign transitional cell papillomas and transitional cell carcinomas in males and females, transitional cell carcinoma in kidney of one male, increase in benign thyroid follicular cell adenomas in males, follicular cell carcinoma in one male Bacterial reverse mutation test 870.5100 41370303 (1989) Acceptable/ guideline 5­ 1000 ug/ plate No evidence of mutagenicity in strains TA1535, TA 1537, TA1538, TA98 and TA100 with and without metabolic activation In vitro mammalian chromosome aberration test (Chinese hamster ovary cells) 870.5385 41370304 (1989) Acceptable/ guideline without S9 activation: 5­ 100 ug/ mL, harvest at 20 hrs.; with S9 activation: 25­ 300 ug/ mL, harvest at 30 hrs Increase in chromosome aberrations with S9 activation In vitro mammalian chromosome aberration test 870.5385 41370302; 41420201 (1989) Unacceptable/ guideline S9 activation: 1­ 300 ug/ mL in 3 trials; without S9 activation: 1­ 300 ug/ mL in 2 trials Results provide no clear indication of a mutagenic response, however study had several deficiencies Mammalian erythrocyte micronucleus test 870. 5395 44069301 (1996) Unacceptable/ guideline single oral gavage dose of 50, 100, 200 mg/ kg Carbaryl did not induce a clastogenic or aneugenic effect, however there was no convincing evidence that MTD was achieved Unscheduled DNA synthesis 870.5550 41370301; 41810601 (1989) Acceptable/ guideline 0.5 ­ 25.0 ug/ mL Negative 870.6200a Acute neurotoxicity screening battery in rats MRID: 43845201­ 43845204 (1995) Acceptable/ guideline 0, 10, 50, 125 mg/ kg (oral gavage) Separate study for ChEI: 0, 10, 30, 50 mg/ kg; ChEI done 1, 8, 24, 48 hrs postdosing Systemic LOAEL = 10 mg/ kg based on decreased RBC, plasma, blood, brain ChEI; NOAEL < 10 mg/ kg Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.6200b Subchronic neurotoxicity screening battery in rats MRID: 44122601 (1996) Acceptable/ guideline 0, 1, 10, 30 mg/ kg/ day (oral gavage) LOAEL for neurotoxicity = 10 mg/ kg/ day based on increased FOB changes; NOAEL = 1 mg/ kg/ day LOAEL for ChEI = 10 mg/ kg/ day based on decreased plasma, blood, RBC, brain ChEI; NOAEL = 1 mg/ kg/ day 870.6300 Developmental neurotoxicity in rats 44393701 (1997) Acceptable/ guideline 0, 0.1, 1.0, 10 mg/ kg (oral gavage) Maternal NOAEL = 1.0 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on decreased BWG; FOB changes; RBC, plasma, whole blood, brain ChEI Offspring tentative NOAEL = 1.0 mg/ kg/ day tentative LOAEL = 10 mg/ kg/ day based on alterations in morphometric measurements (measurements were not done at lower doses) 870.7485 Metabolism and pharmacokinetics in rats 43332101 (1994) Acceptable/ guideline 1 mg/ kg (single and repeated oral doses; intravenous dose) and 50 mg/ kg (single oral dose) Absorption was complete at all doses. At 168 hrs., post­ dose, negligible percentages of dose in any tissues. Kidney and blood contained highest concentrations of radioactivity. Excretion mostly through urine. A metabolic scheme with conjugated and non­ conjugated metabolites was proposed. 870.7485 Metabolism and pharmacokinetics in rats 44402501 (1997) Acceptable/ nonguideline 50 mg/ kg (single oral radiolabeled dose); daily oral radiolabeled dose of 2 mg/ kg for 7 days followed by 83 daily unlabeled doses of 0, 250, 1500 or 7500 ppm; males only In all dosing regimens, urinary and fecal excretion was 93­ 103% of administered dose and tissue levels of radioactivity were minimal at 168 hrs. post­ dosing. Two major metabolites in tissues at 6 hrs. post­ dosing were naphthyl sulfate and naphthyl glucuronide, however quantitation was not possible. A total of 23 and 20 components were identified in the urine and feces, respectively. The sulfate conjugation pathway appears to be saturable following a 83­ day feeding at 7500 ppm. BW and food consumption were decreased at 7500 ppm. Increases in kidney, spleen and thyroid weights were observed at 1500 and 7500 ppm. Non­ neoplastic changes in liver, thyroids and kidneys were observed at 7500 ppm. 870.7600 Dermal penetration in rats 43552901 (1995) 43.9% a. i. Acceptable 35.6, 403, 3450 ug/ cm 2 % absorbed at 10 hrs.: 12.7, 7.44 and 1.93 at 35.6, 403 and 3450 ug/ cm 2 , respectively 870.7600 Dermal penetration in rats 43339701 (1994) 80.1% a. i. Acceptable 63, 626, 3410 ug/ cm 2 % absorbed at 10 hrs: 8.90, 0.62 and 0.48 at 63, 626 and 3410 ug/ cm 2 , respectively Special studies in mice 43282201 (1994) Acceptable/ nonguideline male mice: single radiolabeled dose of 75 mg/ kg; pretreatment with 8000 ppm unlabeled carbaryl for 2 wks., then single radiolabeled dose of 75 mg/ kg Negative for DNA binding in liver Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Special studies in mice 43832601 (1994) Acceptable/ nonguideline continuation of MRID 43282201 in liver from mice treated at 8000 ppm, increase in microsomal protein, cytochrome P450, ethoxyresorufin O­ deethylase, pentoxyresorufin O­ depentylase, and testosterone hydrolases indicates phenobarbital type of induction of metabolizing enzymes Special study in mice 45281801, 45281802, 45236603 (1998­ 1999) Acceptable/ nonguideline 0, 10, 30, 100, 300, 1000 and 4000 ppm (0, 1.8, 5.2, 17.5, 51.2, 164.5 and 716.6 mg/ kg/ day) There was no evidence of neoplastic or preneoplastic changes in vascular tissue in heterozygous p53­ deficient male mice treated with carbaryl for six months. N/ A Not Available APPENDIX 2: Incident Review Conclusions/ Recommendations Based on Incident Review Data on incidents of adverse reactions in humans exposed to carbaryl were evaluated from several sources, including OPP's Incident Data System, Poison Control Centers, California Department of Pesticide Regulation, National Pesticide Telecommunications Network and the open literature. The data from the Incident Data System indicated that a majority of cases from carbaryl exposure involved dermal reactions. A number of cases involved asthmatics and people who experienced hives and other allergic type reactions. According to California data, about half of the cases involved skin and eye effects in handlers. About a quarter of the skin reactions were due to workers that were exposed to residues on crops. Reports from the literature are very limited but tend to support the finding that carbaryl has irritant properties. The Poison Control Center cases involving non­ occupational adults and older children showed an increased risk in five of the six measures reported. These cases were almost twice as likely to require serious health care (hospitalization or treatment in a critical care unit) and were two and a half times more likely to experience major medical outcome lifethreatening effects or significant residual disability) as compared to other pesticides. This pattern of increased risk was not seen among occupational reports or in young children. This may mean careless handling by non­ professionals is a particular hazard. Five case reports suggested that carbaryl may be a cause of chronic neurological or psychological problems. Some of these effects appear to be consistent with those reported from organophosphate poisoning. However, unlike organophosphates, no controlled studies have been undertaken. If such effects occur as a result of over­ exposure to carbaryl, they appear to be relatively rare. The effects reported among the five case reports are too inconsistent to draw any conclusions, but do suggest the need for further study. Carbaryl appears capable of causing dermal and allergic type reactions. Data support the need for personal protective equipment and eye protection for handlers for field workers who may have extensive exposure to carbaryl. Labels for products should advise that carbaryl can cause sensitizing effects in some people. Based on an evaluation of limited incident data on domestic animals in IDS, it is recommended that all labels for carbaryl products used on cats contain the age restriction stated in PR Notice 96­ 6 (should not be used in kittens less than 12 weeks of age). A detailed discussion of the incident data is presented below. Human Incident Data Review A review of the human incident data on carbaryl was prepared by Dr. Jerome Blondell and Ms. Monica Spann (D267127 dated July 17, 2000). The following data bases were consulted for the poisoning incident data on the active ingredient Carbaryl (PC Code: 056801): 1) OPP Incident Data System (IDS) ­ reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. 2) Poison Control Centers ­ as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1998 for all pesticides. Most of the national Poison Control Centers (PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System which obtains data from about 65­ 70 centers at hospitals and universities. 3) California Department of Pesticide Regulation ­ California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required, by statute, to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides. 4) National Pesticide Telecommunications Network (NPTN) ­ NPTN is a toll­ free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984­ 1991 and 1995­ 1999 has been prepared for the categories human incidents, animal incidents, calls for information, and others. Incident Data System There were approximately 500 reports in IDS concerning exposure of humans to carbaryl. At least 380 cases were considered minor (minimal symptoms with no residual disability) and were not included in the review. The most frequently reported symptoms were of a dermatological nature, either dermal irritation or possibly a dermal manifestation of an allergic response (e. g., hives, welts, rash, etc.). Clinical signs or symptoms less frequently reported were nausea, vomiting, diarrhea, respiratory irritation and difficulty breathing. Most of the incidents were associated with dermal exposure; however, a few resulted after inhalation of the product. There was one report of an attempted suicide. In 1993, a 21­ year old man ingested about 75 ml of Beetle Bait (21.3% carbaryl, Registration Number 869­ 134). No information on the symptoms or outcome of the case were provided. There was also one death. In 1996, a woman with a history of chronic asthma experienced shock and severe respiratory distress after she used Mycodex Pet Shampoo (0.5% carbaryl, Registration Number 2097­ 8) on her dog. She was hospitalized but went into a coma and died five days later (IDS 3694­ 1). Poison Control Center (PCC) Data ­ 1993 through 1998 The PCC data base for 1993 through 1998 contained 174 cases involving occupational exposures in adults and older children (outcome determined in 90 cases), 3033 nonoccupational exposures in adults and older children (outcome determined in 1351 cases) and 2147 exposures in children under the age of six (outcome determined in 1248 cases). Cases involving exposures to multiple products were excluded. The data from cases in which the outcome was determined were compared to all other pesticides using six measures: percent with symptoms, percent with moderate or more severe outcome, percent with life­ threatening or fatal outcome, percent of exposed cases seen in a health care facility, percent hospitalized and percent seen in an intensive care facility. For occupational cases, carbaryl appears to be somewhat less hazardous than all pesticides combined, as determined by five of the six measures reported. Cases involving non­ occupational adults and older children showed an increased risk in five of the six measures reported. In particular these non­ occupational cases were nearly twice as likely to require serious health care (hospitalization or treatment in a critical care unit) and were 2.5 times more likely to experience major medical outcome (life­ threatening effects or significant residual disability). These data suggest that some consumers are using this chemical in a careless manner. For cases involving children under six years of age, carbaryl has a similar hazard profile to all other pesticides. California Data ­ 1982 through 1996 Detailed descriptions of 226 cases submitted to the California Pesticide Illness Surveillance Program (1982­ 1996) were reviewed. In 90 of these cases, carbaryl was used alone or was judged to be responsible for the health effects. Only cases with a definite, probable or possible relationship were reviewed. Carbaryl ranked 37 th as a cause of systemic poisoning in California. The number of reports from California declined by over half from the first five years of the reporting period (1982­ 1986) to the last five years (1992­ 1996). It is difficult to determine whether some of this decline might be related to a decrease in usage because the method of collecting use information changed after 1989. Of the 90 persons reported to have illnesses, a total of 43 (48%) had systemic illnesses, 20 (22%) had eye irritation, 21 (23%) had skin irritation, 1( 1%) had respiratory illness and 5 (6%) had a combination of effects. A total of 26 workers were disabled (took time off work, 1 for more than 10 days) as the result of carbaryl exposure. Seven required hospitalization (1­ 5 days). Applicators were associated with the majority of the exposures. Clinical signs/ symptoms in these workers included nausea, vomiting, skin rashes, sore throat, lip swelling, chemical conjunctivitis, dizziness, eye irritation, contact dermatitis, blurry vision, chest pains, and several other symptoms. National Pesticide Telecommunications Network On the list of the top 200 chemicals for which NPTN received calls from 1984­ 1991 inclusively, carbaryl was ranked 5 th with 503 incidents in humans reported and 85 incidents in animals (mostly pets). For the years 1995 through 1998, carbaryl's rank ranged from 7 th to 12 th with 110 incidents in humans reported and 26 incidents in animals. Most of the decline in reported human cases from the earlier time period is due to the reduced level of incident reporting overall. However, even taking this into account, there does appear to be some reduction in carbaryl incidents which is also reflected in the lower rankings reported for the later years (1995­ 1998). Literature Summary Thirteen epidemiological studies/ case reports from the open literature were reviewed. Five case reports suggested that carbaryl may cause long­ term neurological or 12 Branch RA, Jacqz E (1986). Is carbaryl as safe as its reputation? Does it have a potential for causing chronic neurotoxicity in humans?. The American Journal of Medicine 80( 4): 659­ 664. 13 Brewer B (2000). A rare cause of acute confusional state (Letter to the Editor). Journal of Accidental Emergency Medicine 17( 1): 77. 14 Devinsky O, Kernan J, Bear DM (1992). Aggressive behavior following exposure to cholinesterase inhibitors. Journal of Neuropsychiatry 4( 2): 189­ 194. 15 Dickoff DJ, Gerber O, Turovsky Z (1987). Delayed neurotoxicity after ingestion of carbamate pesticide. Neurology 37( 7): 1229­ 1231. 16 Wiener PK, Young RC (1995). Late­ onset psychotic depression associated with carbaryl exposure. American Journal of Psychiatry152( 4): 646­ 647. 17 Savitz DA, Arbuckle T, Kaczor D, Curtis KM. (1997). Male pesticide exposure and pregnancy outcome. American Journal of Epidemiology 146( 12): 1025­ 1036. 18 Whorton DM, Avashia BH, Hull EQ. (1979). Testicular function among carbaryl­ exposed employees. Journal of Toxicology and Environmental Health 5: 929­ 941. 19 Wyrobek AJ, Watchmaker G, Gordon L, Wong K, Moore D 2d, Whorton D (1981). Sperm shape abnormalities in carbaryl­ exposed employees. Environmental Health Perspectives 40: 255­ 265. psychologicalproblems. 12,13,14,15,16 Two of these cases involved attempted suicides in which large doses of carbaryl­ containing products were ingested. Some of the effects from carbaryl exposure are consistent with those reported from organophosphate poisoning. However, no controlled studies have been conducted. If such effects occur as a result of carbaryl overexposure they appear to be relatively rare. The effects observed in the case reports are too inconsistent to draw any conclusions, but do suggest the need for further study. Other literature articles concerned epidemiology studies to evaluate the effects of pesticides on reproduction. In the 1979 Ontario Farm Family Study by Savitz et al 17 , the effects of activities and specific pesticides on male farmer's fertility were considered. The results suggested that thiocarbamates, carbaryl and other pesticides were most strongly associated with miscarriage. The adjusted odds ratio for carbaryl used on crops was 2.1 with a 95 percent confidence interval of 1.1 to 4.1 (borderline significance). Use of carbaryl in the yard was not associated with a significantly increased risk of miscarriage and carbaryl was not a significant risk factor for preterm delivery or small for gestational age births. In a 1979 study of male workers who produced and packaged carbaryl, Whorton et al 18 concluded that there was no evidence of sperm count suppression resulting from exposure to the chemical. Whorton et al. (1979) and Wyrobek et al 19 (1981) used the same cohort in their studies to determine the effects on fertility by checking for infertile marriages and by measuring sperm counts and serum gonadotropins. The carbaryl­ exposed group included nearly three times as many oligospermic men as the control group. Wyrobek et al. (1981) concluded there was a non­ dose related, significant elevation in sperm head abnormalities compared to controls, that may not be reversible. Both of the studies had low participation rates, relied on self­ reporting of exposure levels, and used less than ideal control groups. 20 Senthilselvan A, McDuffie HH, Dosman JA. 1992. Association of asthma with use of pesticides. Results of a cross­ sectional survey of farmers. Am Rev Respir Dis 146( 4): 884­ 887. 21 Sharma VK, Kaur S. 1990. Contact sensitization by pesticides in farmers. Contact Dermatitis 23: 77­ 80. There were also two studies assessing carbaryl's potential to induce an allergic reaction. Senthilselvan et al. (1992) 20 reported on the association between self­ reported asthma and pesticide use in 1,939 farmers. The prevalence of asthma was significantly associated with the use of carbamate insecticides regardless of age, smoking pack­ years, and nasal allergic reactions. The authors concluded that the possibility of exposure to agriculture chemicals could be related to lung dysfunction in exposed farmers. Sharma and Kaur (1990) 21 reported on 30 farmers that had contact dermatitis after using pesticides for several years. The farmers included 25 males and 5 females, between the ages of 28 and 70 years old. Patch testing was conducted on the upper back and readings were taken on the second, third, and seventh day. Allergic reactions to one or more pesticides were seen in 11 patients. One patient was sensitive to carbaryl and two patients to 3 each (2,4­ D, thiram, carbaryl; pendimethalin, methyl parathion and carbofuran). Carbamates, including carbaryl, were the most frequent sensitizers. Allergic reactions did not occur in the twenty controls included in the study. Unpublished Epidemiology Study Rhone­ Poulenc submitted an epidemiologic study of plant workers exposed to carbaryl titled "Standardized Mortality Ratio Analysis of Employees Exposed to Carbaryl at the RhonePoulenc Institute, West Virginia Plant", which was reviewed by Dr. Jerome Blondell (DP Barcode D194815). The results were part of a ten year vital status update undertaken by the National Institute of Occupational Safety and Health. The study included all individuals who were first hired between 1960 (when the production of carbaryl started) and through 1978. The vital status of all workers was determined through 1988 using the National Death Index. A total of 522 employees were identified as belonging to either the production, packing/ distribution, or maintenance facilities. Follow­ up through 1988 showed 25 deaths, including nine due to cancer. Significantly less deaths (50%) were seen compared to the number expected. No category of death resulted in a statistically significant excess. Those categories that exhibited an excess (greater than the number of expected cases) were usually based on a single reported death with very wide confidence intervals. For brain cancer, there were two deaths (0.5 expected), but they had different histologic origin which reduces the likelihood that they were due to the same exposure. HED concluded that the epidemiologic study does not add significant new information concerning adverse health effects of carbaryl. The sample of workers was too small and the period of follow up to too short to permit definitive conclusions. Domestic Animal Incident Review The domestic animal incident review was prepared by Dr. Virginia Dobozy (D266621 dated June 12, 2000). There are approximately 69 active products containing carbaryl with use sites for dogs and cats in OPP's Reference File System (REFS). The majority of the products are 5­ 10% lawn and garden dusts, which may be registered for use on animal bedding and thus are included in the REFS search. Most of the powders for intentional application to dogs and cats for flea and tick control also contain 5­ 10% carbaryl, some in combination with pyrethrins and synergists. However, two products contain 12.5% carbaryl in combination with pyrethrins. Three products contain carbaryl (10­ 12.5%) in combination with 0.25% methoxylchlor. There is one shampoo which contains 0.5% carbaryl, two flea collars with either 9.5% (cats) or 17% (dogs) carbaryl and a dip for dogs with 60% carbaryl. In general, the use of powders, dips and sprays for flea and tick control in dogs and cats has been replaced within the last five years with oral (FDA regulated) or spot­ on formulations. As there are no spot­ on carbaryl preparations, it can be assumed that the use of this chemical for flea and tick control has declined. There are 213 reports in IDS for carbaryl for domestic animals from 1991 to May, 2000. Only those incidents from 1998 (most recent year with complete data) were reviewed in order to provide an evaluation of current adverse reports in domestic animals. In 1998, there were 35 incidents in IDS involving 23 dogs, 9 cats and 1 pig. One incident involved two dogs and in three incidents, the species was not identified. Only two incidents involved products registered for use on dogs and cats. In one, an 8 week­ old kitten treated with Zodiac Flea and Tick Powder for Dogs developed vomiting and anorexia and died the next day. In the other, a dog was reported to have had a reaction to a shampoo with carbaryl; no other data were provided. The majority of the remaining incidents involved products containing a 5% carbaryl dust or a molluscicide which contains 2% metaldehyde and 5% carbaryl. A wide variety of clinical signs were reported. Most of the incidents were evaluated and classified as to causality (doubtful, low, moderate or high suspicion) by the ASPCA/ National Animal Poison Control Center. All were classified as doubtful or low suspicion. A summary review of incidents for a 5% carbaryl powder from one registrant, along with the one report from 1998, provided some evidence that young kittens (< 12 weeks) may be susceptible to adverse reactions to carbaryl. It is recommended that all labels for carbaryl products used on cats contain the age restriction stated in PR Notice 96­ 6 (should not be used in kittens less than 12 weeks of age).

epa

2024-06-07T20:31:42.114605

regulations

EPA-HQ-OPP-2002-0138-0005

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES May 29, 2002 Memorandum SUBJECT: Carbaryl: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document. PC Code 056801; Submission No. S533427 ;DP Barcode: D281418. FROM: Jeffrey L. Dawson, Chemist/ Risk Assessor Reregistration Branch 1 Health Effects Division (7509C) THROUGH: Whang Phang, PhD, Senior Scientist Reregistration Branch 1 Health Effects Division (7509C) TO: Anthony Britten, Chemical Review Manager Reregistration Branch Special Review and Registration Division Reviewers: Science Advisory Committee on Exposure; Alan Nielsen. Risk Assessment Review Committee (June 6, 2001 Report) This document presents updated occupational and residential exposures/ risks which have been calculated due to recent changes in the hazard assessment for carbaryl (April 25, 2002 HIARC Meeting) and changes in the FQPA safety factor from 10 to 1 based on recent policy changes (April 3, 2002 FQPA SFC Report). Several modifications to the exposure assessment have also been incorporated due to recent changes in Exposure SAC Policy (e. g., how risks from pet use products are calculated, the use of ARTF data from greenhouses, and mosquito control applications), the submission of a Sevin XLR Label for mosquito control, and changes in the short­ term/ intermediateterm exposure duration interface from 7 days to 30 days. Also included in this document is a sitespecific assessment of risks associated with a Section 24C (SLN WA­ 900013) where carbaryl is intended to control Ghost and Mud Shrimp in oyster beds. Table of Contents Executive Summary.............................................................. 4 1.0 Occupational and Residential Exposure/ Risk Assessment ......................... 12 1.1 Purpose .............................................................. 12 1.2 Criteria for Conducting Exposure Assessments .............................. 12 1.3 Summary of Hazard Concerns ......................................... 12 1. 4 Incident Reports.................................................... 14 1. 5 Summary of Use Patterns and Formulations .............................. 14 1.5.1 End­ Use Products ............................................ 15 1.5.2 Mode of Action and Targets Controlled ........................... 17 1.5.3 Registered Use Categories and Sites ............................. 18 1.5.4 Application Parameters ....................................... 22 2.0 Occupational Exposures and Risks .......................................... 25 2.1 Occupational Handler Exposures and Risks ................................. 25 2.1.1 Handler Exposure Scenarios .................................... 26 2.1.2 Data and Assumptions For Handler Exposure Scenarios .............. 30 2.1.3 Occupational Handler Exposure and Non­ Cancer Risk Estimates ....... 45 2.1.4 Occupational Handler Exposure and Risk Estimates for Cancer. ........ 56 2.1.5 Summary of Risk Concerns and Data Gaps for Handlers .............. 62 2.1.6 Recommendations For Refining Occupational Handler Risk Assessment . 63 2.2 Occupational Postapplication Exposures and Risks ........................ 63 2.2.1 Occupational Postapplication Exposure Scenarios ................... 63 2.2.2 Data and Assumptions for Occupational Postapplication Exposure Scenarios ........................................................... 69 2.2.3 Occupational Postapplication Exposure and Noncancer Risk Estimates . . 77 2.2.4 Occupational Postapplication Exposure and Risk Estimates for Cancer ........................................................... 86 2.2.5 Summary of Occupational Postapplication Risk Concerns and Data Gaps ........................................................... 92 2.2.6 Recommendations For Refining Occupational Postapplication Risk Assessment.................................................. 93 2. 3 Occupational Risk Characterization .................................... 93 2.3.1 Handler Characterization ....................................... 93 2.3.2 Postapplication Characterization ................................. 95 3.0 Residential and Other Non­ Occupational Exposures and Risks ..................... 97 3.1 Residential Handler Exposures and Risks ................................ 97 3.1.1 Handler Exposure Scenarios .................................... 98 3.1.2 Data and Assumptions For Handler Exposure Scenarios .............. 99 3.1.3 Residential Handler Exposure and Non­ Cancer Risk Estimates ........ 108 3.1.4 Residential Handler Exposure and Risk Estimates for Cancer ......... 113 3.1.5 Summary of Risk Concerns and Data Gaps for Handlers ............. 117 3.1.6 Recommendations For Refining Residential Handler Risk Assessment . . 117 3.2 Residential Postapplication Exposures and Risks ......................... 117 3.2.1 Residential Postapplication Exposure Scenarios .................... 118 3.2.2 Data and Assumptions for Residential Postapplication Exposure Scenarios .......................................................... 123 3.2.3 Residential Postapplication Exposure and Noncancer Risk Estimates . . . 129 3.2.4 Residential Postapplication Exposure and Risk Estimates for Cancer . . . 142 3.2.5 Summary of Residential Postapplication Risk Concerns and Data Gaps . 144 3.2.6 Recommendations For Refining Residential Postapplication Risk Assessment .......................................................... 146 3. 3 Residential Risk Characterization ..................................... 146 3.3.1 Handler Characterization ...................................... 146 3.3.2 Postapplication Characterization ................................ 147 Appendix A: Use Information For Carbaryl Appendix B: Carbaryl Occupational Handler Exposure Data Appendix C: Carbaryl Occupational Handler Risk Assessment Appendix D: Carbaryl Residue Dissipation (DFR & TTR) Data Appendix E: Carbaryl Occupational Postapplication Risk Assessment Appendix F: Carbaryl Residential Handler Exposure Data Appendix G: Carbaryl Residential Handler Risk Assessment Appendix H: Carbaryl Residential Postapplication Risk Assessment For Turf Uses Appendix I: Carbaryl Residential Postapplication Risk Assessment For Garden/ Ornamental Uses Appendix J: Carbaryl Residential Postapplication Risk Assessment For Pet Uses Appendix K: Determination of Deposition Factors For Carbaryl Mosquito Control Uses Appendix L: Carbaryl Residential Postapplication Risk Assessment For Mosquito Control Appendix M: Carbaryl Residential Postapplication Risk Assessment For Oyster Bed Uses 4 Executive Summary Carbaryl [1­ napthyl methylcarbamate] is one of the most widely used broadspectrum insecticides in agriculture, professional turf management, professional ornamental production, and in the residential pet, lawn and garden markets. Carbaryl formulations include baits, dusts, pet collars, flowable concentrates, emulsifiable concentrates, granulars, soluble concentrates, and wettable powders. Carbaryl is used in agriculture to control pests on terrestrial food crops including fruit and nut trees (e. g., apples, pears, almonds, walnuts, and citrus), many types of fruit and vegetables (e. g., cucumbers, tomatoes, lettuce, blackberries, and grapes), and grain crops (e. g., corn, rice, sorghum, and wheat). Carbaryl is also used for direct animal treatments to control pests on poultry and companion animals such as dogs and cats. There are other uses for ornamentals and turf, including production facilities such as greenhouses, golf courses, and residential sites that can be treated by professional applicators (e. g., annuals, perennials, shrubs). Carbaryl can also be used by homeowners on lawns, for home and garden uses, and on companion animals. There are no labels for indoor uses such as crack­ and­ crevice treatments of a residence. In agriculture, groundboom, airblast, and aerial applications are typical. Other applications can also be made using handheld equipment such as low pressure handwand sprayers, backpack sprayers, and turfguns. Homeowners can also use other types of application equipment including trigger sprayers, hose­ end sprayers, and ready­ to­ use dust packaging. Carbaryl also has more specialized uses that can lead to exposures in the general population which were considered in this assessment such as an adulticide for mosquito control and for Ghost and Mud shrimp control in oyster beds in Washington State. A number of studies were considered in the development of the carbaryl risk assessment that include scenario­ and/ or chemical­ specific handler exposure data for occupational uses and also for residential uses. Chemical­ specific residue dissipation data were also considered for agricultural crops, turf, and the oyster bed uses. The occupational handler exposure studies that were used, quantified: exposure to pet groomers using a carbaryl containing shampoo; exposure during application of a granular with two different backpack devices and spoons; application with a trigger sprayer; and application to turf with high volume/ low pressure handgun for liquid sprays and a granular spreader. There are no data compensation issues associated with any of these data. In all other cases, occupational handler exposure was addressed using PHED (Pesticide Handlers Exposure Database). The occupational postapplication assessment was completed using 5 different residue dissipation studies on 4 crops and turf. The dislodgeable foliar residue (DFR) dissipation studies were all conducted by the Agricultural Reentry Task Force (ARTF) using carbaryl on cabbage, olives, sunflowers, and tobacco. Again, there are no data compensation issues associated with the DFR data because Aventis is a member of the ARTF. The sunflower and tobacco data were used only to assess risks for their specific crop groups because of aerial application with the sunflowers and due to various features of the tobacco crop (e. g., leaf type and shape). The olive and cabbage data were generally used to complete the assessments for all tree crops and all other crops, respectively. The turf transferable residue (TTR) data were generated by the Aventis Corporation at sites in California, Georgia, and Pennsylvania. These chemical­ specific dissipation data were all used in conjunction with the Agency's revised policy on transfer coefficients to calculate postapplication exposures and risks (August 7, 2000/ Policy 003.1). All of the studies used by the 5 Agency to assess occupational risks were considered to be the best source of data available for the scenario where it was used. These recent studies are all considered high quality based on current Agency guidance. The oyster bed uses were evaluated using sediment and water concentration data generated by the Washington State Department of Ecology or the Shoalwater Creek Indian Tribe. A number of other studies were submitted by the Aventis Corporation that focused on quantifying exposures during the application of homeowner products. Three studies used carbarylcontaining products to quantify exposures during application of a dust to dogs, application of various products to gardens (i. e., dusts, trigger sprayer, and liquid application with hose­ end sprayer or low pressure handwand), and application of a liquid to trees and shrubs using a hose­ end sprayer or low pressure handwand sprayer. In addition to these studies, which were all conducted by the Aventis Corporation, an additional study completed by the ORETF that quantified exposures during granular application to turf with a rotary spreader and during liquid spray application to turf with a hose­ end sprayer was used. Aventis is a member of the ORETF so there are no data compensation issues associated with the use of this study. For postapplication exposures, Aventis also submitted a study which quantified dermal exposure on turf using oxadiazon (Ronstar formulation). The Agency did not use this study in the risk assessment because of technical issues including levels of transferability compared to the carbaryl TTR data and the dormant timing of the application which is not typical for carbaryl. In cases where chemical­ or scenario­ specific data were unavailable, the Agency relied on guidance provided in the SOPs For Residential Exposure Assessment and various supporting documents. This risk assessment incorporates the recent revisions by the HIARC and reconsideration of the FQPA safety factor based on recently revised policies. Calculations have been completed for short­ term and intermediate­ term exposures for all occupational scenarios. Chronic exposures have also been calculated for a limited number of scenarios in the ornamental/ greenhouse industry where such exposure patterns might be expected. Risks for residential handlers are considered to be shortterm in nature only because homeowner uses are expected to be infrequent. Residential postapplication risks have been calculated based on short­ term and intermediate­ term exposures because repeated postapplication exposures are likely while they are not for handlers based on use patterns. Cancer risks were calculated for all adults scenarios using a linear, low­ dose extrapolation approach (LADD or Lifetime Average Daily Dose and Q1*). The short­ and intermediate­ term dermal risk assessments for carbaryl were based on a 21­ day dermal toxicity study in rats that used technical material where decreases in red blood cell and brain cholinesterase were observed (NOAEL = 20 mg/ kg/ day). The short­ term inhalation and nondietary ingestion risk assessments for carbaryl were based on a developmental neurotoxicity study in rats where alterations in FOB parameters on the first day of dosing were observed (NOAEL = 1 mg/ kg/ day). The results of this study were applied to short­ term exposure durations of up to 30 days. The intermediate­ term inhalation and non­ dietary ingestion risk assessments for carbaryl are based on a subchronic neurotoxicity study in (NOAEL = 1 mg/ kg/ day). The effects that were observed and selected as the basis for the endpoint used in risk assessment included decreases in plasma, red blood cell, whole blood and brain cholinesterase activity and changes in functional observational battery (FOB) parameters. The results of this study were applied to exposure durations greater than 30 days up to several months. The chronic risk assessments for carbaryl were based on a 1 year dog feeding study 6 (LOAEL = 3.1 mg/ kg/ day). The effects that were observed and selected as the basis for the endpoint used in risk assessment included decreases in plasma, and brain cholinesterase activity. The results of this study were applied to chronic exposure durations and to all routes of exposure (i. e., dermal, inhalation, and non­ dietary ingestion). Carbaryl was classified as a Class C carcinogen and was assessed for carcinogenic risk from exposure using a linear, low dose extrapolation approach with a Q1* of 8.75 x 10 ­4 (mg/ kg/ day) ­1 . A dermal absorption factor of 12.7 percent was selected from a rat dermal absorption study using radiolabeled 14 C. A 100 percent inhalation absorption factor was used to convert all inhalation exposures to an oral equivalent inhalation dose. The Agency's level of concern for noncancer risks (i. e., target level for MOEs or Margins of Exposure) is defined by the uncertainty factors that are applied to the assessment. The Agency applies a factor of 100 in cases to account for inter­ species extrapolation to humans from the animal test species and to account for intra­ species sensitivity. In cases where a NOAEL was not identified and a LOAEL was used for risk assessments, an additional uncertainty factor of 3 was applied for chronic exposures. Based on the requirements of the 1996 Food Quality Protection Act, the Agency must also consider sensitive populations in its non­ occupational risk assessments. The Agency reduced the FQPA safety factor to 1x for non­ occupational exposures to carbaryl because there are no residual concerns regarding pre­ or post­ natal toxicity or with the completeness of the toxicity or exposure databases. The total uncertainty factors that have been applied to different noncancer risk assessments include 100 for short­ term and intermediate­ term occupational scenarios. Chronic occupational exposures, which are very limited in scope, have an uncertainty factor of 300 because a LOAEL from the chronic dog study has been used for risk assessment purposes. Since the FQPA safety factor is 1x, all residential scenarios have the same factors applied to each duration of exposure as well. Cancer risk levels were evaluated based on 1996 Agency guidance by then office director Dan Barolo that stipulates a risk concern ranging from 1x10 ­4 to 1x10 ­6 for occupational settings and 1x10 ­6 for residential settings. For occupational handlers, most scenarios have risks associated with them that meet or exceed the Agency's uncertainty factors for noncancer risk assessments (i. e., 100 for short­ term and intermediate­ term and 300 for chronic) and requirements for cancer risk results (i. e., range of 1x10 ­6 to 1x10 ­4 as defined by Office Director Barolo in 1996) at some level of personal protection. Current carbaryl labels typically require that handlers wear long pants, long­ sleeved shirts, and gloves. Respirators are generally not required. For most scenarios, the noncancer risks for this personal protection ensemble do not meet Agency risk requirements and additional levels of personal protection are required to achieve Agency risk targets. In fact, in many cases engineering controls such as closed loading systems or closed cab tractors are needed. The Agency does have risk concerns over the use of carbaryl in some agricultural and other occupational settings (i. e., MOEs at any level of personal protection are <100 or <300, depending on the duration). As would be expected, these scenarios with the highest associated risk also have high daily chemical use based on application rates or high acreages treated or the exposures for the scenarios in question are relatively high. Generally, the areas that appear to be problematic include: large acreage aerial and chemigation applications in agriculture or for wide area treatments such as mosquito control; airblast applications at higher rates; pet grooming; and the use of certain handheld equipment for applications to turf or gardens (e. g., bellygrinder). This general trend was essentially the same for 7 both short­ term and intermediate­ term exposures. Risks for corresponding scenarios based on cancer concerns were generally less than noncancer results across all scenarios. In fact, in all but one scenario, cancer risks were <1x10 ­4 at current carbaryl label requirements of single layer clothing, gloves, and no respirator for both private growers and commercial applicators. Higher levels of personal protection reduce this risk to <1x10 ­4 for all scenarios in both populations. If a 1x10 ­6 risk level is specified as a concern, results are similar in that risks for a majority of scenarios are <1x10 ­6 at current label requirements. In fact, only 8 of the 128 scenarios considered for private applicators have cancer risks >1x10 ­6 (and less than 1x10 ­4 ) even when the most protective ensembles of either protective clothing or engineering controls are considered. For commercial applicators, results indicate that risks for about half of the scenarios considered are <1x10 ­6 at current label requirements and that only 21 of the 128 scenarios considered have cancer risks >1x10 6 (and less than 1x10 ­4 ) even when the most protective ensembles of either protective clothing or engineering controls are considered. Several data gaps were also identified in many different use areas that include: dust use for animal grooming and in agriculture; various specialized hand equipment application methods (e. g., powered backpack, power hand fogger, and tree injection); and nursery operations such as seedling dips. Current label requirements specify 12 hour Restricted Entry Intervals (REIs) while PreHarvest Intervals (PHIs) are less than 7 days for most crops with some as long as 28 days. For all but the lowest exposure scenarios in some crops, MOEs do not meet or exceed required uncertainty factors until several days after application. If short­ term risks are considered, MOEs meet or exceed the Agency uncertainty factor generally in the range of 3 to 5 days after application for lower to medium exposure activities and from 8 to 12 days after application in most higher exposure scenarios. If intermediate­ term risks are considered, MOEs are not of concern based on a 30 day average exposures except for higher level exposures such as harvesting in some crops. Chronic exposures are of concern for the cut flower industry but not for other general greenhouse and nursery production activities based on the most recent ARTF data. Cancer risks were calculated for private growers and professional farmworkers with the only difference being the annual frequency of exposure days. Cancer risks for private growers and commercial farmworkers are generally in the 10 ­8 to 10 ­6 range on the day of application. If a 1x10 ­4 cancer risk is the target, the current REI would be adequate for all scenarios considered in the assessment. If a 1x10 ­6 cancer risk is used, then durations longer than the current REI should be considered for some cases which are not considered low to medium exposures. It should be noted that the cancer risk calculations are less restrictive than noncancer risk estimates for the same scenarios in all cases. Many mechanized or partially mechanized processes are possibly associated with the use of carbaryl that may limit or eliminate exposures (e. g., combines for grain harvest). Mechanized practices can be divided into fully mechanized activities that meet the definition of "No contact" in the Agency's Worker Protection Standard (WPS) and mechanically assisted practices with potential for exposure. In the case of fully mechanized activities, the Agency does not complete a quantitative exposure assessment but applies criteria outlined in the Agency's Worker Protection Standard (WPS). In cases of partially mechanized activities where the potential for exposure exists, the Agency assesses the resulting exposures similarly to those resulting from hand labor activities. The Agency also acknowledges that there is some potential for exposure because individuals 8 engaged in fully mechanized activities have short­ term excursions from the protected area for various reasons (e. g., unclogging machinery or equipment inspection for breakage). In these cases, the WPS § 170.112( c) Exception for short­ term activities applies. Several data gaps exist such as an incomplete DFR database and a lack of exposure data on partially mechanized cultural practices where there is a potential for exposure. Additionally, because of the number and breadth of carbaryl uses, there may be many exposure pathways where the transfer coefficient approach is not an appropriate model (e. g., hand transplanting where no foliar contact occurs) that have not been quantitatively addressed due to a lack of data. For residential handlers, MOEs associated with most scenarios (40 of 52 considered) are generally not of concern because they exceed the Agency's uncertainty factors for noncancer risk assessments (i. e., MOE = 100). The scenarios of concern involve the use of dusts (in gardens and on pets) and for some liquid sprays on gardens. Cancer risks were calculated for a single day of use then the allowable annual number of days exposure was defined based on a cancer risk limit of 1x10 6 . Based on a single day of exposure, cancer risks for most scenarios are in the 10 ­8 to 10 ­10 range although there is one scenario where the risks slightly exceed 1x10 ­6 (dusting dogs ­ 1.09x10 ­6 ) even for a single day of use. It should be noted that there are 5 scenarios where the allowable days per year of exposure is less than or equal to 5 which should be considered in conjunction with the use/ usage data from Aventis that indicates 5 uses per year is the 84 th percentile. The database for carbaryl is fairly complete compared to many other chemicals. Recent, high quality data generated by the Aventis Corporation and the ORETF, of which Aventis is a member, have been used to address the key residential uses of carbaryl on lawns, flower and vegetable gardens, and pets. Use and usage inputs also appear to be essentially consistent with the information provided by the Aventis Corporation at the 1998 SMART meeting. No key data gaps have been identified by the Agency at this time for residential handlers. However, it is likely that there are scenarios that remain unaddressed by the Agency at this time due to a lack of data or other meta information. The Agency will address other appropriate scenarios as they are identified. The Agency considered a number of residential postapplication exposure scenarios for different segments of the population including toddlers, youth­ aged children and adults. Short­ term and intermediate­ term noncancer risks were calculated for all scenarios. Additionally, cancer risks were calculated for the exposure scenarios involving adults. In residential settings, the Agency does not use REIs or other mitigation approaches to limit exposures because they are viewed as impractical and not enforceable. As such, risk estimates on the day of application are the key concern. 9 The Agency considered a number of exposure scenarios for products that can be used in the residential environment representing different segments of the population including toddlers, youthaged children and adults. Short­ term and intermediate­ term noncancer MOEs were calculated for all scenarios. Chronic exposures from pet collars were also considered. Additionally, cancer risks were calculated for the exposure scenarios involving adults where methods are currently available. Cancer risks were not calculated for children per Agency policy. In residential settings, the Agency does not use REIs or other mitigation approaches to limit exposures because they are viewed as impractical and not enforceable. As such, risk estimates on the day of application are the key concern. The Agency has short­ term risk concerns for exposures to adults doing heavy yardwork, for toddlers playing on treated lawns, and for toddlers that have contact with treated pets. Activities associated with home gardening (e. g., harvesting) and golfing for adults, home gardening for youthaged children or any age or activity considered in the adulticide mosquito control or oyster assessment do not have risk concerns even on the day of application (i. e., MOEs $ 100 on the day of application). For adults, the MOEs for heavy yardwork do not meet or exceed risk targets (i. e., MOE = 100) up to 5 days after application. For toddlers, the Agency has concerns for pet treatments and also for lawn uses. In fact, pet uses never reach acceptable levels even 30 days after application and not until 18 days at the maximum application rate considered on turf. Toddler MOEs from pet and turf uses represent total exposures from many pathways. For the pet uses, dermal and hand­ tomouth exposures essentially both equally contribute to the overall estimate. For the turf uses, dermal and hand­ to­ mouth exposures are also the key contributors to the overall estimates. The Agency does not have intermediate­ term risk concerns for adults and youth­ aged children for any of the uses considered including lawncare, home gardens, golfing, and any aspect of adulticide mosquito control. In contrast, the Agency does have intermediate­ term risk concerns for all toddler exposure scenarios considered (i. e., pet treatments and lawncare uses). As with the short­ term MOEs, pet and turf uses represent total exposures where the significant contributions to overall exposures are again made equally from the dermal and hand­ to­ mouth exposure pathways. Cancer risks were calculated only for adults and were found to be in the 10 ­8 to 10 ­11 range, regardless of the scenarios considered, on the day of application (e. g., lawncare, golfing and gardening). Risks did not exceed 1x10 ­6 on the day of application for any scenario considered. All postapplication cancer risks were calculated based on an annual frequency of 1 exposure per year. It is likely that additional events could occur but data linking postapplication activities and carbaryl use patterns are not available. To address this issue, the Agency calculated the number of exposures that can occur under a cancer risk ceiling of 1x10 ­6 and determined that from 20 days per year to exposures every day of the year could occur depending upon the scenario. Results indicate most activities can occur from every day of the year even at residue levels present on the day of application.. 10 Unlike many residential risk assessments, the postapplication residential assessment for carbaryl is based on a number of chemical­ specific studies that have been used to calculate risks from turf uses (e. g., TTR study) and in gardens (i. e., DFR data). There are no transferable residue data available for pet uses which is a key data gap. Additional data could potentially be used to refine risk estimates for the other settings such as additional DFR data on different crops and TTR data which are more appropriate for hand­ to­ mouth and object­ to­ mouth exposures. The Agency combines or aggregates risks resulting from exposures to individual chemicals when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. For carbaryl, the Agency has combined risk values (i. e., MOEs) for different kinds of exposures associated with the turf (dermal, hand­ to­ mouth, object­ to­ mouth, and soil ingestion) and pet scenarios (dermal and hand­ to­ mouth). These represent the standard set of exposures that are typically added together when chemicals are used on turf or on pets because it is logical they can co­ occur. Typically, the Agency only adds exposures from different exposure scenarios together (e. g., spraying and gardening) when risks from both are not already a concern. For carbaryl, there are risk concerns for many residential handler scenarios already so the Agency did not add risk values from any postapplication exposure together with applicator risks. It should also be noted that the Agency considered other sources of information in the development of this assessment. For example, carbaryl residues were identified in the Agency study entitled Pesticide Exposure in Children Living in Agricultural Areas along the United States­ Mexico Border Yuma County, Arizona. Preliminary results of this study indicate that carbaryl residues were identified in the dust of 20 percent of the 152 houses sampled and in approximately 24 percent of 25 samples collected in 6 schools in the same region. Also, in a 1995 study conducted by the Centers For Disease Control, 1000 adults were monitored via urine collection. One of the analytes measured in that study (1­ napthol) is a potential metabolite of carbaryl as well as of napthalene and napropamide. This metabolite was identified in 86 percent of the 1000 adults monitored where the mean value was 17 ppb and the 99 th percentile was 290 ppb. These values were not used quantitatively in the risk assessment for carbaryl because of the uncertainties associated with them such as it cannot be clearly defined if carbaryl or the other chemicals with common metabolites were the key contributors to the measured dose levels. The Agency instead considers them a qualitative indicator that exposures in the general population are likely to occur. Risk estimates using controlled study data are protective when considered in light of the available monitoring data. [Note: The Aventis Corporation is in the process of conducting a biomonitoring study with children who live in households where carbaryl has been used. Preliminary results indicate that levels at the highest percentiles of the distribution are similar to those predicted in the Agency's turf risk assessments for toddlers which are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission.] A total of 16 different studies were used by the Agency to calculate carbaryl risks. Most used carbaryl (some handler studies did not) and were scenario­ specific. Each study is considered to be the best source of information for the scenario in which it was used. Each of the traditional carbaryl exposure studies are considered to be high quality and essentially the current state of the art. There appear to be some data quality issues associated with the Washington State water and 11 sediment monitoring data. Where data were not available, the Agency used PHED, the most current policy for transfer coefficients, and the most current approaches for calculating residential exposures in the assessment. The Agency also extensively incorporated the use and usage information supplied by the Aventis Corporation at the 1998 SMART meeting. The information provided at that meeting essentially confirm the Agency interpretation of carbaryl use patterns which is a key element in the development of a risk assessment. This risk assessment applied the latest exposure data, toxicology information, and use data. The overall results indicate that the Agency has risk concerns for essentially every marketplace where carbaryl is used. Occupational handler risks can be mitigated through the use of additional protective measures over and above the current label such as engineering controls (e. g., closed cabs or loading systems). Current label REIs are 12 hours. For almost every crop/ activity combination considered except some low exposure activities, the current REI appears to be inadequate. Residential handler and postapplication risks also are of concern across many areas. 12 1.0 Occupational and Residential Exposure/ Risk Assessment 1.1 Purpose This document is the occupational and residential non­ dietary exposure and risk assessment for carbaryl which will be used in the reregistration process. 1.2 Criteria for Conducting Exposure Assessments An occupational and/ or residential exposure assessment is required for an active ingredient if (1) certain toxicological criteria are triggered and (2) there is a potential for exposure to handlers (mixers, loaders, applicators) during use or to persons entering treated sites after application is complete. Toxicological endpoints were selected for short­, intermediate­, and long­ term exposures (e. g., NOAEL for short­ and intermediate­ term dermal exposures is 20.0 mg/ kg/ day based on a 21­ day dermal administration toxicity study in rats). Additionally, carbaryl has been classified as a Group C possible human carcinogen (i. e., Q1* = 8.75 x 10 ­4 (mg/ kg/ day) ­1 ). There is a significant potential for exposure in a variety of agricultural, commercial, and residential settings. Therefore, risk assessments are required for occupational and residential handlers and for occupational and residential postapplication exposures that can occur as a result of carbaryl use. 1.3 Summary of Hazard Concerns The toxicological endpoints that were used to complete the occupational and residential risk assessments are summarized below and in Table 1 which has been extracted from the latest HIARC document detailing the April 2002 meeting, the revised Q1* memo of November 8, 2001 (Brunsman, TXR No. 0050265), and the latest FQPA SFC committee report from April 2002. Effects were identified at different durations of exposure ranging from short­ term (up to 30 days) to chronic durations (every working day). Carbaryl was classified as a Class C carcinogen and is assessed for carcinogenic risk using a linear, low dose extrapolation approach with a Q1* of 8.75 x 10 ­4 (mg/ kg/ day) ­1 . Carbaryl is a widely used carbamate insecticide where the use patterns can vary widely ranging from shorter­ term exposures through uses on virtually every working day. As such, when the HIARC recently evaluated the carbaryl hazard database, endpoints were selected to address each duration of exposure. Exposures can occur to occupational users and the general population so both were considered in this assessment. The short­ and intermediate­ term dermal risk assessments for carbaryl are based on NOAEL of 20.0 mg/ kg/ day defined in a dermal toxicity study in rats (MRID 45630601) based on decreases in RBC and brain cholinesterase in males and females. The short­ term inhalation and nondietary ingestion risk assessments for carbaryl are based on a NOAEL of 1.0 mg/ kg/ day defined in a developmental neurotoxicity study in rats (MRIDs 44393701, 45456701, 45456702, and 45456703) based on decreased body weight gain, alterations in FOB measurements, and cholinesterase inhibition (plasma, whole blood, and brain). The LOAEL for this study was observed at 10 13 mg/ kg/ day. The results of this study were applied to exposure durations of up to 30 days and have been applied only to the inhalation and nondietary ingestion routes of exposure. The intermediateterm inhalation and nondietary risk assessments for carbaryl (i. e., durations that exceed 30 days but are not chronic in nature) are based on a NOAEL of 1.0 mg/ kg/ day that was defined in a subchronic neurotoxicity study in rats (MRID 441226­ 01). The LOAEL for this study is also 10 mg/ kg/ day. The effects that were observed and selected as the basis for the endpoint used in risk assessment included decreases in plasma, whole blood, red blood cell, and brain cholinesterase activity and FOB changes. The results of this study were also applied only to the inhalation and nondietary ingestion routes of exposure. The chronic risk assessments for carbaryl are based on a 1 year dog feeding study (MRIDs 401667­ 01 and 420228­ 01). The effects that were observed and selected as the basis for the endpoint used in risk assessment included decreases in plasma, and brain cholinesterase activity. A NOAEL was not defined in the study so the endpoint that was selected was the LOAEL. The results of this study were applied to chronic exposure durations and have been applied to all routes of exposure (i. e., dermal, inhalation, and non­ dietary ingestion). A dermal absorption factor of 12.7 percent was selected from a rat dermal absorption study using radiolabeled 14 C; this value was used to calculate the oral equivalent dermal dose for noncancer chronic duration exposures and for the calculation of cancer risks. No inhalation toxicity studies were selected for risk assessment purposes so a route­ to­ route extrapolation was used to address risks from inhalation exposures. No inhalation absorption study was conducted, therefore a 100 percent inhalation absorption factor is used to convert all inhalation exposures to an oral equivalent inhalation dose. The Agency's level of concern for noncancer risks (i. e., target level for MOEs) is defined by the uncertainty factors that are applied to the assessment. The Agency applies a factor of 100 in cases to account for inter­ species extrapolation to humans from the animal test species and to account for intra­ species sensitivity. In cases where a NOAEL is not identified and LOAEL values have to be used for risk assessments, the Agency generally applies an additional factor of 3 as was done with carbaryl for chronic duration exposures. Based on the requirements of the 1996 Food Quality Protection Act, the Agency must also consider sensitive populations in its non­ occupational risk assessments. The Agency removed the FQPA 1x safety factor for non­ occupational exposures to carbaryl (April 3, 2002 FQPA SFC report). Table 1. Endpoints for Assessing Non­ Dietary Risks for Carbaryl Type of Exposure Study Dose Endpoint UF Short­ and Intermediateterm Dermal (1 day to several months) 21 Dermal Toxicity Study Using Technical Grade Carbaryl ­ Rats (MRID 45630601) 20 mg/ kg/ day (NOAEL) Significant decreases in RBC and brain chlolinesterase (ChE) 100 for residential and 100 for occupational Short­ term Inhalation & Non­ dietary Ingestion (1 to 30 days) Developmental Neurotoxicity Study ­ Rats (MRIDs 44393701, 45456701, 45456702, 45456703) & Acute Neurotoxicity Study ­ Rats (MRIDs 438452­ 01/ 04) 1 mg/ kg/ day (NOAEL) Decreased body weight gain; FOB changes; and decreases in plasma, RBC, whole blood, and brain cholinesterase (ChE) 100 for residential and 100 for occupational Table 1. Endpoints for Assessing Non­ Dietary Risks for Carbaryl Type of Exposure Study Dose Endpoint UF 14 Intermediate­ term Inhalation & Non­ dietary Ingestion (30 days to several months) Subchronic Neurotoxicity Study ­ Rats (MRID 441226­ 01) 1 mg/ kg/ day (NOAEL) Decreases in plasma, RBC and brain cholinesterase (ChE) and FOB changes 100 for residential, and 100 for occupational Chronic Dermal & Inhalation Dog Chronic Toxicity (MRID 401667­ 01 and 420228­ 01) 3.1 mg/ kg/ day (LOAEL) Decreases in brain cholinesterase (ChE) in females 300 for residential, and 300 for occupational Dermal Absorption Rat Dermal Absorption Study 12.7 percent Inhalation Absorption 100% inhalation absorption value ­ no study available Q1* 0. 000875 Based on increased incidence of hemangiomas/ hemangiosarcomas in male mice A series of acute toxicity tests were also conducted using carbaryl (i. e., outside of the rat study which is discussed above). The results indicate that carbaryl is a category III toxicant via the oral and dermal routes and a category IV toxicant via inhalation. It is also a category IV eye and skin irritant. Results were negative for dermal sensitization and delayed acute neurotoxicity in hens. 1.4 Incident Reports An incidence report has been completed by the Agency. It is considered with the information included in this document in the overall human health risk assessment for carbaryl. The identifying information for the incident report (i. e., date and author, etc.) is included in the overall human health risk assessment. 1.5 Summary of Use Patterns and Formulations Carbaryl products are described in this section. Additionally, available information that describes the manner in which registered carbaryl end­ use products are used is provided in this section (e. g. use categories/ sites, application methods and application rates). For more detailed information, please refer to Appendix A of this document. Appendix A contains the Quantitative Usage Analysis For Carbaryl produced in 1998 by the Biological and Economic Analysis Division and the Use Profile Report For Carbaryl also produced in 1998 by the Biological and Economic Analysis Division. 15 1.5.1 End­ Use Products Carbaryl (1­ naphthyl N­ methyl­ carbamate) is a broad­ spectrum carbamate insecticide marketed in a variety of end­ use products for both occupational and homeowner use. End­ use product names include Adios, Bugmaster, Carbamec, Carbamine, Crunch, Denapon, Dicarbam, Hexavin, Karbaspray, Nac, Rayvon, Septene, Sevin, Tercyl, Tornado, Thinsec, and Tricarnam. Use sites include but are not limited to: fruit and nut trees; vegetable crops; field and forage crops; grapes; forestry; lawns and other turf such as golf courses; ornamental trees, shrubbery, annuals, and perennials; wide area treatment targets such as residential mosquito adulticide uses; poultry production facilities; and companion animals (e. g., dogs and cats). Table 2 summarizes the technical and manufacturing products with their respective EPA registration numbers. Table 2: Technical and Manufacturing Carbaryl Products Formulation EPA Reg. No. (% active ingredient) Technical 34704­ 707 (99%); 264­ 324 (99%),­ 325 (97.5%); 19713­ 75 (99%) Manufacturing Product 264­ 328 (80%); 769­ 971 (80%); 19713­ 369 (50 %); 4816­ 270 (97.5%),­ 407 (1%) Based on a review (2/ 27/ 01) of the Office of Pesticide Programs – Reference Files System (REFS), there are 307 active product labels. Carbaryl formulations include dusts, emulsifiable concentrates, soluble concentrates; water dispersible granulars; flowable concentrates; wettable powders; granulars; baits; pet dips and pet shampoos; aerosol sprays; ready­ to­ use pump sprayers; and pet collars (i. e., treated articles). Table 3 outlines the formulations and EPA registration numbers for labels of carbaryl end­ use products according to REFs. Many of the products described in Table 3 can be used in a variety of settings ranging from agriculture and commercial facilities to residential areas. Some products are marketed in a single marketplace while others are sold for use in each setting. From sales information provided by the Aventis Corporation at the SMART meeting with EPA on September 24, 1998 approximately 34 percent of carbaryl end­ use products are used in the homeowner/ residential setting while 59 percent is used in agriculture. The remaining 7 percent is used in nursery, landscape and golf course industries. 16 Table 3: End­ Use Product Formulations and EPA Reg. Number. Formulation Type EPA Registration Number (Percent Active Ingredient) Emulsifiable Concentrates & Flowable Concentrates 7401­ 83,­ 210 (25%),­ 208( 13%); 19713­ 49( 43.4%),­ 89 (22.5%), ­131( 49%); 51036­ 66( 43.3%),­ 123( 22.5%); 10163­ 60 (43.7% ),­ 134( 80%); 10107­ 42 (43.4%),­ 44 (23.4%); 11715­ 207,­ 209,­ 229 (42.6%); 33955­ 533 (23.4%); 67517­ 31( 5%); 9779­ 260 (43.4%); 8660­­ 133 (11.7%); 264­ 321 (40%), ­333 (44.1%), ­334( 22.5%), 335 ­349 (43%), ­422 (48%) ; 2217­ 366 (50%), 600 (23.4%); 4­ 59( 0.5%),­ 122 (0. 3%);­ 237 (22.5%); 192­ 174 (21.3%); 239­ 2628( 21.3%); 270­ 286 (23%); 407­ 383 (24%); 5905­ 251 (40.38%); 5887­ 102,­ 162 (0. 3%) 0; 769­ 493( 42.85%),­ 573 (23%), ­648,­ 865,­ 883 (21.3%); 28293­ 222( 21.3%); 59144­ 6 (21.3%); 46515­ 35 (11.7%); 16­ 76 (21.3%); 34704­ 447( 43%); 8660­ 70 (24.4%); 909­ 103( 21.3%); 46515­ 36( 21.3%); 7401­ 38, ­62 (5%), 386 (13.5); 802­ 585 (21.3%); 50383­ 10 (22.5%); 54705­ 4 (41.2%); 16­ 76 SLNs: CO8800­ 1300, FL8900­ 3700, HI9700­ 0300, NC9600­ 0300, OH9600­ 0300,OR9500­ 0600,PA9600­ 0200, VA9500­ 0100, WA9700­ 2200 Wettable Powders & Soluble Granules 33955­ 450 (50%); 51036­ 151( 80%); 19713 ­50 (80%),­ 52( 50%), ­363 (85%), ­84 (95%); 10163­ 133 (80%); 9779­ 294( 90%); 8660­ 60 (50%); 5905­ 517 (80%); 264­ 314 (50%), ­315 (85%),­ 316 (80%), ­427 (39.7%), ­526 (80%); 5481­ 65 (50%), 242 (0. 5%), 271 (50%); 5887­ 86 (50%); 2217­ 389 (50%); 4­ 157 (13.5%), 387 (50%); 769­ 574 (80%),­ 868 (50%),­ 919 (21.3),­ 920, ­834,­ 972 (50%); 70­ 285 (50%); 1386­ 445; 34704­ 350( 50%),­ 619 (80%); 1386­ 455; 16­ 99( 50%); 407­ 287( 50%); 228­ 249( 5%) SLNs: CA7802­ 070, CA8100­ 5900, CA8300­ 0700, CA8300­ 0701, CA8300­ 0702, FL8900­ 3600, HI9600­ 0900, NC8200­ 0700, NC8700­ 0702, WA9000­ 1300 Dusts 67517­ 32 (10%); 9198­ 141 (2. 37%),­ 147( 5%),­ 148( 10%); 4­ 29 (1. 25%),­ 143 (5%),­ 413, ­415; 16­ 12 (2%),­ 98 (10%),­ 121( 5%),­ 127( 2%); 239­ 1349,­ 1513 (10%), ­2181 (5%); 270­ 272 (5%); 70­ 165 (10%),­ 166( 5%); 16­ 27 (5%); 67572­ 16 (5%),­ 36 (10%); 59144­ 3 (5%),­ 5 (10%); 50383­ 16 (5%); 49585­ 4,­ 24 (5%),­ 26( 10%); 435763 5%); 34911­ 6 (5%); 28293­ 6,­ 10, ­301,­ 302( 5%),­ 14( 12.5%),­ 18,­ 102,­ 301 (10%),­ 237( 5%); 19713­ 53,212 10%),­ 213( 5%),­ 244( 80%); 829­ 128 (5%),­ 131( 1.75%),­ 142( 50%),­ 200( 10%); 2217­ 383,­ 572 (5%); 272475 (5%); 2781­ 25( 5%); 769­ 559,­ 611,­ 613,­ 642,­ 647,­ 906 (5%),­ 835( 1.75%),­ 229,­ 612,­ 665( 10%), 614 12.5%); 655­ 788( 5%),­ 789 (10%); 11715­ 250( 12.5%),­ 255, ­294( 5%),­ 292( 10%); 9779­ 74 (5%); 8660­ 72,234 5%),­ 241( 10%); 7401­ 69,­ 310( 5%),­ 291( 1.75),­ 334( 2%),­ 81,­ 166,­ 154( 10%); 5887­ 43( 5%); 5481­ 275,282 321( 2%),­ 58,­ 98,­ 253,­ 283,­ 316,­ 451 (5%),­ 312,­ 323( 7.5%),­ 108,­ 277,­ 294( 10%),­ 190( 46%); 4758­ 7, 32 34( 5%); 4306­ 10( 5%); 3342­ 100( 5%); 5887­ 77( 0.3%); 2935­ 193 (5%),­ 320( 10%); 3342­ 51( 5%),­ 53( 2%), 56 1.75%),­ 69( 10%); 2393­ 375( 5%); 1386­ 451,­ 630( 5%)­ 633( 10%); 869­ 118( 5%).­ 180( 10%); 802­ 442( 5%); 572­ 107( 5%); 192­ 70( 5%); 228­ 251,­ 252( 5%); 51036­ 13( 10%),­ 48( 5%); 33955­ 462( 5%); 10163­ 124( 10%); 10159­ 2( 5%); 10107­ 43( 10%),­ 45( 5%); 9779­ 81( 10%),­ 61( 50%); 36272­ 14( 5%); 37425­ 13( 12.5%); 497843 12.5%); 71949­ 11( 10%),­ 10( 5%) Granular 28293­ 233 (6. 3%); 9198­ 142 (3. 5%); 5887­ 94,­ 170 (5%); 769­ 728 (5%), ­970*( 3.5%),­ 976( 2%); 59144­ 26*( 1%), 27* (2%); 34704­ 289( 10%),­ 373* (5%); 32802­ 58( 3.9%),­ 59* (1. 43); 10404­ 61*( 6.3%), 62*( 4%); 8378­ 31*( 4.3%),­ 36*( 1.43%); 5481­ 89( 10%),­ 90,­ 97*( 5%),­ 95*( 4%), ­ 100*( 5%); 264­ 430*( 7%); 90983 5%); 869­ 228*( 2%); 9779­ 156*( 5%); 8660­ 28* (1%); 7401­ 43( 3.34%),­ 51( 1.8%); 192­ 199 (2%); 4142 4.6%); 572­ 204( 8%); 802­ 351( 5%); 264­ 429( 7%); 5905­ 169( 10%), 180( 180%); 9198­ 106( 6.2%), 139 4.6%),­ 143( 4%),­ 144( 4.55%),­ 145( 6.3%),­ 146( 8%); 19713­ 334( 10%); 51036­ 225( 5%); 67572­ 81( 1%) Bait 67650­ 2 (2%);; 61282­ 4,­ 21( 10.04%),­ 16,­ 22 (5%); 42057­ 39 (4%); 32802­ 51 (5%); 10370­ 152 (5%); 8278­ 3 (5%); 769­ 729,­ 730 (5%); 802­ 493 (5%); 31282­ 22* (5%); 4­ 333* (5%); 1386­ 655*( 5%); 10107­ 143* (5%); 869­ 119( 5%); 7401­ 72*( 4%),­ 148 (2%),­ 265( 4%); 8119­ 5 (5%); 239­­ 2514 (5%); 70­ 244( 5%); 829182 4.25%),­ 285 (5%); 961­ 290( 7.15%),­ 355( 5.93%); 264­ 312 (10%),­ 320( 5%); 2393­ 209( 5%); 6973­ 10( 4%); 7729­ 7( 5%); 8660­ 111( 5%),­ 188( 4.55%); 10163­ 32( 5%); 11656­ 20( 4%),­ 21( 5%); 28293­ 235( 5%); 34704­ 23,483 5%); 49399­ 1( 2%),­ 2( 5%); 51036­ 61( 5%),,­ 185,­ 210( 13%),­ 204,­ 227( 1.3%),­ 286( 10%); 59639­ 52,60 5%); 2935­ 366( 5%); 19713­ 494( 5%); 34911­ 8( 4%); 67572­ 56( 4%); 71949­ 12( 5%) SLNs: FL9200­ 0800 Dips, Shampoos 28293­ 8( 60%); 2097­ 8 (0. 5%) Pet collars (treated articles) 2724­ 272 (8. 5%), 273 (16%) Table 3: End­ Use Product Formulations and EPA Reg. Number. Formulation Type EPA Registration Number (Percent Active Ingredient) 17 Ready to Use Pump Sprayers & Aerosol Cans 1910­ 2 (1%); 67572­ 75 (0. 126%); 9444­ 98,­ 190 (0. 5%); 769­ 977( 0.126%); 8119­ 3 (5%); 28293­ 97 (0. 5%) 1.5.2 Mode of Action and Targets Controlled Carbaryl (1­ naphthyl methylcarbamate) belongs to the carbamate class of pesticides. Like the other carbamates, carbaryl antagonizes acetylcholine and competes for binding sites on the enzyme cholinesterase. In agriculture and residential/ recreational areas, carbaryl is used as a contact insecticide recommended for use against pests in a variety of settings. These pests include (i. e., based on information provided on labels and in the Use Profile Report included as Appendix A of this document): ° On Fruit Trees and Nut Trees: apple aphid, apple maggot, apple mealybug, apple rust mite, apple sucker, bagworms, California pearlslug, codling moth, eastern tent caterpillar, European apple sawfly, eyespotted bud moth, fruittree leafroller, green fruitworm, Japanese beetle, lesser appleworm, lygusbugs, orange tortrix, pear leaf blister mite, pear psylla, pear rust mite, periodical cicada, plum curculio, redbanded leafroller, scale insects, tarnished plant bug, tentiform leafminers. White apple leafhopper, wooly apple aphid, navel orangeworm, peach twig borer, san Jose scale, European raspberry aphid, omnivorous leafroller, raspberry sawfly, rose chafer, snowy rose tree cricket, blueberry maggot, sherry fruitworm, cranberry fruitworm, European fruit lecanium, chestnut weevil, avocado leafroller, california orangedog, citrus cutworm citrus root weevil, fullers rose beetle, orange tortrix, western tussock moth, west Indian sugarcane borer, filbert aphid, filbert leafroller, filbertworm, eight spotted forester, grape berry moth, grape leaffolder, grape leafhopper, June beetles, saltmarsh caterpillar, western grapeleaf skeletonizer, western yello­ striped armyworm, olive scale, apple pendemis, cucumber beetles, European earwig, lesser peach tree borer, oriental fruit moth, peach twig borer, tarnished plant bug, tussock moth, black margined aphid, fall webworm, pecan leaf phylloxera, pecan nut casebearer, pecan spittlebug, pecan stem phylloxera, pecan weevil, twig girdler, walnut caterpillar, calico scale. ° On Terrestrial Food and Feed Crops: blister beetles, Mexican bean beetles alfalfa caterpillar, beanleaf beetle, cucumber beetle, grasshoppers, green cloverworm, japanese beetle, leafhoppers, three cornered alfalfa hopper, thrips, velvetbean caterpillar, alfalfa weevil larvae, armyworm, cloverhead weevil, cotton fleahopper, cotton leafworm, flea beetle, striped blister beetle, boll weevil, bollworms, cotton leafperforator, plant bugs, saltmarsh caterpillar, corn earworm, corn rootworm adults, southwestern corn borer, japanese beetle, European corn borer, cutworms, Egyptian alfalfa weevil larvae, Essex skipper, European alfalfa beetle, fall armyworm, lygus bugs, webworms, yellowstriped armyworm, asparagus beetle, apache cicada, stinkbugs, tarnished plant bug, webworm, cowpea curculio, aster leafhoppers, harlequin bug, imported cabbageworm, melonworm, 18 pickleworm, squash bugs, pink bollworm, range caterpillars, thrips, white grubs, white fringed beetle adult, Colorado potato beetle, pea leaf weevil, tomato fruitworm, tomato hornworm, grape colaspis, sweet potatoweevil;, tortoise beetles, green June beetle grubs, budworms, cereal leaf beetle (except in CA). ° On Ornamentals: blister beetle, flea beetle, boxelder bug, japanese beetle, June beetle, lace bug, leafhopper, leafroller, mealybug, plant bug, psyllids, rose aphid thrips, apple aphid, bagworm, birch leafminer, cankerworm, eastern spruce gall aphid, elm leaf aphid, elm leaf beetle, gypsy moth, mimosa webworm, oak leafminer, orange tortrix, periodical cicada, puss caterpillar, rose aphid, rose slug, sawfly, scale, tent caterpillar, thrips, willow leaf beetle. ° On Lawns/ Turf: ants, bluegrass billbug, chinch bug, cut worm, crane fly, earwig, European chafer, fall armyworm, fleas, green June beetle, leafhopper, millipedes, mosquitoes, sod webworms (lawn moths), ixoides spp.( deer tick, bear tick, black legged tick), amblyomma spp.( lone star tick). ° Poultry: northern fowl mite, chicken mite, lice, fleas, bedbugs, fowl ticks. ° In and Around Buildings: indoors: ants, crickets, firebrats, silverfish, bees, wasps, brown dog ticks, fleas, carpenter ants, scorpions, centipedes, earwigs, millipedes, cockroaches, spiders. ° Outdoors: ants, bees, wasps, brown dog ticks, carpenter ants, centipedes, cockroaches, crickets, earwigs, firebrats, fire ants (mound treatment), silverfish, fleas millipedes, scorpions and spiders. ° Public Health/ Wide Area: mosquitoes. ° Dogs and cats: fleas and ticks, on animal and in bedding/ housing. 1.5.3 Registered Use Categories and Sites An analysis of the current labeling and available use information was completed using the Office of Pesticide Programs– Label Use Information System (LUIS) in addition to REFs. Carbaryl is registered for use in a variety of occupational and homeowner/ residential scenarios. For reasons of clarity in the risk assessment process, the use patterns have been described in a manner that delineates occupational from homeowner/ residential uses. Occupational Use Sites Occupational populations are potentially exposed while making carbaryl applications to the following targets or after contact with the treated targets after previous carbaryl applications. The following list is a summary of occupational use sites as described in the Carbaryl Use Profile prepared by Don Atwood of the Biological and Economic Analysis Division in November of 1998 19 (see Appendix A). [Note: Modifications to the Use Profile have been made based on label deletions and modifications since November of 1998.] Terrestrial Food Crop Cucurbits ­ cucumber, melons, Chinese okra, pumpkin, and squash Flavoring and Spice Crops ­ dill Fruiting Vegetables ­ tomato, eggplant and pepper Grain Crops ­ prosso millet Leafy and Stem Vegetables ­ beets, broccoli, brussels sprouts, cabbage, chinese cabbage, cauliflower, celery, Swiss chard, collards, dandelion, endive (escarole), hanover salad, kale, kohlrabi, lettuce (head, crisphead types, leaf types), mustard, parsley, rhubarb, and spinach Miscellaneous Fruits ­ olive Miscellaneous Vegetables ­ asparagus Nut Crops ­ almond, chestnut, filbert (hazelnut), pecan, pistachio, and walnut (english/ black) Pome Fruits ­ crabapple, pear, and quince Root Crop Vegetables ­ beets, carrot (including tops), horseradish, radish, rutabaga, salsify, and sweet potato Small Fruits ­ blackberry, blueberry, boysenberry, caneberries, cranberry, dewberry, loganberry, raspberry (black, red), and strawberry Specialized Field Crops ­ okra Stone Fruits ­ apricot, cherry, nectarine, peach, plum, and prune Terrestrial Food+ Feed Crop Citrus Fruits ­grapefruit, lemon, lime, orange, tangerine Crops Grown for Oil ­ field corn, flax, and sunflower Miscellaneous Fruits ­ longan and mango Fiber Crops ­ flax Fruiting Vegetables ­ tomato Grain Crops ­ field corn, rice, sorghum and wheat Groups of Agricultural Crops Which Cross Established Crop Groupings ­ cotton, peanuts, peas, sorghum, soybeans, and vegetables Leafy and Stem Vegetables ­ mustard and turnip Nut Crops ­ almond, chesnuts, filberts, pecans, pistachios and walnuts Pome Fruits ­ apple, pears, loquats, crabapples and oriental pears Root Crop Vegetables ­ parsnip, white/ irish potato, salsify, and turnip Seed and Pod Vegetables ­ beans (dried type), succulent beans (lima and snap), cowpea/ blackeyed pea, cowpea/ sitao, lentils, peanuts, peas (dried type), field peas, southern peas, succulent peas, and soybeans (edible) Small Fruits ­ grapes, caneberries, blueberries, cranberries and strawberries Specialized Field Crops ­ popcorn, sweet corn, and sunflower Sugar Crops ­ sugar beet 20 Terrestrial Feed Crop Forage Grasses ­ corn, grass forage/ fodder/ hay, millet (proso), pastures, rangeland, rice, sorghum, and wheat Forage Legumes and Other Nongrass Forage Crops ­ alfalfa, clover, cotton, and trefoil Grain Crops ­ proso millet Groups of Agricultural Crops Which Cross Established Crop Groupings ­ grasses grown for seed Terrestrial non­ food crop Agricultural Uncultivated Areas ­ Agricultural fallow/ idleland and Agricultural rights­ of way/ fencerows/ hedgerows Commercial/ Industrial/ Institutional Premises and Equipment Commercial/ Institutional/ Industrial premises/ Equipment (Outdoor) Fiber Crops Forest Trees ­ christmas tree plantations Groups of Agricultural Crops Which Cross Established Crop Groupings ­ Fruits (unspecified) Nonagricultural Uncultivated Areas ­ Outdoor buildings/ structures, rights­ ofway fencerows/ hedgerows, uncultivated areas/ soils, and recreational areas Ornamental Lawns and Turf ­ commercial/ industrial lawns, golf course turf, Ornamental sod farm (turf), and recreational area lawns Specialized Field Crops ­ tobacco Wide Area/ General Outdoor Treatments ­ fencerows/ hedgerows, urban areas, and wide area/ general outdoor treatment (public health use) Terrestrial non­ food+ outdoor residential Nonagricultural Uncultivated Areas ­ rights­ of­ way/ fencerows/ hedgerows Ornamental Herbaceous Plants Ornamental Lawns and Turf Ornamental Nonflowering Plants Ornamental Woody Shrubs and Vines Ornamental and/ or Shade Trees Wide Area/ General Outdoor Treatments ­ fencerows/ hedgerows Terrestrial+ Greenhouse non­ food crop Ornamental Herbaceous Plants Ornamental Woody Shrubs and Vines Ornamental and/ or Shade Trees Animal Uses Poultry (chickens, ducks, geese, game birds, turkeys) Livestock (cattle, sheep, horses, etc.) 21 Pets (cats and dogs) Aquatic food crop Aquatic Sites ­ commercial fishery water systems Grain Crops ­ rice Small Fruits ­ cranberry Fish & Shellfish Uses ­ oyster beds Aquatic non­ food industrial Aquatic Sites ­ Drainage systems Forestry Forest Trees ­ forest plantings (reforestation programs, tree farms, tree plantations, etc), forest trees (all or unspecified), maple (forest), and shelterbelt plantings Homeowner/ Residential Use Sites Residential and non­ occupational use sites include those labeled for outdoor applications such as on lawns, gardens, and ornamentals as well as for use on companion animals such as dogs or cats. There are no labels that allow indoor premise treatments (e. g., crack and crevice or broadcast). Carbaryl can be purchased and used by homeowners in residential settings. It can also be used by professionals such as LCOs (Lawn Care Operators) in residential settings. Exposures can also occur as a result of uses in other areas frequented by the general population such as parks and recreational areas, treated Christmas tree plantations, and forests. Veterinary clinic uses can also result in exposures due to contact with treated animals. The following is a list of use sites in the residential environment. ° Trees: fruits, nuts, and shade/ ornamental; ° Lawns and Ornamentals: lawns, house perimeter, shrubs and flowers; ° Vegetables: beans, berries, broccoli, brussels sprouts, cabbage, carrots, cauliflower, corn, cowpeas, cucumbers, eggplant, herbs, lettuce, melon, okra, onions, peas, peppers, potatoes, summer squash, tomatoes; ° Pets: dogs, cats, and housing/ bedding; and ° Fire Ant Mounds 22 1.5.4 Application Parameters Application parameters are generally defined by the physical nature of the use site, the physical nature of the formulation (e. g., formula and packaging), by the equipment required to deliver the chemical to the use site, and by the application rate required to achieve an efficacious dose. As such, the application parameters for major crop groups or application targets have been summarized by identifying the maximum application rates for each group and the equipment that can be used to make applications. All of the information presented below are summarized from the Agency's QUA and Use Profile documents included as Appendix A, from the SMART meeting information provided to the Agency on September 24, 1998 by the Aventis Corporation, from current carbaryl labels, and from the use summary used in the dietary exposure aspect of the risk assessment. Selected crop groupings and application targets along with corresponding typical (if available) and maximum application rates that are used in the risk assessment are presented in Table 4 below. Additionally, the equipment that can be used to make applications are also discussed below for each crop group considered. The Agency could not quantitatively address the use of carbaryl in every specific crop or setting in its risk assessment because of the associated level of complexity that would be added to the risk assessment process. Instead, representative crops or targets were selected that were used as the basis for the assessment. A broad range of rates were used to ensure that use scenarios would be addressed in the range of values selected. Table 4: Representative Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft 2 (units may vary) lb ai/ A/ acre (units may vary) max. apps/ season lb ai/ season Average Rates Alfalfa, clover, trefoil 1. 5 1/ cutting 1. 5/ cutting 1. 1 Asparagus 2 4 ­ postharvest 3 ­ broadcast 2 ­ postharvest 6 ­ broadcast 10 ­ postharvest 0.9 0. 023 ­0. 094 Beans (fresh & dried), cowpeas, peas 1.5 4 6 0. 9 0.012­ 0.047 Beets, carrot, horseradish, radish, parsnip 2 ­ foliar 2.2 ­ soil broadcast 6 ­ foliar 4 ­ soil 6 0. 8 0.012­ 0.047 Blueberries 2 ­ foliar 0.5 lb/ 1000 ft 2 ­ soil 5 10 1. 7 0.012­ 0.047 Cole Crops (broccoli, brussel sprouts, cabbage, cauliflower, chinese cabbage, collards, kale, kohlrabi, mustard greens) 2 ­ foliar 2.2 ­ soil broadcast 4 6 0.8 0. 012­ 0.047 Caneberries 2 ­ foliar 2.2 ­ soil broadcast 5 4 10 Not specified 1.7 0. 012­ 0.047 Celery, Dandelion 2 ­ foliar 2.2 ­ soil broadcast 4 6 1.0 0. 012­ 0.047 Citrus 16 (foliar in CA only) 10 (foliar in FL only) 7.5 ­ foliar 1 lb/ 100 gal. 1 Not specified 8 Not specified 20 Not specified 20 Not specified 2.7 to 3.4 (lemons & oranges) 0.023­ 0.176 Table 4: Representative Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft 2 (units may vary) lb ai/ A/ acre (units may vary) max. apps/ season lb ai/ season Average Rates 23 Corn (field and pop) 2 4 8 1. 0 0.012­ 0.047 Corn (sweet) 2 ­ foliar 2.2 ­ soil broadcast 8 4 16 Not specified 1.3 0. 012­ 0.047 Cranberry 2 5 10 2.0 0. 012­ 0.047 Cucurbits (cucumber, melon, pumpkin, squash) 1 6 6 1. 1 0.012­ 0.047 Fruiting Vegetable (tomato, eggplant, pepper) 2 7 8 1. 0 0.012­ 0.047 Grapes 2 5 10 1.4 0. 012­ 0.047 Grasses Grown For Seed 1.5 2 3 0. 8 (based on hay) Leafy Vegetable (head and leaf lettuce, endive, mustard green) 2 ­ foliar 2.2 ­ soil broadcast 5 4 6 Not specified 1.1 0. 012­ 0.047 Nuts (almond, chestnut, pecan, pistachio, walnut, etc.), foliar or dormant/ delayed 5 4 15 2.5 (pecans) 0.047­ 0.12 Nuts (almond, chestnut, pecan, walnut), foliar in CA 1 lb ai/ 100 gal Not specified Not specified Not specified 0.047­ 0.12 Ornamental 2.2 or 2% solution ­ ­ 1. 5 0.023 Oyster beds (SLN only) 10 Not specified Not specified ­ Peanut 2 5 8 0. 8 0.012­ 0.047 Pome fruit 3 8 15 1. 2 (based on apples) 0.012­ 0.07 Poultry 1/ 1000 ft 2 broiler 0.64­ 0.76/ 100 layers ­­­ Potatoes & Tubers (turnips) 2 6 6 0.8 Rangeland pastures 1 1 1 0. 9 Rice 1.5 2 4 1. 1 Right of Way 1. 5 3 0. 4 Sorghum 2 4 6 1. 1 Stone fruit (apricot, cherry, nectarine, peach, plum/ prune), foliar or dormant/ delayed 3 4 ­ CA only 3 foliar & 1 dormant/ delayed 14 1.1 0. 047­ 0.12 Stone fruit (apricot, cherry, nectarine, peach, plum/ prune), foliar 1 lb ai/ 100 gal Not specified Not specified Not specified 0.047­ 0.12 Strawberries 2 5 10 1.4 0. 012­ 0.047 Sugar beets 1. 5 to 2 2 to 4 4 1.3 0. 012­ 0.047 Sweet Potatoes 2 foliar 8 lb/ 100 gal drip 8 foliar Not specified 8 foliar 1.2 1.6 foliar Not specified 0.012­ 0.047 Sunflower 1. 5 2 3 0.7 0. 012­ 0.047 Tobacco 2 4 8 1. 1 Tree farm 1 ­ 2 0. 7 Turf/ golf 8 ­ liquids 9 ­ granulars ­ 0. 8/ 1000sf 2 to 4 0. 047 to 0.25 (lawns) [max levels for different products] Wheat, flax 1.5 2 3 0. 8 Ants 2% sol ­ ­ ­ 2% sol Mosquito Control 2 ­ ­ ­ Outdoor Banding 2% sol ­ ­ ­ 2% sol Table 4: Representative Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft 2 (units may vary) lb ai/ A/ acre (units may vary) max. apps/ season lb ai/ season Average Rates 24 Domestic Animals (e. g., cats/ dogs) Dust 0.2 lb ai/ dog Sha. 0.01 lb ai/ dog ­ ­ ­ Dust 0.2 lb ai/ dog Sha. 0.01 lb ai/ dog Domestic Animals (e. g., cats/ dogs) 1.3 oz/ dog collar ­ ­ ­ 1.3 oz/ dog collar ° Tree Crops: The application rate for commercial crops is between 2 to 6 lb ai per acre for most crops. Citrus rates are higher at 16 lb ai per acre (CA only). Equipment for commercial use is airblast, aerial and chemigation. ° Grapes: The application rate for commercial crops is 2 lb ai per acre. Equipment for commercial use is airblast, over the row groundboom, power duster, aerial and chemigation. ° Field, forage, fiber, small fruit (i. e., berries) and vegetable crops: The application rate for commercial crops is 1 to 2 lb ai per acre. Equipment for commercial use is groundboom, aerial and chemigation. ° Non crop areas: The application rate for commercial area is 1 lb ai per acre. Equipment is groundboom, aerial and right of way sprayer. ° Ornamentals: The application rate for commercial area is 2.2 lb ai per acre. Equipment for commercial use is low­ pressure handwand, backpack, high­ pressure handwand and airblast/ mist blower. ° Lawn Care (professional certified operator (pco)): The application rate for pco applicators is up to 8 lb ai per acre. The application equipment is hand­ held power sprayers and granular spreaders. ° Evergreens in large stands: the application rate for commercial crops is 1 lb per acre or 1.8 lb ai per 1000 square feet to the seed, mound or trunk. Equipment used for commercial areas is airblast, aerial, and high­ pressure handwand. ° Poultry: The application rates for commercial poultry production vary from 0.0048 lb ai per bird, to 0.08 lb ai per 1000 square feet and are also reported as 1 lb ai per 3.1 gallons. Application equipment for commercial production includes, compressed air sprayer, fogger, backpack sprayer and mist blower and power sprayers. ° Homeowner fruits and nuts: 0.0039 lb ai per gallon or up to 0.8 lb ai per 5 trees. Application equipment includes, hose­ end sprayer and hand held pump sprayer. 25 ° Homeowner vegetables: The application rate for homeowner vegetable gardens is 0.0026 lb ai per 20 foot row. The application equipment includes, hose­ end sprayer, hand held pump sprayer, hand held dusters and shaker cans. ° Homeowner lawn care: Maximum application rates range from 2 lb ai/ acre (0.047 lb ai/ 1000 ft2) up to almost 11 lb ai per acre (0.25 lb ai/ 1000 ft2) depending upon the product/ packaging and the pest. For the vast majority of products (e. g., professional application to residential lawns that could result in postapplication exposures and open packaging for homeowners) the maximum application rates are 8 lb ai/ acre for liquids and 9 lb ai/ acre for granules. Equipment for homeowner use is hose­ end sprayer, granular spreader, and belly grinder. ° Homeowner ornamentals: The application rate for homeowner ornamentals is 0.02 lb ai per gallon of water or 0.5 lb ai per 50 shrubs. Equipment for homeowner is hose­ end or hand held pump sprayers. ° Pets: Pet care products are applied via containers (i. e., powders and dusts by shake can, ready to use and pressurized containers) and rubbed in by hand. Application rate is made by the handler. Shampoos also are applied in the same manner. Pet collar application rate is 1 collar per animal and each collar contains 16 percent ai. Application equipment is a pet collar. ° Pet bedding: Applications are made to cover bedding by dusters or spray formulas including pressurized sprays. 2.0 Occupational Exposures and Risks It has been determined there is a potential for exposure in both occupational and residential/ homeowner scenarios from handling carbaryl products during the application process (i. e., mixer/ loaders, applicators, flaggers and mixer/ loader/ applicators) and from entering areas previously treated with carbaryl (e. g., postapplication worker exposure). As a result, risk assessments have been completed for both occupational handler and postapplication scenarios as well as residential handler and postapplication scenarios. This section includes the occupational aspects of the risk assessment. Occupational handler exposures and risks are addressed in Section 2.1: Occupational Handler Exposures and Risks while occupational post­ application worker risks are presented and summarized in Section 2.2: Occupational Post­ Application Exposures and Risks. The calculated risks are characterized in Section 2.3: Occupational Risk Characterization. 2.1 Occupational Handler Exposures and Risks The Agency uses the term "Handlers" to describe those individuals who are involved in the pesticide application process. The agency believes that there are distinct job functions or tasks related to applications and that exposures can vary depending on the specifics of each task. Job requirements (e. g., amount of chemical to be used in an application), the kinds of equipment used, 26 the crop or target being treated, and the circumstances of the user (e. g., the level of protection used by an applicator) can cause exposure levels to differ in a manner specific to each application event. The scenarios that serve as the basis for the risk assessment are presented in Section 2.1.1: Handler Exposure Scenarios. The exposure data and assumptions that have been used for the calculations are presented in Section 2.1.2: Data and Assumptions For Handler Exposure Scenarios. The calculations and the algorithms that have been used for the noncancer elements of the risk assessment as well as the risk values are presented in Section 2.1.3: Handler Exposure and NonCancer Risk Estimates while the analogous information using the Q1* for cancer estimates are presented in Section 2.1.4: Handler Exposure and Risk Estimates For Cancer. Section 2.1.5: Summary of Risk Concerns and Data Gaps For Handlers presents the overall risk picture for carbaryl. Finally, recommendations are presented in Section 2.1.6: Recommendations For Refining Occupational Handler Risk Assessment. 2.1.1 Handler Exposure Scenarios Exposure scenarios can be thought of as ways of categorizing the kinds of exposures that occur related to the use of a chemical. The use of scenarios as a basis for exposure assessment is very common as described in the U. S. EPA Guidelines For Exposure Assessment (U. S. EPA; Federal Register Volume 57, Number 104; May 29, 1992). The purpose of this section is to describe the exposure scenarios that were used by the Agency in the assessment for carbaryl handlers and to explain how the scenarios were defined. Information from the current labels; use and usage information; toxicology data; and exposure data were all key components in the developing the exposure scenarios. The first step in the handler risk assessment process is to identify the kinds of individuals that are likely to be exposed to carbaryl during the application process. In order to do this in a consistent manner, the Agency has developed a series of general descriptions for tasks that are associated with pesticide applications. Common tasks (as an example) can include: preparation of dilute, waterbased spray solutions for application; transferring or loading dilute spray solutions into sprayers for application; and making applications with specific types of equipment such as a groundboom or airblast sprayer. Tasks associated with occupational pesticide use (i. e., for "handlers") can generally be categorized using one of the following terms: C Occupational Mixer/ loaders: these individuals perform tasks in preparation for an application. For example, they would prepare dilute spray solutions and/ or load/ transfer solid materials (e. g., granulars) or dilute spray solutions into application equipment such as a groundboom tractor or planter prior to application. C Occupational Applicators: these individuals operate application equipment during the release of a pesticide product into the environment. These individuals can make applications using equipment such as groundboom sprayers or tractor­ drawn spreaders for granular materials. C Occupational Mixer/ loader/ applicators: these individuals are involved in the entire pesticide application process (i. e., they do all job functions related to a pesticide application 27 event). These individuals would prepare a dilute spray solution and then also apply the solution. The Agency always considers some exposures to be mixer/ loader/ applicator exposures because of the equipment used and the logistics associated with such applications. For example, if one uses a small handheld device such as a 1 gallon low pressure handwand sprayer it is anticipated that one individual will mix a spray solution and then apply the solution because of labor and logistical considerations. C Occupational Flaggers: these individuals guide aerial applicators during the release of a pesticide product onto an intended target. Next, assessors must understand how exposures to carbaryl occur (i. e., frequency and duration) and how the patterns of these occurrences can cause the effects of the chemical to differ (referred to as dose response). Wherever possible, use and usage data determine the appropriateness of certain types of risk assessments (e. g., a chronic risk assessment is not warranted for a vast majority of carbaryl uses because chronic duration exposure patterns do not occur). Other parameters are also defined from use and usage data such as application rates and application frequency. The Agency always completes risk assessments using maximum application rates for each scenario because what is possible under the label (the legal means of controlling pesticide use) must be evaluated, for complete stewardship, in order to ensure there are no concerns for each specific use. Additionally, whenever the Agency has additional information such as typical application rates for some crops, as in this case, it uses the information to further evaluate the overall risks associated with the use of the chemical in order to allow for a more informed risk management decision. In this case, average application rates (considered to be the same as typical rates for the purposes of this assessment) defined in the recent Quantitative Usage Analysis were available for some crops and integrated into the assessment. A chemical can produce different effects based on how long a person is exposed, how frequently exposures occur, and the level of exposure. It is likely that carbaryl exposures can occur in a variety of patterns. The Agency believes that occupational carbaryl exposures can occur over a single day or up to weeks at a time even though each crop or application target is generally treated only a few times per season. Intermittent exposures over several weeks are also anticipated. Some applicators may apply carbaryl over a period of weeks because they need to cover large acreages, they may be custom or professional applicators that are completing a number of applications within a region, or they may be applying carbaryl over a period of several days (e. g., a veterinary assistant who dips dogs periodically over a period of several weeks). The Agency classifies exposures up to 30 days as short­ term and exposures greater than 30 days up to several months as intermediate­ term. The Agency completes both short­ and intermediate­ term assessments for occupational scenarios in essentially all cases because these kinds of exposures are likely and acceptable use and usage data are not available to justify deleting intermediate­ term scenarios. For carbaryl, the agency has completed both short­ term assessment and intermediate­ term assessments because of likely extended periods of exposure in segments of the user population. [Note: The dermal toxicity study NOAEL has been applied to both durations and the NOAELs from the studies used to evaluate inhalation exposures are the same number so the results for both short­ term and intermediate­ term risks are numerically identical.] Long­ term or chronic exposures (essentially every working day over a year) 28 can also occur for some chemicals including an anticipated small number of carbaryl users, particularly in the greenhouse and floriculture industry. These have been addressed as appropriate. Finally, cancer risks have also been calculated using a amortized lifetime dose (LADD) and linear, low dose extrapolation (i. e., the Q1*). The toxicity of chemicals can also vary based on the route of exposure or how a chemical enters the body. For example, exposures to the skin can result in a different toxic effect and/ or severity of reaction than exposures via inhalation. The effects of a chemical can also vary for different durations of exposure. The toxicology database for carbaryl indicates that the Agency consider exposures to the skin combined with exposures via inhalation because the effects and the dose levels at which effects occur are the same regardless of whether it is deposited on the skin or it is inhaled (e. g., cholinesterase inhibition was the effect noted for the inhalation endpoint defined in the acute neurotoxicity study and for the dermal endpoint defined in the 21 day dermal toxicity study used for the short­ term risk assessment). This is also true for all different durations of exposure as similar effects were observed in all toxicity studies selected as the source of the endpoints used for risk assessment purposes. [Note: For further information regarding the toxicity endpoints, see Section 1.3: Summary of Toxicity Concerns Relating To Occupational/ Residential Exposures.] Occupational handler exposure assessments are completed by the Agency using different levels of personal protection. The Agency typically evaluates all exposures with a tiered approach. The lowest tier is represented by the baseline exposure scenario followed by increasing the levels of personal protection represented by personal protective equipment or PPE (e. g., gloves, extra clothing, and respirators) and engineering controls (e. g., closed cabs and closed loading systems). This approach is always used by the Agency in order to be able to define label language using a riskbased approach and not based on generic requirements for label language. [Note: Current labels mostly require single layer clothing, chemical­ resistant gloves, and no respirator.] In addition, the minimal level of adequate protection for a chemical is generally considered by the Agency to be the most practical option for risk reduction (i. e., over­ burdensome risk mitigation measures are not considered a practical alternative). The levels of protection that formed the basis for the calculations in this assessment include (which were combined to obtain 8 different scenarios): C Baseline: Represents typical work clothing or a long­ sleeved shirt and long pants with no respiratory protection. No chemical­ resistant gloves are included in this scenario. C Minimum Personal Protective Equipment (PPE): Represents the baseline scenario with the use of chemical­ resistant gloves and a dust/ mist respirator with a protection factor of 5. C Maximum Personal Protective Equipment (PPE): Represents the baseline scenario with the use of an additional layer of clothing (e. g., a pair of coveralls), chemical­ resistant gloves, and an air purifying respirator with a protection factor of 10. C Engineering Controls: Represents the use of an appropriate engineering control such as a closed tractor cab or closed loading system for granulars or liquids. Engineering controls are not applicable to handheld application methods which have no known devices that can be used to routinely lower the exposures for these methods. 29 It has been determined that exposure to pesticide handlers is likely during the occupational use of carbaryl in a variety of environments including agriculture, commercial/ industrial premises, and in residential environments. The anticipated use patterns and current labeling indicate 28 major occupational exposure scenarios based on the types of equipment and techniques that can potentially be used to make carbaryl applications. The quantitative exposure/ risk assessment developed for occupational handlers is based on these scenarios. [Note: The scenario numbers correspond to the tables of risk calculations included in the occupational risk calculation aspects of the appendices.] Mixing/ Loading (1a) Dry Flowable for Aerial/ Chemigation in Agriculture; (1b) Dry Flowable for Airblast; (1c) Dry Flowable for Groundboom; (1d) Dry Flowable for High Pressure Handwand and Right of Way Sprayers; (1e) Dry Flowable for LCO Applications; (1f) Dry Flowable for Aerial Wide Area Uses; (2a) Granular for Aerial; (2b) Granular for Broadcast Spreader; (3a) Liquids for Aerial/ Chemigation; (3b) Liquids for Airblast; (3c) Liquids for Groundboom; (3d) Liquids for High Pressure Handwand and Right of Way Sprayers; (3e) Liquids for LCO Applications; (3f) Liquids for Aerial Wide Area Uses; (3g) Liquids for Ground Wide Area Uses; (4a) Wettable Powder for Aerial/ Chemigation; (4b) Wettable Powder for Airblast; (4c) Wettable Powder for Groundboom; (4d) Wettable Powder for High Pressure Handwand and Right of Way Sprayers; (4e) Wettable Powder for LCO Applications; (4f) Wettable Powder for Aerial Wide Area Uses; Applicator: (5a) Aerial/ Liquid Application; (5b) Aerial/ Liquid Wide Area Application; (5c) Aerial/ Granular Application; (6a) Airblast Application; (6b) Wide Area Ground Fogger (Airblast as surrogate); (7) Groundboom Application; (8) Solid Broadcast Spreader Application; (9) Aerosol Can Application; (10) Trigger Sprayer (RTU) Application; (11) Right­ of­ Way Sprayer Application; (12) High Pressure Handwand Application; 30 (13) Veterinary Technician/ Animal Groomer Liquid Application; (14) Veterinary Technician/ Animal Groomer Dust Application; (15) Granulars/ Bait and Pellets Dispersed by Hand; (16) Granulars/ Bait and Pellets Dispersed with Spoon; Mixer/ Loader/ Applicator: (17) Low Pressure/ High Volume Turfgun Application; (18a) Wettable powder, Low pressure handwand; (18b) Liquid: Low Pressure Handwand; (19) Backpack; (20) Granular Belly Grinder; (21) Push­ type Granular Spreader; (22) Handheld Fogger; (23) Powered Backpack; (24) Granular Backpack; (25) Tree Injection; (26) Drenching/ Dipping Seedlings For Propagation; (27) Sprinkler Can; Flaggers: (28a) Flagging For Liquid Sprays; and (28b) Flagging For Granular Applications. 2.1.2 Data and Assumptions For Handler Exposure Scenarios A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis. In addition to these values, exposure values were used to calculate risk estimates. Mostly, these values were taken from the Pesticide Handlers Exposure Database (PHED). In other cases, chemical­ specific data were submitted to support the reregistration of carbaryl. Both PHED and the individual studies are presented below. 31 The assumptions and factors used in the risk calculations include: C Carbaryl is one of the most widely used pesticide chemicals. It has an extraordinary number of use patterns that are impossible to completely capture in this document. As such, the Agency has patterned this risk assessment on a series of likely representative scenarios that are believed by the Agency to represent the vast majority of carbaryl uses. Refinements to the assessment will be made as more detailed information about carbaryl use patterns become available. C The carbaryl 80 S label EPA Reg 264­ 316 has a 24( c) label (SLN WA­ 900013) that allows application to oyster beds to control ghost and mud shrimp. The application rate is 8 lb ai/ acre based on information from Bob Merkel of the Washington State Department of Agriculture (WSDA) [contained in email from CRM Anthony Britten of 1/ 3/ 02]. WSDA information also indicates that applications are completed with helicopters over a 3 day period in July and that approximately 800 acres are treated usually with 3 aircraft. Beds are treated with 10 gallons of spray solution per acre at a concentration of 0.8 lb ai/ gallon. With this information, the Agency calculated that approximately 89 acres would be treated per day by each helicopter and that 711 lb ai would also be used. The Agency did not calculate risks specifically for this scenario. However, the Agency considered a wide range of aerial application scenarios in this assessment. For all formulations and for pilots, the vegetable scenario based on 2 lb ai/ acre and 350 acres treated per day (i. e., 700 lb ai applied per day) yields essentially the same risk numbers that would be associated with treating oyster beds. As a result, please refer to the aerial vegetable scenarios to obtain risk estimates for treating oyster beds. C Average body weight of an adult handler is 70 kg because the toxicity endpoint values used for the assessments are appropriate for average adult body weight representing the general population. This is the case because none of the effects identified in the selected toxicity studies were sex specific (i. e., NOAELs selected by HIARC were the same for males and females). C All analyses were completed using chemical­ specific exposure data or data that were deemed to be a source of acceptable surrogate exposure data for the scenario in question. Several handler assessments were completed using "low quality" PHED data due to the lack of a more acceptable dataset. Additionally, in some cases, no empirical data were available for the scenario but an exposure assessment approach was developed based on an approach outlined in the SOPs For Residential Exposure Assessment. In these cases, the assumptions and approached included in the SOPs served as the basis for the assessment (e. g., some pet uses). The PHED unit exposure values range between the geometric mean and the median of the available exposure data. Factors derived from the SOPs For Residential Exposure Assessment are generally considered to be conservative. When data from other studies were used, the appropriate statistical measure of central tendency was used (see each study summary below for data descriptor). 32 C Several generic protection factors were used to calculate handler exposures. The protection factors used for clothing layers (i. e., 50%) and gloves (90%) have not been completely evaluated by the Agency. Additionally, the Agency uses a 98% reduction factor to estimate exposures that involve the use of engineering controls. There is an ongoing project through NAFTA to address the issue of protection factors (a draft document assessing protection factors using PHED has been completed). The results of this effort show that the protection factors being currently used by the Agency are within those predicted in the analysis. The values used for respiratory protection (i. e., PF 5 or PF 10) are based on the NIOSH Respirator Decision Logic. C Exposure factors used to calculate daily exposures to handlers are based on applicable data if available. For lack of appropriate data, values from a scenario deemed similar enough by the assessor might be used. As a example, mixer/ loader/ applicator data for hose­ end sprayers were used to assess sprinkler can applications. The nature of these application methods are believed to be similar enough to bridge the data. There are other instances where the Agency has bridged specific data to represent other scenarios. C Separate short­ term, intermediate­ term, and chronic risk assessments were completed for the noncancer endpoints based on the toxicity endpoints that were identified. The Agency believes that there are exposure scenarios that fit each of these categories. All noncancer scenarios are expected to be short­ or intermediate­ term in nature. The Agency only anticipates a limited number of scenarios that are chronic in nature which are included in the greenhouse and ornamental industry. The Agency also calculated cancer risks for private growers (i. e., those growers who would treat their own fields) and for more frequent carbaryl users such as a commercial applicator. The range in the cancer risk assessments is intended to address the large population of growers who likely complete their own applications but also to address likely smaller, more highly exposed commercial applications. The Agency has used a value of 30 application events per year for all commercial applicator scenarios and 10 days per year to account for private growers (i. e., 1/ 3rd of the analogous professional job function, this is also used for the postapplication risk assessment). These values are supported by the data included in the University of California studies of seasonal labor in California and the recent Department of Labor National Agricultural Worker Survey (NAWS). C The exposure duration (i. e., years per lifetime) values used by the Agency in the cancer risk assessment are consistent with those used for other chemicals (i. e., 35 working years and 70 year lifetime). 33 C In many scenarios it is likely that a grower would mix, load, and apply chemicals all in one day because of limited labor, efficiency, or many other reasons. In most cases, however, the Agency considers mixing/ loading, and application as separate job functions. This is done primarily due to a lack of data that allows additivity between tasks to be appropriately assessed. Also, this approach allows for more flexibility in the risk management process. For example, if a closed loading system might be required for mixer/ loaders but engineering controls might not be required to reduce applicator exposures. If combined exposure estimates were considered, engineering controls might have been required for both tasks. C The Agency has evaluated scenarios that may be limited in nature such as flagging during aerial applications because engineering controls (i. e., Global Positioning Satellite technology) are now predominantly used as indicated by the 1998 National Agricultural Aviation Association (NAAA) survey of their membership. It appears, however, flaggers are still used in approximately 10 to 15 percent of aerial application operations. In cases like these, the Agency strongly encourages the use of the engineering control system but will continue to evaluate risks for flaggers and any other population where a clear exposure pathway exists until the potential for exposure is eliminated. C The Agency always considers the maximum application rates allowed by labels in its risk assessments in order to be able to consider what is legally possible based on the label. If additional information such as average or typical rates are available, these values are used as well in order to allow risk managers to make a more informed risk management decision. Average application rates were available from the SMART meeting and BEAD's QUA. These data indicate that in most cases, average application rates differ from maximum application rates on average by a factor of two. For example, when interpreting the results of the cancer assessment, the small differences generally seen in the available rates should be considered along with the overall magnitude of the cancer risk results. However, it should be noted that because there appears to be little difference between the typical and maximum application rates, overall risk results are not expected to be sensitive to changes in this parameter. C The average occupational workday is assumed to be 8 hours. The daily areas to be treated were defined for each handler scenario (in appropriate units) by determining the amount that can be reasonably treated in a single day (e. g. acres, animals). The factors used for the carbaryl assessment are the same as those detailed in the Health Effects Division Science Advisory Committee on Exposure Policy 9: Standard Values for Daily Acres Treated in Agriculture which was completed on July 5, 2000. The following daily volumes handled and acres, excerpted from the policy, to be treated in each occupational scenario include: C Aerial applications: 1200 acres for large field crops and forest treatments, 350 acres for other field crops, and 7500 acres for mosquito control adulticide applications; C Groundboom: 200 acres for large field crops (e. g., wheat and corn), 80 acres treated for other field crop groundboom applications, and 40 acres on golf course turf; C Airblast: 40 acres treated for agricultural applications; 34 C Ground fogger: 3000 acres for mosquito control (airblast as surrogate); C 8 pet animals treated per day for veterinary and professional groomer uses; C 1000 gallons of spray solution prepared when mixing/ loading liquids for high pressure handwand application or making the application; C 40 gallons when mixing/ loading/ applying liquids with a backpack sprayer or a low pressure handwand sprayer; C 10 mounds per day treated for fire ant applications. [Note: The veterinary and fireant treatments are not included in the policy but represent values that have been used by the Agency in previous assessments. Some carbaryl use patterns may not be summarized above, refer to Policy 9 for further information.] C For direct pet animal treatments, Agency policy outlined in the Residential SOPs, was used to define the amount of chemical applied in animal treatments. For pet treatments, the SOPs prescribe that ½ of a container is used to treat each animal. Dusts and liquid shampoos for carbaryl are available in a 6 ounce bottle (0.5% solution) and a 4 lb container (10% dust). C Currently the Agency has no exposure monitoring data on dust applications to crops in agriculture. There are other data gaps that have been identified for carbaryl applications. Each is identified in the calculation tables and is also noted in the summary of risk calculations. C Ultra­ low volume applications for uses such as mosquito control adulticides were considered using a large acreage estimate to aerial applicators. The mosquito adulticide uses that were evaluated in the same manner as other chemicals used for that purpose (e. g., the same acreage estimates were used as for other chemicals like fenthion and naled). C The impact of using large area (i. e., acreage) estimates should be considered when interpreting the results such as with the scenarios intended to address wide area treatments. For wide area treatments, the Agency considered large acreage aerial applications but did not quantitatively consider ground/ truck fogging which is another likely application method. In the past, the Agency has used airblast application exposure data to address this scenario. However, already given the complexity of the handler risk assessment and the rangefinder nature of using airblast data, the Agency has not completed these calculations. A qualitative estimate of risks can be made by considering the airblast results for agriculture and adjusting the risk values as appropriate for acres treated (3000 acres/ day for ground foggers) and application rate. The Agency uses a concept known as unit exposure as the basis for the scenarios used to assess handler exposures to pesticides. Unit exposures numerically represent the exposures one would receive related to an application. They are generally presented as (mg active ingredient exposure/ pounds of active ingredient handled). The Agency has developed a series of unit exposures that are unique for each scenario typically considered in our assessments (i. e., there are different unit exposures for different types of application equipment; job functions; and levels of protection). The unit exposure concept has been established in the scientific literature and also 35 through various exposure monitoring guidelines published by the U. S. EPA and international organizations such as Health Canada and OECD (Organization For Economic Cooperation and Development). The concept of unit exposures can be illustrated by the following example. If an individual makes an application using a groundboom sprayer with either 10 pounds of chemical A or 10 pounds of chemical B using the same application equipment and protective measures, the exposures to chemicals A and B would be similar. The unit exposure in both cases would be 1/ 10th of the total exposure (measured in milligrams) received during the application of either chemical A or chemical B (i. e., milligrams on the skin after applying 10 pounds of active ingredient divided by 10 pounds of active ingredient applied). The unit exposure values that were used in this assessment were based on one carbarylspecific occupational handler exposure monitoring study during professional dog grooming, three other studies which were used as sources of surrogate exposure information that are not currently included in the Pesticide Handler Exposure Database (PHED) Version 1.1 August 1998, and PHED itself. A brief summary of these studies is provided below in this section. Along with these data, unit exposures from PHED were used to complete remaining aspects of this risk assessment. Each is discussed and summarized below. Occupational Handler Exposure Studies: A total of five studies are described in this section. One study monitored carbaryl use during professional dog grooming activities. The other studies were not completed with carbaryl but were completed with other active ingredients and used as a source of surrogate exposure information for various carbaryl use patterns. Each study can be identified with the following information. A summary of each is also provided below. °" Dermal Exposure and Inhalation Exposure to Carbaryl by Commercial Pet Groomers During Applications of Adams ™ Carbaryl Shampoo." EPA MRID 446584­ 01, September 1998 Report dated August 10, 1998; Author; Thomas C. Mester, Ph. D. Sponsor: Pfizer Animal Health. °" Worker Exposure Study During Application In Banana Plantation With Temik 10G, RP Study SA 98337, EPA MRID 451672­ 01, Vol. 3 of 4" EPA MRID 451672­ 01; November 1999 Report; Author: Michel Urtizberea; Sponsor: Aventis Crop Protection; EPA DER Completed on 10/ 17/ 00 (DP Barcode D267546). °" Worker Exposure Study During Application Of Regent 20GR In Banana Plantation, (RP Study 94/ 136 ­ Amended, EPA MRID 452507­ 01, Vol. 4 of 4, Analytical Lab. CP/ Man/ ENH/ 338/ 95/ 0072)" EPA MRID 452507­ 02; June 1996 Report; Author: P. G. Pontal; Sponsor: Aventis Crop Protection; EPA DER Completed on 1/ 05/ 01 (DP Barcode 270065). 36 °" Exposure of Applicators to Propoxur During Trigger­ Pump Spray Applications of a Liquid Product " EPA MRID 410547­ 01; November 1, 1988; Author: R. D. Knarr, Ph. D., CIH; Sponsor: Bayer Corporation; EPA review (9/ 29/ 89) by Versar, Inc. for PHED purposes under Contract 68­ 02­ 4254, Task 220. °" Integrated Report For Evaluation of Potential Exposures To Homeowners and Professional Lawncare Operators Mixing, Loading, and Applying Granular And Liquid Pesticides To Residential Lawns " EPA MRID 449722­ 01; October 10, 1999; Author: Dennis R. Klonne, Ph. D.; Sponsor: Outdoor Residential Exposure Task Force; EPA Review by Gary Bangs (April 30, 2001). [Note to Chemical Review Manager: There are no data compensation issues associated with the use of non­ ORETF data included in MRIDs 451672­ 01 and 452507­ 01 as these studies were sponsored and submitted by the Aventis Corporation and the propoxur trigger sprayer study has a signed PHED data waiver but just has not been included into PHED at this time. Appendix B contains the data excerpted from MRID 446585­ 01 in various tables which is a carbaryl­ specific study recently completed by the Aventis Corporation. Data from the other referenced studies are not included in Appendix B because separate reviews exist for each which can be independently referenced. Some of the handler exposure data used in this assessment are from the Outdoor Residential Exposure Task Force (ORETF). There is also no data compensation issue associated with the use of the ORETF data in the carbaryl risk assessment because the Aventis Corporation, the registrant for carbaryl, is a member of the ORETF. The task force recently submitted proprietary data to the Agency on hose­ end sprayers, push­ type granular spreaders, and handgun sprayers (MRID # 44972201). The ORETF data were used in this assessment in place of PHED data. The ORETF data were designed to replace the present PHED data with higher­ confidence, higher quality data that contains more replicates than the PHED data for those scenarios. Finally, the Agency identified several occupational exposure studies from the literature by investigators such as Popendorf and Wolfe. These data have not been used by the Agency quantitatively in this assessment because of several issues but were qualitatively considered and also used to confirm the currently used exposure data.] MRID 446584­ 01 (carbaryl­ specific dog groomer data): The data collected reflect the dermal and respiratory exposure of commercial pet groomers applying the end use product, Adams® Carbaryl Flea and Tick Shampoo containing 0.50 percent carbaryl. These data meet most of the criteria specified in Series 875 Occupational and Residential Exposure Test Guidelines. The data are of sufficient scientific quality to be used in the reregistration of carbaryl. The protocol was reviewed by the then Occupational and Residential Exposure Branch of the Health Effects Division. The protocol was accepted as written with the stipulation that protective latex gloves not be worn by groomers because "this protocol was required as a worst case estimate of exposure. Therefore, the use of gloves in this study needs to be deleted" (From George Tompkins to Michael Metzger, dated November 26, 1996). In this study, applications of Adams® Carbaryl Flea and Tick Shampoo were made by professional pet groomers to 8 dogs at 2 sites in Georgia. A total of 16 replicates were monitored for dermal and inhalation exposure. Eight dogs of various sizes and hair lengths were shampooed during each replicate. Dermal exposure was monitored with face and neck swabs, 100 37 percent cotton union suit dosimeter worn underneath a short­ sleeved t­ shirt, long pants and a 65/ 35 polyester cotton long­ sleeved smock (i. e., represents a short­ sleeved shirt under a long­ sleeved coat/ smock). Hand exposure was quantified using handwash rinses (no protective gloves were worn). Inhalation exposure was monitored using personal air pumps with XAD2 resin tubes. Between 373.3 to 3719.95 mg carbaryl (average use was 1360 mg ai) was used to shampoo 8 dogs. According to label directions, the application rate is a subjective determination by the individual groomers based on amount needed to create the desired lather. The dogs were wetted, shampooed to a lather (lather remained on dogs for 5 minutes) and rinsed. It is not clear how many or which of the dogs got further post­ shampoo attention such as grooming or drying. After completing 8 dog shampoos the dosimeters were collected. Face/ neck swabs and 2 hand rinses were performed along with collection of the 100 percent cotton union suit. Only wholebody dosimeter values were adjusted for field recovery (87 percent). No other samples were corrected for recovery as the field and laboratory recoveries generally were >90 percent. Dermal exposures ranged between 0.88 mg and 17 mg ai and inhalation exposures range between 0.05 µg (non­ detect) and 1.96 µg ai. The limit of detection (LOD) was 0.010 µg/ ml. The limit of quantitation (LOQ) was 1 µg per whole body dosimeter, 0.10 µg/ ml for 50 ml hand wash aliquot, 0.10 µg per facial wipe, 0.10 µg per resin tube, and 0.10 µg for glass fiber filter/ support pad. Table 5 contains the results which have been normalized based on each of the following factors: ° mg ai exposed per lb ai handled; ° ai exposed per hour, and ° mg ai per lb dog shampooed. ° The geometric mean of the normalized numbers was used in reregistration calculations because it is a measure of central tendency. Even though the study protocol was approved prior to completion of the field work, the following factors should be considered when interpreting these results. In this task, direct contact of the dipping solution with the hands represents a major potential source of exposure. Therefore, obtaining accurate hand exposure estimates is critical in defining the risks for this use. The study measured the amount of carbaryl left on the hands after 8 shampoos and rinses using an aqueous handwash method. Shampoo was applied, a lather was created and rinsed off with a large degree of hand contact with the shampoo and water stream. Carbaryl repeatedly contacted the hand for the duration of the grooming and some was removed during the rinsing of each dog. Because of this potential flux of residues off and on the groomer's hands and the presence of surfactants which may impact dermal absorption levels, the handwash method may underestimate exposures. This study should not be used for residential exposure assessments because protective clothing (i. e., smock and long pants) were worn over the whole­ body dosimeters and adjusting the data using negative protection factors which is generally not considered appropriate. 38 Table 5: Unit Exposure Values Obtained From Professional Dog Groomer Study (MRID 446584­ 01) Dermal Inhalation Unit Arithmetic Mean Geometric Mean Median Unit Arithmetic Mean Geometric Mean Median mg ai / lb ai handled 1900 1800 1800 µg ai / lb ai handled 24 12 19 mg ai / hour application 1.6 1. 1 1.1 µg ai / hour application 0.20 0.96 0.21 mg ai / lb of dog treated 0.18 0.13 0.14 µg ai / lb of dog treated 0.020 0.011 0.020 Appendix B contains the data excerpted from MRID 446585­ 01. Data from none of the other studies are included in Appendix B because separate reviews exist for each of the other studies which can be independently referenced. EPA MRID 45167201 (Temik granular backpack study): A total of 12 mixer/ loader/ applicator events during granular backpack (i. e., a specialized device manufactured by Swissmex Rapid) application to bananas were monitored during August of 1998 on the island of Martinique which is in the French West Indies. Weather was typical of the application season in that it was hot, humid, and rainy at points. Monitoring was completed using whole body dosimeters, handwashes, facial wipes, and personal sampling pumps equipped with XAD resin/ filter combination samplers. Temik 10G was supplied in 22 pound boxes which was loaded directly into the backpack devices (i. e., 4 to 8 boxes were used per replicate). The application rate for aldicarb used in this study is 20 grams of Temik 10G (i. e., 2 grams ai/ plant) which is equivalent to about 3.56 lb ai/ acre at approximately 2000 plants per acre. The numbers of acres treated ranged from approximately 2.5 to 5 acres. The pounds of active ingredient handled ranged from 8.8 up to 17.6 per replicate. Each applicator wore the whole body dosimeters covered by a cotton coverall, Tyvek gloves supplied with the Temik 10G formulation, and an apron on their backs between their backs and the backpack applicator. The Tyvek gloves were changed with each box of Temik 10G used. In many instances, the gloves were compromised because they were ripped. In one case, the gloves filled with rainwater. In many other cases, when the whole body dosimeters were removed, they were found to be wet and muddy. Analysis of aldicarb and its sulfoxide and sulfone degradates was completed. The residue levels were added together to obtain total exposure levels. The limits of quantification (LOQ) were 1.0 µg per sample for the whole­ body dosimeters and handwashes (600 mL volume). The LOQ for the facial wipes was 0.10 µg per sample and 0.050 0.10 µg per sample for the air filters. Field and laboratory recovery data were generated for all media for all residues measured (i. e., parent and metabolites). Field recovery data were generated in a manner that addressed field sampling, field storage, transport, laboratory storage, and analysis. Residues were corrected for the overall average field recovery for each residue/ matrix combination. Generally, recovery was adequate for all media/ residue combinations. If the PHED grading criteria are applied, all residue/ matrix combinations (except facial wipes with sulfone residues) have at least grade "B" data and in many cases the data meet the grade "A" criteria. The grade "B" criteria require laboratory recovery data with an average of at least 80 percent and a coefficient of variation of 25 or less 39 accompanied with field recoveries that are at least 50 percent but not exceeding 120 percent. The grade "A" criteria require laboratory recovery data with an average of at least 90 percent and a coefficient of variation of 15 or less accompanied with field recoveries that are at least 70 percent but not exceeding 120 percent. Unit exposure values were calculated using the data from the study and a commercial spreadsheet program (Table 6). The exposures that were calculated were normalized by the amount of chemical used, the duration of the application interval, and by the body weight of the individual applicators. For each calculation, the arithmetic mean, geometric mean, and various percentiles were calculated. No analyses were completed with these data to ascertain the exact type of distribution. The Agency typically uses the best fit values from the Pesticide Handlers Exposure Database which are representations of the central tendency. Considering the standard practice, the Agency will use the geometric mean for risk assessment purposes. The other values are presented for comparative purposes. Table 6: Unit Exposure Values Obtained From Granular Backpack Application Study (MRID 451672­ 01) Type (mg exp./ lb ai handled) (mg exp./ hour) (mg exp./ kg body weight/ day) Dermal Inhalation Dermal Inhalation Dermal Inhalation Arith. Mean 0.1391 0.0046 0.5473 0.0179 0.0585 0.0018 Geo. Mean 0.0995 0.0042 0.3979 0.0169 0.0409 0.0017 25th %tile 0.0474 0.0031 0.2511 0.0134 0.0220 0.0015 75th %tile 0.1691 0.0062 0.7436 0.0229 0.0765 0.0023 90th %tile 0.2217 0.0068 0.8489 0.0264 0.0947 0.0027 95th %tile 0.3510 0.0076 1.2119 0.0282 0.1390 0.0028 99th %tile 0.4722 0.0083 1.5594 0.0298 0.1805 0.0030 EPA MRID 452507­ 01 (Fipronil Spoon Application Study): A total of 18 mixer/ loader/ applicator events during granular backpack (i. e., a specialized device manufactured by Horstine Farmery) or spoon application to bananas were monitored during applications on three different days in June, 1994 on the same banana plantation in Cameroon. [Note: Only the spoon application data included in this study are used in the carbaryl risk assessment as backpack granular applications have been assessed using the data presented above.] The 18 replicates were distributed over the 3 sampling days as follows: 6 spoon/ hand applications on day 1; 4 spoon/ hand applications on day 2; and 8 backpack events on day 3. Weather was typical of the application season in that it was hot and humid. Monitoring was completed using whole body dosimeters, cotton gloves, cotton caps, and personal sampling pumps equipped with filters. Regent 20GR was supplied in 22 pound boxes which was loaded directly into the backpack devices or buckets for the spoon applicators. The application rate for fipronil used in this study is 7.5 grams of Regent 20GR (i. e., 0.15 grams ai/ plant) which is equivalent to about 0.26 lb ai/ acre (0.00033 lb ai/ plant) at approximately 800 plants per acre. The numbers of acres treated ranged from approximately 0.75 to 1 acre. The pounds of active ingredient handled ranged from about a quarter to half a pound per replicate. Each 40 applicator wore whole body dosimeters that also served as the normal work clothing. PVC gloves were also worn over cotton gloves which served as the dosimeters. A protection factor of 50 percent was used by the Agency to calculate exposure levels under a layer of normal work clothing. Dosimeter samples were segmented into arms, legs, and torso for analysis. Analysis of fipronil residues was completed with gas chromatography and electron capture detection. The limits of quantification (LOQ) were 9.7 µg per sample for all media used. The limit of detection (LOD) varied for each media. The LOD for the cotton gloves was 0.5 µg per sample, 0.10 µg per sample for the air filters, and 2.0 to 4.0 µg per sample for the whole body dosimeters depending upon the sample analyzed. Field and laboratory recovery data were generated for all media. Field recovery data were generated in a manner that addressed field sampling, field storage, transport, laboratory storage, and analysis. However, the laboratory recovery data were indeterminate because the sample media could not be identified for each reported result. The overall recovery values do appear to be quantitative. Residues were corrected for the overall average field recovery for each residue/ matrix combination. Generally, recovery was adequate for all media/ residue combinations (i. e., all correction factors were greater than 85 percent). If the PHED grading criteria are applied and the overall laboratory recovery averages are used all residue/ matrix combinations are considered grade "A" data. The grade "A" criteria require laboratory recovery data with an average of at least 90 percent and a coefficient of variation of 15 or less accompanied with field recoveries that are at least 70 percent but not exceeding 120 percent. Unit exposure values were calculated using the data from the study and a commercial spreadsheet program. The exposures that were calculated were normalized by the amount of chemical used, the duration of the application interval, and by the body weight of the individual applicators (see table below). The values are based on a 50 percent clothing penetration factor and are separated for each equipment type monitored in this study. For each normalization factor, the arithmetic mean, geometric mean, and various percentiles were calculated. No analyses were completed with these data to ascertain the exact type of distribution. The Agency typically uses the best fit values from the Pesticide Handlers Exposure Database which are representations of the central tendency. Considering the standard practice, the Agency will use the geometric mean for risk assessment purposes. The other values are presented for comparative purposes. Table 7: Unit Exposure Values Obtained From Granular Spoon Application Study (MRID 452507­ 01) Type (mg exp./ lb ai handled) (mg exp./ hour) (mg exp./ kg body weight/ day) Dermal Inhalation Dermal Inhalation Dermal Inhalation Applications with a Spoon Arith. Mean 2.875 0.106 0.433 0.016 0.025 0.001 Geo. Mean 1.978 0.045 0.246 0.006 0.014 0.0003 Median 1.889 0.039 0.221 0.005 0.011 0.0003 25th %tile 0.990 0.024 0.104 0.003 0.006 0.0001 75th %tile 4.140 0.066 0.677 0.007 0.035 0.0004 90th %tile 6.113 0.316 0.999 0.052 0.059 0.003 95th %tile 7.276 0.402 1.190 0.066 0.072 0.004 99th %tile 8.207 0.471 1.342 0.077 0.082 0.005 41 EPA MRID 410547­ 01 (Propoxur trigger sprayer study): A total of 15 applicator events during residential applications using a hand­ operated trigger pump sprayer, attached with an 18 inch hose to half gallon cans containing 0.95 percent propoxur, were completed in this study. The study was completed between October 26 and November 1, 1988 in the Kansas City Missouri metro area. Each person monitored in the study was a Bayer (the sponsor corporation) employee. Three employees were used to complete all replicates. In each replicate, "each applicator used a separate one­ half gallon can of Raid for each house. The cap was removed from the top of the can and the hose sprayer was attached by inserting the dip tube into the can and tightening the screw cap. The sprayer was primed by pumping the trigger. The applicator treated the outside of the home in areas where pests were likely to be found, such as screens, door and window frames, foundation walls, patios, porches, stoops, and decks. When the application was completed, the hose sprayer was secured under the handle of the can." The data included in the study indicate that exposure durations ranged from 9 to 21 minutes per replicate and the amount of active ingredient handled ranged from 0.16 to 0.4 oz (i. e., 0.01 to 0.025 lb ai). Dermal (nonhand) exposure monitoring during each replicate was completed using gauze sponges held in "aluminized paper holders" with an open sampling surface area of 24.6 cm 2 while hand exposures were quantified with the handwash technique (2 ­ 200 mL aliquots of ethanol per hand for a total volume of 800 mL per person). Inhalation exposures were monitored using standard personal sampling pumps operating a 1 liter per minute with quartz microfiber filters. Samples were collected in this study to represent exposures when a person was wearing normal work clothing (i. e., long pants and long­ sleeved shirts) and chemical­ resistant gloves. Analysis of propoxur residues was completed with high performance liquid chromatography, post­ column derivatization, and fluorescence detection. The limits of quantification (LOQ) were 10 µg per sample for the handwash solutions, 0.1 µg/ sample for the inhalation filters, and 0.03 µg/ cm 2 for the dermal patch samples. Field and laboratory recovery data were generated for all media. This study was reviewed in September 1989 under EPA contract 68­ 02­ 4254 by Versar. The values used for regulatory purposes have been excerpted from that review (including recovery results). Average laboratory recovery for all media ranged from 99.2 to 109 percent while the coefficients of variation for each media were generally less than 5 (i. e., for the patches, the CV = 16.5). Patches and filters were fortified at 1 µg/ sample while hand rinses were fortified at either 200 or 1000 µg/ sample. Average field recovery results ranged from 90.3 to 102.2 percent while coefficients of variation also were generally less than 5 (i. e., inside patch CV= 6.9). Patches were fortified at levels from 1 to 50 µg/ sample, hand rinses were fortified at 200 µg/ sample, and filters were fortified at 0.2 µg/ sample. Unit exposure values were calculated using the data from the study and a commercial spreadsheet program. The exposures that were calculated were normalized by the amount of chemical used by individual applicators (Table 8). 42 Table 8: Unit Exposure Values Obtained From Propoxur Trigger Pump Sprayer Study (MRID 410547­ 01) Type (mg exp./ lb ai handled) Dermal Inhalation Geometric Mean 13.5 0. 123 Unit exposure values excerpted from Versar PHED Data review under Contract 68­ 02­ 4254 (9/ 29/ 89). EPA MRID 449722­ 01 (ORETF Handler Studies): A report was submitted by the ORETF (Outdoor Residential Exposure Task Force) that presented data in which the application of various products used on turf by homeowners and lawncare operators (LCOs) was monitored. All of the data submitted in this report were completed in a series of studies. The two studies that monitored LCO exposure scenarios used a granular spreader (ORETF Study OMA001) and a low pressure, high volume turf handgun (ORETF Study OMA002) are summarized below. OMA001: A loader/ applicator study was performed by the Outdoor Residential Exposure Task Force (ORETF) using Dacthal (active ingredient DCPA, dimethyl tetrachloroterephthalate) as a surrogate compound to determine "generic" exposures of lawn care operators (LCOs) applying a granular pesticide formulation to residential lawns. Surrogate chemicals were chosen by the Task Force for their representativeness based on physical chemical properties and other factors. Dacthal, which was the surrogate chemical used for the granular spreader and low­ pressure hand gun sprayer studies, has a molecular weight of 331.97 and a vapor pressure of 1.6 x 10 ­6 , and is believed to be an appropriate surrogate for many relatively nonvolatile pesticides. The study was designed to simulate a typical work day for a LCO applying granular pesticide formulation to home lawns. Each LCO replicate involved loading and applying approximately 3.3 lb ai (360 lb formulated product) over a period of about 4 hours to 15 simulated residential lawns (6480 ft 2 each) with a rotary type spreader. The average industry application rate of 2 lb ai/ acre was simulated (actual rate achieved was about 1.9 lb ai/ acre). The monitoring period included driving, placing the spreader onto and off of the truck, carrying and loading the formulation in the spreader, and the actual application. Incidental activities such as repairs, cleaning up spills, and disposing of empty bags were monitored. A total of 40 replicates (individual application events) were monitored using passive dosimetry (inner and outer whole body dosimeters, hand washes, face/ neck wipes, and personal inhalation monitors with OVS tubes). The inner samples represent a single layer of clothing. Inhalation exposure was calculated using an assumed respiratory rate of 17 Lpm for light work (NAFTA, 1999), the actual sampling time for each individual, and the pump flow rate. In 20 of the replicates, the subjects wore chemical­ resistant gloves while in the remaining replicates, no gloves were worn. No gloves were worn in any replicate while driving. All results were normalized for the amount of active ingredient handled. Nearly all samples (for every body part and for inhalation) were above the level of quantitation (LOQ) for dacthal. Where results were less 43 than the reported LOQ, ½ LOQ value was used for calculations, and no recovery corrections were applied. The overall laboratory recoveries (83­ 101%) and field recoveries (73­ 98%). The unit exposure values are presented in Table 9 below. [Note the inhalation exposure value is a median because the data were found to be neither normally nor lognormally distributed. All dermal values are geometric means as the data were lognormally distributed.] OMA002: A mixer/ loader/ applicator study was performed by the Outdoor Residential Exposure Task Force (ORETF) using Dacthal as a surrogate compound to determine "generic" exposures to individuals applying a pesticide to turf with a low­ pressure "nozzle gun" or "hand gun" sprayer. Dermal and inhalation exposures were estimated using wholebody passive dosimeters and breathing­ zone air samples on OVS tubes. Inhalation exposure was calculated using an assumed respiratory rate of 17 Lpm for light work (NAFTA, 1999), the actual sampling time for each individual, and the pump flow rate. All results were normalized for lb ai handled. A total of 90 replicates were monitored using 17 different subjects. Four different formulations of dacthal [75% wettable powder (packaged in 4lb and 24 lb bags), 75% wettable powder in water soluble bags (3 lb bag), 75% water dispersible granules ( 2 lb bag) and 55% liquid flowable (2.5 Gal container)] were applied by five different LCOs to actual residential lawns at each site in three different locations (Ohio, Maryland, and Georgia) for a total of fifteen replicates per formulation. An additional ten replicates at each site were monitored while they performed spray application only using the 75 percent wettable powder formulation. A target application rate of 2 lb ai/ acre was used for all replicates (actual rate achieved was about 2.2 lb ai/ acre). Each replicate treated a varying number of actual client lawns to attain a representative target of 2.5 acres (1 hectare) of turf. The exposure periods averaged five hours twenty­ one minutes, five hours thirty­ nine minutes, and six hours twenty­ four minutes, in Ohio, Maryland and Georgia, respectively. Average time spent spraying at all sites was about two hours. All mixing, loading, application, adjusting, calibrating, and spill clean up procedures were monitored, except for typical end­ of­ day clean­ up activities, e. g. rinsing of spray tank, etc. Dermal exposure was measured using inner and outer whole body dosimeters, hand washes, face/ neck washes, and personal air monitoring devices. All test subjects wore one­ piece, 100 percent cotton inner dosimeters beneath 100 percent cotton long­ sleeved shirt and long pants, rubber boots and nitrile gloves. Gloves are typically worn by most LCOs, and required by many pesticide labels for mixing and loading. Overall, residues were highest on the upper and lower leg portions of the dosimeters In general, concurrent lab spikes produced mean recoveries in the range of 78­ 120 percent, with the exception of OVS sorbent tube sections which produced mean recoveries as low as 65.8 percent. Adjustment for recoveries from field fortifications were performed on each dosimeter section or sample matrix for each study participant, using the mean recovery for the closest field spike level for each matrix and correcting the value to 100 percent. The unit exposure values are presented in Table 9 below. [Note the data were found to be lognormally distributed. As a result, all exposure values are geometric means.] 44 Table 9: Unit Exposure Values Obtained From ORETF LCO Studies (MRID 449722­ 01) Type (mg exp./ lb ai handled) Dermal Inhalation Single Layer, No Gloves Single Layer, Gloves Double Layer, Gloves LCO Push Granular Spreader 0.35 0.22 0.11 0.0071 LCO Turfgun (WP Formulation) No Data 0.65 0.36 0.0066 All unit exposure values are geometric means except inhalation value for granular spreader. Double layer value calculated using a 50% protection factor. Turfgun, no glove data were not back calculated using a 90 percent protection factor as it is deemed unreliable. WP formulation in WSP packaging used for turfgun assessment as the unit exposures for this scenario were slightly higher than for the other scenarios and deemed representative of current products/ packaging. Pesticide Handler Exposure Database (PHED) Version 1.1 (August 1998): Chemical­ specific data for assessing human exposures during pesticide handling activities were submitted to the Agency in support of one occupational exposure scenario for the reregistration of carbaryl. It is the policy of HED to combine submitted chemical­ specific data with that from the Pesticide Handlers Exposure Database (PHED) Version 1.1 when appropriate to assess handler exposures for regulatory actions 4 . The scenario/ chemical­ specific study submitted has no corresponding scenario in PHED, therefore, unit exposure values from the study are used to calculate exposure and risk for the use pattern. For all other remaining scenarios, data from PHED were used to complete the assessment. PHED was designed by a task force of representatives from the U. S. EPA, Health Canada, the California Department of Pesticide regulation, and member companies of the American Crop Protection Association. PHED is a software system consisting of two parts ­­ a database of measured exposure values for workers involved in the handling of pesticides under actual field conditions and a set of computer algorithms used to subset and statistically summarize the selected data. Currently, the database contains values for over 1,700 monitored individuals (i. e., replicates) Users select criteria to subset the PHED database to reflect the exposure scenario being evaluated. The subsetting algorithms in PHED are based on the central assumption that the magnitude of handler exposures to pesticides are primarily a function of activity (e. g., mixing/ loading, applying), formulation type (e. g., wettable powders, granulars), application method (e. g., aerial, groundboom), and clothing scenarios (e. g., gloves, double layer clothing). Once the data for a given exposure scenario have been selected, the data are normalized (i. e., divided by) by the amount of pesticide handled resulting in standard unit exposures (milligrams of exposure per pound of active ingredient handled). Following normalization, the data are statistically summarized. The distribution of exposure values for each body part (e. g., chest upper arm) is categorized as normal, lognormal, or "other" (i. e., neither normal nor lognormal). A central tendency value is then selected from the distribution of the exposure values for each body part. These values are the arithmetic mean for normal distributions, the geometric mean for lognormal distributions, and the median for all "other" distributions. Once selected, the central tendency values for each body part are composited into a "best fit" exposure value representing the entire body. 45 The unit exposure values calculated by PHED generally range from the geometric mean to the median of the selected data set. To add consistency and quality control to the values produced from this system, the PHED Task Force has evaluated all data within the system and has developed a set of grading criteria to characterize the quality of the original study data. The assessment of data quality is based on the number of observations and the available quality control data. These evaluation criteria and the caveats specific to each exposure scenario are summarized in Appendix C, Table C1. While data from PHED provide the best available information on handler exposures, it should be noted that some aspects of the included studies (e. g., duration, acres treated, pounds of active ingredient handled) may not accurately represent labeled uses in all cases. HED has developed a series of tables of standard unit exposure values for many occupational scenarios that can be utilized to ensure consistency in exposure assessments. Unit exposures are used which represent different levels of personal protection as described above. Protection factors were used to calculate unit exposure values for varying levels of personal protection if data were not available. 2.1.3 Occupational Handler Exposure and Non­ Cancer Risk Estimates The occupational handler exposure and non­ cancer risk calculations are presented in this section. Noncancer risks were calculated using the Margin of Exposure (MOE) which is a ratio of the body burden to the toxicological endpoint of concern. Body burden values are calculated by first calculating exposures by considering application parameters (i. e., rate and area treated) along with unit exposure levels. Exposures were then normalized by body weight and adjusted for absorption factors as appropriate to calculate dose levels (i. e., body burdens). MOEs were then calculated. Daily Exposure: The daily exposure, daily dose and hence the risks, to handlers were calculated as described below. The first step was to calculate daily exposure (dermal or inhalation) using the following formula: Daily Exposure (mg ai/ day) = Unit Exposure (mg ai/ lb ai) x Application Rate (lb ai/ A) x Daily Acres Treated (A/ day) Where: Daily Exposure = Amount deposited on the surface of the skin that is available for dermal absorption or amount that is inhaled, also referred to as potential dose (mg ai/ day); Unit Exposure = Normalized exposure value derived from August 1998 PHED Surrogate Exposure Table and various referenced exposure studies noted above (mg ai/ lb ai); Application Rate = Normalized application rate based on a logical unit treatment such as acres or gallons, maximum and typical values are generally used (lb ai/ A); and Daily Acres Treated = Normalized application area based on a logical unit treatment such as acres (A/ day) or gallons per day can be substituted (gal/ day). 46 Inhalation exposure values were calculated in a similar manner. The only difference is that unit exposure values representing the inhalation route were used that were calculated using PHED and standard human breathing rates (29 liters/ minute and an 8 hour exposure). [Note: In some cases, the above equation has been substituted by an algorithm excerpted from the Agency's SOPs For Residential Exposure Assessment (chapter 9) that calculates exposures based on the percent of active ingredient applied (e. g., pet treatment calculations). It should also be noted that HED has agreed to use the NAFTA recommended values for breathing rate rather than the existing rate in Series 875 Group A (i. e., previously known as Subdivision U). Series 875 Group A recommends an inhalation rate of 29 L/ min. The new NAFTA recommended inhalation rates are 8.3, 16.7, and 26.7 L/ min for sedentary activities (e. g., driving a tractor), light activities (e. g., flaggers and mixer/ loaders < 50 lb containers), and moderate activities (e. g., loading > 50 lb containers, handheld equipment in hilly conditions), respectively. These inhalation reduction factors are 3.5 for tractor drivers, 1.7 for mixer/ loaders and flaggers, and 1.1 for handheld equipment. These changes in exposure factors will be programmed into the next version of the handler exposure data base and are characterized in this document for regulatory risk management decisions.] Daily Dose: Daily dose (inhalation or dermal) was then calculated by normalizing the daily dermal exposure value by body weight and accounting for dermal absorption (i. e., a biologically available dose resulting from dermal exposure was then calculated). For adult handlers using carbaryl, an average adult body weight of 70 kg was used for all exposure scenarios because all scenarios were occupational and the toxic effect was seen in males and females. Additionally, a dermal absorption factor of 12.7 percent was used for all chronic duration dermal calculations based on an absorption study in rats. A 21­ day dermal administration toxicity study in rats was used to calculate risks for short­ and intermediate­ term dermal exposure. In cases such as this, a default value of 100 percent is used in the calculation. It should also be noted that there is no specific inhalation absorption factor that is available for carbaryl. Therefore, a factor of 100 percent has been used for all calculations. Daily dose was calculated using the following formula: Where: Average Daily Dose = The amount as absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/ kg body weight/ day, also referred to as ADD); Daily Exposure = Amount deposited on the surface of the skin that is available for dermal absorption or amount that is inhaled, also referred to as potential dose (mg ai/ day); Absorption Factor = A measure of the flux or amount of chemical that crosses a biological boundary such as the skin (% of the total available absorbed); and Body Weight = Body weight determined to represent the population of interest in a risk assessment (kg). The handler exposure assessment does not include any dietary or drinking water inputs. 47 Margins of Exposure: Finally, the calculations of daily dermal dose and daily inhalation dose received by handlers were then compared to the appropriate endpoint (i. e., NOAEL or LOAEL) to assess the total risk to handlers for each exposure route within the scenarios. Short­ and intermediate­ term dermal MOEs were calculated using a NOAEL of 20.0 mg/ kg/ day defined in the rat 21 day dermal toxicity study (Table 1). Short­ term inhalation MOEs were calculated using a NOAEL of 1.0 mg/ kg/ day defined in the rat developmental neurotoxicity and rat acute neurotoxicity studies (Table 1). Intermediate­ term inhalation MOEs were calculated using a NOAEL of 1.0 mg/ kg/ day defined in a subchronic neurotoxicity study in rats. Additionally, when required for a limited number of scenarios, chronic dermal and inhalation MOEs were calculated using a LOAEL of 3.1 mg/ kg/ day that was defined in a 1 year dog feeding study. All MOE values were calculated separately for dermal and inhalation exposure levels using the formula below: Where: MOE = Margin of exposure, value used by the Agency to represent risk or how close a chemical exposure is to being a concern (unitless); ADD = (Average Daily Dose) or the amount as absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/ kg body weight/ day); and NOAEL or LOAEL = Dose level in a toxicity study, where no observed adverse effects occurred (NOAEL) in the study or the lowest dose level where an adverse effect occurred (LOAEL) in the study (mg pesticide active ingredient/ kg body weight/ day). It is important to present risk values for each route of exposure (i. e., dermal or inhalation) in each scenario because it makes determining appropriate risk mitigation measures easier. For example, if overall risks are driven by dermal exposures and not inhalation, it would not advisable to require respirators as they may marginally reduce overall risks. It is also important to present overall risk estimates for each scenario considered by calculating total MOEs. A total MOE was calculated because common toxicity endpoints were used to calculate dermal and inhalation risks for each exposure duration. The following formula is used to calculate total MOE values by combining the route­ specific MOEs: MOE total = 1/(( 1/ MOE a) + (1/ MOE b) +.... (1/ MOE n)) Where: MOE a, MOE b, and MOE n represent MOEs for each exposure route of concern A margin of exposure (MOE) uncertainty factor of 100 is considered an appropriate risk level for the short­ and intermediate­ term risk assessments because a NOAEL was used as the basis for the 48 assessment. A margin of exposure (MOE) uncertainty factor of 300 is considered an appropriate risk level for the chronic risk assessment because a LOAEL was selected from the1 year dog feeding study as the basis for the assessment. Noncancer Risk Summary: All of the noncancer risk calculations for occupational carbaryl handlers completed in this assessment are included in Appendix C (Tables 1 ­ 9). The specifics of each of table included in Appendix C are described below. A summary of the results for each exposure scenario is also provided below (please refer to Appendix C for more details). C Appendix C/ Table 1: Sources of Exposure Data Used in the Occupational Carbaryl Handler Exposure and Risk Calculations Describes the sources and quality of the exposure data used in all of the occupational handler calculations. C Appendix C/ Table 2: Input Parameters For Carbaryl Occupational Handler Exposure and Risk Calculations Presents the numerical unit exposure values and other factors used in the occupational handler risk assessments. C Appendix C/ Table 3: Margins of Exposure For Carbaryl Occupational Handler Risk Assessment At The Baseline Level of Personal Protection Risk values are presented for each exposure duration considered in the assessment (i. e., short­, intermediate­, and chronic duration exposures). Represents typical work clothing or a long­ sleeved shirt and long pants with no respiratory protection. No chemical­ resistant gloves are included in this scenario. Note that some scenarios have no baseline dermal exposure values (see notes on Tables 1 and 2). [Note: The calculations from this table have been used to develop the summary in Tables 7, 8, and 9.] C AppendixC/ Table 4: Margins of Exposure For Carbaryl Occupational Handler Risk Assessment At The Minimum Level of Personal Protection Risk values are presented for each exposure duration considered in the assessment (i. e., short­, intermediate­, and chronic duration exposures). Represents the baseline scenario with the use of chemical­ resistant gloves and PF 5 respirators. [Note: The calculations from this table have been used to develop the summary in Tables 7, 8, and 9.] C Appendix C/ Table 5: Margins of Exposure For Carbaryl Occupational Handler Risk Assessment At The Maximum Level of Personal Protection Risk values are presented for each exposure duration considered in the assessment (i. e., short­, intermediate­, and chronic duration exposures). Represents the baseline scenario with the use of an additional layer of clothing (e. g., a pair of coveralls), chemical­ resistant gloves, and a PF 10 respirator. [Note: The calculations from this table have been used to develop the summary in Tables 7, 8, and 9.] C Appendix C/ Table 6: Margins of Exposure For Carbaryl Occupational Handler Risk Assessment Using Engineering Controls Risk values are presented for each exposure duration considered in the assessment (i. e., short­, intermediate­, and chronic duration 49 exposures). Represents the use of an appropriate engineering control such as a closed tractor cab or closed loading system for granulars or liquids. Engineering controls are not applicable to handheld application methods there are no known devices that can be used to routinely lower the exposures for these methods. [Note: The calculations from this table have been used to develop the summary in Tables 7, 8, and 9.] C Appendix C/ Table 7: Combined Short­ Term Margins Of Exposure For Carbaryl Occupational Handler Risk Assessment Presents combined dermal and inhalation MOEs with each possible combination of dermal and respiratory protection considered in this assessment. Results for exposure durations # 30 days are only included in this table based on the use of the developmental neurotoxicity and acute neurotoxicity studies in rats to define the NOAEL for this duration. [Note: See tables 3 through 6 for calculations of specific MOE values.] C Appendix C/ Table 8: Combined Intermediate­ Term Margins Of Exposure For Carbaryl Occupational Handler Risk Assessment Presents combined dermal and inhalation MOEs with each possible combination of dermal and respiratory protection considered in this assessment. Results for exposure durations >30 days up to several months are only included in this table based on the use of a subchronic neurotoxicity study in rats to define the NOAEL for this duration. [Note: See tables 3 through 6 for calculations of specific MOE values.] C Appendix C/ Table 9: Combined Chronic Margins Of Exposure For Carbaryl Occupational Handler Risk Assessment Presents combined dermal and inhalation MOEs with each possible combination of dermal and respiratory protection considered in this assessment. Results for exposures that occur essentially each working are only included in this table based on the use of a chronic dog feeding study to define the LOAEL for this duration. [Note: See tables 3 through 6 for calculations of specific MOE values.] Tables 1 through 6 of Appendix C provide the inputs and illustrate how the calculations were performed to define the noncancer risks (i. e., Margins of Exposure or MOEs) for carbaryl handlers. The exposure data and other factors which were used represent the best sources of data currently available to the Agency for completing these kinds of assessments. For example, maximum application rates were derived directly from carbaryl labels. The recent use and usage report was also reviewed to define average application rates for each crop or group of crops considered. Exposure factors (e. g., body weight, amount treated per day, protection factors, etc.) are all standard values that have been used by the Agency over several years and are derived from peer reviewed sources whenever possible (e. g., Exposure Factors Handbook). The unit exposure values are the best available estimates of exposure. Some unit exposure values are high quality while others represent low quality, but the best available, data. Data quality should be considered in the interpretation of the uncertainties associated with each risk value presented. Please identify these scenarios based on information provided in Appendix C/ Table 1. Additionally, it should be noted that the animal grooming scenario with dusts calculations were based on the SOPs For Residential Exposure Assessment (i. e., 10% of applied is considered equivalent to the dermal exposure). This 50 calculation should be considered only as a rangefinder. Tables 7, 8, and 9 in Appendix C provide the overall results of the risk assessment for each distinct exposure duration considered because they contain the combined risk values for each scenario using several combinations of personal protection (e. g., short­ term combined MOEs are presented in Table 7). When protective measures are used to reduce risks it is appropriate to consider how each method will reduce the associated risks and the burden associated with the use of that method (e. g., gloves are thought to routinely reduce risks from dermal exposures by 90 percent based on the Agency protection factor for gloves). It should be noted that there were several scenarios which were identified for which no appropriate exposure data are known to exist. These include: C Animal Grooming Dust Application; C Dust applications in agriculture (not included on handler tables in Appendix C but considered a major data gap); C Handheld Fogging For Mosquito and Other Pest Treatments; C Power Backpack Application; C Tree Injection; and C Drenching/ dipping seedlings [Note: The mixing/ loading component only of this scenario has been addressed quantitatively.] Short­ term and Intermediate­ term Risk Summary: Short­ term and intermediate­ term risks were calculated for different exposure scenarios at different levels of personal protection as illustrated in Tables 7 and 8 of Appendix C, respectively. The results and trends for both the short­ term and intermediate­ term calculations are identical because all exposure inputs were similar and the NOAEL values of 20 mg/ kg/ day for dermal exposures and 1 mg/ kg/ day for inhalation exposures are the same for both durations. The only difference is the source of the NOAELs selected for the inhalation risk assessment. The short­ term values were determined based on rat developmental neurotoxicity and acute neurotoxicity studies while the intermediate­ term NOAEL was defined using a subchronic neurotoxicity study in rats. Therefore, for economy, the results for both shortand intermediate­ term occupational handlers have been summarized together in this section. [Note: If risk estimates were altered because of additional data or other reason, then separate sections would be presented as appropriate.] In most scenarios, MOEs meet or exceed the required uncertainty factor of 100 at some level of personal protection. For the most part, current label requirements for personal protection (single layer clothing, gloves, and no respirator) appear to be generally inadequate for most scenarios except 51 for operations where exposures and/ or the amount of chemical used is low. Table 10 summarizes the results for short­ term and intermediate­ term occupational handlers. [Note: Scenarios where MOEs are still of concern (i. e., <100) for any personal protection considered are highlighted and the minimum required PPE is also highlighted if it exceeds current label requirements.] Table 10: Summary of Short­/ Intermediate­ Term Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE Mixer/ Loaders 1a Dry Flowable: Aerial/ Chemigation 1­ 2 (wheat/ corn) 2­ 5 (veg., stone fruit, 24C on oysters) 1200 350 363­ 726 498­ 1244 EC EC 1b Dry Flowable: Airblast 7.5­ 16 (various fruit & nut trees) 5 (nuts) 1.1­ 3 (pome & stone fruit, grapes) 40 40 40 1360­ 2902 101 143­ 391 EC SL/ GL/ PF5 Baseline 1c Dry Flowable: Groundboom 1.5­ 2 (wheat/ corn) 2 (strawberry/ veg) 8 (turf/ golf courses) 4 (turf/ golf courses) 200 80 40 40 2177­ 2902 107 2721 108 EC Baseline EC Baseline 1d Dry Flowable: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 430 Baseline 1e Dry Flowable: Low press./ High Vol. Turfgun 4 ­8 (LCO on turf) 5 430­ 860 Baseline 1f Dry Flowable: Wide area aerial 2 (rangeland/ forestry) 7500 58 MOE < 100 2a Granular: Aerial Application 2 (corn) 2 (corn) 1200 350 688 146 EC SL/ GL/ PF5 2b Granular: Solid broadcast spreader 1.5 (wheat/ corn) 2 (wheat/ corn) 2 (vegetables) 6 (turf/ golf courses) 9 (turf/ golf courses) 200 200 80 40 40 110 256 206 138 284 Baseline SL/ GL/ PF5 Baseline Baseline SL/ GL/ PF5 3a Liquid: Aerial/ Chemigation 1.5­ 2 (wheat, max corn) 1 (avg. corn) 5 (stone fruit) 2 (vegetables) 1200 1200 350 350 57­ 76 114 78 103 All MOEs < 100 EC MOE< 100 DL/ GL/ PF10 3b Liquid: Airblast Application 16 (Citrus­ 24C in California) 7.5 (Citrus) 5 (Nuts) 1.1­ 3 (Grapes, pome & stone fruit) 40 40 40 40 100 168 149 248­ 677 DL/ GL/ PF10 SL/ GL/ PF5 SL/ GL/ NR SL/ GL/ NR 3c Liquid: Groundboom 1.5 (wheat) 2 (corn) 2 (strawberries) 8 (turf/ golf courses) 4 (turf/ golf courses) 200 200 80 40 40 168 126 186 157 186 SL/ GL/ PF5 SL/ GL/ PF5 SL/ GL/ NR SL/ GL/ PF5 SL/ GL/ NR 3d Liquid: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 745 SL/ GL/ NR Table 10: Summary of Short­/ Intermediate­ Term Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE 52 3e Liquid: Low press./ High Vol. Turfgun 4 ­8 (LCO on turf) 5 745­ 1489 SL/ GL/ NR 3f Liquid: Wide area aerial 2 (Range/ Forestry) 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 7500 7500 7500 7500 9 248 121 18 MOE < 100 SL/ GL/ NR EC MOE < 100 3g Liquid: Wide area ground 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 3000 3000 3000 621 112 45 SL/ GL/ NR SL/ GL/ PF5 MOE < 100 4a Wettable Powders: Aerial 1­ 2 (Wheat/ corn) 5 (stone fruit) 2 (vegetables) 1200 350 350 40­ 80 55 137 All MOEs < 100 MOE < 100 EC 4b Wettable Powders: Airblast 16 (Citrus­ 24C in California) 1.1­ 7.5 (Citrus, nuts, grapes, pome & stone fruit) 40 40 150 320­ 2180 EC EC 4c Wettable Powders: Groundboom 1.5­ 2 (wheat/ corn) 2 (strawberries) 4­ 8 (turf/ golf courses) 200 80 40 240­ 320 599 299­ 599 EC EC EC 4d Wettable Powders: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 102 SL/ GL/ PF5 4e Wettable Powders: Low press./ High Vol. Turfgun 4 (LCO on turf) 8 (LCO on turf) 5 5 102 205 SL/ GL/ PF5 SL/ GL/ PF5 4f Wettable Powders: Wide area aerial 2 (Range/ Forestry) 7500 6 MOE< 100 Applicators 5a Aerial: Agricultural uses, liquid sprays 1­ 1.5 (wheat/ avg. corn) 2 (max corn) 5 (stone fruit) 2 (vegetables, 24C on oysters) 1200 1200 350 350 113­ 170 85 116 292 EC MOE< 100 EC EC 5b Aerial: Wide area uses, liquid sprays 2 (Range/ Forestry) 0.016­ 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 7500 7500 7500 14 181­ 1700 27 MOE< 100 EC MOE< 100 5c Aerial: Agricultural uses, granular applications 2 (corn) 2 (corn) 1200 350 21 72 MOE< 100 MOE< 100 6a Airblast: Agricultural uses 16 (Citrus 24C in California) 2­ 7.5 (Citrus, nuts, grapes, pome & max. stone fruit) 1.1 (avg. stone fruit) 40 40 40 105 224­ 841 123 EC EC SL/ GL/ PF5 6b Airblast: Wide area uses, liquid sprays 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 3000 3000 3000 113 150 22 SL/ GL/ PF5 EC MOE< 100 Table 10: Summary of Short­/ Intermediate­ Term Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE 53 7 Groundboom 1.5­ 2 (Wheat, corn) 2 (Strawberries) 4­ 8 (Turf/ golf course) 200 80 40 122­ 162 304 152­ 304 Baseline Baseline Baseline 8 Solid broadcast spreader (granular) 1. 5­ 2 (Wheat, corn) 2 (Strawberries) 4­ 8 (Turf/ golf course) 200 80 40 103­ 138 258 115­ 172 Baseline Baseline Baseline 9 Aerosol Can 0. 01 lb ai/ can 2 cans 324 Baseline 10 Trigger pump sprayer 0. 01 lb ai/ can 1 can 8772 SL/ GL/ NR 11 Right of way sprayer 1. 5 lb ai/ 100 gallons 1000 gallons 199 SL/ GL/ NR 12 High pressure handwand 4 lb ai/ 100 gallons 1000 gallons 66 MOE< 100 13 Animal groomer, liquid application 0.01 lb ai/ dog 8 dogs 9.7 MOE< 100 14 Animal groomer, dust application (see App C/ Table 3) 0.2 lb ai/ dog 8 dogs 8750 Baseline (dermal exp only) 15 Granulars & baits applied by hand 9 (Ornamentals & gardens) 1 3.8 MOE< 100 16 Granulars & baits applied by spoon 9 (Ornamentals & garderns) 1 75.1 MOE< 100 Mixerr/ Loader/ Applicators 17 Low pressure, high volume turfgun (ORETF Data) 8 (LCO Use on turf) 4 (LCO Use on turf) 5 5 94 104 MOE< 100 SL/ GL/ PF5 18a Wettable powder, low pressure handwand 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 8.3 135 MOE< 100 SL/ GL/ PF5 18b Liquids, low pressure handwand 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 127 1699 SL/ GL/ PF5 SL/ GL/ NR 19 Backpack sprayer 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 42 565 MOE< 100 Baseline 20 Granular, bellygrinder 9 (Turf) 1 27 MOE< 100 21 Granular, push­ type spreader 9 (Turf) 5 124 SL/ GL/ PF5 22 Handheld fogger No data No data No data No data 23 Power backpack No data No data No data No data 24 Granular, backpack 9 (Ornamentals) 1 1562 DL/ GL/ NR 25 Tree injection No data No data No data No data 26 Drench/ dipping forestry/ ornamentals 1.5 lb ai/ 100 gallons (Ornamental/ seedling dip) 100 gallons 199 SL/ GL/ NR 27 Sprinkler can 2% solution (Ornamentals) 10 gallons 226 Baseline Table 10: Summary of Short­/ Intermediate­ Term Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE 54 Flaggers 28a Flagger: liquid sprays 2 (Corn) 2 (Vegetables) 1200 350 249 111 EC Baseline 28b Flagger: granular applications 2 (Corn) 2 (Vegetables) 1200 350 101 345 Baseline Baseline Baseline = Long pants, long­ sleeved shirts, no gloves SL = Single layer clothing with or without gloves (GL or NG) DL = Double layer clothing (i. e., coveralls over SL) with or without gloves (GL or NG) EC = Engineering controls NR = No respirator PF5 = Protection factor 5 respirator PF10 = Protection factor 10 respirator Current label = SL/ GL/ NR Min. Req. PPE = level of PPE where MOEs > 100, where current label is exceeded or no adequate PPE is found, results are bold. MOEs which never exceed 100 are for highest feasible type of mitigation (e. g., engineering control in most cases). Chronic Risk Summary: MOEs were calculated for only a limited number of exposure ornamental use scenarios where the Agency believes that this kind of exposure pattern may exist. These calculations were also completed at different levels of personal protection as illustrated in Table 11 (Table 9 of Appendix C summarized below). For most scenarios (3 of 5), MOEs meet or exceed the required uncertainty factor of 300 at some level of personal protection. The granular hand application scenarios are problematic. The uncertainty factor of 300 is required for the chronic exposure scenarios because a LOAEL and not a NOAEL was used for risk assessment purpose as defined in a chronic dog feeding study using carbaryl. It is Agency policy to apply an additional factor of 3 to the overall uncertainty factor when using a LOAEL for risk assessment purposes. Table 11: Summary of Chronic Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE Applicators 15 Granulars & baits applied by hand 9 (Ornamentals & gardens) 1 4.7 MOE< 300 16 Granulars & baits applied by spoon 9 (Ornamentals & garderns) 1 92.6 MOE< 300 Mixer/ Loader/ Applicators 18a Wettable powder, low pressure handwand 2% solution (ornamentals) 40 gallons 302 DL/ GL/ PF10 18b Liquids, low pressure handwand 2% solution (ornamentals) 40 gallons 3206 SL/ GL/ NR Table 11: Summary of Chronic Occupational Handler Noncancer Risks Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary MOEs Min. Req. PPE 55 19 Backpack sprayer 2% solution (ornamentals) 40 gallons 781 Baseline Baseline = Long pants, long­ sleeved shirts, no gloves SL = Single layer clothing with or without gloves (GL or NG) DL = Double layer clothing (i. e., coveralls over SL) with or without gloves (GL or NG) EC = Engineering controls NR = No respirator PF5 = Protection factor 5 respirator PF10 = Protection factor 10 respirator Current label = SL/ GL/ NR Min. Req. PPE = level of PPE where MOEs > 300, where current label is exceeded or no adequate PPE is found, results are bold. MOEs which never exceed 300 are for highest feasible type of mitigation (e. g., PPE in most cases). 2.1.4 Occupational Handler Exposure and Risk Estimates for Cancer. The occupational handler exposure and cancer risk calculations are presented in this section. Cancer risks were calculated using a linear low­ dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated and then compared with a Q1* that has been calculated for carbaryl based on dose response data in the appropriate toxicology study (Q1* = 8.75 x 10 ­4 (mg/ kg/ day) ­1 ). Absorbed average daily dose (ADD) levels were used as the basis for calculating the LADD values. Section 2.1.3 above describes how the ADD values were first calculated for the noncancer MOE calculations. These values also serve as the basis for the cancer risk estimates. Dermal and inhalation ADD values were first added together to obtain combined ADD values. LADD values were then calculated and compared to the Q1* to obtain cancer risk estimates. Lifetime Average Daily Dose: After the development of the ADD values, the next step required to calculate the carcinogenic risk is to amortize these values over the working lifetime of occupational handlers based on use patterns, this results in the LADD for that use. Product labels limit use to every 7 to 10 days or a seasonal "lb ai per acre" limit. Also, according to available use/ usage data, on average, carbaryl is applied more than once per year for most crops. Based on this information and due to the number and variety of target insects and crops registered for carbaryl applications, the Agency considered two distinct populations in the cancer risk assessment including private growers at 10 use events per year and commercial applicators that would have a more frequent use pattern of 30 days per year. Finally, a 35 year career and a 70 year lifespan was used to complete the calculations. LADD values were calculated using the following equation: LADD ADD TreatmentFrequency Days year WorkingDuration Lifetime = × × 365 / Where: Lifetime Average Daily Dose = The amount as absorbed dose received from exposure to a 56 pesticide in a given scenario over a lifetime (mg pesticide active ingredient/ kg body weight/ day, also referred to as LADD); Average Daily Dose = The amount as absorbed dose received from exposure to a pesticide in a given scenario on a daily basis (mg pesticide active ingredient/ kg body weight/ day, also referred to as ADD); Treatment Frequency = The annual frequency of an application by an individual (days/ year); Working Duration = The amount of a lifetime that an individual spends engaged in a career involving pesticide exposure (35 years); Lifetime = The average life expectancy of an individual (70 years). Cancer Risks : Finally, cancer risk calculations were completed by comparing the LADD values calculated above to the Q1* for carbaryl (Q1* = 8.75 x 10 ­4 (mg/ kg/ day) ­1 , see Table 1 for further information). The Agency considered more typical users in these calculations (i. e., private growers at 10 events per year) as well as more frequent users that might represent commercial applicators (i. e., 30 events per year). Cancer risk values were calculated using the following equation: Risk LADD Q = × 1 * Where: Risk = Probability of excess cancer cases over a lifetime (unitless); Lifetime Average Daily Dose = The amount as absorbed dose received from exposure to a pesticide in a given scenario over a lifetime (mg pesticide active ingredient/ kg body weight/ day, also referred to as LADD); and Q1* = Quantitative dose response factor used for linear, lowdose response cancer risk calculations (mg/ kg/ day) ­1 . The Agency has defined a range of acceptable cancer risks based on a policy memorandum issued in 1996 by then office director, Mr. Dan Barolo. This memo refers to a predetermined quantified "level of concern" for occupational carcinogenic risk. In summary, this policy memo indicates occupational carcinogenic risks that are 1 x 10 ­6 or lower require no risk management action. For those chemicals subject to reregistration, the Agency is to carefully examine uses with estimated risks in the 10 ­6 to 10 ­4 range to seek ways of cost­ effectively reducing risks. If 57 carcinogenic risks are in this range for occupational handlers, increased levels of personal protection would be warranted as is commonly applied with noncancer risk estimates (e. g., additional PPE or engineering controls). Carcinogenic risks that remain above 1.0 x 10 ­4 at the highest level of mitigation appropriate for that scenario remain a concern. Cancer Risk Summary All of the cancer risk calculations for occupational carbaryl handlers completed in this assessment are included in Appendix C (Tables 10 and 11). The specifics of each of table included in Appendix C are described below. A brief summary of the results for each exposure scenario is also provided below. C Appendix C/ Table 10: Carbaryl Occupational Handler Risks For Private Growers Presents cancer risks for combined dermal and inhalation for private growers (i. e., 10 applications per year) with each possible combination of dermal and respiratory protection considered in this assessment. C Appendix C/ Table 11: Carbaryl Occupational Handler Risks For Commercial Applicators Presents cancer risks for combined dermal and inhalation for commercial applicators (i. e., 30 applications per year) with each possible combination of dermal and respiratory protection considered in this assessment. Tables 1 through 6 of Appendix C should also be considered as they illustrate how the route­ specific ADD values were calculated which are the basis for the cancer risk values. These route­ specific ADD values were added and applied to the Q1* value to calculate the cancer risks as described above. Cancer risks for private growers (i. e., 10 applications per year) were calculated for different exposure scenarios at different levels of personal protection (Table10 of Appendix C). All scenarios for private growers have risks that are <1x10 ­4 at some level of personal protection specified in the Barolo memo. In fact, for all but one scenario (Scen 4f: Mixing/ loading Wettable Powders for wide area aerial applications) cancer risks are <1x10 ­4 at current label requirements for personal protection. If a 1x10 ­6 risk level is specified as a concern, results are similar in that risks for a majority of scenarios are <1x10 ­6 at current label requirements. In fact, only 8 of the 128 scenarios considered for private applicators have cancer risks >1x10 ­6 (and less than 1x10 ­4 ) even when the most protective ensembles of either protective clothing or engineering controls are considered. As with the risks calculated for private growers, cancer risks for commercial applicators (i. e., 30 applications per year) were calculated for different exposure scenarios at different levels of personal protection (Table 11 of Appendix C). Again, risks for all but one scenario (Scen 4f: Mixing/ loading Wettable Powders for wide area aerial applications) are less than the 1x10 ­4 level specified in the Barolo memo at current label requirements for personal protection (i. e., risks for this scenario are < 1x10 ­4 if additional protective clothing or equipment is used). If a 1x10 ­6 risk level is specified as a concern for commercial applicators, results indicate that risks for about half of the scenarios considered are <1x10 ­6 at current label requirements and that only 21 of the 128 scenarios considered have cancer risks >1x10 ­6 (and less than 1x10 ­4 ) even when the most protective ensembles of either protective clothing or engineering controls are considered. In 58 general, the cancer risk estimates would lead to less restrictive measures when compared to the noncancer results. Table 12 below provides a summary of the cancer risks that have been calculated for private growers and commercial applicators. Table 12: Summary of Occupational Handler Cancer Risks For Private Growers and Commercial Applicators Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary Private Growers Commercial Applicators Risk Min. Req. PPE Risk Min. Req. PPE Mixer/ Loaders 1a Dry Flowable: Aerial/ Chemigation 1­ 2 (wheat/ corn) 5 (stone fruit) 2 (vegetables, 24C on oysters) 1200 350 350 3.7 to 7.4x10 ­8 5.4x10 ­8 1.0x10 ­6 EC EC SL/ GL/ PF10 1.1 to 2.2x10 ­7 1.6x10 ­7 6.5x10 ­8 EC EC EC 1b Dry Flowable: Airblast 16 (Citrus, 24C in CA) 1.1­ 7.5 (grapes, various fruit & nut trees) 40 40 1.0x10­ 6 6.9x10 ­8 to 4.7x10 ­7 Baseline Baseline 5.9x10 ­8 1.4 to 9.3x10 ­7 EC DL/ GL/ PF10 1c Dry Flowable: Groundboom 2 (corn) 1.5 (wheat) 2 (strawberry/ veg) 8 (turf/ golf courses) 4 (turf/ golf courses) 200 200 80 40 40 4.7x10 ­7 6.3x10 ­7 2.5x10 ­7 5.0x10 ­7 2.5x10 ­7 Baseline Baseline Baseline Baseline Baseline 1.0x10 ­6 3.7x10 ­8 7.5x10 ­7 1.0x10 ­6 7.5x10 ­7 DL/ GL/ NR EC Baseline DL/ GL/ PF5 Baseline 1d Dry Flowable: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 6.3x10 ­8 Baseline 1.9x10 ­7 Baseline 1e Dry Flowable: Low press./ High Vol. Turfgun 4 ­8 (LCO on turf) 5 3.1 to 6.3x10 ­8 Baseline 9.4x10 ­8 to 1.9x10 ­7 Baseline 1f Dry Flowable: Wide area aerial 2 (rangeland/ forestry) 7500 4.6x10 ­7 EC 1.4x10 ­6 All < 1x10 ­6 2a Granular: Aerial Application 2 (corn) 2 (corn) 1200 350 5.0x10 ­7 3.3x10 ­7 SL/ GL/ PF5 Baseline 9.5x10 ­7 9.9x10 ­7 DL/ GL/ PF5 Baseline 2b Granular: Solid broadcast spreader 1.5­ 2 (wheat/ corn) 2 (vegetables) 6­ 9 (turf/ golf courses) 200 80 40 1.4 to 1.9x10 ­7 7.6x10 ­8 1.1 to 1.7x10 ­7 Baseline Baseline Baseline 4.3 to 5.7x10 ­7 2.3x10 ­7 3.4 to 5.1x10 ­7 Baseline Baseline Baseline 3a Liquid: Aerial/ Chemigation 1 (avg. corn) 1.5 (wheat) 2 (corn) 5 (stone fruit) 2 (vegetables) 1200 1200 1200 350 350 9.7x10 ­7 9.9x10 ­7 8.5x10 ­7 9.5x10 ­7 4.9x10 ­7 SL/ GL/ PF5 DL/ GL/ PF5 SL/ GL/ NR SL/ GL/ PF5 SL/ GL/ NR 1.1x10 ­6 1.4x10 ­6 7.2x10 ­7 1.1x10 ­6 8.6x10 ­7 All < 1x10 ­6 All < 1x10 ­6 EC All < 1x10 ­6 DL/ GL/ PF5 3b Liquid: Airblast Application 16 (citrus, 24C in CA) 1.1­ 7.5 (grapes, various fruit & nut trees) 40 40 4.5x10 ­7 3.1x10 ­8 to 2.1x10 ­7 SL/ GL/ NR SL/ GL/ NR 1.0x10­ 6 9.3x10 ­8 to 6.4x10 ­7 SL/ GL/ PF5 SL/ GL/ NR 3c Liquid: Groundboom 1.5­ 2 (wheat/ corn) 2 (strawberries) 4­ 8 (turf/ golf courses) 200 80 40 2.1 to 2.8x10 ­7 1.1x10 ­7 1.1 to 2.3x10 ­7 SL/ GL/ NR SL/ GL/ NR SL/ GL/ NR 6.4 to 8.5x10 ­7 3.4x10 ­7 3.4 to 6.8x10 ­7 SL/ GL/ NR SL/ GL/ NR SL/ GL/ NR 3d Liquid: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 2.8x10 ­8 SL/ GL/ NR 8.5x10 ­8 SL/ GL/ NR 3e Liquid: Low press./ High Vol. Turfgun 4 ­8 (LCO on turf) 5 1.4 to 2.8x10 ­8 SL/ GL/ NR 4.2 to 8.5x10 ­8 SL/ GL/ NR Table 12: Summary of Occupational Handler Cancer Risks For Private Growers and Commercial Applicators Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary Private Growers Commercial Applicators Risk Min. Req. PPE Risk Min. Req. PPE 59 3f Liquid: Wide area aerial 2 (Range/ Forestry) 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 7500 7500 7500 7500 3.0x10 ­6 8.5x10 ­8 7.9x10 ­7 1.5x10 ­6 All < 1x10 ­6 SL/ GL/ NR SL/ GL/ NR All < 1x10 ­6 9.1x10 ­6 2.5x10 ­7 6.8x10 ­7 4.5x10 ­6 All < 1x10 ­6 SL/ GL/ NR EC All < 1x10 ­6 3g Liquid: Wide area ground 0.016 (Mosquito Adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 3000 3000 3000 3.4x10 ­8 3.2x10 ­7 6.0x10 ­7 SL/ GL/ NR SL/ GL/ NR EC 1.0x10 ­7 9.5x10 ­7 1.8x10 ­6 SL/ GL/ NR SL/ GL/ NR All < 1x10 ­6 4a Wettable Powders: Aerial 1.5 (Wheat) 2 (Corn ­ max) 1 (Corn ­ typ) 5 (stone fruit) 2 (vegetables) 1200 1200 1200 350 350 4.6x10 ­7 6.1x10 ­7 3.1x10 ­7 4.4x10 ­7 1.8x10 ­7 EC EC EC EC EC 1.4x10 ­6 1.8x10 ­6 9.2x10 ­7 1.3x10 ­6 5.3x10 ­7 All < 1x10 ­6 All < 1x10 ­6 EC All < 1x10 ­6 EC 4b Wettable Powders: Airblast 16 (Citrus­ 24C in California) 7.5 (Citrus) 5 (Nuts) 3 (Pome & stone fruit) 2 (Grapes) 1.1( Avg. stone fruit) 40 40 40 40 40 40 1.6x10 ­7 7.6x10 ­8 1.0x10 ­6 6.2x10 ­7 8.8x10 ­7 4.9x10 ­7 EC EC SL/ GL/ PF5 SL/ GL/ PF5 SL/ GL/ NR SL/ GL/ NR 4.9x10 ­7 2.3x10 ­7 1.5x10 ­7 9.2x10 ­8 1.0x10 ­6 5.7x10 ­7 EC EC EC EC DL/ GL/ PF5 DL/ GL/ PF5 4c Wettable Powders: Groundboom 1.5 (wheat) 2 (corn) 2 (strawberries) 8 (turf/ golf courses) 4 (turf/ golf courses) 200 200 80 40 40 7.6x10 ­8 1.0x10 ­7 8.3x10 ­7 8.1x10 ­8 8.3x10 ­7 EC EC SL/ GL/ PF5 EC SL/ GL/ PF5 2.3x10 ­7 3.1x10 ­7 1.2x10 ­7 2.4x10 ­7 1.2x10 ­7 EC EC EC EC EC 4d Wettable Powders: High Press HW/ ROW Sprayer 4 lb ai/ 100 gal (poultry) 1000 gal 4.4x10 ­7 SL/ GL/ NR 5.2x10 ­7 DL/ GL/ PF5 4e Wettable Powders: Low press./ High Vol. Turfgun 4 (LCO on turf) 8 (LCO on turf) 5 5 2.2x10 ­7 4.4x10 ­7 SL/ GL/ NR SL/ GL/ NR 6.6x10 ­7 6.2x10 ­7 SL/ GL/ NR SL/ GL/ PF5 4f Wettable Powders: Wide area aerial 2 (Range/ Forestry) 7500 3.8x10 ­6 All < 1x10 ­6 1.1x10 ­5 All < 1x10 ­6 Applicators 5a Aerial: Agricultural uses, liquid sprays 1­ 2 (wheat/ corn) 5 (stone fruit) 2 (vegetables, 24C on oysters) 1200 350 350 1.6 to 3.2x10 ­7 2.3x10 ­7 9.2x10 ­8 EC EC EC 4.7 to 9.5x10 ­7 6.9x10 ­7 2.8x10 ­7 EC EC EC 5b Aerial: Wide area uses, liquid sprays 2 (Range/ Forestry) 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 7500 7500 7500 7500 2.0x10 ­6 1.6x10 ­8 1.5x10 ­7 9.8x10 ­7 All < 1x10 ­6 EC EC EC 5.9x10 ­6 4.7x10 ­8 4.4x10 ­7 3.0x10 ­6 All < 1x10 ­6 EC EC All < 1x10 ­6 5c Aerial: Agricultural uses, granular applications 2 (corn) 2 (corn) 1200 350 6.2x10 ­7 1.8x10 ­7 EC EC 1.9x10 ­6 5.5x10 ­7 All < 1x10 ­6 EC 6a Airblast: Agricultural uses 16 (Citrus 24C in California) 7.5 (Citrus) 5 (Nuts) 3 (Pome & stone fruit) 2 (Grapes) 1.1 (Avg pome & stone fruit) 40 40 40 40 40 40 2.7x10 ­7 1.3x10 ­7 9.9x10 ­7 1.0x10 ­6 6.9x10 ­7 3.8x10 ­7 EC EC DL/ GL/ PF5 Baseline Baseline Baseline 8.2x10 ­7 3.9x10 ­7 2.6x10 ­7 1.5x10 ­7 1.0x10 ­7 7.9x10 ­7 EC EC EC EC EC SL/ GL/ NR Table 12: Summary of Occupational Handler Cancer Risks For Private Growers and Commercial Applicators Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary Private Growers Commercial Applicators Risk Min. Req. PPE Risk Min. Req. PPE 60 6b Airblast: Wide area fogger 0.016 (Mosquito adulticide) 0.15 (Mosquito adulticide) 1 (Mosquito adulticide) 3000 3000 3000 4.1x10 ­7 1.9x10 ­7 1.3x10 ­6 Baseline EC All < 1x10 ­6 8.6x10 ­7 5.8x10 ­7 3.9x10 ­6 SL/ GL/ NR EC All < 1x10 ­6 7 Groundboom 1.5­ 2 (Wheat/ corn) 2 (Strawberries) 8 (Turf/ golf course) 4 (Turf/ golf course) 200 80 40 40 1.3 to 1.7x10 ­7 6.9x10 ­8 1.4x10 ­7 6.9x10 ­8 Baseline Baseline Baseline Baseline 3.9 to 5.2x10 ­7 2.1x10 ­7 4.1x10 ­7 2.1x10 ­7 Baseline Baseline Baseline Baseline 8 Solid broadcast spreader (granular) 1.5­ 2 (Wheat/ corn) 2 (Strawberries) 4­ 8 (Turf/ golf course) 200 80 40 1.3 to 1.7x10 ­7 6.7x10 ­8 1.0 to 1.5x10 ­7 Baseline Baseline Baseline 3.8 to 5.0x10 ­7 2.0x10 ­7 3.0 to 4.5x10 ­7 Baseline Baseline Baseline 9 Aerosol Can 0.01 lb ai/ can 2 cans 8.7x10 ­8 Baseline 2.6x10 ­7 Baseline 10 Trigger pump sprayer 0.01 lb ai/ can 1 can 3.1x10 ­9 SL/ GL/ NR 9.4x10 ­9 SL/ GL/ NR 11 Right of way sprayer 1.5 lb ai/ 100 gallons 1000 gallons 4.3x10 ­7 Baseline 4.1x10 ­7 SL/ GL/ NR 12 High pressure handwand 4 lb ai/ 100 gallons 1000 gallons 6.6x10 ­7 SL/ GL/ PF5 1.1x10 ­6 All < 1x10 ­6 13 Animal groomer, liquid application 0.01 lb ai/ dog 8 dogs 3.1x10 ­6 All < 1x10 ­6 9.4x10 ­6 All < 1x10 ­6 14 Animal groomer, dust application 0.2 lb ai/ dog 8 dogs 3.5x10 ­9 Baseline 1.0x10 ­8 Baseline 15 Granulars & baits applied by hand 9 (Ornamentals & gardens) 1 8.0x10 ­6 All < 1x10 ­6 2.4x10 ­5 All < 1x10 ­6 16 Granulars & baits applied by spoon 9 (Ornamentals & garderns) 1 4.6x10 ­7 SL/ GL/ NR 1.2x10 ­6 All < 1x10 ­6 Mixerr/ Loader/ Applicators 17 Low pressure, high volume turfgun (ORETF Data) 8 (LCO Use on turf) 4 (LCO Use on turf) 5 5 3.1x10 ­7 6.1x10 ­7 SL/ GL/ NR SL/ GL/ NR 9.7x10 ­7 9.2x10 ­7 DL/ GL/ PF5 SL/ GL/ NR 18a Wettable powder, low pressure handwand 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 3.1x10 ­6 3.0x10 ­7 All < 1x10 ­6 SL/ GL/ NR 9.2x10 ­6 9.0x10 ­7 All < 1x10 ­6 SL/ GL/ NR 18b Liquids, low pressure handwand 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 2.1x10 ­7 1.2x10 ­8 SL/ GL/ PF5 SL/ GL/ NR 6.2x10 ­7 3.5x10 ­8 SL/ GL/ PF5 SL/ GL/ NR 19 Backpack sprayer 1 lb ai/ 1000 ft 2 (poultry house) 2% solution (ornamentals) 20,000 ft 2 40 gallons 7.0x10 ­7 4.8x10 ­8 DL/ GL/ PF5 Baseline 2.2x10 ­6 1.4x10 ­7 All < 1x10 ­6 Baseline 20 Granular, bellygrinder 9 (Turf) 1 1.1x10 ­6 All < 1x10 ­6 3.4x10 ­6 All < 1x10 ­6 21 Granular, push­ type spreader 9 (Turf) 5 4.0x10 ­7 Baseline 8.2x10 ­7 SL/ GL/ NR 22 Handheld fogger No data No data No data No data No data No data 23 Power backpack No data No data No data No data No data No data 24 Granular, backpack 9 (Ornamentals) 1 1.9x10 ­8 DL/ GL/ NR 5.8x10 ­8 DL/ GL/ NR 25 Tree injection No data No data No data No data No data No data Table 12: Summary of Occupational Handler Cancer Risks For Private Growers and Commercial Applicators Scenario Rate (lb ai/ acre) [unless noted] Area Treated (acres/ day) [unless noted] Risk Summary Private Growers Commercial Applicators Risk Min. Req. PPE Risk Min. Req. PPE 61 26 Drench/ dipping forestry/ ornamentals 1.5 lb ai/ 100 gallons (Ornamental/ seedling dip) 100 gallons 1.1x10 ­7 SL/ GL/ NR 3.2x10 ­7 SL/ GL/ NR 27 Sprinkler can 2% solution (Ornamentals) 10 gallons 1.3x10 ­7 Baseline 4.0x10 ­7 Baseline Flaggers 28a Flagger: liquid sprays 2 (Corn) 2 (Vegetables) 1200 350 7.2x10 ­7 2.1x10 ­7 Baseline Baseline 3.5x10 ­7 6.3x10 ­7 EC Baseline 28b Flagger: granular applications 2 (Corn) 2 (Vegetables) 1200 350 2.1x10 ­7 6.1x10 ­8 Baseline Baseline 6.2x10 ­7 1.8x10 ­7 Baseline Baseline Baseline = Long pants, long­ sleeved shirts, no gloves SL = Single layer clothing with or without gloves (GL or NG) DL = Double layer clothing (i. e., coveralls over SL) with or without gloves (GL or NG) EC = Engineering controls NR = No respirator PF5 = Protection factor 5 respirator PF10 = Protection factor 10 respirator Current label = SL/ GL/ NR Min. Req. PPE = level of PPE where cancer risks > 1x10 ­6 , where current label is exceeded or no adequate PPE is found, results are bold. Risks which never exceed 1x10 ­6 are for highest feasible type of mitigation (e. g., engineering control in most cases). 2.1.5 Summary of Risk Concerns and Data Gaps for Handlers Generally, most scenarios have risks associated with them that meet or exceed the Agency's uncertainty factors for noncancer risk assessments (i. e., 100 for short­ term and intermediate­ term and 300 for chronic) and requirements for cancer risk results (i. e., range of 1x10 ­6 to 1x10 ­4 as defined by Office Director Barolo in 1996) at some level of personal protection. Current carbaryl labels typically require that handlers wear long pants, long­ sleeved shirts, and gloves. Respirators are generally not required. For most scenarios, the noncancer risks for this personal protection ensemble do not meet Agency risk requirements and additional levels of personal protection are required to achieve Agency risk targets. In fact, in many cases engineering controls such as closed loading systems or closed cab tractors are needed. The Agency does have risk concerns over the use of carbaryl in some agricultural and other occupational settings (i. e., MOEs at any level of personal protection are <100 or <300, depending on the duration). As would be expected, these scenarios with the highest associated risk also have high daily chemical use amounts based on application rates or high acreages treated or the exposures for the scenarios in question are relatively high. Generally, the areas that appear to be problematic include: large acreage aerial and chemigation applications in agriculture or for wide area treatments such as mosquito control; airblast applications at higher rates; pet grooming; and the use of certain handheld equipment for applications to turf or gardens (e. g., bellygrinder). This general trend was essentially the same regardless of the noncancer toxicity endpoints which were considered (e. g., short­ term, intermediate­ term). Risks for corresponding scenarios based on cancer concerns were generally less than noncancer results across all scenarios. In fact, in all but one scenario, cancer risks were <1x10 ­4 at current carbaryl label requirements of single layer clothing, gloves, and no respirator. 62 Several data gaps were also identified in many different use areas that include: dust use for animal grooming and in agriculture; various specialized hand equipment application methods (e. g., powered backpack, power hand fogger, and tree injection); and nursery operations such as seedling dips. 2.1.6 Recommendations For Refining Occupational Handler Risk Assessment In order to refine this occupational risk assessment, data on actual use patterns including rates, timing, and acreages treated would better characterize carbaryl risks. Exposure studies for many equipment types that lack data or that are not well represented in PHED (e. g., because of low replicate numbers or data quality) should also be considered based on the data gaps identified above and based on a review of the quality of the data used in this assessment. Risk managers should consider that the risks associated with current label requirements for personal protection generally do not meet Agency risk targets. 2.2 Occupational Postapplication Exposures and Risks The Agency uses the term "postapplication" to describe exposures to individuals that occur as a result of working in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). The agency believes that there are distinct job functions or tasks related to the kinds of activities that occur in previously treated areas such as harvesting vegetables in a treated field. Job requirements (e. g., the kinds of jobs to cultivate a crop), the nature of the crop or target that was treated, and the how chemical residues degrade in the environment can cause exposure levels to differ over time. Each factor has been considered in this assessment. The scenarios that serve as the basis for the risk assessment are presented in Section 2.2.1: Occupational Postapplication Exposure Scenarios. The exposure data and assumptions that have been used for the calculations are presented in Section 2.2.2: Data and Assumptions For Occupational Postapplication Exposure Scenarios. The calculations and the algorithms that have been used for the noncancer elements of the risk assessment as well as the calculated risk values are presented in Section 2.2.3: Occupational Postapplication Exposure and Noncancer Risk Estimates while the analogous information using the Q1* for cancer estimates are presented in Section 2.2.4: Occupational Postapplication Exposure and Risk Estimates For Cancer. Section 2.2.5: Summary of Occupational Postapplication Risk Concerns and, Data Gaps presents the overall risk picture for carbaryl. Finally, recommendations are presented in Section 2.2.6: Recommendations For Refining Occupational Postapplication Risk Assessment. 2.2.1 Occupational Postapplication Exposure Scenarios Carbaryl uses are extremely varied as it can be used in agriculture, on ornamentals, on turf (golf courses and lawns) and on companion animals (e. g., on dogs and cats). As a result, a wide array of individuals can potentially be exposed by working in areas that have been previously treated. The Agency is concerned about these kinds of exposures one could receive in the workplace. The purpose of this section is to explain how postapplication exposure scenarios were developed for each occupational setting where carbaryl can be used. Exposure scenarios can be thought of as ways of categorizing the kinds of exposures that occur related to the use of a 63 chemical. The use of scenarios as a basis for exposure assessment is very common as described in the U. S. EPA Guidelines For Exposure Assessment (U. S. EPA; Federal Register Volume 57, Number 104; May 29, 1992). The agency uses a concept known as the transfer coefficient to numerically represent the post­ application exposures one would receive (i. e., generally presented as cm 2 /hour). The transfer coefficient concept has been established in the scientific literature and through various exposure monitoring guidelines published by the U. S. EPA and international organizations such as Health Canada and OECD (Organization For Economic Cooperation and Development). The establishment of transfer coefficients also forms the basis of the work of the Agricultural Reentry Task Force, of which, Aventis is a member. The transfer coefficient is essentially a measure of the contact with a treated surface one would have while doing a task or activity. These values are defined by calculating the ratio of an exposure for a given task or activity to the amount of pesticide on leaves (or other surfaces) that can rub off on the skin resulting in an exposure. For postapplication exposures, the amounts that can rub off on the skin are measured using techniques that specifically determine the amount of residues on treated leaves or other surfaces (referred to as transferable residues) rather than the total residues contained both on the surface and absorbed into treated leaves. Transfer coefficients can be illustrated by the following example. Consider two vegetable fields where the amount of chemical on treated leaf surfaces that can rub off on the skin is the same. One field has been treated with chemical A while the other field has been treated in a similar manner with chemical B. If an individual harvests the same vegetables for a day in each field, the exposures the individual would receive would be similar. The transfer coefficient would also be similar for each field and chemical because the ratio of exposure to residue would be the same. If the same individual would do another activity in those fields such as scout the vegetables for pests or tie the vegetables, the exposures would be different as would the resulting transfer coefficients because the activity that resulted in the exposures is different. In this example, three distinct transfer coefficients could be determined for vegetable crops: harvesting; scouting; and tying. The Agency has developed a series of standard transfer coefficients that are unique for variety of job tasks or activities that are used in lieu of chemical­ and scenario­ specific data. As with the handler risk assessment process, the first step in the post­ application risk assessment process is to identify the kinds of individuals that are likely to be exposed to carbaryl after application. In order to do this in a consistent manner, the Agency has developed a series of general descriptions for tasks that are associated with post­ application exposures. The Agency also considers whether or not individuals are exposed to pesticides as part of their employment (referred to as occupational risk assessments). Common examples include: agricultural harvesters, scouting activities in agriculture, crop maintenance tasks (e. g., irrigating, hoeing and weeding), and turf maintenance (golf course mowing and sod harvesting). 64 The next step in the risk assessment process is to define how and when chemicals are applied in order to determine the level of transferable residues to which individuals could be exposed over time. Wherever available, use and usage data are included in this process to define values such as application rates and application frequency. The Agency always completes risk assessments using maximum application rates for each scenario because what is possible under the label (the legal means of controlling pesticide use) must be evaluated, for complete stewardship, in order to ensure the Agency has no concern for the specific use. Additionally, whenever the Agency has additional information, such as typical or average application rates or frequency data, it uses the information to further evaluate the overall risks associated with the use of the chemical. In order to define the amount of transferable residues to which individuals can be exposed, the Agency relies on chemical­ and crop­ specific studies as described in the Agency guidelines for exposure data collection (Series 875, Occupational and Residential Exposure Test Guidelines: Group B Postapplication Exposure Monitoring Test Guidelines). The Agency has also developed a standard modeling approach that can also be used to predict transferable residues over time in lieu of chemical­ and scenario­ specific data (best described in the Agency's SOPs For Residential Exposure Assessment). All scenarios were evaluated using carbaryl­ specific DFR dissipation data. Next, assessors must understand how exposures to carbaryl occur (i. e., frequency and duration) and how the patterns of these occurrences can alter the effects of the chemical in the population after being exposed (referred to as dose response). The Agency believes that carbaryl exposures can occur from over a single day up to every working day depending on the crop and industry being considered. This is supported by the fact that several areas within a work environment may be treated at different times. For example, parts of agricultural fields in a localized area might be treated over several weeks because of an infestation with a concurrent need for hand labor activities. Therefore, individuals working in those fields might be exposed from contact with treated foliage over an extended period of time that could be categorized as an intermediate­ term exposure as they work on different sections of fields. Three different types of noncancer risk calculations were required for each exposure duration considered. The durations of exposure that were considered for noncancer toxicity were short­ term ( 30 days), intermediateterm (30 days up to several months), and chronic (every working day). A complete array of calculations was completed for all identified exposure scenarios using the short­ and intermediateterm endpoints because the Agency believes that carbaryl uses fit the criteria for both of these durations. The only calculations that were completed using the chronic endpoint were limited and those associated with the greenhouse and floriculture industries where these kinds of exposures may occur. Cancer risks were also calculated using a linear, low­ dose extrapolation model (i. e., Q1*) for both private growers (i. e., 10 days per year) and for those who may more actively use carbaryl such as a professional farmworker (i. e., 30 days per year). Inhalation exposures are thought to be negligible in outdoor postapplication scenarios because of the low vapor pressure and due to the infinite dilution expected outdoors. As such, inhalation postapplication exposures are not considered in this assessment. The use of personal protective equipment or other types of equipment to reduce exposures for post­ application workers is not considered a viable alternative for the regulatory process except in specialized situations (e. g., a rice scout will wear rubber boots in flooded paddies). This is described in some detail in the Agency's Worker Protection Standard (40CFR170). As such, an 65 administrative approach is used by the Agency to reduce the risks and is referred to as the Restricted Entry Interval or REI. The REI is a measure of the amount of time required to pass after application of a pesticide before engaging in a task or activity in a treated field. Postapplication risk levels are generally calculated in the risk assessment process on a chemical­, crop­, and activityspecific basis. To establish REIs, the Agency considers postapplication risks on varying days after application. [Note: Current labels specify REIs of 12 hours after application for all crop/ cultural practice combinations while Pre­ Harvest Intervals (PHIs) are less than 7 days for most crops with some as long as 28 days.] The Agency has used the basic approach described above since the mid 1980s for calculating postapplication risks to pesticides. From that time to the present, several revisions and modifications were made to Agency policies as data which warranted such changes became available. In 1995, the Agency issued a Data Call­ In for postapplication agricultural data that prompted the formation of the Agricultural Reentry Task Force (ARTF), of which Aventis is a member. This task force has generated a number of exposure studies and associated documents that are currently under review by the Agency. The work of the ARTF is not yet complete, however, sufficient data were available from the group that warranted a significant interim change in Agency policy related to the data which were already available as the efforts of the ARTF paralleled the Agency push for tolerance reassessment stipulated by the timelines established by FQPA. As a result of the need for the revision and using the latest data, the Agency developed a revised policy on August 7, 2000 entitled Policy 003.1 Science Advisory Council For Exposure Policy Regarding Agricultural Transfer Coefficients. The revision to this policy entailed linking worker activities to more specific crop/ agronomic groupings and making better use of the available occupational postapplication exposure data. In the new policy, transfer coefficients were selected to represent the activities associated with 18 distinct crop/ agronomic groupings based on different types of vegetables, trees, berries, vine/ trellis crops, turf, field crops, and bunch/ bundle crops (e. g., tobacco). In this new scheme which the Agency uses to develop scenarios for occupational postapplication exposures, carbaryl uses were identified in all of the crop groupings in the policy. These crop groups include: C Low Berry (e. g., lowbush blueberries, cranberries, strawberries); C Bunch/ bundle (e. g., bananas, hops, tobacco); C Field/ row crops, low/ medium (e. g., alfalfa, barley, beans, cotton, peanuts, peas); C Field/ row crops, tall (e. g., corn, sorghum, sunflowers); C Cut flowers (e. g., floriculture crops); C Sugarcane; C Trees/ fruit, deciduous (e. g., apples, apricots, cherry, peaches, pears); C Trees/ fruit, evergreen (e. g., avocados, Christmas trees, citrus); C Trees/ nut (e. g., almonds, hazelnuts, macadamia, pecans, walnuts); C Turf/ sod (e. g., golf courses, sod farms); C Vegetable/ root (e. g., beets, carrots, onions, potatoes, turnips); C Vegetable/ cucurbit (e. g., cantelope, cucumber, squash, watermelon); C Vegetable/ fruiting (e. g., eggplant, pepper, tomato, okra); C Vegetable/ head and stem brassica (e. g., brocolli, cauliflower, brussel sprouts, cauliflower); C Vegetables/ leafy (e. g., collards, greens, lettuce, parsley, spinach, napa); 66 C Vegetables/ stem and stalk (e. g., artichoke, asparagus, pineapple); C Vine/ trellis (e. g., blackberries, blueberries, grapes, kiwi, raspberries); and C Nursery crops (e. g., container and B& B ornamentals). Within each agronomic group, a variety of cultural practices are required to maintain the included crops. These practices are varied and typically involve light to heavy contact with immature plants as well as with more mature plants. The Agency selected transfer coefficient values in its revision of Policy 003 to represent this range of exposures within each agronomic group. In the policy, transfer coefficients were placed in 1 of 5 generic categories based on the exposures relative to that group. These 5 categories include: very low exposure, low exposure, medium exposure, high exposure, and very high exposure. Numerical values were not necessarily assigned to each category for each crop group. Selections depended upon the actual agronomic practices that were identified by the Agency for each group (i. e., some groups had 2 assigned transfer coefficients while others had 5). Carbaryl can be used in each of the agronomic crop groupings described above. As such, all agronomic crop group/ transfer coefficients were used to calculate postapplication risks for carbaryl. [Note: Specific transfer coefficient values are included in Appendix E of this document which contains all of the calculations. The transfer coefficient values which have been used are excerpted directly from Agency policy 003. The nursery crop group data have not yet been formally included in EPA Policy 3. However, the studies in this area submitted by ARTF have been reviewed and used since they will be integrated into Policy 3 in a short timeframe.] The revised policy on transfer coefficients has been significantly expanded to more closely link job practices to one of 18 crop/ agronomic groups as indicated above. It has also more clearly defined the scope of the policy as the types of tasks/ job functions that should be addressed using transfer coefficients are more clearly defined and described. The policy also describes which kinds of jobs result in exposures that cannot be addressed with transfer coefficients such as hand harvesting asparagus (i. e., because there is no foliar contact) or those that are of special concern such as vacuuming while harvesting tree nuts. The revised policy also describes in more detail those exposures that are considered to be negligible as outlined in HED Exposure SAC Policy 11: Mechanized Agricultural Practices and Post­ Application Exposure Assessments (e. g., mechanical harvesting). It should be noted that mechanical harvesting and other similar low/ no exposure activities should be addressed by the guidance contained in Policy 11 which is based on the Worker Protection Standard guidance for such activities (40CFR 170). If there are exposures that are of special concern, then additional data or characterization in the risk mitigation phase of the reregistration process should be considered. Exposures that are thought to be out of the scope of Policy 003 for carbaryl are presented below. A discussion of associated mechanized practices is also provided. 67 2.2.2 Data and Assumptions for Occupational Postapplication Exposure Scenarios A series of assumptions and exposure factors served as the basis for completing the occupational postapplication worker risk assessments. Each assumption and factor is detailed below on an individual basis. In addition to these values, transfer coefficient values were used to calculate risk estimates. Several chemical­ specific residue dissipation studies were also submitted which were used in the development of the risk values . The transfer coefficients were taken from the Agency's revised policy entitled Policy 003.1 Science Advisory Council For Exposure Policy Regarding Agricultural Transfer Coefficients (August 7, 2000). Each of these factors are presented below. The assumptions and factors used in the risk calculations include: C There are many factors that are common to handler and postapplication risk assessments such as body weights, duration, and ranges of application rates. Please refer to the assumptions and factors in Section 2.1.2 for further information concerning these values which are common to both handler and postapplication risk assessments. In the postapplication risk assessment, generally only maximum application rates were considered because of the complexity of the calculations (i. e., short­ term, intermediate­ term, chronic, and cancer endpoints for each of the agronomic groups contained in Policy 003). [Note: The transfer coefficient in Policy 003 for tree fruit thinning has been reduced since the issuance of the policy from 8000 cm2/ hour to 3000 cm2/ hour based on a re­ evaluation of the data from the cited study. This modification has been made in the tree fruit group and any other scenarios which have used this value.] C The available dislodgeable foliar residue and turf transferable residue data for were used to complete all postapplication risk assessments. The chemical­ specific residue data are described in detail below and summarized in Appendix D. These data indicate that the percent of transferability averages approximately 16 percent of the application rate for the agricultural crops using the Iwata aqueous solution/ leaf punch method and approximately 1.1 percent for the turf measurements taken using the new ORETF roller method. Given these values, the Agency has used them for all postapplication crops and scenarios as the transferability is in the appropriate range for use in risk assessments. C Aventis Crop Science is in the process of conducting a biomonitoring study for carbaryl during apple and peach thinning and harvesting activities. Based on discussions with Aventis scientists, it appears the preliminary results of this study essentially confirm the dose levels calculated in the Agency's assessment of these practices. A complete review of these data will be completed once they have been submitted to the Agency. 68 C The use of common engineering controls as well as personal protective equipment or clothing is not considered a practical solution for mitigating postapplication worker risks as described in the Agency's Worker Protection Standard (40CFR170). Of course, when well recognized mechanized options are available such as for harvesting the Agency considers them in the overall risk picture for each applicable crop/ chemical/ cultural practice combination (i. e., mechanized operations are also discussed in 40CFR170 and in the Agency's recently revised transfer coefficient policy 003). In lieu of PPE or engineering controls to mitigate risks, the Agency uses an administrative approach by establishing Restricted­ Entry Intervals which are essentially the time it takes for chemical residues to dissipate to levels where jobs can be done at exposure levels that are not a concern. C Exposures were calculated to reflect chemical­ specific residue dissipation rates over time coupled with surrogate transfer coefficients as outlined in the Agency's revised policy. Carbaryl is used in virtually every aspect of agriculture but only 4 dislodgeable foliar residue studies were submitted that meet current Agency guidelines for sampling techniques and data quality. Studies identified in the literature such as those completed by Zweig on strawberries in 1984 (t1/ 2 = 4.1 days) and Iwata in 1979 on lemons and oranges at 11.5 lb ai/ acre (t1/ 2 = 14 days and t1/ 2 = 22 days, respectively) were considered qualitatively by the Agency to confirm the more current data. [Note: The Iwata data indicate a longer ½ life than seen in the current data. This is probably due to the high application rate compared to the current carbaryl labels.] The chemical­ specific dissipation data used in this current assessment were generated in studies completed by the ARTF as part of their data generation effort. These studies were conducted using Iwata's DFR sampling method on tobacco, olives, sunflowers, and cabbage. A turf transferable residue (TTR) study was also completed by the ORETF using the new roller method. The Agency uses transfer coefficients in different agronomic groups as described above to complete risk assessments. The 5 DFR and TTR studies were used as the transferable residue source term for each of these groups. These data were extrapolated to other groups based on the nature of the crop and application method. For example, the olive data were used to calculate risks for all tree crops because airblast (which was used in the olive study) would be the application method of choice for tree crops, the rates are similar, and the plant canopies are similar (i. e., can impact light and precipitation levels which in turn impact DFRs). A more complete description of how the data have been used is provided below. C As described in the handler section and throughout the document, short­ term noncancer risks were calculated by comparing single day exposures. This same approach was used in the postapplication assessment where single day exposures based on the dissipation of carbaryl residues were calculated to complete the short­ term risk assessment (i. e., single day risks were calculated based on daily DFR dissipation values over time). The intermediate and chronic postapplication risk calculations, however, differ from the handler calculations for these extended periods. In a handler assessment, the exposures are the same from day to day because there is no residue dissipation involved (i. e., if one sprays whether it is the 1 st or the 50 th day in a row using the same equipment, the exposures would be similar because the source of exposure is similar). In postapplication assessments, the source term is expected to diminish because of residue dissipation. Hence, for the intermediate­ term and chronic 69 postapplication risk assessments, averages based on DFR dissipation and an appropriate duration for the endpoint were used to calculate postapplication risks. In the intermediateterm assessment, a 30 day average was used to calculate risks because the HIARC identified exposures longer than 30 days as intermediate­ term in nature. In the chronic assessment, a 30 day average was used based on the likelihood that carbaryl could be sprayed at least once a month in the ornamental industry (which are the only scenarios identified as chronic by the Agency). There are many approaches that can be used in the calculation of intermediateterm postapplication risks including using single day dose levels like in the short­ term assessment and just comparing them to the intermediate­ term endpoint. This is effective as a screening approach but is unlikely to actually occur based on simple probability (e. g., finding a freshly treated field 30 days in a row would be less likely than working in a field where residues are dissipating over time). C Risks were calculated using the generic transfer coefficients that represent many different types of cultural practices. Transfer coefficients are thought to be generic (i. e., specific to a crop/ activity combination but independent of the chemical used to generate them). Several values, however, included in the Agency's revised policy were developed using carbaryl data. Because carbaryl can be used so widely, every crop/ cultural practice combination represented by different transfer coefficients included in the Agency policy was completed. C A pseudo­ first order kinetics analysis was used to analyze carbaryl residue dissipation over time as outlined in the Agency's draft Series 875 Postapplication Exposure Monitoring Guidelines. A more sophisticated curve­ fitting approach was not warranted because the correlation coefficients in the analysis were appropriate and the data have been used generically to extrapolate to a variety of other crops where decay rates and mechanisms may differ (i. e., any sophistication gained with a curve fitting technique would be lost in an extrapolation to another crop). C When the Agency extrapolated the available DFR data to other crops, it adjusted the data for differences in application rate using a simple proportional approach. This approach seems to be the most appropriate given the data which are available. This approach is commonly used in Agency postapplication risk assessments. C The exposure frequency values for the postapplication cancer risk assessment are intended to consider the exposures of professional farmworkers and those growers/ users who do their own hand labor (e. g., harvesting as well as other cultural activities) concurrently with carbaryl applications. As a result, cancer risks for all postapplication scenarios have been assessed using 30 days per year for professional farmworkers and 1/ 3rd of that for private growers analogous to the handler assessment completed above. C In postapplication cancer risk assessments, the Agency uses a tiered approach. In this case LADD (Lifetime Average Daily Dose) levels were calculated by amortizing single day exposures which are the same values used in the short­ term assessment over a lifetime using the 10 and 30 days per year frequency values. This may introduce a level of conservatism into the assessment. However, it does not appear that cancer risks would drive decisions for 70 postapplication exposure scenarios because of the concerns for reentry workers from noncancer risks. Therefore, the analysis was not refined further. Potential refinements may have included the use of an average exposure to amortize over a lifetime or the area under the appropriate DFR curve could be integrated and amortized. Postapplication Studies: A total of five studies are described in this section.. One study, conducted by the Aventis Corporation, quantifies carbaryl­ specific turf transferable residues in 3 different states. The other studies were all conducted by the ARTF for use in defining generic transfer coefficients. Carbaryl is one of the compounds that was selected by the ARTF as a surrogate chemical for their efforts. These studies quantified residue dissipation and exposure during tobacco harvesting, during scouting in sunflowers, while weeding cabbage, and while pruning olive trees. The DFR component of those studies has been extracted for chemical­ specific use in this risk assessment. The transfer coefficients used in this assessment are from Agency's interim transfer coefficient policy developed by HED's Science Advisory Council for Exposure using proprietary data from the Agricultural Re­ entry Task Force (ARTF) database (policy # 3.1). Each study can be identified with the following information. Detailed information is provided in Tables 1 through 8 of Appendix D. Tables 1 through 7 contain results from individual studies while Table 8 contains a summary of the critical data and statistical results. The studies which have been used in this assessment are identified below followed by a brief summary of each: C "Determination of Dermal and Inhalation Exposure To Reentry Workers During Harvesting In Tobacco, Study Number: ARF024" EPA MRID 450059­ 11; Report dated July 20, 1999; Authors; Dennis R. Klonne, Susan C. Artz, Cassie Prochaska, Aaron Rotondaro; Sponsor: Agricultural Reentry Task Force; Performing Laboratories: Field Grayson Research LLC and Analytical ­ Morse Laboratories. C "Determination of Dermal and Inhalation Exposure To Reentry Workers During Pruning of Olive Trees, Study Number: ARF033" EPA MRID 451751­ 02; Report dated February 8, 2000; Authors; Dennis R. Klonne, Randy Fuller, Richard Honeycutt; Sponsor: Agricultural Reentry Task Force; Performing Laboratories: Field ­ HERAC, Inc. and Analytical ­ Morse Laboratories. C "Determination of Dermal and Inhalation Exposure To Reentry Workers During Scouting in Sunflower, Study Number: ARF022" EPA MRID 450059­ 09; Report dated September 28, 1999; Authors; Dennis R. Klonne, Eric Bruce, Susan Artz, Casey Howell; Sponsor: Agricultural Reentry Task Force; Performing Laboratories: Field ­ ABC Laboratories and Analytical ­ Maxim Technologies. 71 C "Determination of Dermal and Inhalation Exposure To Reentry Workers During Weeding In Cabbage, Study Number: ARF037" EPA MRID 451917­ 01; Report dated May 30, 2000; Authors; Dennis R. Klonne, Randy Fuller, Tami Belcher; Sponsor: Agricultural Reentry Task Force; Performing Laboratories: Field ­ Excel Research Services and Analytical ­ Maxim Technologies. C "Carbaryl: Determination of Transferable Residues From Turf Treated With Dragon® Sevin® Liquid" EPA MRID 451143­ 01; Report dated November 4, 1999; Author; Thomas C. Mester; Sponsor: Aventis Corporation; Performing Laboratory: ABC Laboratories. [Note to Risk Managers: There are no data compensation issue associated with the use of the ARTF data in the carbaryl risk assessment because the Aventis Corporation, the registrant for carbaryl, is a member of the ARTF. The task force has submitted proprietary data that were generated using carbaryl. It is the intention of HED's Science Advisory Council for Exposure that the transfer coefficient policy will be periodically updated to incorporate additional information about agricultural practices in crops and new data on transfer coefficients. Much of this information will originate from exposure studies currently being conducted by the ARTF, from further analysis of studies already submitted to the Agency, and from studies in the published scientific literature.] MRID 450059­ 11 (tobacco DFR data): This study contained a human exposure element which was reviewed separately by the Agency during the development of the revised policy 003 on transfer coefficients. The DFR component of the data only has been summarized below for use in the carbaryl risk assessment. The field phase of this study was conducted at a single site near Zebulon, North Carolina which is in a major growing region for flue­ cured tobacco. The field phase of the study was conducted during the period from July 1 to August 13, 1998. Sample analyses were completed by October, 1998. A tractor mounted groundboom sprayer was used to make 2 applications of Sevin XLR Plus, a liquid flowable formulation, 8 days apart at an application rate of 2 lb ai/ acre. Spray volume was 20 gallons of water per acre. The tobacco plants were approximately 4.5 feet tall and were spaced approximately 2 feet within each row while the rows were spaced 4 feet apart (i. e., ~5400 plants/ acre). No significant precipitation was observed in this study until at least 7 days after application. Triplicate DFR samples were collected out to 35 days after the last application using the Iwata method (i. e., a total surface area sampled of 400 cm2/ sample collected with a 1 inch diameter Birkestrand leaf punch and dislodged with a 0.01 percent Aerosol solution). The Limit of Quantitation (LOQ) in this study was 1 µg/ sample or 0.0025 µg/ cm 2 . There were still measurable residues 35 days after application. The percent transferability of the 0 day sample was 19 percent of the application rate. Average field recovery over all fortification levels was 114 percent with a coefficient of variation of 6.1. The results of the study are presented in detail in Table 1 of Appendix D. The results of the pseudo­ first order statistical analysis of the data presented in Appendix D are summarized below in Table 13. 72 Table 13: Tobacco DFR Dissipation Data (MRID 450059­ 11) Location App. Rate (lb ai/ acre) App. Method Corr. Coeff. Slope (Ln TTR vs. t) [T0] (µg/ cm 2 ) T1/ 2 (days) Day 0 (% trans.) NC 2 Groundboom 0.957 ­0.205 4.26 3.4 19.0 MRID 451751­ 02 (olive DFR data): This study contained a human exposure element which was reviewed separately by the Agency during the development of the revised policy 003 on transfer coefficients. The DFR component of the data only has been summarized below for use in the carbaryl risk assessment. The field phase of this study was conducted at a single site near Terra Bella, California which is in a major growing region for olives. The field phase of the study was conducted during the period from November 2 to November 17, 1998. Sample analyses were completed by January, 1999. A typical airblast sprayer was used to make a single application of Sevin XLR Plus, a liquid flowable formulation, at an application rate of 7.65 lb ai/ acre. Spray volume was 758 gallons of water per acre. The olive trees were approximately 20 feet tall and were spaced approximately 28 feet within each row while the rows were spaced 28 feet apart (i. e., ~56 trees/ acre). No significant precipitation was observed in this study until at least 7 days after application. Triplicate DFR samples were collected out to 14 days after application using the Iwata method (i. e., a total surface area sampled of 400 cm2/ sample collected with a 1 inch diameter Birkestrand leaf punch and dislodged with a 0.01 percent Aerosol solution). The Limit of Quantitation (LOQ) in this study was 1 µg/ sample or 0.0025 µg/ cm 2 . There were still measurable residues 14 days after application. The percent transferability of the 0 day sample was 3.6 percent of the application rate. Average field recovery over all fortification levels was 109.7 percent with a coefficient of variation of 4.8. The results of the study are presented in detail in Table 2 of Appendix D. The results of the pseudo­ first order statistical analysis of the data presented in Appendix D are summarized below in Table 14. Table 14: Olive DFR Dissipation Data (MRID 451751­ 02) Location App. Rate (lb ai/ acre) App. Method Corr. Coeff. Slope (Ln TTR vs. t) [T0] (µg/ cm 2 ) T1/ 2 (days) Day 0 (% trans.) CA 7.65 Airblast 0.913 ­0.0988 3.067 7 3. 6 MRID 450059­ 09 (sunflower DFR data): This study contained a human exposure element which was reviewed separately by the Agency during the development of the revised policy 003 on transfer coefficients. The DFR component of the data only has been summarized below for use in the carbaryl risk assessment. The field phase of this study was conducted at a single site near Northwood, North Dakota which is in a major growing region for sunflowers. The field phase of the study was conducted during the period from July 20 to August 25, 1998. Sample analyses were completed by December, 1998. A fixed­ wing aircraft was used to make 2 applications of Sevin XLR Plus, a liquid flowable formulation, 7 days apart at an application rate of 1.5 lb ai/ acre. Spray volume was 3 gallons of water per acre. The sunflower plants were approximately 4 feet tall and were spaced approximately 0.5 feet within each row while the rows were spaced 2.5 feet apart (i. e., ~35000 plants/ acre). No significant precipitation was observed in this study until at least 14 days after application. DFR samples were collected out to 28 days after the last application using the Iwata method (i. e., a 73 total surface area sampled of 400 cm2/ sample collected with a 1 inch diameter Birkestrand leaf punch and dislodged with a 0.01 percent Aerosol solution). The Limit of Quantitation (LOQ) in this study was 1 µg/ sample or 0.0025 µg/ cm 2 . There were still measurable residues 28 days after application. The percent transferability of the 0 day sample was 32 percent of the application rate. Average field recovery over all fortification levels was 93.1 percent with a coefficient of variation of 9.1. The results of the study for each site are presented in detail in Table 3 of Appendix D. The results of the pseudo­ first order statistical analysis of the data presented in Appendix D are summarized below in Table 15. Table 15: Sunflower DFR Dissipation Data (MRID 450059­ 09) Location App. Rate (lb ai/ acre) App. Method Corr. Coeff. Slope (Ln TTR vs. t) [T0] (µg/ cm 2 ) T1/ 2 (days) Day 0 (% trans.) ND 1.5 FW Aerial 0.986 ­0.134 5.35 5.2 31.8 MRID 451917­ 01 (cabbage DFR data): This study contained a human exposure element which was reviewed separately by the Agency during the development of the revised policy 003 on transfer coefficients. The DFR component of the data only has been summarized below for use in the carbaryl risk assessment. The field phase of this study was conducted at a single site near Fresno, California which is in a major growing region for cabbage. The field phase of the study was conducted during the period from September 29 to November 10, 1999. Sample analyses were completed by May, 2000. A tractor drawn groundboom sprayer was used to make 2 applications of Sevin XLR Plus, a liquid flowable formulation, 7 days apart at an application rate of 2.07 lb ai/ acre. Spray volume was 31.1 gallons of water per acre. The cabbage plants were approximately 8 to 10 inches tall and were spaced approximately 1 feet within each row while the rows were spaced 3 feet apart (i. e., ~15000 plants/ acre). No significant precipitation was observed in this study. All irrigation was in­ furrow which is not believed to impact DFR levels. Triplicate DFR samples were collected out to 35 days after the last application using the Iwata method (i. e., a total surface area sampled of 400 cm2/ sample collected with a 1 inch diameter Birkestrand leaf punch and dislodged with a 0.01 percent Aerosol solution). The Limit of Quantitation (LOQ) in this study was 1 µg/ sample or 0.0025 µg/ cm 2 . There were still measurable residues 35 days after application in 1 of the 3 samples collected while all samples on day 28 contained detectable residues. The percent transferability of the 0 day sample was 10.9 percent of the application rate. Average field recovery over all fortification levels was 97.2 percent with a coefficient of variation of 8.3. The results of the study for each site are presented in detail in Table 4 of Appendix D. The results of the pseudo­ first order statistical analysis of the data presented in Appendix D are summarized below in Table 16. Table 16: Cabbage DFR Dissipation Data (MRID 451917­ 01) Location App. Rate (lb ai/ acre) App. Method Corr. Coeff. Slope (Ln TTR vs. t) [T0] (µg/ cm 2 ) T1/ 2 (days) Day 0 (% trans.) CA 2.07 Groundboom 0.956 ­0.190 2.46 3.6 10.6 74 MRID 451143­ 01 (turf transferable residue data): A TTR study was conducted at individual sites in three states using the ORETF roller sampling method. The locations were in California, Georgia, and Pennsylvania. Tall fescue was the variety in California and Pennsylvania. Bermudagrass was the variety in Georgia. Field work took place over three week intervals at each site. Applications were made and samples were collected essentially in October of 1998 in California and Georgia while the Pennsylvania study was completed essentially in May 1999. Two applications were made 7 days apart at each site. All applications in this study were completed at a rate of 8.17 lb ai/ acre. In California and Georgia, applications were made with typical groundboom sprayers using approximately 55 and 31 gallons of water per acre, respectively. In Pennsylvania, the applications were made with a CO2 powered sprayer in approximately 45 gallons of water per acre. All applications were made using Dragon Sevin Liquid which is a flowable concentrate formulation that contains carbaryl at a nominal concentration of 21 percent by weight or 2 lb ai/ gallon. There was approximately from 1 inch up to 2.7 inches of irrigation water on the day of the final application at each site. Additionally, on the day of the final application, rain was noted that ranged in accumulations from 0.2 to 1.23 inches. California and Pennsylvania also received additional rain in the week after the last application (i. e., both events < 1 inch). It could not be determined, based on the study data, if the rain and irrigation events on the day of the last application at each site occurred prior to or after the application. Mowing events were also noted in the data except in Georgia where no mowing was done. The other sites were mowed prior to the last application and at some point at least 6 days after the last application. Triplicate TTR samples were collected using the ORETF roller method at 8 intervals out to 14 days after the last application. All but two samples at each site were collected during the 1 st week of the study. The Limit of Quantitation (LOQ) for carbaryl residues was 2 µg/ sample which is equivalent to 0.00035 µg/ cm 2 based on a sample surface area of 5690 cm 2 . Average field recovery values across levels from all sites was greater than 90 percent. Additionally, the variability in the field recovery data as defined using the coefficient of variation was also low (< 10) except for the Georgia site where the CV was 28. However, at the Georgia and Pennsylvania sites, the dosespecific recovery value that closest approximated the field sample levels warranted that the results be corrected by the investigators (i. e., 119 % in Georgia and 89% in Pennsylvania, respectively). Residue levels were not corrected for recovery at the California site. In all cases, residue levels exceeded the LOQ even at 14 days after application. The results of the study for the California, Georgia, and Pennsylvania sites, respectively, are presented in Tables 5, 6, and 7 of Appendix D. The data and the results of the pseudo­ first order statistical analysis of the data presented in Appendix D are summarized below in Table 17. 75 Table 17: TTR Dissipation Data Measured Using ORETF Roller In 3 States (MRID 451143­ 01) Location App. Rate (lb ai/ acre) App. Method Corr. Coeff. Slope (Ln TTR vs. t) [T0] (µg/ cm 2 ) T1/ 2 (days) Day 0 (% trans.) CA 8.17 Groundboom 0.971 ­0.543 0.927 1.3 1. 0 GA 8.17 Groundboom 0.887 ­0.168 1.12 4.1 1. 2 PA 8.17 CO2 0.984 ­0.248 1.12 2.8 1. 2 The Georgia data were used to calculate short­ term and intermediate­ term risks because of the added persistence (i. e. to consider a 30 day average residue). Note that intermediate­ term risks could not even be calculated for PA and CA data because of the shorter decay time. The California data were used to calculate cancer risks because of the quicker dissipation which may represent more typical uses. 2.2.3 Occupational Postapplication Exposure and Noncancer Risk Estimates The occupational postapplication exposure and non­ cancer risk calculations are presented in this section. Noncancer risks were calculated using the Margin of Exposure (MOE) which is a ratio of the body burden to the toxicological endpoint of concern. Body burden values were determined by first calculating exposures by considering transferable residue levels in areas where people work (i. e., the potential sources of exposure) and the kinds of jobs or tasks required to produce agricultural commodities or to maintain other areas such as golf courses. These factors are represented by DFR or TTR concentrations and transfer coefficients. Exposures were calculated by multiplying these factors by an 8 hour work day. Exposures are then normalized by body weight and adjusted for dermal absorption to calculate absorbed dose (i. e., body burdens). MOEs were then calculated. Postapplication risks diminish over time because carbaryl residues eventually dissipate in the environment. As a result risk values were calculated over time based on changing residue levels. Dissipation Kinetics: The first step in the postapplication risk assessment was to complete an analysis of the available dislodgeable foliar and turf transferable residue (DFR) data. All residue data generated in the referenced studies are summarized in Appendix D as well as in Tables 13 through 17 above. As discussed in Section 2.2.2 above, data from the 4 DFR studies were used to calculate risks for all agronomic crop groups. Best fit DFR levels were calculated based on empirical data using the equation D2­ 16 from Series 875­ Occupational and Residential Test Guidelines: Group B­ Postapplication Exposure Monitoring Test Guidelines. The summary of the available chemical­ specific DFR data, presented in tables 13 through 17 above, were developed based on a semilog regression of the empirical dissipation data using a commercial spreadsheet linear regression function. Half­ lives were calculated using the algorithm (T1/ 2 = ­Ln 2/ slope). The results of those statistical analyses were used to calculate best fit concentrations over time using the following pseudo­ first order equation: 76 Where: Cenvir( t) = dislodgeable foliar or turf transferable residue concentration ( g/ cm 2 ) that represents the amount of residue on the surface of a contacted leaf surface that is available for dermal exposure at time (t); Cenvir( o) = dislodgeable foliar or turf transferable residue concentration ( g/ cm 2 ) that represents the amount of residue on the surface of a contacted leaf surface that is available for dermal exposure at time (0); e =natural logarithms base function; PAIt = postapplication interval or dissipation time (e. g., days after treatment or DAT); and M = slope of line generated during linear regression of data [ln( Cenvir) versus postapplication interval (PAI)]. In cases where no chemical­ specific residue dissipation data are available, the Agency typically uses a generic dissipation model to complete risk calculations. In this case, the Agency determined that it is more appropriate, however, to extrapolate using carbaryl­ specific dissipation data in the risk assessment for other currently labelled crops than it is to use the generic dissipation model. This approach is consistent with current Agency policies for generating transferable/ dislodgeable residue data. The existing residue data were extrapolated to the currently labelled crops as follows: C Tobacco DFR Data: These data have been used to complete all assessments for the crop/ activity combinations included in the bunch/ bundle, sugarcane, and vine/ trellis agronomic crop groups defined in the Agency's revised transfer coefficient policy 003. This extrapolation was completed because of similarities in application methods between the study and selected crop groups, the crop canopy, and application rates (i. e., between the study and current labels). C Olive DFR Data: These data have been used to complete all assessments for the crop/ activity combinations included in all of the tree fruit and nut crop groups defined in the Agency's revised transfer coefficient policy 003. This extrapolation was completed because of similarities in application methods between the study and selected crop groups, the crop canopy, and application rates (i. e., between the study and current labels). C Sunflower DFR Data: These data have been used to complete all assessments for the crop/ activity combinations in the tall field/ row crop group defined in the Agency's revised transfer coefficient policy 003. No extrapolation was required in this assessment. An additional consideration was that the cabbage study was based on groundboom application and not aerial application. Groundboom applications are thought to be much more prevalent in the overall use pattern for carbaryl. 77 C Cabbage DFR Data: These data have been used to complete all assessments for the crop/ activity combinations included in the berry, cut flower, low/ medium field and row, and all vegetable (i. e., stem/ stalk, brassica, leafy, fruiting, cucurbits, root) agronomic crop groups defined in the Agency's revised transfer coefficient policy 003. This extrapolation was completed because of similarities in application methods between the study and selected crop groups, the crop canopy, and application rates (i. e., between the study and current labels). C Turf TTR Data: These data have been used to complete all assessments for the crop/ activity combinations for the turf agronomic crop group defined in the Agency's revised transfer coefficient policy 003. No extrapolation was required in this assessment. Daily Exposure: The next step in the risk assessment process was to calculate dermal exposure values (remembering that inhalation exposures are not assessed for these scenarios) on each post­ application day after application using the following equation (see equation D2­ 20 from Series 875­ Occupational and Residential Test Guidelines: Group B­ Postapplication Exposure Monitoring Test Guidelines and Residential SOP 3.2: Postapplication Dermal Potential Doses From Pesticide Residues On Gardens): DE( t) (mg/ day) = (TR( t) (µg/ cm 2 ) x TC (cm 2 /hr) x Hr/ Day)/ 1000 (µg/ mg) Where: DE( t) = Daily exposure or amount deposited on the surface of the skin at time (t) attributable for activity in a previously treated area, also referred to as potential dose (mg ai/ day); TR( t) = Transferable residues that can either be dislodgeable foliar or turf transferable residue at time (t) where the longest duration is dictated by the decay time observed in the studies (µg/ cm 2 ); TC = Transfer Coefficient (cm 2 /hour); and Hr/ day = Exposure duration meant to represent a typical workday (hours). Note that the (TR( t)) input may represent levels on a single day after application in the case of shortterm risk calculations. For intermediate­ term calculations, rolling 7 day average concentrations were calculated based on the applicability of the toxicology data (i. e., intermediate­ term endpoint is applied to exposures >30 days). In the limited number of chronic calculations, a 30 day average was also used based on a likely frequency between applications. Daily Dose and Margins of Exposure: The use of dissipation data and the manner in which daily postapplication dermal exposure values were calculated are inherently different than with handler exposures. Once daily exposure values are calculated, the calculation of daily absorbed dose and the resulting Margin of Exposure values use the same algorithms that are described above for the handler exposures (See Section 2.1.3). These calculations are completed for each day or appropriate block of time after application. 78 Noncancer Risk Summary: All of the noncancer risk calculations for occupational carbaryl handlers completed in this assessment are included in Appendix E. The specifics of each of table included in Appendix E are described below. A summary of the results for each crop/ activity combination considered for each timeframe is also provided below. C Appendix E/ Table 1: Inputs For Carbaryl Occupational Postapplication Risk Assessment Presents the numerical unit exposure values and other factors used in the occupational handler risk assessments. C Appendix E/ Table 2: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Low Berry Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 4: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Bunch/ Bundle Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 6: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Short/ Medium Field Row Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 8: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Tall Field Row Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 10: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Cut Flower Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). [Note: Table 10 also contains chronic risk values.] C Appendix E/ Table 12: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Sugarcane Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 14: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Deciduous Tree Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 16: Carbaryl Occupational Postapplication Noncancer Risk 79 Assessment For Evergreen Tree Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 18: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Tree Nut Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 20: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Turf Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 22: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Root Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 24: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Cucurbit Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 26: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Fruiting Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 28: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Brassica Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 30: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Leafy Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 32: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Root Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 34: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Vine Crop Group Risk values are presented for each exposure duration 80 considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 36: Carbaryl Occupational Postapplication Noncancer Risk Assessment For Nursery Stock Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). [Note: Table 36 also contains chronic risk values.] It should be noted that there were several scenarios for which no appropriate exposure data are known to exist or ongoing transfer coefficient studies have not yet been submitted (e. g., ARTF nursery and ornamental data). The scope of the Agency's revised policy 003 for transfer coefficients should also be considered as it only quantitatively addresses risks where the transfer coefficient model is appropriate (i. e., where foliar contact is known to exist). There are many kinds of potential exposure pathways that do not involve foliar contact that have not been addressed in this risk assessment (as defined in policy 003, refer to that document for a complete list). The scenarios include: C Transplanting many crops including in the ornamental and forestry industry; C Thinning some crops such as hops; C Some partially mechanized operations that also involve human contact (e. g., cotton harvesting where module builders and trampers are used, see below); C Hand weeding some crops such as wheat; C Various operations with Christmas trees such as pruning or baling; and C Various operations with nut production such as sweeping for harvest. [Note: Additional DFR data on different crops could refine exposure and risk estimates.] Mechanized practices can be divided into fully mechanized activities that meet the definition of "No contact" in the Agency's Worker Protection Standard (WPS) and mechanically assisted practices with potential for exposure. In the case of fully mechanized activities, the Agency does not complete a quantitative exposure assessment but addresses these types of potential exposures qualitatively by allowing early entry as described in the WPS. 81 "A worker may enter a treated area during a restricted­ entry interval if the agricultural employer assures that both of the following are met: (1) The worker will have no contact with anything that has been treated with the pesticide to which the restricted­ entry interval applies including, but not limited to, soil, water, air, or surfaces of plants; and (2) no such entry is allowed until any inhalation exposure level listed in the labeling has been reached or any ventilation criteria established by § 170.110 (c)( 3) or in the labeling have been met." In cases of partially mechanized activities where the potential for exposure exists, the Agency assesses the resulting exposures similarly to those resulting from hand labor activities for "high exposure potential" activities (i. e., transfer coefficients are used to represent exposures associated with the activity). Partially mechanized activities with "low exposure potential" are assessed qualitatively. Available use and usage information have been used to characterize the predominance of these activities that meet the fully mechanized (" No contact") and the mechanically assisted definitions in the risk assessment to allow risk managers flexibility in their decisions with regard to various segments of the exposed population for carbaryl. The Agency also acknowledges that there is some potential for exposure because individuals engaged in fully mechanized activities have short­ term excursions from the protected area for various reasons (e. g., unclogging machinery or equipment inspection for breakage). In these cases, the WPS § 170.112( c) Exception for short­ term activities applies. The level of concern for all assessments is established by the uncertainty factor that is associated with a specific duration of exposure. Uncertainty factors are defined for occupational exposures under FIFRA and account for intra­ species sensitivity and inter­ species extrapolation. In other cases, like carbaryl, additional factors can also be required (i. e., 3x) because a Lowest Observed Adverse Effect Level (i. e., LOAEL) has been selected as the dose level upon which the risk assessment is based and not on the No Observed Adverse Effect Level (i. e., NOAEL). In this case, three distinct durations of exposure were considered for postapplication workers including: short­ term ( 30 days), intermediate­ term (> 30 days to several months), and chronic (essentially every working day). The toxicological endpoints and uncertainty factors which have been applied to each exposure duration are those described in Section 1.3/ Table 1. The results for each exposure duration are presented separately below. Noncancer short­ term, intermediate­ term, and chronic risks were calculated for different crop groups as described above. Table 18 below provides a summary of these risks for each crop/ activity combination considered. For each crop group/ activity combination, the short­ term MOE value at the current REI of 12 hours is presented (i. e., the Day 0 MOE) as well as the number of days required for short­ term MOEs to reach the Agency's uncertainty factor of 100. Additionally, the intermediate­ term and chronic MOEs which have been calculated using 30 day average exposures based on the dissipation of carbaryl residues are also included. The uncertainty factor for intermediate­ term exposures is 100 and for chronic exposures is 300. 82 Current label requirements specify 12 hour REIs. For all but the lowest exposure scenarios in some crops, short­ term MOEs are of concern (i. e., less than the required uncertainty factor of 100) at the current REI. Generally, short­ term MOEs meet or exceed the Agency uncertainty factor in the range of 3 to 5 days for lower to medium exposure activities and from 8 to 12 days after application in most higher exposure scenarios. Intermediate­ term MOEs are not of concern generally for low to medium level exposures but are of concern for higher level exposures such as harvesting in some crops. Chronic exposures are of concern for the cut flower industry but not for general greenhouse and nursery production activities. Table 18: Summary of Carbaryl Noncancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (See Appendix E) Very Low Low Medium High Very High Low Berry ST MOE Day 0 NA 184 NA 49 NA Days For ST MOE > UF NA 0 NA 4 NA IT 30 Day Avg MOE NA 991 NA 264 NA Bunch/ Bundle ST MOE Day 0 NA 411 32 21 NA Days For ST MOE > UF NA 0 6 8 NA IT 30 Day Avg MOE NA 2365 182 118 NA Low /Med. Field/ Row Crops ST MOE Day 0 NA 982 65 39 NA Days For ST MOE > UF NA 0 3 5 NA IT 30 Day Avg MOE NA 5286 352 211 NA Tall Field/ Row Crops ST MOE Day 0 NA 245 61 25 <1 Days For ST MOE > UF NA 0 4 11 +30 IT 30 Day Avg MOE NA 970 242 97 6 Cut Flowers ST MOE Day 0 NA 30 18 11 NA Days For ST MOE > UF NA 7 9 12 NA IT 30 Day Avg MOE NA 159 99 57 NA Chronic MOE NA 194 121 69 NA Sugarcane ST MOE Day 0 NA NA 55 27 NA Days For ST MOE > UF NA NA 3 7 NA IT 30 Day Avg MOE NA NA 315 158 NA Decid. Fruit Trees ST MOE Day 0 1455 146 NA 49 NA Days For ST MOE > UF 0 0 NA 8 NA IT 30 Day Avg MOE 4450 445 NA 148 NA Table 18: Summary of Carbaryl Noncancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (See Appendix E) Very Low Low Medium High Very High 83 Evergreen Fruit Trees ST MOE Day 0 582 58 19 NA NA Days For ST MOE > UF 0 6 17 NA NA IT 30 Day Avg MOE 1780 178 59 NA NA Nut Trees ST MOE Day 0 NA 175 NA 35 NA Days For ST MOE > UF NA 0 NA 11 NA IT 30 Day Avg MOE NA 534 NA 107 NA Turf/ Sod ST MOE Day 0 NA 312 NA 10 NA Days For ST MOE > UF NA 0 NA 14 NA IT 30 Day Avg MOE NA 1505 NA 46 NA Root Veg. ST MOE Day 0 NA 245 49 29 NA Days For ST MOE > UF NA 0 4 7 NA IT 30 Day Avg MOE NA 1322 264 159 NA Cucurbit Veg. ST MOE Day 0 NA 147 49 29 NA Days For ST MOE > UF NA 0 4 7 NA IT 30 Day Avg MOE NA 793 264 159 NA Fruiting Veg. ST MOE Day 0 NA 147 105 74 NA Days For ST MOE > UF NA 0 0 2 NA IT 30 Day Avg MOE NA 793 566 396 NA Brassica ST MOE Day 0 NA 37 18 15 NA Days For ST MOE > UF NA 6 9 11 NA IT 30 Day Avg MOE NA 198 99 79 NA Leafy Veg. ST MOE Day 0 NA 147 49 29 NA Days For ST MOE > UF NA 0 4 7 NA IT 30 Day Avg MOE NA 793 264 159 NA Stem/ stalk Veg. ST MOE Day 0 NA 137 82 41 NA Days For ST MOE > UF NA 0 1 5 NA IT 30 Day Avg MOE NA 788 473 236 NA Table 18: Summary of Carbaryl Noncancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (See Appendix E) Very Low Low Medium High Very High 84 Vine/ trellis ST MOE Day 0 NA 147 74 15 7 Days For ST MOE > UF NA 0 2 11 14 IT 30 Day Avg MOE NA 793 396 79 40 Nursery/ Ornamentals ST MOE Day 0 NA 669 421 184 NA Days For ST MOE > UF NA 0 0 0 NA IT 30 Day Avg MOE NA 3604 2266 991 NA Chronic MOE NA 4399 2765 1210 NA ST = Short­ term, IT = Intermediate­ term, 30 Day Avg.= Average exposure level over 30 day interval. NA = Exposure descriptor not applicable for that crop group. UF = uncertainty factor or target MOE of 100. 2.2.4 Occupational Postapplication Exposure and Risk Estimates for Cancer The occupational exposure and cancer risk calculations for postapplication workers are presented in this section. Cancer risks were calculated using a linear low­ dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated and then compared with a Q1* that has been calculated for carbaryl based on dose response data in the appropriate toxicology study (Q1* = 8.75 x 10 ­4 (mg/ kg/ day) ­1 ). Absorbed average daily dose (ADD) levels were used as the basis for calculating the LADD values. Section 2.1.3 above describes how the ADD values were first calculated for the noncancer MOE calculations. These values also serve as the basis for the cancer risk estimates. Dermal and inhalation ADD values were first added together to obtain combined ADD values. LADD values were then calculated and compared the Q1* to obtain cancer risk estimates. LADD and Cancer Risk Calculations: The use of dissipation data and the manner in which daily postapplication dermal exposure values were calculated are inherently different than with handler exposures. Once daily exposure values are calculated, the calculation of LADD (Lifetime Average Daily Dose) and the resulting cancer risks use the same algorithms that are described above for the handler exposures (See Section 2.1.4). To reiterate, occupational carcinogenic risks that are 1 x 10 ­6 or lower require no risk management action based on the 1996 Barolo memo. For those chemicals subject to reregistration, the Agency is to carefully examine uses with estimated risks in the 10 ­6 to 10 ­4 range to seek ways of cost­ effectively reducing risks. If carcinogenic risks are in this range for postapplication workers, an increase in time after application prior to allowing a reentry activity would be warranted as is commonly applied to noncancer risk estimates. 85 Cancer Risk Summary All of the cancer risk calculations for carbaryl postapplication workers are included in Appendix E (various tables). The specifics of each of table included in Appendix E are summarized below. C Appendix E/ Table 1: Inputs For Carbaryl Occupational Postapplication Risk Assessment Presents the numerical unit exposure values and other factors used in the occupational handler risk assessments. C Appendix E/ Table 3: Carbaryl Occupational Postapplication Cancer Risk Assessment For Low Berry Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 5: Carbaryl Occupational Postapplication Cancer Risk Assessment For Bunch/ Bundle Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 7: Carbaryl Occupational Postapplication Cancer Risk Assessment For Short/ Medium Field Row Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 9: Carbaryl Occupational Postapplication Cancer Risk Assessment For Tall Field Row Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 11: Carbaryl Occupational Postapplication Cancer Risk Assessment For Cut Flower Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 13: Carbaryl Occupational Postapplication Cancer Risk Assessment For Sugarcane Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 15: Carbaryl Occupational Postapplication Risk Assessment For Deciduous Tree Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 17: Carbaryl Occupational Postapplication Cancer Risk Assessment 86 For Evergreen Tree Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 19: Carbaryl Occupational Postapplication Cancer Risk Assessment For Tree Nut Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 21: Carbaryl Occupational Postapplication Cancer Risk Assessment For Turf Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 23: Carbaryl Occupational Postapplication Cancer Risk Assessment For Root Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 25: Carbaryl Occupational Postapplication Cancer Risk Assessment For Cucurbit Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 27: Carbaryl Occupational Postapplication Cancer Risk Assessment For Fruiting Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 29: Carbaryl Occupational Postapplication Cancer Risk Assessment For Brassica Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 31: Carbaryl Occupational Postapplication Cancer Risk Assessment For Leafy Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 33: Carbaryl Occupational Postapplication Cancer Risk Assessment For Root Vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 35: Carbaryl Occupational Postapplication Cancer Risk Assessment For Vine Crop Group Risk values are presented for each exposure duration considered in 87 the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix E/ Table 37: Carbaryl Occupational Postapplication Cancer Risk Assessment For Nursery Stock Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). Cancer risks for private growers (i. e., 10 exposures/ year) and commercial farmworkers (i. e., 30 exposures/ year) were calculated for different crop groups as described above and summarized in Table 19 below. Within each crop group, differing transfer coefficients were used to represent various types of cultural practices. Current label requirements specify 12 hour REIs. For all scenarios, cancer risks are <1x10 ­4 on the day of application (i. e., at the current REI). Likewise, cancer risks are <1x10 ­6 on the day of application for most crop/ activity scenarios with private growers and also for low to medium exposures for commercial farmworkers. In fact, risks for all scenarios were in the 10 ­6 range in all but three scenarios for commercial farmworkers participating in very high exposure activities (e. g., sweetcorn handharvesting) on the day of application. In these three cases, risks were in the 10 ­5 range on the day of application. For private growers, it takes up to approximately 5 days for risks to decline to <1x10 ­6 for crop/ activity combinations that exceed 1x10 ­6 on the day of application. For commercial farmworkers, it takes up to approximately 8 days for risks to reach the target level of concern of <1x10 ­6 . The 1996 Barolo memo which focused on cancer risk management should be considered in the interpretation of these results. Current label requirements appear to be adequate for all postapplication cancer risks if the 10 ­4 range is used for risk management. If the 10 ­6 risk range is considered, it also appears that the current REI appears adequate to address cancer risks for many crop/ activity combinations. However, for higher exposure situations, longer duration REIs are predicted. In all cases, REIs predicted based on cancer risks are less restrictive or similar (i. e., within a day or two for commercial farmworkers) than those predicted based on the noncancer effects of carbaryl. In no cases do cancer risks indicate more restrictive REIs than for noncancer risks calculated for the corresponding crop/ activity exposure scenario. Table 19: Summary of Carbaryl Cancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (From Policy 003/ See Appendix E) Very Low Low Medium High Very High Low Berry Private Grower Day 0 Risk NA 1.7 x 10 ­7 NA 6.2x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 NA 0 NA Com.. Farmworker Day 0 Risk NA 5.0 x 10 ­7 NA 1.9x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 NA 4 NA Table 19: Summary of Carbaryl Cancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (From Policy 003/ See Appendix E) Very Low Low Medium High Very High 88 Bunch/ Bundle Private Grower Day 0 Risk NA 7.4 x 10 ­8 9.6x 10 ­7 1.5x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 0 2 NA Com.. Farmworker Day 0 Risk NA 2.2 x 10 ­7 2.9x 10 ­6 4.4x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 5 8 NA Low /Med. Field/ Row Crops Private Grower Day 0 Risk NA 3.1x 10 ­8 4.7x 10 ­7 7.8x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 9.3x 10 ­8 1.4x 10 ­6 2.3x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 2 5 NA Tall Field/ Row Crops Private Grower Day 0 Risk NA 1.2 x 10 ­7 5.0 x 10 ­7 1.2 x 10 ­6 2.1 x 10 ­5 Private Grower Days < 1x10 ­6 NA0 0 223 Com.. Farmworker Day 0 Risk NA 3.7 x 10 ­7 1.5 x 10 ­6 3.7 x 10 ­6 8.5 x 10 ­5 Com.. Farmworker Days < 1x10 ­6 NA 0 3 10 31 Cut Flowers Private Grower Day 0 Risk NA 1.0 x 10 ­6 1.7 x 10 ­6 2.9 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 3 6 NA Com.. Farmworker Day 0 Risk NA 3.1 x 10 ­6 5.0 x 10 ­6 8.7 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 6 9 12 NA Sugarcane Private Grower Day 0 Risk NA NA 5.6 x 10 ­7 1.1 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA NA 0 1 NA Com.. Farmworker Day 0 Risk NA NA 1.7 x 10 ­6 3.3 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA NA 3 6 NA Decid. Fruit Trees Private Grower Day 0 Risk 2.1 x 10 ­8 2.1 x 10 ­7 NA 6.3 x 10 ­7 NA Private Grower Days < 1x10 ­6 0 0NA0NA Com.. Farmworker Day 0 Risk 6.3 x 10 ­8 6.3 x 10 ­7 NA 1.9 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 0 0NA6NA Evergreen Fruit Trees Private Grower Day 0 Risk 5.2 x 10 ­8 5.2 x 10 ­7 1.6 x 10 ­6 NA NA Private Grower Days < 1x10 ­6 0 0 5 NA NA Com.. Farmworker Day 0 Risk 1.6 x 10 ­7 1.6 x 10 ­6 4.7 x 10 ­6 NA NA Com.. Farmworker Days < 1x10 ­6 0 5 16 NA NA Nut Trees Private Grower Day 0 Risk NA 1.7 x 10 ­7 NA 8.7 x 10 ­7 NA Table 19: Summary of Carbaryl Cancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (From Policy 003/ See Appendix E) Very Low Low Medium High Very High 89 Private Grower Days < 1x10 ­6 NA 0 NA 0 NA Com.. Farmworker Day 0 Risk NA 5.7 x 10 ­7 NA 2.6 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 NA 10 NA Turf/ Sod Private Grower Day 0 Risk NA 8.1 x 10 ­8 NA 2.7 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 NA 2 NA Com.. Farmworker Day 0 Risk NA 2.4 x 10 ­7 NA 8.0 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 NA 4 NA Root Veg. Private Grower Day 0 Risk NA 1.2 x 10 ­7 6.2 x 10 ­7 1.0 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 3.7 x 10 ­7 1.9 x 10 ­6 3.1 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 4 6 NA Cucurbit Veg. Private Grower Day 0 Risk NA 2.1 x 10 ­7 6.2 x 10 ­7 1.0 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 6.2 x 10 ­7 1.9 x 10 ­6 3.1 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 4 6 NA Fruiting Veg. Private Grower Day 0 Risk NA 2.1 x 10 ­7 2.9 x 10 ­7 4.1 x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 6.2 x 10 ­7 8.7 x 10 ­7 1.2 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 0 1 NA Brassica Private Grower Day 0 Risk NA 8.3 x 10 ­7 1.7 x 10 ­6 2.1 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 3 4 NA Com.. Farmworker Day 0 Risk NA 2.5 x 10 ­6 5.0 x 10 ­6 6.2 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 5 9 10 NA Leafy Veg. Private Grower Day 0 Risk NA 2.1 x 10 ­7 6.2 x 10 ­7 1.0 x 10 ­6 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 6.2 x 10 ­7 1.9 x 10 ­6 3.1 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 4 6 NA Stem/ stalk Veg. Private Grower Day 0 Risk NA 2.2 x 10 ­7 3.7 x 10 ­7 7.4 x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Table 19: Summary of Carbaryl Cancer Postapplication Worker Risks Crop Group Result Type Exposure Descriptor (From Policy 003/ See Appendix E) Very Low Low Medium High Very High 90 Com.. Farmworker Day 0 Risk NA 6.7 x 10 ­7 1.1 x 10 ­6 2.2 x 10 ­6 NA Com.. Farmworker Days < 1x10 ­6 NA 0 1 4 NA Vine/ trellis Private Grower Day 0 Risk NA 2.1 x 10 ­7 4.1 x 10 ­7 2.1 x 10 ­6 4.1 x 10 ­6 Private Grower Days < 1x10 ­6 NA0 0 4 8 Com.. Farmworker Day 0 Risk NA 6.2 x 10 ­7 1.2 x 10 ­6 6.2 x 10 ­6 1.2 x 10 ­5 Com.. Farmworker Days < 1x10 ­6 NA 0 1 10 13 Nursery/ Ornamentals Private Grower Day 0 Risk NA 4.5 x 10 ­8 7.2 x 10 ­8 1.7 x 10 ­7 NA Private Grower Days < 1x10 ­6 NA 0 0 0 NA Com.. Farmworker Day 0 Risk NA 1.4 x 10 ­7 2.2 x 10 ­7 5.0 x 10 ­7 NA Com.. Farmworker Days < 1x10 ­6 NA 0 0 0 NA NA = Exposure descriptor not applicable for that crop group. 2.2.5 Summary of Occupational Postapplication Risk Concerns and Data Gaps Current label requirements specify 12 hour REIs. For all but the lowest exposure scenarios in some crops, MOEs do not meet or exceed required uncertainty factors until several days after application. If short­ term risks are considered, MOEs meet or exceed the Agency uncertainty factor generally in the range of 3 to 5 days after application for lower to medium exposure activities and from 8 to 12 days after application in most higher exposure scenarios. If intermediate­ term risks are considered, MOEs are not of concern based on a 30 day average exposures except for higher level exposures such as harvesting in some crops. Chronic exposures are of concern for the cut flower industry but not for other general greenhouse and nursery production activities based on the most recent ARTF data. Cancer risks were calculated for private growers and professional farmworkers with the only difference being the annual frequency of exposure days. Cancer risks for private growers and commercial farmworkers are generally in the 10 ­8 to 10 ­6 range on the day of application. If a 1x10 ­4 cancer risk is the target, the current REI would be adequate for all scenarios considered in the 91 assessment. If a 1x10 ­6 cancer risk is used, then durations longer than the current REI should be considered for some cases which are not considered low to medium exposures. It should be noted that the cancer risk calculations are less restrictive than noncancer risk estimates for the same scenarios in all cases. The Agency has used the latest information to complete this postapplication risk assessment for carbaryl. Several data gaps exist such as a lack of exposure data on mechanized or partially mechanized cultural practices where there is a potential for exposure. Additionally, because of the number and breadth of carbaryl uses, there may be many exposure pathways where the transfer coefficient approach is not an appropriate model (e. g., hand transplanting where no foliar contact occurs) that have not been quantitatively addressed due to a lack of data. 2.2.6 Recommendations For Refining Occupational Postapplication Risk Assessment To refine this occupational risk assessment, data on actual use patterns including rates, timing, and the kinds of tasks that are required to produce agricultural commodities and other products would better characterize carbaryl risks. Exposure studies for many cultural practices that lack data or that are not well represented in the revised transfer coefficient policy should also be considered based on the data gaps identified above. Risk managers should consider that the risks associated with the current label REI generally do not meet Agency risk targets. 2.3 Occupational Risk Characterization 2.3.1 Handler Characterization The occupational handler assessment for carbaryl is complex in that three different types of noncancer risk calculations were required based on the recently selected endpoints. The durations of exposure that were considered for noncancer toxicity were short­ term ( 30 days), intermediateterm (30 days up to several months), and chronic (every working day). A complete array of calculations was completed for all identified exposure scenarios using the short­ and intermediateterm endpoints because the Agency believes that carbaryl uses fit the criteria for both of these durations. The only calculations that were completed using the chronic endpoint were limited and those associated with the greenhouse and floriculture industries where these kinds of exposures may occur. Cancer risks were also calculated using a linear, low­ dose extrapolation model (i. e., Q1*) for both private growers (i. e., 10 application days per year) and for those who may more actively use carbaryl such as a commercial applicator (i. e., 30 application days per year). Cancer calculations were completed as well for every scenario that has been identified for both private growers and commercial applicators. For all of the different types of endpoints selected (except chronic where a limited number of calculations were completed), the Agency identified exposures that fit into 28 different scenarios which are defined based on the equipment used to make applications or the type of formulation used. Within each of these categories, different application rates and acres treated values were considered to evaluate the broad range of applications that may occur with each kind of equipment (e. g., a groundboom may be used for turf or agriculture). All totaled, 128 different crop/ rate/ acres combinations were considered within the 28 scenarios for the short­ and 92 intermediate­ term toxicity categories plus 4 chronic crop/ rate/ acre combinations. The overall result is that 4 sets of 128 calculations each (516 total calculations) were completed for occupational carbaryl handlers. Finally, it should be noted that each calculation was completed at different levels of personal protection to allow for a more informed risk management decision. Even given the scope of the calculations that have already been completed, it is likely that there are some uses of carbaryl that have not been quantitatively addressed in this document either through lack of exposure data or other information and because carbaryl is such a widely used chemical. These scenarios will be addressed by the Agency when they are identified as carbaryl progresses through the reregistration process. Readers are also encouraged to evaluate novel scenarios by considering the range of estimates already completed as it is likely that many uses could be quantitatively assessed by reviewing those calculations as a wide array of chemical use combinations and equipment types have already been considered. The data that were used in the carbaryl occupational handler risk assessment represent the best data and approaches that are currently available. While some of the data which have been used may not be of optimal quality, they represent the best available data for the scenario in question. In many cases, the Pesticide Handlers Exposure Database (PHED) was used to develop the unit exposure values. The quality of the data included in PHED vary widely from scenarios that meet guideline requirements for studies to others where a limited number of poor quality datapoints are available. The results for each scenario should be reviewed in the context of the quality of these data. In addition to PHED, the Agency used a number of studies to define unit exposure values. Generally, the quality of these studies is excellent. Most, except for the trigger sprayer data, are very recent and based on the newest analytical requirements and monitoring techniques. PHED unit exposure values represent a central tendency of the data (i. e., geometric mean, median or arithmetic mean depending upon the distribution of the data). As such, the values based on the recent studies also are measures of central tendency (e. g., the geometric means were selected from each study for assessment purposes in most cases). Along with the unit exposure values used in the assessment, other inputs include application rates and daily acres treated values. Selected application rates represent a range for each major market in which carbaryl is used including agriculture, turf (lawncare, golf courses, etc.), ornamentals, and for wide area applications such as mosquito control. Many application rates also represent maximum amounts that are allowed by the label for certain settings. Where available, average use rates were also used to provide for a more informed risk management decision. The application rates that were selected for use in the risk assessment were defined based on labels, information provided by the Aventis Corporation at the September 24, 1998 SMART Meeting for carbaryl, and based on various analyses of carbaryl use patterns completed by the Agency's Biological and Economic Analysis Division. The other key input for completing handler risk assessments used for defining how much chemical can be used in a day is how much can be treated in a day which is generally expressed as the number of acres treated per day. The values that were used for this parameter represent the latest Agency thinking on this issue. In fact, the Science Advisory Council For Exposure recently updated the policy for these inputs (July 2000 Exposure SAC Policy 9: Standard Values for Daily Acres Treated in Agriculture). These most recent values have been used for the calculations. In addition to the key sources of information considered above, there are many underlying factors that may impact the overall results of a risk assessment. For example, the protection factors 93 used for adding additional levels of dermal and respiratory protection may impact the overall risk picture. The factors used in this assessment by the Agency are the ones that have been used for several years. Other such factors may include the fact that average application rates have been generally used to represent typical application rates to calculate ranges of risks when it is clear that the two values could differ greatly. The Agency has taken this approach because the data required to define typical application rates within each crop are generally unavailable. There are also exposure monitoring issues that should be considered. For example, in many cases the data included in PHED are based on the use of cotton gloves for hand exposure monitoring which are thought by many to overestimate exposure because they potentially retain residues more than human skin would over time (i. e., they may act like a sponge compared to the actual hand). A similar issue was noted with the carbaryl­ specific dog grooming study that used the handwash approach to monitor exposure after shampooing several dogs. These intangible elements of the risk assessment reflect many of the hidden uncertainties associated with exposure data. The overall impacts of these uncertainties is hard to quantify. The factor to again consider is that the Agency used the best available data to complete the risk assessment for carbaryl. In summary, the Agency believes that the risk values presented in this occupational assessment represent the highest quality results that could be produced given the exposure, use, and toxicology data that are available. Certainly risk managers and other interested parties should consider the quality of individual inputs when interpreting the results and make decisions accordingly. It is difficult to ascertain where on a distribution the values which have been calculated fall because the distributional data for exposure, application rates, acres treated and many other parameters are unrefined. The Agency does believe, however, that the risks represent conservative estimates of exposure because maximum application rates are coupled with large acreage estimates to define risk estimates that likely fall in the upper percentiles of the actual exposure distributions. Additionally, risk estimates are thought to be conservative even when measures of central tendency are combined because values that would be considered to be in the lower percentile aspect of any input parameter have not been used in the calculations. 2.3.2 Postapplication Characterization Like the occupational handler risk assessment discussed above, the postapplication worker risk assessment for carbaryl is also complex in that three different types of noncancer risk calculations were required based on the recently selected endpoints along with cancer risk calculations using a linear, low­ dose extrapolation model. For all of the different types of endpoints selected (except chronic where a limited number of calculations were completed), the Agency identified exposures that fit into 18 different crop groups which are defined essentially based on the nature of the crop where a work activity would take place. Within each of these crop groups, ranges of transfer coefficients were considered to reflect differences in exposures that would be associated with the variety of cultural practices that are required to produce the crop/ product. All totaled, 54 different cultural practices were considered within the 18 crop groups for each toxicity category. The overall result is that 4 sets of 54 calculations each (216 plus a few chronic values) were completed for postapplication workers. Finally, it should be noted that each calculation was completed at different days after application to reflect residue dissipation over time in the environment and to allow for a more informed risk management decision. Even given the scope of 94 the calculations that have already been completed, it is likely that there are some uses of carbaryl that have not been quantitatively addressed in this document either through lack of exposure data or other information and because carbaryl is such a widely used chemical. These scenarios will be addressed by the Agency when they are identified as carbaryl progresses through the reregistration process. Readers are also encouraged to evaluate novel scenarios by considering the range of estimates already completed as it is likely that many uses could be quantitatively assessed by reviewing existing calculations as a wide array of crop/ activity combinations have already been considered. The data that were used in the carbaryl postaapplication worker risk assessment represent the best data and approaches that are currently available. The latest Agency transfer coefficient values have been used to complete this assessment including the recently submitted ARTF studies on greenhouse workers. Most of the values in the current Agency policy are based on the work of the Agricultural Reentry Task Force (ARTF) of which, Aventis is a member. The current Agency policy is interim in nature but represents all of the data that have been submitted by the ARTF and evaluated by the Agency. The work of the ARTF is still ongoing so additional data may become available to refine the exposure estimates as more data are submitted to the Agency. Also, it is possible that there are exposure scenarios that have not been addressed by the Agency because the transfer coefficient model is not appropriate as there is little or no foliar contact associated with the activity. There are also potentially, partially mechanized activities that could lead to exposure where the Agency has no information. These will need to be carefully considered in the reregistration process. In addition to the exposure inputs for specific activities (i. e., transfer coefficients), the Agency used 4 carbaryl­ specific DFR (Dislodgeable Foliar Residue) dissipation studies and a single TTR (Turf Transferable Residue) study to calculate risks for all postapplication workers in every region in the country. It is standard practice for the Agency to use these kinds of studies in this manner but it is likely that additional crop­ and region­ specific data could be used to further refine the risk assessment. Several other key pieces of data and information were considered in the development of the postapplication risk values including use and usage information and exposure frequency in the cancer risk assessment. For many agricultural crops, the maximum application rate is low (e. g., 1.5 to 2 lb ai/ acre) in many crops. As a result, postapplication risks were generally calculated at maximum rate levels because of the already inherent complexity of the assessment and because it is likely that results may not be extremely sensitive to changes in this value. In addition to the key sources of information considered above, there are many underlying factors that may impact the overall results of a risk assessment. For example, subtle differences between activities in similar crops within each of the 18 agronomic groups considered in the assessment may not be accurately reflected in the current transfer coefficient values. The use of 4 DFR studies to represent all crops and all regions within the country could lead to results that do not reflect actual use practices and conditions in some parts of the country. Additionally, the exposure frequency values that were used for private growers and professional farmworkers tend to be supported by available data but could be refined if data on work patterns and regional carbaryl use becomes available. As with the handler assessment above, the intangible elements reflect many of the hidden uncertainties associated with exposure data. The overall impacts of these uncertainties is hard to quantify. The factor to again consider is that the Agency used the best available data to 95 complete the risk assessment for carbaryl. In summary, the Agency believes that the risk values presented in this postapplication assessment represent the highest quality results that could be produced given the exposure, use, and toxicology data that are available. Certainly risk managers and other interested parties should consider the quality of individual inputs when interpreting the results and make decisions accordingly. It is difficult to ascertain where on a distribution the values which have been calculated fall because the distributional data for exposure, residue dissipation and many other parameters are unrefined. The Agency does believe, however, that the risks represent conservative estimates of exposure because maximum application rates are used to define residue levels upon which the risk calculations are based. Additionally, risk estimates are thought to be conservative even when measures of central tendency (e. g., most transfer coefficients are thought to be central tendency) are used because values that would be considered to be in the lower percentile aspect of any input parameter have not been used in the calculations. 3.0 Residential and Other Non­ Occupational Exposures and Risks It has been determined there is a potential for exposure in residential settings during the application process for homeowners who purchase and use products containing carbaryl. There is also a potential for exposure from entering areas previously treated with carbaryl such as lawns where children might play or golf courses and homegardens that could lead to exposures for adults. Carbaryl is also labeled for mosquito adulticide use which has been considered in this assessment. As a result, risk assessments have been completed for both residential handler and postapplication scenarios. Residential handler exposures and risks are addressed in Section 3.1: Residential Handler Exposures and Risks while residential post­ application risks for adults and children are presented and summarized in Section 3.2: Residential Post­ Application Exposures and Risks. The calculated risks are characterized in Section 3.3: Residential Risk Characterization. 3.1 Residential Handler Exposures and Risks The Agency uses the term "Handlers" to describe those individuals who are involved in the pesticide application process. The agency believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task as was described above for occupational handlers. Residential handlers are addressed somewhat differently by the Agency as homeowners are assumed to complete all elements of an application with little use of any protective equipment. The scenarios that serve as the basis for the risk assessment are presented in Section 3.1.1: Handler Exposure Scenarios. The exposure data and assumptions that have been used for the calculations are presented in Section 3.1.2: Data and Assumptions For Handler Exposure Scenarios. The calculations and the algorithms that have been used for the noncancer elements of the risk assessment as well as the risk values are presented in Section 3.1.3: Handler Exposure and Non­ Cancer Risk Estimates while the analogous information using the Q1* for cancer estimates are presented in Section 3.1.4: Handler Exposure and Risk Estimates For Cancer. Section 3.1.5: Summary of Risk Concerns and Data Gaps For Handlers presents the overall risk picture for carbaryl. Finally, recommendations are presented in Section 3.1.6: Recommendations For Refining Residential Handler Risk Assessment. 96 3.1.1 Handler Exposure Scenarios Scenarios are again used, as with the occupational handler risk assessment above, to define risks based on the U. S. EPA Guidelines For Exposure Assessment (U. S. EPA; Federal Register Volume 57, Number 104; May 29, 1992). The purpose of this section is to describe how the exposure scenarios were defined. Much of the process for residential uses is identical to that considered for the occupational assessment with a few notable exceptions that include: ° Residential handler exposure scenarios are only considered to be short­ term in nature due to the episodic uses associated with homeowner products, as a result, no intermediate­ term or chronic assessments were completed for handlers; ° A tiered approach for personal protection using increasing levels of PPE is not used in residential handler risk assessments, rather than using PPE, homeowner handler assessments are completed based on individuals using shorts and short­ sleeved shirts; ° Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product including mixing/ loading if needed as well as the application; ° Label use rates and use information specific to residential products serve as the basis for the risk calculations as opposed to the rates used in the occupational assessment; and ° Area/ volumes of spray or chemical used in the risk assessment are based on Agency guidance specific to residential use patterns. It has been determined that exposure to pesticide handlers is likely during the residential use of carbaryl in a variety of environments including on lawns, gardens and ornamentals, and pets. The anticipated use patterns and current labeling indicate 17 major residential exposure scenarios based on the types of equipment and techniques that can potentially be used to make carbaryl applications. The quantitative exposure/ risk assessment developed for residential handlers is based on these scenarios. [Note: The scenario numbers correspond to the tables of risk calculations included in the occupational risk calculation aspects of the appendices.] (1) Garden Uses: Ready­ to­ use Trigger Sprayer; (2) Garden Uses: Ornamental Duster; (3) Garden Uses: Hose­ end Sprayer; (4) Garden Uses: Low Pressure Handwand; (5) Tree/ ornamental Uses: Low Pressure Handwand; (6) Tree/ ornamental Uses: Hose­ end Sprayer; (7) Garden Uses: Backpack Sprayer; (8) Lawncare Liquid Uses: Hose­ end Sprayer; (9) Pet (Dog and Cat) Uses: Dusting; (10) Pet (Dog and Cat) Uses: Liquid Application; (11) Lawncare Granular and Bait Uses: Belly Grinder; (12) Lawncare Granular and Bait Uses: Push­ type Spreader; 97 (13) Ornamental and Garden Uses: Granulars and Baits By Hand; (14) Various Pest Uses: Aerosol Cans; (15) Pet (Dog and Cat) Uses: Collars; (16) Garden and Ornamental Uses: Sprinkler Can; and (17) Garden and Ornamental Uses: Paint­ on. 3.1.2 Data and Assumptions For Handler Exposure Scenarios A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below. In addition to these factors, unit exposure values were used to calculate risk estimates. Mostly, these unit exposure values were taken from the Pesticide Handlers Exposure Database (PHED). In other cases, chemical­ specific exposure data were submitted to support the reregistration of carbaryl. Both PHED and the individual studies are presented below. [Note: Several of the assumptions and factors used for the assessment are similar to those used in the occupational assessment presented above. As such, only factors that are unique to the residential scenarios are presented below.] Assumptions and Factors: The assumptions and factors used in the risk calculations include: C Carbaryl is one of the most widely used pesticide chemicals. It has an extraordinary number of use patterns that are impossible to completely capture in this document. As such, the Agency has patterned this risk assessment on a series of likely representative scenarios that are believed to represent the vast majority of carbaryl uses. Refinements to the assessment will be made as more detailed information about carbaryl use patterns become available. C Exposure factors used to calculate daily exposures to handlers were based on applicable data if available. For lack of appropriate data, values from a scenario deemed similar enough by the assessor might be used. As an example, mixer/ loader/ applicator data for hose­ end sprayers were used to assess sprinkler can applications. The nature of these application methods are believed to be similar enough to bridge the data. There were other instances where the Agency bridged specific data to represent other scenarios. See Appendix G/ Table 1 for more details. 98 C The exposure duration (i. e., years per lifetime) values used by the Agency in the cancer risk assessment were consistent with those used for other chemicals (i. e., 50 years with home­ use chemicals and 70 year lifetime). C The Agency always considers the maximum application rates allowed by labels in its risk assessments to consider what is legally possible based on the label. If additional information such as average or typical rates are available, these values are also used to allow risk managers to make a more informed risk management decision. Average application rates were available from the SMART meeting and BEAD's QUA. These data indicated that in most cases, average application rates differed from maximum application rates on average by a factor of two. In some other cases, the average application rates identified from the studies conducted by Aventis were also used to define "average study use rate values" which were included in the calculations to provide for a more informed risk management decision. ° Residential risk assessments were not based on what could be applied in a typical workday like with the occupational risk assessments presented above. Instead, the Agency based calculations on what would reasonably be treated by homeowners such as the size of a lawn, or the size of a garden. This information was used by the Agency to define chemical throughput values for handlers which in turn were coupled with unit exposure values to calculate risks. The factors used for the carbaryl assessment were those dictated in the Health Effects Division Science Advisory Committee Policy 12: Recommended Revisions To The Standard Operating Procedures For Residential Exposure Assessment which was completed on February 22, 2001. [Note: Information presented at SMART meeting did not include event­ specific information that would cause the Agency to use different values than those presented below.] The following daily volumes handled and area treated, excerpted from the policy and used in each residential scenario, include: ° 1 container of each ready­ to­ use non­ pet product including garden dusts, trigger sprayers and aerosol cans (scenarios for 25 and 50 % used of the total product volume were also presented for the trigger sprayer and garden dust scenarios to allow for a more informed risk management decision); ° ½ container of each ready­ to­ use pet products including dusts and liquid shampoos; ° 1 pet collar; ° 100 gallons of finished spray output for hose­ end sprayers; ° 5 gallons when mixing/ loading/ applying liquids with a backpack sprayer or a low pressure handwand sprayer, value was also used for sprinkler can applications; ° 1 gallon of paint­ on solution for ornamental/ garden uses; ° 20,000 square feet is used to represent the surface area treated for broadcast applications to lawns; ° 1000 square feet is used as the treatment area for many spot applications in lawns, gardens, and ornamentals (this value used as appropriate when application rates were based on a square foot basis for spot­ type treatments); and ° 5 mounds per day treated for fire ant applications. 99 ° At the September 24, 1998 SMART Meeting with the Agency, the Aventis Corporation supplied data focused on the use patterns for carbaryl. The information presented at that meeting supports the inputs used by the Agency in this risk assessment. Several key factors have been summarized below for residential users of carbaryl: ° Carbaryl accounted for approximately 9 percent of the residential insecticide market and was ranked 4 th on the list behind the pyrtethroids, chlorpyrifos, and diazinon [Note: This may be different in 2001 because of registration changes for other chemicals]; ° The maximum turf application rate noted was 8 lb ai/ acre by lawns/ landscape services on residential turf; ° Insect control on vegetables (~ 58% of users), annuals (~ 50% of users), lawns (~ 35% of users), trees/ shrubs (~ 34% of users) account for the majority of uses for carbaryl; ° Pet uses account for ~13 percent of users; ° The annual frequency for use was reported to be 1 (34 th %tile) to 2 times per year (60 th %tile) and 5 times per year (84 th %tile); ° Aphids, ants, fire ants, fleas, and slugs/ snails are the most predominantly controlled pests by residential carbaryl users (~ 30% down to 15% of uses, respectively); ° Most (75%) of vegetable gardens treated with carbaryl are <800 ft 2 but ~8 percent are between 800 and 1500 ft 2 , ~9 percent are between 1500 and 5000 ft 2 , and ~6 percent are greater than 5000 ft 2 ; ° Tomatoes, peppers, cucumbers, beans, and fruit trees represent the most treated garden plants; ° Most (82%) of flower gardens treated with carbaryl are <500 ft 2 but ~10 percent are between 500 and 1200 ft 2 , and ~8 percent are greater than 1200 ft 2 ; ° Roses, shrubs, and certain annuals represent the most treated flowering/ ornamental plants; and ° Dusts (65%) and liquid concentrate (25%) account for most carbaryl sales in the residential annual market of ~2.2M pounds active ingredient per year. ° The Aventis Corporation provided data for freqency of annual use among residential applicators that had been used to calculate cancer risks for adults in the general population. These data show that the 50 th percentile is between 1 and 2 uses per year so all cancer risks have been calculated based on a single use event per year. Risk managers should consider this element in their interpretation of the overall results. For example, there might be a smaller population of more frequent users (e. g., 84 th %tile = 5 times per year) that maintain high frequencies of use over their lifetimes which is critical for consideration in cancer risk assessment. Longitudinal data, however, were not available to establish that such populations definitively exist. Additionally, the Agency calculated the number of days exposure per year that would be required to exceed a risk level of 1.0x10 ­6 to illustrate an exposure limit in order to allow for a more informed risk management decision. ° For pet collar uses, Agency policy outlined in the Residential SOPs, was used to define the exposure level associated with putting the collar on an animal. The SOPs specify 1 percent of the total active ingredient in the collar is considered equal to the exposure. 100 ° For turf, the maximum application rate that was indicated at the SMART meeting was 8 lb ai/ acre even though current labels allow for applications by homeowners at up to 11 lb ai/ acre for Lock­ n­ load type packages and 9 lb ai/ acre for granulars. Residential Handler Exposure Studies: The unit exposure values that were used in this assessment were based on three carbaryl­ specific residential handler studies which quantified exposures during pet treatments with a dust; applications to gardens using a ready­ to­ use trigger sprayer, a dust, a hose­ end sprayer, and a low­ pressure handwand; and during applications to trees using a low­ pressure handwand and a hose­ end sprayer. Two other studies completed by the Outdoor Residential Exposure Task Force and the Pesticide Handler Exposure Database (PHED, Version 1.1 August 1998) were also used as sources of surrogate information. For pet collars only, a scenario from the SOPs For Residential Exposure Assessment not based on monitoring data was used to calculate exposures. A citation for each study as well as a brief summary is provided below. [Note: PHED is described above in Section 2.1.2, refer to that section for further information.] ° Carbaryl Applicator Exposure Study During Application of Sevin ® 5 Dust to Dogs By the Non­ Professional. Agrisearch Study No. 1517. EPA MRID 444399­ 01. Report date August 22, 1997; Authors: D. Larry Merricks, Ph. D., Sponsor: Rhone Poulenc Ag Company. ° Carbaryl Mixer/ Loader/ Applicator Exposure Study during Application of RP­ 2 Liquid (21%) Sevin ® Ready to Use Insect Spray or Sevin ® 10 Dust to Home Garden Vegetables. Agrisearch Study No. 1519. EPA MRID 444598­ 01. Report dated August 22, 1998, Author; Thomas C. Mester, Ph. D., Sponsor: Rhone Poulenc Ag Company. ° Carbaryl Mixer/ Loader/ Applicator Exposure Study during Application of RP­ 2 Liquid (21%) to Fruit Trees and Ornamental Plants. Agrisearch Study No. 1518. MRID 445185­ 01. Report dated January 23, 1998. Author D. Larry Merricks, Ph. D., Sponsor: Rhone Poulenc Ag Company. °" Integrated Report For Evaluation of Potential Exposures To Homeowners and Professional Lawncare Operators Mixing, Loading, and Applying Granular And Liquid Pesticides To Residential Lawns " EPA MRID 449722­ 01; October 10, 1999; Author: Dennis R. Klonne, Ph. D.; Sponsor: Outdoor Residential Exposure Task Force; EPA Review by Gary Bangs (April 30, 2001). [Note to Chemical Review Manager: Appendix F contains the data excerpted from each of the carbaryl­ specific studies which were recently completed by the Aventis Corporation. Some of the handler exposure data used in this assessment are from the Outdoor Residential Exposure Task Force (ORETF). There is no data compensation issue associated with the use of the ORETF data in the carbaryl risk assessment because the Aventis Corporation, the registrant for carbaryl, is a member of the ORETF. The task force recently submitted proprietary data to the Agency on hoseend sprayers and push­ type granular spreaders for residential handlers (MRID # 44972201). The ORETF data were used in this assessment in place of PHED data. The ORETF data were designed to replace the present PHED data with higher­ confidence, higher quality data that contains more 101 replicates than the PHED data for those scenarios. Finally, the Agency identified several occupational exposure studies from the literature by investigators such as Kurtz and Bode. These data have not been used by the Agency quantitatively in this assessment because of several issues but were qualitatively considered and also used to confirm the currently used exposure data.] MRID 44439901 (Carbaryl homeowner dog dusting study): The objective of the study was to measure homeowner dermal and respiratory exposure to carbaryl while dusting 3 dogs for fleas using Sevin® 5 Dust. The dogs were from a local facility and varied in size and fur length. The product was supplied to the handlers in 1 lb. Ortho Sevin ® 5 Dust canisters. The handlers opened the can, shook the product onto the dogs coat and rubbed the dust into the fur. The first replicate consisted of each applicator applying dust to 3 dogs of varying size with chemical resistant gloves on. The first set of monitoring devices, handwashes and face/ neck wipes and air monitors were taken and replaced with a clean set of dosimeters on the same person for the second set of replicates. The second replicate was the same handler applying Ortho ® Sevin ® 5 Dust without gloves on 3 dogs. A total of 40 replicates were collected, 20 replicates with gloves and 20 replicates without gloves. Each replicate wore inner and outer dosimeters to simulate skin and clothing respectively. The inner dosimeter layer consisted of 100 percent cotton long leg and long sleeved underwear worn beneath the outer dosimeter of long leg and long sleeved 100 percent cotton work clothes. Each dosimeter was cut into six separate dermal body part samples (i. e., lower and upper arms, lower and upper legs, front and back torso) for a total of 480 dermal samples for handlers with gloves and without gloves. The cloth dosimeter parts (inner and outer), handwashes, face/ neck wipes and air monitoring devices frozen, sent to a laboratory and analyzed for carbaryl. The amount of product used to dust 3 dogs averaged 65.3 grams or 3.51 grams ai. On average to dust 3 dogs required 7 minutes. Field fortification recoveries for passive dosimeters averaged >90 percent for inner and outer dosimeters. Face and neck wipe fortifications average 87.6 percent. Inhalation OVS tube field fortification averaged 100 percent, however one sample of 30 was damaged in shipping and one day does not have field fortification data. Dosimeter field fortification results that were >90 percent were not adjusted, therefore only the face and neck wipe were adjusted for field recovery. Laboratory method validation for each matrix fell within the acceptable range of 70 to 120 percent. Storage stability tests were done and acceptable. Unit exposure values were calculated using the data from the study and a commercial spreadsheet program. The study reported the total exposure to carbaryl as only the inner dosimeter. Since this is a residential product, inner dosimeter upper arm and upper legs, front and back torso were combined with the outer dosimeter lower arms and lower legs to account for the handler wearing, a short­ sleeved shirt, short pants and no gloves. The exposures that were calculated were normalized by the amount of chemical used and by the body weight of the dogs treated by the individual applicators. For each calculation, the arithmetic mean, geometric mean, and median of the data are presented in Table 20 below. No analyses were completed with these data to ascertain the exact type of distribution. The Agency typically uses the best fit values from the Pesticide Handlers Exposure Database which are representations of the central tendency. Considering the 102 standard practice, the Agency will use the geometric mean for risk assessment purposes. The other values are presented for comparative purposes. Table 20: Unit Exposure Values Obtained From Carbaryl Homeowner Dog Dusting Study (MRID 444399­ 01) Type (mg exp./ lb ai handled) (mg exp./ lb treated dog) Dermal Inhalation Dermal Inhalation Applications with a dust to dogs Arith. Mean 3800 33 0.0080 5.0 x 10 ­12 Geo. Mean 3300 25 0.0052 3.8 x 10 ­12 Median 3300 27 0.0057 3.9 x 10 ­12 MRID 44459801 (Carbaryl application to vegetables study): The data collected reflect the dermal and respiratory exposure of homeowners mixing, loading and applying RP­ 2 Liquid (21%), a carbaryl end­ use product. Applications were made by volunteers to two 18 foot rows of tomatoes and one 18 foot row of cucumber. The only test field was located in Florida. For this study, RP­ 2 Liquid (21%) exposures were monitored using hose­ end sprayers and low­ pressure handwand sprayers. Exposures to Sevin ® 10 Dust, using a separate duster device that required transfer from the package and Sevin ® Ready To Use Insect Spray (RTU) in a trigger sprayer package were also monitored. Exposure for each spray method/ product combination was monitored using 40 handlers (replicates). Of the 40 replicates per spray method/ product combination, 20 wore household latex gloves and 20 performed tasks without gloves. The 20 dust product replicates loaded the dusters and applied without gloves only. Each replicate opened the end­ use product, added it to the application implement (except the RTU product), adjusted the setting and applied it to the vegetable rows. After application to the vegetable rows, dosimeters were collected. Inhalation exposure was monitored with personal air sampling pumps with OVS tubes attached to the shirt collar in the breathing zone. Dermal exposure was assessed by extraction of carbaryl from inner and outer 100 percent cotton dosimeters, face/ neck wipes, and glove and hand washes. The inner and outer dosimeters were segmented into: lower and upper arms, lower and upper legs, front and back torso. Field fortification recoveries for passive dosimeters averaged 84.3 percent for inner and 77.7 percent for outer dosimeters. Face and neck wipe fortifications average 84.8 percent. Handwash and Inhalation OVS tube field fortification averaged >90 percent. Inner and outer dosimeter and face and neck wipe residues were adjusted for field fortification results. Handwash and inhalation residues were not adjusted. Laboratory method validation for each matrix fell within the acceptable range of 70 to 120 percent. The limit of quantitation (LOQ) was 1.0 µg/ sample for all media except the inhalation monitors where the LOQ was 0.01 µg/ sample. The limit of detection (LOD) was 0.5 µg/ sample for all media except the inhalation monitors where the LOQ was 0.005 µg/ sample. Dermal exposure was determined by adding the values from the bare hand rinses, face/ neck wipes to the outer dosimeter lower legs and lower arms plus the inner dosimeter front and rear torso, upper legs, lower legs, lower arms, and upper arms. This accounts for the residential handler wearing short­ sleeved shirt and short pants. Unit exposures for each application method are 103 presented below in Table 21. Table 21: Unit Exposure Values Obtained From Carbaryl Homeowner Vegetable Treatment Study (MRID 444598­ 01) Scenario Monitored Dermal Unit Exposure (mg ai/ lb handled) Inhalation Unit Exposure (µg ai /lb handled) Geometric Mean Median Geometric Mean Median Hand Held Pump­ Spray 38 35 9 11 Hose­ End Sprayer 34 31 2 2.3 Ready­ to­ Use Spray 54 53 67 34 Duster 148 140 870 1200 MRID 44518501 (Carbaryl application to trees and shrubs study): Applications of Sevin Liquid® Carbaryl insecticide [RP­ 2 liquid (21%)] were made by volunteers to two young citrus trees and two shrubs in each replicate that was monitored in the study. The test field was located only in Florida. Twenty (20) replicates were monitored using hose­ end sprayer (Ortho® DIAL or Spray® hose end sprayer), and 20 replicates were monitored using hand held pump sprayers (low pressure handwands). Each replicate opened the end­ use product, added it to the hose­ end sprayer or hand held pump and then applied it to the trees and shrubs. After application to two trees and two shrubs dosimeters were collected. Inhalation exposure was monitored with personal air sampling pumps with OVS tubes attached to the shirt collar in the breathing zone. Dermal exposure was assessed by extraction of carbaryl from inner and outer 100 percent cotton dosimeters. The inner and outer dosimeters were segmented into: lower and upper arms, lower and upper legs, front and back torso. No gloves were worn therefore hand exposure was assessed with 400 ml handwash with 0.01 percent Aerosol OT­ 75 sodium dioctyl sulfosuccinate (OTS). One hundred (100) percent cotton handkerchiefs wetted with 25 ml OTS were used to wipe face and neck to determine exposure. Field fortification recoveries for passive dosimeters averaged 88.3 percent for inner and 76.2 percent for outer dosimeters. Face and neck wipe fortifications average 82.5 percent. Handwash and inhalation OVS tube field fortification averaged >90 percent. Inner and outer dosimeter and face and neck wipe residues were adjusted for field fortification results. Handwash and inhalation residues were not adjusted. Laboratory method validation for each matrix fell within the acceptable range of 70 to 120 percent. The limit of quantitation (LOQ) was 1.0 µg/ sample for all media except the inhalation monitors where the LOQ was 0.01 µg/ sample. The limit of detection (LOD) was 0.5 µg/ sample for all media except the inhalation monitors where the LOQ was 0.005 µg/ sample. For use in reregistration documents, the dermal exposure was calculated by adding the values from the hand rinses, face/ neck wipes to the outer dosimeter lower legs and lower arms plus the inner dosimeter front and rear torso, upper legs, lower legs, lower arms, and upper arms. This accounts for the residential handler wearing short­ sleeved shirt and short pants. The results are 104 summarized in Table 22 below. Table 22: Unit Exposure Values Obtained From Carbaryl Homeowner Ornamental Treatment Study (MRID 44518501) Scenario Monitored Hose End Pump Sprayer Applied (lb ai) Dermal Exposure (mg ai/ lb handled) Inhalation (ug ai/ lb handled) Applied (lb ai) Dermal Exposure (mg ai/ lb handled) Inhalation (ug ai/ lb handled) Geo. Mean 0.033 39 2.5 0. 017 56 6.5 Median 0.026 44 2.6 0. 018 49 4.3 EPA MRID 449722­ 01 (ORETF Handler Studies): A report was submitted by the ORETF (Outdoor Residential Exposure Task Force) that presented data in which the application of various products used on turf by homeowners and lawncare operators (LCOs) was monitored. All of the data submitted in this report were completed in a series of studies. The two studies that monitored homeowner exposure scenarios used a granular spreader (ORETF Study OMA003) and a hose­ end sprayer (ORETF Study OMA004) are summarized below. OMA003: A total of 30 volunteer test subjects were monitored using passive dosimetry (inner and outer whole body dosimeters, hand washes, face/ neck wipes, and personal inhalation monitors). Each test subject carried, loaded, and applied two 25­ lb bags of fertilizer (0.89% active ingredient) with a rotary type spreader to a lawn (a turf farm in North Carolina) covering 10,000 ft 2 (one bag to each of the two 5000 ft 2 test plots). Application to each subplot continued until the hopper was empty. Each participant also disposed of the empty bags at the end of the replicate. The target application rate was 2 lb ai/ acre (actual rate achieved was about 1.9 lb ai/ acre). The average application time was 22 minutes, including loading the rotary push spreader and disposing of the empty bags. Approximately 0.45 lb ai was handled in each replicate. Dermal exposure was measured using inner and outer whole body dosimeters, hand washes, face/ neck washes, and personal air monitoring devices with OVS tubes. Overall, residues were highest on the upper and lower leg portions of the dosimeters. Inhalation exposure was calculated using an assumed respiratory rate of 17 Lpm for light work (NAFTA, 1999), the actual sampling time for each individual, and the pump flow rate. All results were normalized for lb a. i. handled. All fortified samples and field samples collected on the same study day were stored frozen and analyzed together, eliminating the need for storage stability determination. Seventyseven percent (77%) of the face and neck washes were below the level of quantitation (LOQ) for dacthal, and ten percent (10%) of the air samples were also at or below the LOQ. Where results were less than the reported LOQ, ½ LOQ value was used for calculations, and no recovery corrections were applied. Lab spike recoveries for all matrices were in the range of 83­ 99 percent. Mean field fortification recoveries over the four study days for each fortification level ranged from 83 to 97 percent. OMA004: Dermal and inhalation exposures were estimated using passive dosimetry techniques (biological monitoring data were not collected). A total of 60 replicates were monitored using 30 test subjects (two replicates each) during applications to residential lawns in Frederick, Maryland. Thirty applicator replicates were monitored using a ready­ to­ 105 use (RTU) product (Bug­ B­ Gon) packaged in a 32 fl. oz. screw­ on container. These containers were attached to garden hose­ ends. An additional 30 mixer/ loader/ applicator replicates were monitored using Diazinon Plus also packaged in 32 fl. oz. plastic bottles. This product required the test subjects to pour the product into dial­ type sprayers (DTS) that were attached to garden hose­ ends. A nominal application rate of 4 lb ai/ acre was used for all replicates. Each replicate monitored the test subject treating 5,000 ft 2 of turf and handling a total of 0.5 lb ai/ replicate. The average time per replicate was 75 minutes. Dermal and inhalation exposure were measured using inner and outer whole body dosimeters (long pants and long sleeved shirt over long underwear), hand washes, face/ neck washes, and personal air monitoring devices. Lab­ fortified dosimeters had recoveries of 87­ 103 percent; field­ fortified dosimeters had a mean range of 79­ 104 percent recovery, with very little variance. The study results are corrected for field recoveries using the correction factor for the level of fortification closest to the field result. The route­ specific exposure data (dermal and inhalation) from both studies were lognormally distributed. Therefore, the geometric mean of the dermal and inhalation data should be used for exposure assessments. The unit exposure values are presented in Table 23 below. Table 23: Unit Exposure Values Obtained From ORETF Homeowner Studies (MRID 449722­ 01) Scenario (mg exp./ lb ai handled) Dermal Inhalation Homeowner Push Granular Spreader 0.68 0.00091 Homeowner Hose­ End 11.0 0. 016 All unit exposure values are geometric means. Exposure values represent individuals wearing shorts and short­ sleeved shirts. Hose­ end sprayer data for mix your own (not the locking/ no contact package) considered. 3.1.3 Residential Handler Exposure and Non­ Cancer Risk Estimates The residential handler exposure and non­ cancer risk calculations are presented in this section. Noncancer risks were calculated using the Margin of Exposure (MOE) as described in Section 2.1.3. Much of the process for residential uses is identical to that considered for the occupational assessment with a few notable exceptions as described above in Section 3.1.1 (e. g., all are short­ term exposures and people wear shorts and short­ sleeved shirts). The other major difference with residential risk assessments is that the uncertainty factor which defines the level of risk concern also has the additional FQPA safety factor applied. In the case of carbaryl, in January and February 2002 meetings of the FQPA Safety Factor Committee, it was decided that the factor should be reduced to 1 based on the recently revised FQPA SFC standard operating procedures. Therefore, the overall uncertainty factor applied to carbaryl for residential handler risk assessments is 100 which is based on the FQPA safety factor of 1 along with the 100 applied for inter­ species extrapolation, intra­ species sensitivity, and the use of a NOAEL for risk assessment. Noncancer Risk Summary: All of the noncancer risk calculations for occupational carbaryl handlers completed in this assessment are included in Appendix G (Tables 1 ­ 3). The 106 specifics of each of table included in Appendix G are described below. A brief summary of the results for each exposure scenario is also provided below. C Appendix G/ Table 1: Sources of Exposure Data Used In The Carbaryl Homeowner Handler Exposure and Risk Calculations Describes the sources and quality of the exposure data used in all of the residential handler calculations. C Appendix G/ Table 2: Input Parameters For Carbaryl Homeowner Handler Exposure and Risk Calculations Presents the numerical unit exposure values and other factors used in the residential handler risk assessments. C Appendix G/ Table 3: Carbaryl MOEs Attributable To Combined Homeowner Handler Dermal and Inhalation Exposures Risk values are presented for each exposure scenario considered in the assessment. Exposures represent individuals wearing shortsleeved shirts and short pants. The data submitted by the Aventis Corporation accompanied by the other data used by the Agency have provided a basic broad overview of the uses of carbaryl around a residential environment (i. e., the database is fairly complete). As indicated above, however, it is likely that carbaryl can be used in a myriad of ways that have not been identified in this assessment because of different pests or types of application equipment. The Agency will consider risks from these additional scenarios as data become available. It should also be noted that there were many other scenarios where medium to low PHED quality data were used to complete the assessment. Data quality should be considered in the interpretation of the uncertainties associated with each risk value presented. Short­ term risks for residential handlers (intermediate­ term scenarios are not thought to exist because of the sporadic nature of applications by homeowners) are presented in Table 24 (Appendix G/ Table 3 summarized below for the convenience of the reader). For most scenarios (40 out of 52), risks are not of concern because MOEs exceed the required uncertainty factor of 100. As expected, the scenarios for which MOEs do not meet or exceed 100 have a relatively high unit exposure associated with them or the amount of chemical used over a day is relatively high (based on high application rates and/ or high amounts of area treated). The use of dusts in gardens and for pet grooming along with some liquid sprays on ornamentals appear to be the most problematic scenarios. Unlike the occupational handler scenarios, the use of different levels of personal 107 protective clothing and equipment is not considered for residential handlers because of a lack of availability, training, and maintenance. [Note: Scenarios where MOEs are still of concern (i. e., <100) for are highlighted in the table.] TABLE 24 CARBARYL MOEs ATTRIBUTABLE TO COMBINED SHORT­ TERM HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS DERMAL MOEs INHALATION MOEs COMBINED MOEs APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 1 Garden: Ready­ to­ Use Trigger Sprayer (MRID 444598­ 01) Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 0.25 0.00075 34567.9 1393034.8 33730.9 Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 0.5 0.0015 17284.0 696517.4 16865.4 Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 1 0.003 8642.0 348258.7 8432.7 Average Study Use Rate 0.012 (lb ai/ 1000 ft2) 1 0.012 2160.5 87064.7 2108.2 2 Garden/ Ornamental Dust (MRID 444598­ 01) Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 0.25 0.1 94.6 804.6 84.6 Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 0.5 0.2 47.3 402.3 42.3 Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 1 0.4 23.6 201.1 21.2 Average Study Use Rate 0.079 (lb ai/ 1000 ft2) 1 0.079 119.7 1018.5 107.1 3 Garden: Hose­ End (MRID 444598­ 01) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 100 2 20.6 17500.0 20.6 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 216.7 184210.5 216.5 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 3431.4 2916666.7 3427.3 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 1790.3 1521739.1 1788.2 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 876.1 744680.9 875.1 Average Study Use Rate 0.26 (lb ai/ 1000 ft2) 1 0.26 158.4 134615.4 158.2 Fire Ant 0.0075 (lb ai/ gal spray) 100 0.75 54.9 46666.7 54.8 4 Garden: Low Pressure Handwand (MRID 444598­ 01) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 5 0.1 368.4 77777.8 366.7 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 193.9 40935.7 193.0 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 3070.2 648148.1 3055.7 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 1601.8 338164.3 1594.3 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 783.9 165484.6 780.2 Average Study Use Rate 0.083 (lb ai/ 1000 ft2) 1 0.083 443.9 93708.2 441.8 Fire Ant 0.0075 (lb ai/ gal spray) 5 0.0375 982.5 207407.4 977.8 TABLE 24 CARBARYL MOEs ATTRIBUTABLE TO COMBINED SHORT­ TERM HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS DERMAL MOEs INHALATION MOEs COMBINED MOEs APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 108 5 Trees/ Ornamentals: Low Pressure Handwand (MRID 445185­ 01) Ornamental 0.023 (lb ai/ 1000 ft2) 1 0.176 1087.0 468227.4 1084.4 Pome Fruit 0.07 (lb ai/ 1000 ft2) 1 0.07 357.1 153846.2 356.3 Nuts/ Stone Fruit 0.12 (lb ai/ 1000 ft2) 1 0.12 208.3 89743.6 207.9 Citrus 0.176 (lb ai/ 1000 ft2) 1 0.023 142.0 61188.8 141.7 Average Study Use Rate 0.0047 (lb ai/ gal, 17g ai/ 4 min at 2GPM) 5 0.024 1063.8 458265.1 1061.4 6 Trees/ Ornamentals: Hose End Sprayer (MRID 445185­ 01) Ornamental 0.023 (lb ai/ 1000 ft2) 1 0.176 1560.8 1217391.3 1558.8 Pome Fruit 0.07 (lb ai/ 1000 ft2) 1 0.07 512.8 400000.0 512.2 Nuts/ Stone Fruit 0.12 (lb ai/ 1000 ft2) 1 0.12 299.1 233333.3 298.8 Citrus 0.176 (lb ai/ 1000 ft2) 1 0.023 204.0 159090.9 203.7 Average Study Use Rate 0.005 (lb ai/ gal spray) 100 0.5 71.8 56000.0 71.7 7 Garden: Backpack Sprayer (PHED) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 5 0.1 2745.1 23333.3 2456.1 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0.19 1444.8 12280.7 1292.7 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0.012 22875.8 194444.4 20467.8 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0.023 11935.2 101449.3 10678.9 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0.047 5840.6 49645.4 5225.8 Average Study Use Rate 0.083 (lb ai/ 1000 ft2) 1 0.083 3307.3 28112.5 2959.2 Fire Ant 0.0075 (lb ai/ gal spray) 5 0.0375 7320.3 62222.2 6549.7 8 Lawn Care: Hose End Sprayer (MRID 449722­ 01/ ORETF OMA 004) Lawn (broadcast) 0.25 (lb ai/ 1000 ft2) 20 5 25.5 875.0 24.7 Lawn (spot) 0.25 (lb ai/ 1000 ft2) 1 0.25 509.1 17500.0 494.7 9 Dusting Dog (MRID 444399­ 01) Average Study Use Rate 0.0026 (lb ai/ dog) 1 0.0026 163.2 1076.9 141.7 Dog (10% & 1/ 2 of 2 lb) 0.1 (lb ai/ dog) 1 0.1 4.2 28.0 3.7 Dog (5% & 1/ 2 of 2 lb) 0.05 (lb ai/ dog) 1 0.05 8.5 56.0 7.4 10 Dogs: Liquid Application Dog (0.5% & 1/ 2 of 6 oz) 0.001 (lb ai/ dog) 1 0.001 14000000.0 No Data No Data 11 Granular & Baits Lawn Care: Belly Grinder Lawn (spot) 0.21 (lb ai/ 1000 ft2) 1 0.21 60.6 5376.3 59.9 Lawn (spot) 0.1 (lb ai/ 1000 ft2) 1 0.1 127.3 11290.3 125.9 12 Granular & Baits Lawn Care: Push­ Type Spreader (MRID 449722­ 01/ ORETF OMA 003) Lawn (broadcast) 0.21 (lb ai/ 1000 ft2) 20 4.2 490.2 18315.0 477.4 Lawn (broadcast) 0.1 (lb ai/ 1000 ft2) 20 2 1029.4 38461.5 1002.6 13 Granulars & Baits By Hand Ornamentals and Gardens 0.21 (lb ai/ 1000 ft2) 1 0.21 15.5 713.8 15.2 14 Aerosol Various 0.005 (0.5 % ai in soln./ 1 pt can) 16 0.08 79.5 364.6 65.3 15 Collar Dog 0.013 (16 % ai per 1.3 oz collar) 1 0.013 10769230.8 No Data No Data 16 Sprinkler Can (Source: Scenario 6) Ornamentals (2% Soln) 0.02 (2% soln used ad libitum) 5 0.1 359.0 280000.0 358.5 TABLE 24 CARBARYL MOEs ATTRIBUTABLE TO COMBINED SHORT­ TERM HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS DERMAL MOEs INHALATION MOEs COMBINED MOEs APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 109 17 Ornamental Paint On Ornamentals (2% Soln) 0.02 (2% soln used ad libitum) 1 0.02 304.3 12323.9 297.0 3.1.4 Residential Handler Exposure and Risk Estimates for Cancer The residential handler exposure and cancer risk calculations are presented in this section. Cancer risks were calculated using a linear, low­ dose extrapolation approach (Q1*) using the same formula as described above in Section 2.1.4. In addition to the cancer risk estimates for an annual frequency of 1 time per year, the number of days of exposure per year required to get a 1x10 ­6 cancer risk have been calculated. In this calculation, the 1x10 ­6 cancer risk limit was divided by the calculated cancer risk for each scenario for a single day of exposure. Much of the process for residential uses is identical to that considered for the occupational assessment with a few notable exceptions as described above in Section 3.1.1 (e. g., all are short­ term exposures and people wear shorts and short­ sleeved shirts). The other major difference with residential risk assessments is that the annual frequency of use is lower for homeowners (i. e., 1 day use per year has been used to complete the calculations). Cancer Risk Summary All of the cancer risk calculations for residential carbaryl handlers completed in this assessment are included in Appendix G (Table 4). The specifics of this table as well as a brief summary of the results for each exposure scenario is also provided below. C Appendix G/ Table 4: Carbaryl Cancer Risks Attributable To Combined Homeowner Handler Dermal and Inhalation Exposures Presents cancer risks for combined dermal and inhalation exposures considered in the assessment (i. e., 1 time/ year). Additionally, the number of days of exposure that are allowed per year (i. e., up to a 1x10 ­6 cancer risk limit) are also presented. Table 25 presents the quantitative risks associated with each scenario considered in the assessment. For all but one scenario (i. e., treating dogs with ½ bottle of 10 percent dust), cancer risks are less than 1x10 ­6 (most are in the 10 ­8 or 10 ­10 range) when a single application per year is evaluated. This table also includes the allowable number of days exposure per year. There are 5 scenarios where 5 days or less of exposure per year is allowable. These results should be considered in conjunction with the use and usage information supplied by the Aventis Corporation that indicates the 50 th percentile annual frequency of use is between 1 and 2 uses per year and that 5 uses per year is at the 84 th percentile (see Section 3.1.2: Data and Assumptions For Handler Exposure Scenarios above). As with the noncancer risks, the use of dusts in gardens and for pet grooming along with some liquid sprays on ornamentals appear to be the most problematic scenarios. [Note: Scenarios where risks are still of concern (i. e., <1x10 ­6 ) for are highlighted in the table.] 110 TABLE 25: CARBARYL CANCER RISKS ATTRIBUTABLE TO COMBINED HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS CANCER RISK ALLOWED DAYS/ YR APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 1 Garden: Ready­ to­ Use Trigger Sprayer (MRID 444598­ 01) Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 0.25 0.00075 1.27e­ 10 >365 Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 0.5 0. 0015 2.54e­ 10 >365 Vegetables/ Ornamentals 0.003 32 oz bottle 0.126 % (769­ 977) 1 0. 003 5.08e­ 10 >365 Average Study Use Rate 0.012 (lb ai/ 1000 ft2) 1 0. 012 2.03e­ 09 >365 2 Garden/ Ornamental Dust (MRID 444598­ 01) Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 0.25 0.1 4. 81e­ 08 21 Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 0.5 0. 2 9.62e­ 08 10 Vegetables/ Ornamentals 0.4 4 lb bottle 10% (239­ 1513) 1 0. 4 1.92e­ 07 5 Average Study Use Rate 0.079 (lb ai/ 1000 ft2) 1 0. 079 3.80e­ 08 26 3 Garden: Hose­ End (MRID 444598­ 01) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 100 2 2. 11e­ 07 5 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0. 19 2. 01e­ 08 50 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0. 012 1.27e­ 09 >365 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0. 023 2.43e­ 09 >365 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0. 047 4.97e­ 09 201 Average Study Use Rate 0.26 (lb ai/ 1000 ft2) 1 0. 26 2. 75e­ 08 36 Fire Ant 0. 0075 (lb ai/ gal spray) 100 0.75 7.93e­ 08 13 4 Garden: Low Pressure Handwand (MRID 444598­ 01) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 5 0. 1 1.18e­ 08 85 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0. 19 2. 25e­ 08 45 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0. 012 1.42e­ 09 >365 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0. 023 2.72e­ 09 >365 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0. 047 5.56e­ 09 180 Average Study Use Rate 0.083 (lb ai/ 1000 ft2) 1 0. 083 9.82e­ 09 102 Fire Ant 0. 0075 (lb ai/ gal spray) 5 0. 0375 4.44e­ 09 225 5 Trees/ Ornamentals: Low Pressure Handwand (MRID 445185­ 01) Ornamental 0.023 (lb ai/ 1000 ft2) 1 0. 176 4.01e­ 09 250 Pome Fruit 0. 07 (lb ai/ 1000 ft2) 1 0. 07 1. 22e­ 08 82 Nuts/ Stone Fruit 0.12 (lb ai/ 1000 ft2) 1 0. 12 2. 09e­ 08 48 Citrus 0.176 (lb ai/ 1000 ft2) 1 0. 023 3.06e­ 08 33 Average Study Use Rate 0.0047 (lb ai/ gal, 17g ai/ 4 min at 2GPM) 5 0. 47 4. 09e­ 09 244 TABLE 25: CARBARYL CANCER RISKS ATTRIBUTABLE TO COMBINED HOMEOWNER HANDLER DERMAL AND INHALATION EXPOSURES SCEN. SCEN. DESCRIPTOR CROP TYPE OR TARGET EXPOSURE FACTORS CANCER RISK ALLOWED DAYS/ YR APPL. RATE (lb ai/ unit) BASIS FOR RATE (defines unit treated) TREATED UNITS ACTIVE USED (lb ai/ event) 111 6 Trees/ Ornamentals: Hose End Sprayer (MRID 445185­ 01) Ornamental 0.023 (lb ai/ 1000 ft2) 1 0. 176 2.79e­ 09 359 Pome Fruit 0. 07 (lb ai/ 1000 ft2) 1 0. 07 8. 49e­ 09 118 Nuts/ Stone Fruit 0.12 (lb ai/ 1000 ft2) 1 0. 12 1. 45e­ 08 69 Citrus 0.176 (lb ai/ 1000 ft2) 1 0. 023 2.13e­ 08 47 Average Study Use Rate 0.005 (lb ai/ gal spray) 100 0.025 6.06e­ 08 16 7 Garden: Backpack Sprayer (PHED) General Use (2% soln) 0.02 (lb ai/ gal spray applied) 5 0. 1 1.66e­ 09 >365 Perimeter Nuisance Pest 0.19 (lb ai/ 1000 ft2) 1 0. 19 3. 15e­ 09 317 Vegetables 0.012 (lb ai/ 1000 ft2) 1 0. 012 1.99e­ 10 >365 Vegetables/ Ornamentals 0.023 (lb ai/ 1000 ft2) 1 0. 023 3.81e­ 10 >365 Vegetables 0.047 (lb ai/ 1000 ft2) 1 0. 047 7.79e­ 10 >365 Average Study Use Rate 0.083 (lb ai/ 1000 ft2) 1 0. 083 1.38e­ 09 >365 Fire Ant 0. 0075 (lb ai/ gal spray) 5 0. 0375 6.22e­ 10 >365 8 Lawn C are: H ose E nd Sprayer (MRID 449722­ 01/ ORETF OMA 004) Lawn (broadcast) 0.25 (lb ai/ 1000 ft2) 20 5 1. 73e­ 07 6 Lawn (spot) 0. 25 (lb ai/ 1000 ft2) 1 0. 25 8. 64e­ 09 116 9 Dusting Dog (MRID 444399­ 01) Average Study Use Rate 0.0026 (lb ai/ dog) 1 0. 0026 2.82e­ 08 35 Dog (10% & 1/ 2 of 2 lb) 0.1 (lb ai/ dog) 1 0. 1 1.09e­ 06 1 Dog (5% & 1/ 2 of 2 lb) 0.05 (lb ai/ dog) 1 0. 05 5. 43e­ 07 2 10 Dogs: Liquid Application Dog (0. 5% & 1/ 2 of 6 oz) 0.001 (lb ai/ dog) 1 0. 001 3.11e­ 13 >365 11 Granular & Baits Lawn Care: Belly Grinder Lawn (spot) 0. 21 (lb ai/ 1000 ft2) 1 0. 21 7. 21e­ 08 14 Lawn (spot) 0. 1 (lb ai/ 1000 ft2) 1 0. 1 3.43e­ 08 29 12 Granular & Baits Lawn Care: Push­ Type Spreader (MRID 449722­ 01/ ORETF OMA 003) Lawn (broadcast) 0.21 (lb ai/ 1000 ft2) 20 4.2 8. 97e­ 09 112 Lawn (broadcast) 0.1 (lb ai/ 1000 ft2) 20 2 4. 27e­ 09 234 13 Granulars & Baits By Hand Ornamentals and Gardens 0.21 (lb ai/ 1000 ft2) 1 0. 21 2. 83e­ 07 4 14 Aerosol Various 0.005 (0. 5 % ai in soln./ 1 pt can) 16 0.08 5.94e­ 08 17 15 Collar Dog 0.013 (16 % ai per 1.3 oz collar) 1 0. 013 4.04e­ 13 >365 16 Sprinkler Can (Source: Scenario 6) Ornamentals (2% Soln) 0.02 (2% soln used ad libitum) 5 0. 1 1.21e­ 08 82 17 Ornamental Paint On Ornamentals (2% Soln) 0.02 (2% soln used ad libitum) 1 0. 02 1. 44e­ 08 69 112 3.1.5 Summary of Risk Concerns and Data Gaps for Handlers Generally, MOEs associated with most scenarios (40 of 52 considered) are not of concern because they exceed the Agency's uncertainty factors for noncancer risk assessments (i. e., 100 uncertainty factor). The scenarios of concern involve the use of dusts in gardens and on pets and some liquid sprays on gardens. Cancer risks for most scenarios are in the 10 ­8 to 10 ­10 range although there is one scenario where the risks slightly exceed 1x10 ­6 (dusting dogs 1.09x10 ­6 ). It should be noted that there are 5 scenarios where the allowable days per year of exposure is less than or equal to 5 which should be considered in conjunction with the use/ usage data from Aventis that indicates 5 uses per year is the 84 th percentile. The database for carbaryl is fairly complete compared to many other chemicals. Recent, high quality data generated by the Aventis Corporation and the ORETF, of which Aventis is a member, have been used to address the key residential uses of carbaryl on lawns, flower and vegetable gardens, and pets. Use and usage inputs also appear to be essentially consistent with the information provided by the Aventis Corporation at the 1998 SMART meeting. No key data gaps have been identified by the Agency at this time for residential handlers. However, it is likely that there are scenarios that remain unaddressed by the Agency at this time due to a lack of data or other meta information. The Agency will address other appropriate scenarios as they are identified. 3.1.6 Recommendations For Refining Residential Handler Risk Assessment In order to refine this residential risk assessment, more data on actual use patterns including rates, timing, and areas treated would better characterize carbaryl risks. Exposure studies for many equipment types that lack data or that are not well represented in PHED (e. g., because of low replicate numbers or data quality) should also be considered based on the data gaps identified above and based on a review of the quality of the data used in this assessment. 3.2 Residential Postapplication Exposures and Risks The Agency uses the term "postapplication" to describe exposures to individuals that occur as a result of being in an environment that has been previously treated with a pesticide. Carbaryl can be used in many areas that can be frequented by the general population including residential areas (e. g., home lawns and gardens), parks, athletic fields, and golf courses. As a result, individuals can be exposed by entering these areas if they have been previously treated. Carbaryl can also be used on companion animals which can lead to exposures by contact with the treated animal. Finally, carbaryl can also be used as a mosquito adulticide which can result in exposures to the general population because it involves wide area, ultra­ low volume spraying in residential areas. The Agency generically refers to these exposures as "residential" in nature. Another definition could be any exposures that do not occur as a result of employment or exposures to the general population. The scenarios that serve as the basis for the risk assessment are presented in Section 3.2.1: Residential Postapplication Exposure Scenarios. The exposure data and assumptions that have been used for the calculations are presented in Section 3.2.2: Data and Assumptions For Residential Postapplication Exposure Scenarios. The calculations and the algorithms that have been used for the noncancer elements of the risk assessment as well as the calculated risk values are presented in Section 3.2.3: Residential Postapplication Exposure and Noncancer Risk Estimates 113 while the analogous information using the Q1* for cancer estimates are presented in Section 3.2.4: Residential Postapplication Exposure and Risk Estimates For Cancer. Section 3.2.5: Summary of Residential Postapplication Risk Concerns and, Data Gaps presents the overall risk picture for carbaryl. Finally, recommendations are presented in Section 3.2.6: Recommendations For Refining Residential Postapplication Risk Assessment. 3.2.1 Residential Postapplication Exposure Scenarios Carbaryl uses are extremely varied and include home gardens, ornamentals, turf (golf courses and lawns) and companion animals (e. g., on dogs and cats). Carbaryl also has more limited uses that were considered including as a mosquito adulticide in residential areas and for Ghost/ Mud shrimp control in Washington. As a result, a wide array of individuals of varying ages can potentially be exposed when they do activities in areas that have been previously treated or have contact with treated companion animals. The Agency is concerned about these kinds of exposures. The purpose of this section is to explain how postapplication exposure scenarios were developed for each residential setting where carbaryl can be used. Exposure scenarios can be thought of as ways of categorizing the kinds of exposures that occur related to the use of a chemical. The use of scenarios as a basis for exposure assessment is very common as described in the U. S. EPA Guidelines For Exposure Assessment (U. S. EPA; Federal Register Volume 57, Number 104; May 29, 1992). The processes that were used by the Agency in the development of scenarios for occupational exposure assessment (Section 2.2.1 above) are essentially the same as those used for residential exposure patterns. There are key differences, however, in the residential exposure assessment that include exposures were calculated for children of differing ages as well as adults; non­ dietary ingestion exposures were calculated (i. e., soil ingestion, hand­/ object­ to­ mouth); a dermal "hug" approach has been used instead of transfer coefficients to calculate exposures to companion animals; exposures to swimmers, oyster harvesters, and children playing on a beach were calculated; and cancer risks were not calculated for children per Agency policy. The Agency relies on a standardized approach for completing residential risk assessments that is based on current carbaryl labels and guidance contained in the following five documents: ° Series 875, Residential and Residential Exposure Test Guidelines: Group B Postapplication Exposure Monitoring Test Guidelines (V 5.4, Feb. 1998) This document provides general risk assessment guidance and criteria for analysis of residue dissipation data. ° Standard Operating Procedures For Residential Exposure Assessment (Dec. 1997) This document provides the overarching guidance for developing residential risk assessments including scenario development, algorithms, and values for inputs. ° Science Advisory Council For Exposure Policy 003.1 (Aug. 2000): Agricultural Transfer Coefficients This document provides transfer coefficients which have been used to assess exposures in home gardens. 114 ° Science Advisory Council For Exposure Policy 12 (Feb. 2001): Recommended Revisions To The Standard Operating Procedures (SOPs) For Residential Exposure Assessment This document provides additional, revised guidance for completing residential exposure assessments. ° Overview of Issues Related To The Standard Operating Procedures For Residential Exposure Assessment (August 1999 Presentation To The FIFRA SAP) This document provides rationale for Agency changes in SOPs. Companion animal approach included in document used for risk assessment. The Agency also completed a specific, screening level risk assessment for Mud and Ghost shrimp control in Washington State. The assessment considering swimming in areas that have been treated as well as oyster harvesting for adults and playing on a beach for toddlers. The calculations for these scenarios were based on the Agency's SOPs described above, the Agency's program, and data generated by the Washington Department of Ecology. The specific documents that were consulted include: ° RAGS, Part A ­ Risk Assessment Guidance For Superfund, Volume 1: Human Health Evaluation Manual (Part A), Interim Final (EPA/ 540/ 1­ 89/ 002, December 1989) This document was consulted for overall guidance on how to address risks from exposure to contaminated sediments. ° RAGS, Part E ­ Risk Assessment Guidance For Superfund, Volume 1: Human Health Evaluation Manual (Part E, Supplemental Guidelines For Dermal Risk Assessment), Interim Review Draft For Public Comment (EPA/ 540/ R/ 99/ 005, September 2001) This document was consulted for overall guidance on how to address risks from exposure to contaminated sediments. Specific soil adherence values were also obtained from Exhibit 3­ 3, page 3­ 18. ° Carbaryl Concentrations In Willapa Bay and Recommendations For Water Quality Guidelines (March 2001, Pub No. 01­ 03­ 005, Author: Art Johnson) Water concentration data were obtained from this document. It presented monitoring data collected by the Washington Department of Ecology as well as data collected by the Shoalwater Bay Tribe. ° Screening Survey of Carbaryl (Sevin) and 1­ napthol Concentrations in Willapa Bay Sediments (May 1999, Pub No. 99­ 323, Author: Cynthia Stonick) Sediment and water concentration data were obtained from this document. 115 When the guidance in current labels and these documents is considered, it is clear that the Agency should consider children of differing ages as well as adults in its assessments. It is also clear that different age groups should be considered in different situations. The populations that were considered in the assessment include: C Residential (homeowner) Adults: these individuals are members of the general population that are exposed to chemicals by engaging in activities at their residences (e. g., in their lawns or gardens) and also in areas not limited to their residence (e. g., golf courses or parks) previously treated with a pesticide. These kinds of exposures are attributable to a variety of activities and usually addressed by the Agency in risk assessments by considering a representative activity as the basis for the exposure calculation. C Residential Children: children are members of the general population that can also be exposed in their residences (e. g., on lawns, in gardens, or from contact with treated pets) as well as other areas previously treated with a pesticide (e. g., parks). These kinds of exposures are attributable to a variety of activities such as playing outside, home gardening, or playing with a companion animal. Toddlers have been selected as a sentinel (or representative) population for turf and companion animal assessments. Youth­ aged children (ages 10 to 12) are considered the sentinel population for a fruit harvesting assessment because it is likely that children of this age would help with garden maintenance. They are usually addressed by the Agency in risk assessments by considering a representative activities for each age group in an exposure calculation. The SOPs For Residential Exposure Assessment define several scenarios that apply to uses specified in current labels. These scenarios served as the basis for the residential postapplication assessment along with the modifications to them and the additional data/ approaches described above. The Agency used this guidance to define the exposure scenarios that essentially include child exposure on treated lawns (dermal and nondietary ingestion considered), child exposure in treated gardens, exposure to children from treated companion animals, and the exposure of adults while doing gardening, lawncare, or golfing. The SOPs and the associated scenarios are presented below: C Dose from dermal exposure on treated turf calculated using SOP 2.2: Postapplication dermal dose among toddlers from playing on treated turf; C Dose from ingestion of carbaryl granules from treated turf calculated using SOP 2.3.1: Postapplication dose among toddlers from episodic nondietary ingestion of pesticide granules picked up from treated turf (i. e., those residues that end up in the mouth from a child touching turf and then putting their hands in their mouth); 116 C Dose from hand­ to­ mouth activity from treated turf calculated using SOP 2.3.2: Postapplication dose among toddlers from incidental nondietary ingestion of pesticide residues on treated turf from hand­ to­ mouth transfer (i. e., those residues that end up in the mouth from a child touching turf and then putting their hands in their mouth); C Dose from object­ to­ mouth activity from treated turf calculated using SOP 2.3.3: Postapplication dose among toddlers from incidental nondietary ingestion of pesticide residues on treated turf from object­ to­ mouth transfer (i. e., those residues that end up in the mouth from a child mouthing a handful of treated turf); C Dose from soil ingestion activity from treated turf calculated using SOP 2.3.4: Postapplication dose among toddlers from incidental nondietary ingestion of pesticide residues from ingesting soil in a treated turf area (i. e., those soil residues that end up in the mouth from a child touching treated soil and turf then putting their hands in their mouth); C Dose from dermal exposure while working in treated gardens or with various trees (nut, fruit, and ornamentals) calculated using SOPs 3.2 & 4.2: Postapplication dermal dose among adults and youth­ aged children (ages 10 to 12) while gardening [Note: These series of SOPs also call for addressing nondietary ingestion, these types of exposures have been included in the turf/ toddler calculations. The transfer coefficients used are from updated Agency.]; C Postapplication Potential Dose From Incidental Nondietary Ingestion if Pesticide Residues While Swimming calculated using SOP 5.2.1: Postapplication potential dose among adults while swimming ­ the general guidance applies, updates to this SOP have been completed in the form of the SWIMODEL (V2.0) which was used for this assessment; C Dose from dermal contact with treated pets calculated using SOP 9.2.1: Postapplication potential dose among toddlers from the dermal contact with a treated pet and absorption through the skin (i. e., residues that end up as body burden after deposition on and absorption through the skin); and C Dose from hand­ to­ mouth activity calculated using SOP 9.2.2: Postapplication potential dose among toddlers from nondietary ingestion of pesticide residues on treated pets from hand­ to­ mouth transfer (i. e., those residues that end up in the mouth from a child touching a pet and then putting their hands in their mouth). The detailed residential postapplication calculations are presented in Appendices H through M of this document. Please refer to them to review the specifics of the risk assessment. Appendix H contains the turf risk assessment for adults and children. Appendix I contains the risk assessment for uses in gardens and fruit trees that addresses such activities as harvesting for adults and youthaged children. Appendix J presents the risks associated with uses on pets. Appendix K provides the background information on how deposition patterns for wide area applications such as mosquito adulticides were calculated. Appendix L presents the risks that result from the use of carbaryl as a mosquito adulticide. This assessment is essentially the same as that done for turf with the addition 117 of a factor to account for the limited amount of residues that are deposited on turf because of how mosquito adulticides are applied. Appendix M presents the data and risk calculations used to address carbaryl use for Ghost and Mud Shrimp control in Washington State. 3.2.2 Data and Assumptions for Residential Postapplication Exposure Scenarios A series of assumptions and exposure factors served as the basis for completing the residential postapplication risk assessments. Each assumption and factor are detailed below. In addition to these values, a study was also submitted by the Aventis Corporation which was not used by the Agency in this assessment. The study, however, is identified below for recordkeeping purposes along with the rationale for not using it in the assessment. The assumptions and factors used in the risk calculations are consistent with current Agency policy for completing residential exposure assessments (i. e., SOPs For Residential Exposure Assessment). [Note: More detail about the origin of each factor can be obtained in the SOP document and associated documents such as the Agency's 1999 Overview document presented to the FIFRA SAP.] The values used in this assessment include: C There are many factors that are common to the occupational and residential postapplication risk assessments such as body weights for adults, analysis of residue dissipation data, and transfer coefficients used for the garden exposure scenarios. Please refer to the assumptions and factors in Section 2.1.2 for further information concerning these common values. [Note: The transfer coefficients have not been adjusted for the clothing that someone working in their home garden might be anticipated to wear such as shorts and short­ sleeved shirt.] ° Carbaryl labels allow for wide area applications in mosquito control (for adulticides) and for the control of other pest species such as black fly. When the Agency considers these use patterns in risk assessments, the amount deposited on the turf is determined by the using the AgDrift model for aerial applications (9.5 percent deposits on turf) and published data from the scientific literature for ground fogger applications (5 percent deposits on turf) as described in Appendix K. All other components are similar to a residential turf risk assessment. The Sevin XLR label for mosquito and fly control was key in defining the input parameters for the AgDrift calculations. This label specified a range of application rates from 0.016 to 1 lb ai/ acre. The label also indicated that the optimal droplet size range is from 8 to 30 µm. However, the label also had specific requirements for aerial applications for droplets "with a calculated VMD of less than 50 µm" and an allowance that "no more than 5 percent of the droplets should be larger than 80 µm." Once the deposition patterns have been defined, a turf­ type risk assessment was completed accounting for different deposition patterns, compared to a typical turf risk assessment. Different deposition patterns were accounted for in the calculation of the turf transferable residues to which adults and children are exposed. The calculations are presented in Appendix L. ° Exposure frequency values used in cancer risk assessments for adults are the same as those used for residential handlers (1 time per year). However, the Agency does believe that there 118 are higher frequency golfers (i. e., average golfers over all ages play 18 rounds year) based on a 1992 report (Golf Course Operations, Cost of Doing Business/ Profitability by the Center For Golf Course Management). The Agency also believes that individuals may reenter treated home gardens more than one time per year. However, exact information linking the timing of applications and the frequency of reentry is not available. It should be noted that this issue is being addressed by the Agency in the development of calendar­ based, residential modeling programs such as Lifeline. Therefore, until calendar­ based approaches are implemented, only single reentry events have been considered in the cancer risk assessment. Risk managers should consider the likelihood of additional reentry events when interpreting the results of the cancer risk assessment. To refine these results, the Agency has also calculated the number of exposure days allowed per year to achieve a 1x10 ­6 cancer risk ceiling just as with the residential handler assessment above. Risk managers should also consider the likelihood of intermediate­ term exposures occurring for adults. The Agency calculated intermediate­ term postapplication risks for adults yet, in reality, the population where these exposures would be expected is likely very small except for maybe home gardeners. The Agency also calculated intermediate­ term exposures for youth­ aged children and toddlers where the behaviors used as the basis for the risk assessment are thought to more likely occur on a routine basis (i. e., the population would be expected to be larger). ° The Agency combines or aggregates risks resulting from exposures to individual chemicals when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. Within a residential assessment, this can take two forms. The first is to add together risks for individual exposure scenarios from all likely sources of exposure such as after an application to turf or use on a pet. For carbaryl, the Agency has added together risk values (i. e., MOEs) for different kinds of exposures within the turf (dermal, hand­ to­ mouth, object­ to­ mouth, and soil ingestion) and pet scenarios (dermal and hand­ to­ mouth). These represent the standard set of exposures that are typically added together when chemicals are used on turf or on pets because it is logical they can co­ occur. The second is to add exposures from different residential exposure scenarios that can possibly co­ occur such as when a homeowner makes an application and then checks their garden for bugs a few hours later on the same day. Typically, the Agency only adds exposures from different exposure scenarios together (e. g., spraying and gardening) when risks from both are not already a concern. For carbaryl, however, there are risk concerns for many residential handler scenarios so the Agency did not add risk values from any postapplication exposure together with applicator risks. 119 ° The frequency of retreatment could not be determined based on information provided by the Aventis Corporation at the SMART meeting or other associated information. Labels generally specify a minimum interval of 1 week between applications. The risk assessments are based on five different residue (DFR or TTR) studies. In all studies except on olives, multiple applications were completed at 1 week intervals so any additivity between applications would also be accounted for in the empirical data used for risk assessment. C Exposures to children playing on treated turf as well as adults on turf (lawncare and golfing) have been addressed using the latest Agency approaches for this scenario including: ° 5 percent of the application rate has been used to calculate the 0­ day residue levels used for defining risks from hand­ to­ mouth behaviors, measured TTR values are not used because of differences in transferability versus what would be expected during hand­ to­ mouth behaviors; ° 20 percent of the application rate has been used to calculate the 0­ day residue levels used for defining risks from object­ to­ mouth behaviors, measured TTR values are not used because of differences in transferability versus what would be expected during hand­ to­ mouth behaviors, a higher percent transfer has been used for objectto mouth behaviors because it involves a teething action believed to be more analogous to DFR/ leaf wash sample collection where 20 percent is also used; ° the measured TTR levels quantified in MRID 451143­ 01 have been used to complete the dermal exposure calculations as the 0­ day transferability was > 1 percent of the application rate for the short­ and intermediate­ term data sources, studies where transferability is less than 1 percent are not used for risk assessment purposes because the transfer coefficients used by the Agency for defining exposures are based on Jazzercize studies in which TTR values were measured by techniques where transferability is generally in the 1 to 5 percent range other than the ORETF roller method where transferability tends to be lower; ° short­ and intermediate­ term exposures have been calculated because play and mouthing behaviors are assumed to routinely occur daily and for extended periods such as over 30 days, carbaryl residues are also expected to be present based on residue dissipation data (i. e., slow dissipation rate); ° in cases where 0 day residues have been calculated based on application rates (i. e., hand­/ object­ to­ mouth residues and for soil dissipation), dissipation over time measured in the TTR study (i. e., slope of decay curve) has been used to predict TTR and soil levels over time, carbaryl residues were detectable even at 14 days after application (i. e., final sampling interval) at all sites in the TTR studies used in this assessment, at 14 days average residues at the Georgia and Pennsylvania study sites were still orders of magnitude above the quantitation limit, this indicates that predicted residue levels for extended durations should be considered appropriate based on the empirical data (e. g., critical for consideration of intermediate­ term exposures); 120 ° the transfer coefficients used, except golfing, are those presented at the 1999 Agency presentation before the FIFRA Science Advisory Panel that have been adopted in routine practice by the Agency; ° transfer coefficients have been adjusted for differences between short­ and intermediate­ term exposures; ° adult golfers have been assessed using a transfer coefficient of 500 cm 2 /hour [Note: The Agency is currently developing a policy on golfer exposures and has used this value in other assessments]; ° 3 year old toddlers are expected to weigh 15 kg; ° hand­ to­ mouth exposures are based on a frequency of 20 events/ hour and a surface area per event of 20 cm 2 representing the palmar surfaces of three fingers; ° saliva extraction efficiency is 50 percent meaning that every time the hand goes in the mouth approximately ½ of the residues on the hand are removed; ° object­ to­ mouth exposures are based on a 25 cm 2 surface area; ° exposure durations are expected to be 2 hours based on information in the Agency's Exposure Factors Handbook except for golfers where the exposure duration for an 18 hole round of golf is 4 hours based on a 1992 report (Golf Course Operations, Cost of Doing Business/ Profitability by the Center For Golf Course Management); ° soil residues are contained in the top centimeter and soil density is 0.67 mL/ gram; ° dermal, hand­ and object­ to­ mouth, and soil ingestion are added together to represent an overall risk from exposure to turf while granular ingestion is considered to be a much more episodic behavior and is considered separately by the Agency; and ° children of various ages down to the very young (e. g., 4 or 5 years old) are currently playing golf, the Agency recognizes that age may impact exposures because of changes in behavior and skin surface area to body weight ratios but has not yet developed a quantitative approach for calculating their risks. C Exposures to children and adults working in home gardens have been addressed using the latest Agency approaches for this scenario including: ° youth­ aged children are considered along with adults; ° 12 year old youth are expected to weigh 39.1 kg; ° exposure durations are expected to be 40 minutes; ° Pre­ Harvest Intervals (PHIs) are less than 7 days for most crops with some as long as 28 days; ° transfer coefficients for youth were calculated by adjusting the appropriate adult transfer coefficients by a 50% factor as has been done by the Agency since the inception of the SOPs For Residential Exposure Assessment; ° the updated transfer coefficients specified in Agency policy 003 described above in the occupational risk assessment have been used rather than those currently specified in the SOPs because they represent more refined estimates of exposure for the fruiting vegetable and deciduous tree crop groups, these crop groups have been used in the SOPs to represent home garden exposures; 121 ° the combination of adjusting transfer coefficients for youth­ aged children and using appropriate body weights for the age group results in dose levels that are slightly lower than that of adults in the same activity (the TC reduction and body weight reduction is essentially a 1: 1 ratio); and ° the DFR data used for the assessments are the same as those used in the occupational risk assessment for the selected crop groups. C Exposures to children after contact with treated pets have been addressed using the latest Agency approaches for this scenario including: ° only toddlers are considered because their exposures are thought to be highest (i. e., they are considered the sentinel population by the Agency); ° a equilibrium approach based on a single child "hug" of the treated animal is used to assess dermal exposure as described in the 1999 Agency SAP Overview document (i. e., the skin loads after a single contact with the treated animal and additional contacts don't proportionally add exposures), the surface area of the dermal hug is based on a toddler skin surface area and typical clothing; ° residue dissipation is 5 percent per day for the shampoo and dust products (based on data from J. Chambers at Mississippi State University on other pet use products); ° the transferability of residues from fur is 20 percent; ° the active lifetime of a collar is expected to be 120 days based on label statements which was used by the Agency, a daily emission term from the collar of 0.000290 mg/ cm 2 /gram ai/ day is also based on measured data from Mississippi State University for a pet collar; ° risks are based on an even loading of residues across the entire surface of a 30 lb dog which has been chosen as a representative animal, the animal surface area was calculated using (12.3 * Body Weight (g) 0.65 ) from the Agency's 1993 Wildlife Exposure Factors Handbook (i. e., dog surface area of 5986 cm 2 ); ° the daily frequency of hand­ to­ mouth contact with dogs is 40 events per day, in each event, the palmar surface of the hands (i. e., 20cm 2 /event) is placed in the mouth of the child contributing to nondietary ingestion exposure; and ° the Agency is currently in the process of considering revisions in its methodologies for completing risk assessments for pet products, some of the key inputs that are potentially subject to modification include the amount of residues which are transferable from pet fur, defining the number of hand­ to­ mouth events, and evaluating the emission term for collars. ° For turf, the maximum application rate indicated at the SMART meeting was 8 lb ai/ acre even though current labels allow for applications by homeowners at up to 11 lb ai/ acre for Lock­ n­ load type packages and 9 lb ai/ acre for granulars. The TTR study was conducted also, it should be noted, at 8 lb ai/ acre (see below for more details). Based on the design of the TTR study and what was indicated at the SMART meeting, the Agency completed the postapplication assessment using the data directly from the TTR study without any adjustment for application rate. Risks at higher application rates would be worse than those presented at the 8 lb ai/ A application rate (see below). ° For pet uses, the Agency is considering modifications in its pet risk assessment methods. 122 These revisions are based on the availability and interpretation of data from academic researchers and the pesticide industry. These data will be used to refine and better characterize risks associated with uses on pets as they become available. C Postapplication residential risks are based generally on maximum application rates or values specified in the SOPs For Residential Exposure Assessment. C The Jazzercise approach is the basis for the dermal transfer coefficients as described in the Agency's Series 875 guidelines, SOPs For Residential Exposure Assessment, and the 1999 FIFRA SAP Overview document C There are many likely studies focused on carbaryl in the published literature or available from various governmental Agencies because it is so widely used. For example, the Agency's Office of Research and Development along with other Agencies have funded a project entitled Pesticide Exposure in Children Living in Agricultural Areas along the United States­ Mexico Border Yuma County, Arizona. Preliminary results of this study indicate that carbaryl residues were identified in the dust of 20 percent of the 152 houses sampled and in approximately 24 percent in 25 samples collected in 6 schools in the same region. At this point, the Agency has not identified any data from the literature or other sources that would alter the conclusions of this risk assessment. As more data become available, the Agency will consider the information in efforts to refine the assessment (i. e., use additional information to alter numeric risk estimates or to characterize existing estimates if warranted). With regard to this specific example, current Agency policy is not to use house dust estimates to calculate risks because of a lack of an appropriate exposure model. Also, in a 1995 study conducted by the Centers For Disease Control (Hill et al) entitled Pesticide Residues In Urine Of Adults Living In The United States: Reference Range Concentrations, 1000 adults were monitored via urine collection. One of the analytes measured in that study (1­ napthol) is a potential metabolite of carbaryl as well as of napthalene and napropamide. This metabolite was identified in 86 percent of the 1000 adults monitored where the mean value was 17 ppb and the 99 th percentile was 290 ppb. These values were not used quantitatively in the risk assessment for carbaryl because of the uncertainties associated with them such as the exact contribution of each possible compound to the overall levels and no linked exposure information. The investigators also reported results for (2­ napthol) which is also a metabolite of napthalene and indicated a common source of exposure because 1­ napthol and 2­ napthol levels were similar based on a Pearson correlation of 0.64 (P= 0.0001). The mean for 2­ napthol is 7.2 ppb and the 99 th percentile was 54 ppb. These levels were The Agency instead considers them a qualitative indicator that exposures in the general population are likely to occur. C The Aventis Corporation is in the process of conducting a biomonitoring study with children who live in households where carbaryl has been used. Preliminary results indicate that levels at the highest percentiles of the distribution are similar to those predicted in the Agency's turf risk assessments for toddlers which are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission. Aventis is also a member of the Residential Exposure Joint Venture where the 123 objective is to collect use data for consumer products containing pesticides. These data will also be considered if submitted to the Agency. C In Washington state, carbaryl is used under a 24C label (WA­ 900013) to control Ghost and Mud shrimp in Willapa Bay. The Agency considered contact with sediments (e. g., oyster digging for adults and playing on beach for toddlers) and water (adult swimming) that could contain carbaryl residues using commonly accepted risk assessment methods (i. e., RAGS Superfund Guidance and SWIMODEL (V2.0)), water monitoring data, and sediment data. In these assessments, conservative inputs for sediment and water concentrations were used and also conservative exposure factors were used to ensure the screening level nature of the calculations. Such inputs included selection of the highest water concentration estimate from all available data sources for swimmers and highest sediment concentrations for oyster digging or children playing. Other conservative inputs included the permeation coefficient from the SWIMODEL, the use of a 90 th percentile value for the duration of swimming for a noncompetitive swimmer of 3 hours (which would be expected to be conservative in the areas where this use occurs), and the entire surface area of a toddler used for playing on a beach. [Note: The water and sediment concentration data have been reviewed by the Agency's Environmental Fate and Effects Division (D279109, Thomas Steeger ­ author).] Postapplication Study: One study, conducted by the Aventis Corporation, which measured concurrent dermal exposure using Jazzercize and turf transferable residues of Ronstar 50WP (oxadiazon) was submitted for use in the risk assessment. The use of this study was not accepted because it is very specific to the use of oxadiazon on turf. In particular, the study was conducted on a dormant grass and the transfer coefficients differ from those currently used in standard Agency risk assessments. In fact, the ORETF, of which Aventis is a member, considered this study for purchase and use in its generic approach to dermal exposures on turf. Based on essentially the same reasons as the Agency has used, the study was not purchased. For clarification purposes, the following information can be used to identify the study: C Evaluation of Turf Reentry Exposure To a Broadcast Application of Ronstar 50WP EPA MRID 447425­ 01; Report dated January 18, 1995; Authors: Leah Rosenheck and Shirley Sanchez; Sponsor: Aventis Corporation (formerly Rhone Poulenc). 3.2.3 Residential Postapplication Exposure and Noncancer Risk Estimates The residential postapplication exposure and non­ cancer risk calculations are presented in this section. Noncancer risks were calculated using the Margin of Exposure (MOE) which is a ratio of the body burden to the toxicological endpoint of concern. Exposures were calculated by considering the potential sources of exposure (i. e., DFRs on garden plants, TTRs on lawns, and transferable residues on treated pets) then calculating dermal and nondietary ingestion exposures. The major difference with residential risk assessments is that the uncertainty factor which defines the level of risk concern also has to consider application of the additional FQPA safety factor specified by the legislation. In the case of carbaryl, in January and February 2002 meetings of the FQPA Safety Factor Committee, it was decided that the FQPA factor should be reduced to 1. Therefore, the overall uncertainty factor applied to carbaryl for residential postapplication risk 124 assessments is 100 which is based on the FQPA safety factor of 1 along with the 100 applied for inter­ species extrapolation, intra­ species sensitivity, and the use of a NOAEL for risk assessment. Dermal exposures and risks from lawn and garden uses were calculated in the same manner as described above in Section 2.2.3. Dermal exposures from treated pets were calculated using a slightly different approach where a "hug" contact is expected to lead to an equilibrium concentration on the skin of the affected individual. Exposures to sediment and water while swimming were calculated using a soil adherence approach analogous to that used in Superfund risk assessments and swimmer exposures were calculated using the SWIMODEL which has been validated and also brought before the FIFRA SAP. Along with calculating these dermal exposures, other aspects of the turf, treated pet, and sediment exposure scenarios involved calculating dose from non­ dietary ingestion. The algorithms used for each type of calculation are presented below which have not been previously addressed in Section 2.2.3. Nondietary Ingestion Exposure From Treated Turf: Nondietary ingestion exposure levels from turf were calculated using the following equations. These values were then used to calculate MOEs as illustrated above. The following illustrates the approach used to calculate the nondietary ingestion exposures that are attributable to hand­ to­ mouth behavior on treated turf (SOP 2.3.2): where: D = dose from hand­ to­ mouth activity (mg/ day); TTR = Turf Transferable Residue where dissipation is based on TTR study and the 0­ day value is based on the 5% initial transferability factor (µg/ cm 2 ); SE = saliva extraction factor (%); SA = surface area of the hands (cm 2 ); Freq = frequency of hand­ to­ mouth events (events/ hour); and Hr = exposure duration (hours). The following illustrates the approach used to calculate exposures that are attributable to object­ to­ mouth behavior on treated turf that is represented by a child mouthing on a handful of turf (SOP 2.3.3): where: D = dose from mouthing activity (mg/ day); TTR = Turf Transferable Residue where dissipation is based on TTR study and the 0­ day value is based on the 20% initial transferability factor (µg/ cm 2 ); and IgR = ingestion rate for mouthing of grass per day (cm 2 /day). The following illustrates the basics of the approach, used to calculate exposures that are attributable to soil ingestion (SOP 2.3.4): 125 where: D = dose from soil ingestion activity (mg/ day); SR = Soil Residue where dissipation is based on TTR study and the 0­ day value is based on the application rate, 1 cm depth of surface soil, and the density of soil (µg/ cm 3 ); and IgR = ingestion rate for daily soil ingestion (mg/ day). Dermal Exposure From Treated Pets: Dermal exposure from treated pets was calculated using the following equation. These values were then used to calculate MOEs as illustrated above. This approach is based on the Agency presentation at the 1999 FIFRA Science Advisory Panel and is detailed in the accompanying overview document. where: D = dose from dermal pet contact (mg/ day); AR = application rate or amount applied to animal in a single treatment (mg ai/ animal); FAR = fraction of the application rate available for dermal contact as transferable residue (%/ 100); SApet = surface area of a treated dog (cm 2 /animal); t = time after application (days); DR = fractional dissipation rate per day (% per day/ 100); and SA hug = surface area of a child hug (cm 2 contact/ hug). [Note: For collars, the (( AR/ FAR)/ SApet) term is replaced with a measured emission term of 0.00029 mg/ cm 2 /gram ai in collar/ day which is then multiplied by the amount of active ingredient in the collar to calculate risks.] Nondietary Exposure From Treated Pets: Nondietary exposure from treated pets was calculated using the following equation (SOP 9.2.2). This exposure pathway occurs when children touch animals then put their hands in their mouths. These values were then used to calculate MOEs as illustrated above. 126 where: D = nondietary ingestion dose from with treated pets (mg/ day); AR = application rate or amount applied to animal in a single treatment (mg ai/ animal); FAR = fraction of the application rate available for dermal contact as transferable residue (%/ 100); SApet = surface area of a treated dog (cm 2 /animal); t = time after application (days); DR = fractional dissipation rate per day (% per day/ 100); SAL = saliva extraction factor (% extractability); SAhands = surface area of the hands (cm 2 ); Freq = frequency of hand­ to­ mouth events (events/ day). [Note: Collar emissions are defined as described above for dermal exposures.] Mosquito Control Applications: Mosquito control and other uses (e. g., black fly treatments) have been addressed using a methodology that involves defining how much material is deposited on the ground in impacted areas then using the same methodology that is used for a turf risk assessment. The calculations for defining how much deposited on the ground after such applications involved published literature for ground­ based techniques and the AgDrift model for aerial application methods (see Appendix K for further information). See above for turf risk assessment calculations. Ghost and Mud Shrimp 24C Applications: Applications to Willapa Bay in Washington state have been addressed using the SWIMODEL and guidance from RAGS. The SWIMODEL provides exposure rates (mg/ day) from several routes of exposure. Dermal exposures were separated out to apply the NOAEL from the 21 day dermal rat study (i. e., 20 mg/ kg/ day) using a simple proportion. All other calculations were similar to other scenarios for MOEs and dose. Sediment exposures included a dermal component for adults and toddlers and a hand­ tomouth component for toddlers. Dermal exposures to sediments were calculated using the following: where: D = potential dose from dermal sediment contact (mg/ kg/ day); Sed = concentration of carbaryl in sediment (µg/ kg or ppb), varies over time with concentration data obtained from WA state reports and linear extrapolation between Day 2 and Day 30 data; Adh = soil adherence factor (mg/ cm 2 ); SA = surface area of the body parts contacted (cm 2 ); and BW = body weight (kg). 127 Nondietary ingestion exposures that are attributable to hand­ to­ mouth behavior for toddlers on beaches were calculated as follows: where: D = dose from hand­ to­ mouth activity (mg/ kg/ day); Sed = concentration of carbaryl in sediment (µg/ kg or ppb), varies over time with concentration data obtained from WA state reports and linear extrapolation between Day 2 and Day 30 data; SE = saliva extraction factor (%); SA = surface area of the hands (cm 2 ); Adh = soil adherence factor (mg/ cm 2 ); and BW = body weight (kg). Noncancer Risk Summary: All of the noncancer risk calculations for the various residential carbaryl assessments are included in Appendices H, I, J, K, L and M for the turf, home garden, pet, mosquito control and oyster bed scenarios, respectively. [Note: Both Appendices K and L pertain to mosquito control.] The specifics of each of table included in these Appendices are described below. A summary of the results for each scenario considered for each timeframe is also provided below. C Appendix H/ Table 1 : Carbaryl Postapplication Residential Turf Risk Assessment Inputs Contains each numerical input utilized in the calculation of the residential postapplication risk values. C Appendix H/ Table 2 : Residue Levels Used For Carbaryl Residential Risk Assessment On Turf Presents the turf transferable residue values used for the dermal, hand­ to­ mouth, object­ to­ mouth, and soil ingestion risk assessments. Includes daily values which have been used for short­ term exposures and 30 day average values which have been used for intermediate­ term exposures. C Appendix H/ Table 3: Adult Noncancer Risk Values For Carbaryl Residential Risk Assessment on Turf Presents the risks for short­ term and intermediate­ term adult dermal exposures in on turf while engaged in high contact activity such as heavy lawncare (" On Residential Turf") or while playing golf on a treated course. C Appendix H/ Table 5: Toddler Dermal Risk Values For Carbaryl on Turf Presents the risks for short­ term and intermediate­ term toddler dermal exposures in on turf while engaged in high contact activity. C Appendix H/ Table 6: Toddler Hand­ to­ Mouth Risk Values For Carbaryl on Turf Presents the risks for short­ term and intermediate­ term toddler hand­ to­ mouth exposures in on turf while engaged in high contact activity. C Appendix H/ Table 7: Toddler Object­ to­ Mouth Risk Values For Carbaryl on Turf 128 Presents the risks for short­ term and intermediate­ term toddler object­ to­ mouth exposures in on turf while engaged in high contact activity. ° Appendix H/ Table 8: Toddler Soil Ingestion Risk Values For Carbaryl on Turf Presents the risks for short­ term and intermediate­ term toddler soil ingestion exposures in on turf while engaged in high contact activity. ° Appendix H/ Table 9: Toddler Aggregate Risk Values For Carbaryl on Turf Presents the risks for short­ term and intermediate­ term toddler aggregate exposures in on turf while engaged in high contact activity. C Appendix I/ Table 1: Carbaryl Postapplication Residential Garden and Tree Use Risk Assessment Inputs Presents the numerical unit exposure values and other factors used in the tree and garden postapplication risk assessments. C Appendix I/ Table 2: Carbaryl Residential Postapplication Adult Risk Assessment For Deciduous Tree Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix I/ Table 4: Carbaryl Residential Postapplication Youth Risk Assessment For Deciduous Tree Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix I/ Table 5: Carbaryl Residential Postapplication Adult Risk Assessment For Fruiting vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix I/ Table 7: Carbaryl Residential Postapplication Youth Risk Assessment For Fruiting vegetable Crop Group Risk values are presented for each exposure duration considered in the assessment (i. e., short­ term and intermediate­ term duration exposures, respectively). C Appendix J/ Table 1: Carbaryl Residential Pet Risk Assessment For Toddlers Presents the risks for short­ term and intermediate­ term toddler exposure after contact with treated pets. C Appendix K: Determination of Deposition Factors For Carbaryl Mosquito Control Uses Presents the calculations and the data used to determine the amount of residues deposited in treated residential areas after mosquito control applications by air and ground. C Appendix L/ Table 1 : Carbaryl Postapplication Residential Mosquito Control Risk 129 Assessment Inputs Contains each numerical input utilized in the calculation of the residential mosquito control postapplication risk values. C Appendix L/ Table 2 : Residue Levels Used For Carbaryl Residential Risk Assessment On Turf After Aerial Mosquito Control Application Presents the turf transferable residue values used for the dermal, hand­ to­ mouth, object­ to­ mouth, and soil ingestion risk assessments. Includes daily values which have been used for short­ term exposures and 30 day average values which have been used for intermediate­ term exposures. These values have been adjusted for deposition from ULV aerial application. C Appendix L/ Table 3 : Residue Levels Used For Carbaryl Residential Risk Assessment On Turf After Ground Mosquito Control Application Presents the turf transferable residue values used for the dermal, hand­ to­ mouth, object­ to­ mouth, and soil ingestion risk assessments. Includes daily values which have been used for short­ term exposures and 30 day average values which have been used for intermediate­ term exposures. These values have been adjusted for deposition from ULV ground application. C Appendix L/ Table 4: Adult Noncancer Risk Values For Carbaryl Residential Risk Assessment on Turf After Aerial Mosquito Control Application Presents the risks for short­ term and intermediate­ term adult dermal exposures in on turf while engaged in high contact activity such as heavy lawncare (" On Residential Turf") or while playing golf on a treated course after the area has been treated for mosquito control using aerial equipment. C Appendix L/ Table 5: Adult Noncancer Risk Values For Carbaryl Residential Risk Assessment on Turf After Ground Mosquito Control Application Presents the risks for short­ term and intermediate­ term adult dermal exposures in on turf while engaged in high contact activity such as heavy lawncare (" On Residential Turf") or while playing golf on a treated course after the area has been treated for mosquito control using ground equipment. C Appendix L/ Table 8: Toddler Dermal Risk Values For Carbaryl on Turf After Aerial Mosquito Control Application Presents the risks for short­ term and intermediate­ term toddler dermal exposures on turf while engaged in high contact activity after the area has been treated for mosquito control using aerial equipment. C Appendix L/ Table 9: Toddler Dermal Risk Values For Carbaryl on Turf After Ground Mosquito Control Application Presents the risks for short­ term and intermediate­ term toddler dermal exposures on turf while engaged in high contact activity after the area has been treated for mosquito control using ground equipment. 130 C Appendix L/ Table 10: Toddler Hand­ to­ Mouth Risk Values For Carbaryl on Turf After Aerial Mosquito Control Application Presents the risks for short­ term and intermediate­ term toddler hand­ to­ mouth exposures in on turf while engaged in high contact activity after the area has been treated for mosquito control using aerial equipment. C Appendix L/ Table 11: Toddler Hand­ to­ Mouth Risk Values For Carbaryl on Turf After Ground Mosquito Control Application Presents the risks for short­ term and intermediate­ term toddler hand­ to­ mouth exposures in on turf while engaged in high contact activity after the area has been treated for mosquito control using ground equipment. C Appendix L/ Table 12: Toddler Object­ to­ Mouth Risk Values For Carbaryl on Turf After Aerial Mosquito Control Application Presents the risks for short­ term and intermediate­ term toddler object­ to­ mouth exposures in on turf while engaged in high contact activity after the area has been treated for mosquito control using aerial equipment. C Appendix L/ Table 13: Toddler Object­ to­ Mouth Risk Values For Carbaryl on Turf After Ground Mosquito Control Application Presents the risks for short­ term and intermediate­ term toddler object­ to­ mouth exposures in on turf while engaged in high contact activity after the area has been treated for mosquito control using ground equipment. ° Appendix L/ Table 14: Toddler Soil Ingestion Risk Values For Carbaryl on Turf After Aerial Mosquito Control Application Presents the risks for short­ term and intermediateterm toddler soil ingestion exposures in on turf while engaged in high contact activity after the area has been treated for mosquito control using aerial equipment. ° Appendix L/ Table 15: Toddler Soil Ingestion Risk Values For Carbaryl on Turf After Ground Mosquito Control Application Presents the risks for short­ term and intermediateterm toddler soil ingestion exposures in on turf while engaged in high contact activity after the area has been treated for mosquito control using ground equipment. ° Appendix L/ Table 16: Toddler Aggregate Risk Values For Carbaryl on Turf After Aerial Mosquito Control Application Presents the risks for short­ term and intermediateterm toddler aggregate exposures in on turf while engaged in high contact activity after the area has been treated for mosquito control using aerial equipment. ° Appendix L/ Table 17: Toddler Aggregate Risk Values For Carbaryl on Turf After Ground Mosquito Control Application Presents the risks for short­ term and intermediate­ term toddler aggregate exposures in on turf while engaged in high contact activity after the area has been treated for mosquito control using ground equipment. ° Appendix M/ Table 1: Summary of Carbaryl Data From Ecology's Post­ Spray Samples (July 31 ­August 4, 2000) Presents summary water data for monitoring conducted by the Washington State Department of Ecology in Willapa Bay during 2000. 131 ° Appendix M/ Table 2: Summary of Carbaryl Data From Shoalwater Bay Tribe (July 17 & 19, 2000) Presents summary water data for monitoring conducted by the Shoalwater Bay Indian Tribe in Willapa Bay during 2000. [Note: These data were used as summarized from 2001 Washington State Dept of Ecology Report.] ° Appendix M/ Table 3: Carbaryl and 1­ napthol Concentrations In Willapa Bay PostSpray Sediment Presents summary sediment data for monitoring conducted by the Washington State Department of Ecology in Willapa Bay during 1999. ° Appendix M/ Table 4: Carbaryl Concentrations In Day 60 Willapa Bay Pore Water Presents summary water data for monitoring conducted 60 days after spraying by the Washington State Department of Ecology in Willapa Bay during 1999. [Note: Samples were collected in this study at 2 and 30 days after sampling which were not reported due to analytical problems.] ° Appendix M/ Table 5: Carbaryl Oyster Harvest/ Beach Play Risk Assessment For Adults and Toddlers Presents noncancer and cancer risk estimates for adults and toddlers while oyster harvesting or playing on a beach. This assessment is based on dermal contact with contaminated sediment and hand­ to­ mouth behavior for toddlers. The highest sediment concentration detected in any data available to the Agency was used to assure screening level nature of assessment. ° Appendix M/ Table 6: Carbaryl Oyster Harvest/ Beach Play Risk Assessment For Adults and Toddlers Presents noncancer and cancer risk estimates for adults if they were to swim in Willapa Bay. All calculations were completed with the Agency's SWIMODEL (V2.0). Results and model inputs are included in this table. The Agency has addressed residential postapplication exposures to carbaryl using the standard set of scenarios that are prescribed in current guidance. There are many issues associated with the development of these scenarios and, in general, residential exposure methods. Readers should refer to the guidance documents that are presented above for further information concerning the development of scenarios for residential exposure assessment purposes. The uncertainty factors are similar to those applied to the residential handler assessments described above (i. e., 100 for both short­ term and intermediate­ term exposures). Risk Summary: Adult Short­ term MOEs only for lawncare (i. e., heavy yardwork) exceed the Agency's level of concern on the day of application (i. e., 43 to 88). For this activity, it takes 1 and 5 days, respectively at the 4 and 8 lb ai/ acre application rates, for residues to dissipate to a point where short­ term MOEs are $ 100. In all other scenarios considered, short­ term MOEs are $ 100 on the day of application. These other scenarios include vegetable gardening, golfing, tending fruit trees. More localized exposures that occur after mosquito control or from exposures associated with oyster bed treatments are also included. Intermediate­ term MOEs were calculated using 30 day average exposures and the dissipation rate for carbaryl. In all cases, intermediate­ term MOEs are 132 $ 100. Table 26 presents the postapplication MOE values calculated for adults after lawn and home garden applications of carbaryl. Table 26: Summary of Carbaryl Noncancer Postapplication Residential MOEs For Adults Scenario Descriptor Results Short­ term MOE on Day 0 Days Short­ term MOE UF Intermediateterm MOE Residential Turf (Lawncare) Max Rate at 4 lb ai/ A 88 1 842 Max Rate at 8 lb ai/ A 43 5 412 Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 3700­ 231268 0 35463­ 2216454 Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 7031­ 439409 0 67380­ 4211262 Golfing Max Rate at 4 lb ai/ A 1274 0 12297 Max Rate at 8 lb ai/ A 624 0 6021 Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 53654­ 3353387 0 517764­ 32360224 Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 101943­ 6371435 0 983751­ 61484426 Home Garden (Deciduous Tree) Very Low Exposure (propping) 17373 0 53139 Low Exposure (irrigation, scout, weed) 1737 0 5314 High Exposure (harvest, prune, train, tie, thin) 579 0 1771 Home Garden (Fruiting Vegetable) Low Exposure (irrigation, scout, thin, weed) 1758 0 9468 Medium Exposure (irrigation, scout) 1256 0 6763 High Exposure (harvest, prune, stake, tie) 879 0 4734 Oyster Beds Oyster Harvest 967137 0 2680745 Swimming 293651 0 No Data 133 Youth­ aged children (10 to 12 years old) were only considered in the home garden scenarios per Agency guidance. Short­ term MOEs for these children were similar to those calculated for adults in that they were $ 100 for all of the gardening scenarios considered. Intermediate­ term MOEs were calculated using 30 day average exposures and the dissipation rate for carbaryl. In all cases, intermediate­ term MOEs are $ 100. Table 27 below summarizes the postapplication MOE values calculated for youth home garden applications of carbaryl. Table 27: Summary of Carbaryl Noncancer Postapplication Residential MOEs For Youth­ Aged Children Scenario Descriptor Results Short­ term MOE on Day 0 Days Short­ term MOE UF Intermediateterm MOE Home Garden (Deciduous Tree) Very Low Exposure (propping) 19408 0 59364 Low Exposure (irrigation, scout, weed) 1941 0 5936 High Exposure (harvest, prune, train, tie, thin) 647 0 1979 Home Garden (Fruiting Vegetable) Low Exposure (irrigation, scout, thin, weed) 1964 0 10577 Medium Exposure (irrigation, scout) 1403 0 7555 High Exposure (harvest, prune, stake, tie) 982 0 5289 Toddler (3 year old) MOEs were calculated for the lawncare and pet uses of carbaryl. Table 28 presents a summary of the MOE estimates for toddlers. Exposures were also addressed that resulted from residential application of carbaryl as a mosquito adulticide. Toddler MOEs from treated turf were calculated at the lower and upper ends of the maximum application rate range (i. e., different maximum rates of 4 to 8 lb ai/ acre were specified for different pests). A range of application rates were also considered for the mosquito control uses. Short­ term MOEs from exposure to treated turf (in products labeled for direct application to turf) were <100 on the day of application for both rates considered (i. e., 4 and 8 lb ai/ acre). In fact, short­ term MOEs from individual pathways were not $ 100 for any turf scenario considered on the day of application except for the soil ingestion component of the turf assessment which is a very minor contributor to overall exposures. As a reminder, dermal, hand­ to­ mouth, and object­ to­ mouth exposure pathways were also considered. Total short­ term MOEs (all pathways) were $ 100 at the lower 4 lb ai/ acre application rate 14 days after application and 18 days at the higher 8 lb ai/ acre application rate. Dermal and hand­ to­ mouth exposures were the key contributors while soil ingestion was a minor contributor to the total MOE estimates. See Appendix H for more detailed information on how each exposure pathway contributed to the overall exposures. Intermediate­ term MOEs were calculated using 30 day average exposures and the dissipation rate for carbaryl. For 134 both rates, intermediate­ term MOEs were <100. Exposures to toddlers were also considered after application of carbaryl as a mosquito adulticide. Regardless of how applications are made (i. e., by ground or air), both short­ term MOEs on the day of application and intermediate­ term MOEs were $ 100. See Appendix L for more detailed information on how each exposure pathway contributed to the overall exposures. Ingestion of carbaryl granules is also a potential source of exposure because children can eat them if they are found in treated lawns or gardens. This scenario is considered an episodic scenario by the Agency (i. e., acute dietary endpoints are always used). The concentration of carbaryl in granular products ranges generally from 2 to 10 percent. If this information is coupled with the body weight of a toddler (15 kg), the endpoint of 1 mg/ kg/ day for short­ term assessments (which is also the same value used for the APAD), and the uncertainty factor of 100 the amount of formulation that can be consumed at the uncertainty factor MOE level can be calculated. The Agency generally presents these results based on the number of carbaryl granules that can be ingested. However, the number of homeowner formulations is extensive and impossible to characterize in that much detail so a general weight estimate is presented. If a 2 percent formulation is ingested, 7.5 mg represents exposure at an MOE of 100 (i. e., 1.6 x 10 ­5 lb). If a 10 percent formulation is ingested, 1.5 mg represents exposure at an MOE of 100 (i. e., 3.3 x 10 ­6 lb). For illustrative purposes, if one considers a 2 percent formulation and the density of soil (0.67 mL/ gram, many granulars are clay based), only 0.005 mL of formulation would need to be ingested to have a risk concern (i. e., 7.5 mg * 1g/ 1000mg * 0.67 mL/ gram). Note that this volume is orders of magnitude less than a teaspoon of granular formulation (i. e., 0.1% of a teaspoon where a tsp. = 5 mL). The assessments for pet uses considered dermal and nondietary ingestion exposures and also calculated total MOEs. Short­ term MOEs for pet uses were <100 even 30 days after application regardless of whether the formulation used was a dust, liquid or collar. This trend was observed for each separate exposure pathway as well as the total MOE estimates. Hand­ to­ mouth and dermal exposures are approximately equal contributors to the overall estimates for each product type. The results are similar for the intermediate­ term MOEs for each scenario. There is one pet use which is also considered to be a chronic exposure by the Agency. Pet collars are assumed to be worn all of the time so chronic exposure can potentially occur. The chronic MOE for pet collars mirrors the short­ and intermediate­ term results. See Appendix J for more detailed information on how each exposure pathway contributed to the overall exposures. The assessments for beach play for toddlers after oyster bed treatement considered dermal and nondietary ingestion exposures and also calculated total MOEs. Short­ term MOEs were >100 even if the highest monitored sediment concentration value from any study available to the Agency was used as the basis for the calculations. The intermediate­ term results were similar. See Appendix M for more information on how each pathway contributed to the overall exposures. 135 Table 28: Summary of Carbaryl Noncancer Postapplication Residential Aggregate MOEs For Toddlers Scenario Descriptor Results Short­ term MOE on Day 0 Days For Short­ term MOE UF Intermediateterm MOE Chronic MOE Pet Treatments Liquids 2.0 +30 4 NA Dusts 0. 02 +30 0.04 NA Collars 18 +30 18 43 Residential Turf (High Activity) Max Rate at 4 lb ai/ A 11 14 91 NA Max Rate at 8 lb ai/ A 5 18 45 NA Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 448­ 27983 0 3826­ 239095 NA Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 851­ 53167 0 7269­ 454280 NA Oyster Beds Beach Play 29532 0 81859 NA 3.2.4 Residential Postapplication Exposure and Risk Estimates for Cancer The residential postapplication exposure and cancer risk calculations are presented in this section. Cancer risks were calculated using a linear low­ dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated and then compared with a Q1* that has been calculated for carbaryl based on dose response data in the appropriate toxicology study (Q1* = 8.75 x 10 ­4 (mg/ kg/ day) ­1 ). Absorbed average daily dose (ADD) levels were used as the basis for calculating the LADD values. Section 2.1.3 above describes how the ADD values were first calculated for the noncancer MOE calculations. These values also serve as the basis for the cancer risk estimates. Dermal and inhalation ADD values were first added together to obtain combined ADD values. LADD values were then calculated and compared the Q1* to obtain cancer risk estimates. LADD and Cancer Risk Calculations: The use of dissipation data and the manner in which daily postapplication dermal exposure values were calculated were inherently different than with handler exposures. Once daily exposure values were determined, the calculation of LADD (Lifetime Average Daily Dose) and the resulting cancer risks use the same algorithms that were described above for the handler exposures (See Section 2.1.4). As mentioned previously, the Agency has defined a range of acceptable cancer risks based on a policy issued in 1996. This memo refers to a predetermined quantified "level of concern" for residential carcinogenic risk. In summary, residential carcinogenic risks that are 1 x 10 ­6 or lower require no risk management action. In addition to the cancer risk estimates for an annual frequency of 1 time per year, the number of days of exposure per year required to get a 1x10 ­6 cancer risk have 136 been calculated. In this calculation, the 1x10 ­6 cancer risk limit was divided by the calculated cancer risk for each scenario for a single day of exposure. This calculation would only be completed for situations where the cancer risks were less than 1x10 ­6 on the day of application. Cancer Risk Summary All of the cancer risk calculations for the various residential carbaryl assessments are included in Appendices H, I, L and M for the turf, home garden, mosquito adulticide, and oyster treatment scenarios, respectively. The specifics of each of table included in these Appendices are described below. A summary of the results for each scenario considered for each timeframe is also provided below. C Appendix H/ Table 4: Adult Cancer Risk Values For Carbaryl Residential Risk Assessment on Turf Presents the risks for activities on turf including lawncare and golfing at the two application rates considered in the assessment. C Appendix I/ Tables 3: Carbaryl Residential Postapplication Adult Cancer Risk Assessment For Deciduous Tree Crop Group Risk values are presented for different activities in home tree crops. C Appendix I/ Tables 6: Carbaryl Residential Postapplication Adult Cancer Risk Assessment For Fruiting Vegetable Crop Group Risk values are presented for different activities in home vegetable gardens. ° Appendix M/ Table 5: Carbaryl Oyster Harvest/ Beach Play Risk Assessment For Adults and Toddlers Presents noncancer and cancer risk estimates for adults and toddlers while oyster harvesting or playing on a beach. This assessment is based on dermal contact with contaminated sediment and hand­ to­ mouth behavior for toddlers. The highest sediment concentration detected in any data available to the Agency was used to assure screening level nature of assessment. ° Appendix M/ Table 6: Carbaryl Oyster Harvest/ Beach Play Risk Assessment For Adults and Toddlers Presents noncancer and cancer risk estimates for adults if they were to swim in Willapa Bay. All calculations were completed with the Agency's SWIMODEL (V2.0). Results and model inputs are included in this table. For all scenarios on turf, cancer risks are in the 10 ­8 range or less on the day of application when a single reentry event per year during lawncare activities is evaluated. For home gardening, golfing or from mosquito control, risks are slightly lower in the 10 ­9 to 10 ­12 range when a single reentry event per year is evaluated on the day of application. Table 29 below summarizes the postapplication risk values calculated for adults after applications of carbaryl. Risk managers should consider these values represent a single reentry day into a treated area over each year of a 50 year lifetime on the day of application and that the Agency lacks data to link the annual frequency of reentry activity to residential applications. As with the residential handler risks above, the Agency calculated the number of exposure days needed to reach a risk level of 1x10 ­6 for each scenario on the day of application, values range from 20 to over 365 days per year while most exceed 365 days per year. 137 Table 29: Summary of Carbaryl Postapplication Residential Cancer Risks For Adults Scenario Descriptor Results Risk on Day 0 Allowed Days/ Year Residential Turf (Lawncare) Max Rate at 4 lb ai/ A 2.5 x 10 ­8 40 Max Rate at 8 lb ai/ A 5.1 x 10 ­8 20 Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 9.5 x 10 ­12 to 5.9 x 10 ­10 >365 Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 5.0 x 10 ­12 to 3.1 x 10 ­10 >365 Golfing Max Rate at 4 lb ai/ A 1.7 x 10 ­9 >365 Max Rate at 8 lb ai/ A 3.5 x 10 ­9 287 Aerial ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 6.5 x 10 ­13 to 4.1 x 10 ­11 >365 Ground ­ Mosquito Adulticide 0.016 to 1.0 lb ai/ A 3.4 x 10 ­13 to 2.1 x 10 ­11 >365 Home Garden (Deciduous Tree) Very Low Exposure (propping) 2.5 x 10 ­10 >365 Low Exposure (irrigation, scout, weed) 2.5 x 10 ­9 >365 High Exposure (harvest, prune, train, tie, thin) 7.5 x 10 ­9 133 Home Garden (Fruiting Vegetable) Low Exposure (irrigation, scout, thin, weed) 2.5 x 10 ­9 >365 Medium Exposure (irrigation, scout) 3.5 x 10 ­9 289 High Exposure (harvest, prune, stake, tie) 4.9 x 10 ­9 202 Oyster Beds Oyster Harvest 4. 5 x 10 ­12 >365 Swimming 6.1 x 10 ­12 >365 3.2.5 Summary of Residential Postapplication Risk Concerns and Data Gaps The Agency considered a number of exposure scenarios for products that can be used in the residential environment representing different segments of the population including toddlers, youthaged children and adults. Short­ term and intermediate­ term noncancer MOEs were calculated for all scenarios. Additionally, cancer risks were calculated for the exposure scenarios involving adults where methods are currently available. Cancer risks were not calculated for children per Agency policy. In residential settings, the Agency does not use REIs or other mitigation approaches to limit exposures because they are viewed as impractical and not enforceable. As such, risk estimates on the day of application are the key concern. 138 The Agency has short­ term risk concerns for exposures to adults doing heavy yardwork, for toddlers playing on treated lawns, and for toddlers that have contact with treated pets. Activities associated with home gardening (e. g., harvesting) and golfing for adults, home gardening for youthaged children or any age or activity considered in the adulticide mosquito control or oyster assessment do not have risk concerns even on the day of application (i. e., MOEs $ 100 on the day of application). For adults, the MOEs for heavy yardwork do not meet or exceed risk targets (i. e., MOE = 100) up to 5 days after application. For toddlers, the Agency has concerns for pet treatments and also for lawn uses. In fact, pet uses never reach acceptable levels even 30 days after application and not until 18 days at the maximum application rate considered on turf. Toddler MOEs from pet and turf uses represent total exposures from many pathways. For the pet uses, dermal and hand­ to­ mouth exposures essentially both equally contribute to the overall estimate. For the turf uses, dermal and hand­ to­ mouth exposures are also the key contributors to the overall estimates. The Agency does not have intermediate­ term risk concerns for adults and youth­ aged children for any of the uses considered including lawncare, home gardens, golfing, and any aspect of adulticide mosquito control or oyster bed uses. In contrast, the Agency does have intermediateterm risk concerns for all toddler exposure scenarios considered (i. e., pet treatments and lawncare uses). As with the short­ term MOEs, pet and turf uses represent total exposures where the significant contributions to overall exposures are again made equally from the dermal and hand­ tomouth exposure pathways. Cancer risks were calculated only for adults and were found to be in the 10 ­8 to 10 ­12 range, regardless of the scenarios considered, on the day of application (e. g., lawncare, golfing and gardening). Risks did not exceed 1x10 ­6 on the day of application for any scenario considered. All postapplication cancer risks were calculated based on an annual frequency of 1 exposure per year. It is likely that additional events could occur but data linking postapplication activities and carbaryl use patterns are not available. To address this issue, the Agency calculated the number of exposures that can occur under a cancer risk ceiling of 1x10 ­6 and determined that from 20 days per year to exposures every day of the year could occur depending upon the scenario. Results indicate most activities can occur from every day of the year even at residue levels present on the day of application.. Unlike many residential risk assessments, the postapplication residential assessment for carbaryl is based on a number of chemical­ specific studies that have been used to calculate risks from turf uses (e. g., TTR study) and in gardens (i. e., DFR data). There are no transferable residue data available for pet uses which is a key data gap. Additional data could potentially be used to refine risk estimates for the other settings such as additional DFR data on different crops and TTR data which are more appropriate for hand­ to­ mouth and object­ to­ mouth exposures. The Agency combines risks resulting from total exposures to individual chemicals when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. For carbaryl, the Agency has combined risk values (i. e., MOEs) for different kinds of exposures associated with the turf (dermal, hand­ to­ mouth, object­ to­ mouth, and soil 139 ingestion) and pet scenarios (dermal and hand­ to­ mouth). These represent the standard set of exposures that are typically added together when chemicals are used on turf or on pets because it is logical they can co­ occur. Typically, the Agency only adds exposures from different exposure scenarios together (e. g., spraying and gardening) when risks from both are not already a concern. For carbaryl, there are risk concerns for many residential handler scenarios already so the Agency did not add risk values from any postapplication exposure together with applicator risks. 3.2.6 Recommendations For Refining Residential Postapplication Risk Assessment In order to refine this residential assessment, data on actual use patterns including rates, timing, and the kinds of tasks that are required to better characterize carbaryl risks. Exposure studies for many cultural practices that lack data or that are not well represented in the current Agency guidance should also be considered based on the data gaps identified above (e. g., pet uses). Risk managers should consider that the risks associated with current label generally do not meet Agency targets, especially for the turf, pet and high exposure garden scenarios. 3.3 Residential Risk Characterization 3.3.1 Handler Characterization The residential handler assessment for carbaryl is complex in that calculations were completed for 54 different equipment and application rate scenarios. Unlike the occupational assessments, only short­ term exposures were considered for handlers because homeowner use patterns are not believed by the Agency to lead to intermediate­ term exposures because of their sporadic nature. Cancer risks were also calculated using a linear, low­ dose extrapolation model (i. e., Q1*) for typical residential users (1 event/ year). Cancer risks were also considered by calculating the number of days exposure that would be required per year to achieve a cancer risk of 1x10 ­6 to illustrate risk levels from another perspective. All totaled, when each type of calculation is considered, 108 different crop/ application method calculations were completed for residential handlers. The data that were used in the in the carbaryl residential handler assessment represent the best data and approaches that are currently available. For most of the major use patterns, carbarylspecific data or data generated by the Outdoor Residential Exposure Task Force were used. These data generally are considered to be high quality by the Agency and the best source of information available for the scenarios where they were used. Carbaryl­ specific data were used to address the garden and tree/ ornamental scenarios with several types of equipment and formulations including liquid trigger sprayers, dusts, and liquid sprays using low pressure handwand and hose­ end sprayers. Carbaryl­ specific data were also available for dusting dogs. The ORETF data for hoseend sprayer applications to turf and granular applications to turf were also used to address those scenarios. In the remaining scenarios, the Pesticide Handlers Exposure Database (PHED) was used to develop the unit exposure values. The quality of the data included in PHED vary widely from scenarios that meet guideline requirements for studies to others where a limited number of poor quality datapoints are available. All data that have been used may not be of optimal quality but 140 represent the best available data. The inputs for application rate and other use/ usage information (e. g., area treated and frequency of use) used by the Agency were supported by the available carbaryl labels and information supplied by the Aventis Corporation at the September 24, 1998 SMART Meeting. It is also very clear that because carbaryl is such as widely used chemical that it is likely every potential exposure scenario has not been captured because of difference in use pattern. As more refined information becomes available on carbaryl use, the Agency will refine its assessment accordingly. There are also many uncertainties in the assessment that are common with the occupational assessment as well. These factors and their impacts on the results should be considered as well in the interpretation of the results for residential handlers. Section 2.3.1 provides a summary of these issues. In summary, with respect to residential handler risks, the Agency believes that the values presented in this assessment represent the highest quality results that could be produced given the exposure, use, and toxicology data that are available. However, there are certain elements where additional data are required. For example, it is difficult to ascertain where on a distribution certain input values may fall because the distributional data for exposure, application rates, acres treated and many other parameters are unrefined. 3.3.2 Postapplication Characterization Like the residential handler assessment discussed above, the postapplication residential assessment for carbaryl is also complex in that noncancer MOE calculations were required based on the recently selected endpoints along with cancer risk calculations using a linear, low­ dose extrapolation model. Carbaryl residues persist in the environment as indicated in the available DFR and TTR data for periods where intermediate­ term as well as short­ term noncancer risk estimates are required. Cancer risks were calculated only for adults per current Agency policy. The general population can be exposed through many different pathways that result from uses on lawns and turf, in gardens, on ornamental plants, and from treated pets. People can also be exposed from mosquito adulticide applications and uses in oyster beds. Carbaryl labels do not currently allow for indoor residential uses (e. g., crack and crevice). Settings where such exposures could occur would include around personal residences and in other areas frequented by the general public including parks, ball fields, and playgrounds. To represent the wide array of possible exposures, the Agency relies on the scenarios that have been defined in the SOPs For Residential Exposure Assessment and accompanying documents such as the overview presented to the FIFRA Science Advisory Panel. For turf uses, the Agency considered adults and toddlers (3 year olds) in the assessments. Adult activities included lawncare/ maintenance and also golfing. Toddler MOEs were calculated for playing on turf (using exposure data from the Jazzercize model) and also addressed nondietary ingestion (hand­/ object­ to­ mouth and soil ingestion). Exposures from tree and garden uses were evaluated by considering adults and youth­ aged children (10 to 12 years old) doing gardening activities such as weeding and harvesting for different crop groups. Transfer coefficients from the fruiting vegetable crop group and the deciduous tree crop group were used, as 141 described in the SOPs For Residential Exposure Assessment to represent exposures for these scenarios. MOEs from treated pets were evaluated for toddlers again for whom exposures may occur from dermal contact and hand­ to­ mouth behavior. Adulticide mosquito applications were considered by first defining how much residues are deposited on the ground after a mosquito control application then using the same methods approaches from the lawncare assessment to address adults doing heavy yardwork or golfing and also children playing on treated turf. The data that were used in the carbaryl residential postapplication assessment represent the best data and approaches that are currently available. To the extent possible, the Agency has attempted to use carbaryl­ specific data such as with the dislodgeable foliar residue (DFR) data used for the garden scenarios and the turf transferable residue (TTR) data used for the dermal component of the turf scenarios. When chemical­ specific data were unavailable, the Agency used the current approaches for residential assessment, many of which include recent upgrades to the SOPs. For example, for the toddler hand­ to­ mouth calculations, the TTR data were not used but a 5 percent transferability factor was applied to calculate residue levels appropriate for this exposure pathway. Another key approach to consider is the use of the dermal hug approach for pet products which was proposed at the September 1999 meeting of the FIFRA Science Advisory Panel. Oyster bed uses were evaluated based on guidance from Superfund and the Agency's SWIMODEL. There are also many embedded uncertainties that should be considered in the interpretation of this assessment such as those associated with the use of Jazzercize and with the nondietary ingestion calculations. Readers should consider these in the interpretation of the overall risk estimates. Readers should also consider the screening nature of the SOPs For Residential Exposure Assessment and how additional data could refine the results. Finally, the Agency believes that the values presented in this assessment represent the highest quality results that could be produced based on the currently available postapplication exposure data. Readers of this document should consider the quality of individual inputs when interpreting the results and make decisions accordingly. It is difficult to ascertain where, on a distribution, the calculated values fall because the distributional data for exposure, residue dissipation and many other parameters are unrefined. The Agency does believe, however, that the risks represent conservative estimates of exposure because maximum application rates are used to define residue levels upon which the calculations are based. Additionally, estimates are thought to be conservative even when measures of central tendency (e. g., most transfer coefficients are thought to be central tendency) are used because values that would be considered to be in the lower percentile aspect of any input parameter have not been used in the calculations. Appendix A: Use Information For Carbaryl Quantitative Usage Analysis for Carbaryl Case Number: 0080 PC Code: 56801 Date: July 21, 1998 Analyst: Frank Hernandez Based on available pesticide survey usage information for the years of 1987 through 1996, an annual estimate of carbaryl total domestic usage averaged approximately two and one half million pounds active ingredient (a. i.) for over one and one half million acres treated. Carbaryl is an insecticide with its largest markets in terms of total pounds active ingredient allocated to pecans (12%), apples (9%), grapes( 6%), oranges (5%), alfalfa (5%), and corn (4%). Most of the usage is in AR, CA, GA, IL, IN, MI, MS, OH, OK, and TX. Crops with a high percentage of the total U. S. planted acres treated include avocados (67%), Chinese cabbage (57%), asparagus (43%), cranberries (39%), and Brussels sprouts (33%). Crops with less than 1 percent of the crop treated include alfalfa, dry beans, canola, corn, cotton, flax, oats, pasture, green peas, safflower, sod, sorghum, soybeans, sugar cane, sunflowers, sweet corn, walnuts, wheat, and woodland. Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ y r #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) Alfalfa 23,949 120 263 0.50 1.10 130 365 1.1 1.0 1.1 NE SD OK MT ND IL 77% Almonds 429 7 16 1.72 3.61 16 49 2.1 1.0 2.1 CA 100% Apples 572 131 175 22.92 30.59 230 282 1.8 1.4 1.2 WA MI NY CA CT IN 77% Asparagus 88 38 77 43.35 86.69 46 117 1.2 1.3 0.9 MI WA 97% Avocados 82 55 70 66.93 85.18 1 2 0.0 1.5 0.0 Beans, Dry 1,802 12 51 0.65 2.86 6 28 0.5 1.0 0.5 CA ND CO 88% Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ y r #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) Beans, Lima, Fresh 6 1 2 12.49 29.88 1 2 1.1 1.2 0.9 GA 100% Beans, Snap, Fresh 81 11 17 14.12 21.03 16 23 1.4 1.6 0.9 NC FL 84% Beans, Snap, Proc. 228 24 36 10.39 15.83 28 43 1.2 1.6 0.7 IL St OR 83% Beets 12 2 3 16.87 27.45 1 2 0.5 1.0 0.5 WI TX OR 94% Blackberries 5 1 2 28.39 44.05 2 4 1.7 1.0 1.7 OR 100% Blueberries 59 13 26 22.43 44.85 26 53 2.0 1.2 1.7 ME MI 83% Broccoli 114 5 10 4.43 8.86 4 8 0.8 1.0 0.8 CA OR TX 88% Brussels Sprouts 3 1 2 33.33 66.67 1 2 1.0 1.1 0.9 Cabbage, Chinese 9 5 7 57.47 80.46 1 2 0.2 1.1 0.2 CA 90% Cabbage, Fresh 84 1 4 1.78 4.40 2 6 1.6 1.6 1.0 NC NY 84% Canola 39 0 2 0.31 4.64 0 1 0.5 1.0 0.5 MT 100% Cantaloupes 113 8 11 7.27 9.39 8 13 0.9 1.1 0.8 CA IL GA TX 83% Carrots 107 4 6 3.67 5.75 9 23 2.3 2.5 0.9 WI MI MN 88% Cauliflower 58 1 2 1.55 3.60 1 2 1.1 1.0 1.1 OR CA WA 83% Celery 37 1 2 2.97 6.13 2 4 1.8 1.8 1.0 MI WI 89% Cherries, Sweet 47 12 17 25.29 36.45 32 46 2.7 1.4 1.9 WA MI CA 84% Cherries, Tart 49 6 11 11.79 23.59 13 27 2.3 1.3 1.9 MI NY 88% Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ y r #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) Citrus, Other 51 2 3 2.98 5.65 5 12 3.2 1.8 1.8 FL 86% Collards 11 0 1 3.72 10.13 0 1 0.9 1.0 0.9 NJ 88% Corn 72,284 82 164 0.11 0.23 110 228 1.3 1.3 1.0 MO NE MS IN GA IL 51% Cotton 12,689 26 77 0.20 0.61 32 94 1.2 1.1 1.1 TN MS TX CA 83% Cranberries 29 11 24 38.97 83.65 23 48 2.0 1.0 2.0 WI MA 95% Cucumbers 146 20 46 14.03 31.83 23 51 1.1 1.0 1.1 NC OH SC NY VA DE 73% Cucumbers, Proc. 117 5 11 4.69 9.37 7 15 1.3 2.2 0.6 NC MI 85% Eggplant 119 11 25 8.87 20.59 22 54 2.0 2.1 1.0 FL NJ TX IL OR CA 64% Flax 188 1 2 0.46 0.91 1 2 1.1 1.0 1.1 ND 100% Grapefruit 194 8 11 4.05 5.59 18 20 2.3 1.6 1.4 FL TX 95% Grapes 825 64 97 7.77 11.81 150 217 2.3 1.7 1.4 NY CA OR PA MI AR 77% Hay, Other 33,427 91 267 0.27 0.80 87 273 1.0 1.2 0.8 TX SD FL NC CA LA 81% Hazelnuts (Filberts) 27 1 3 3.90 12.18 3 8 2.5 1.0 2.5 Lemons 63 2 4 2.77 6.55 6 14 3.4 1.3 2.7 CA 91% Lettuce, Head 212 7 17 3.08 8.10 8 22 1.3 1.2 1.1 CA 82% Lots/ Farmsteads/ etc 24,815 58 152 0.23 0.61 60 174 1.0 2.5 0.4 MA AZ FL PA TX KY 62% Melons, Honeydew 27 5 12 19.09 43.69 4 10 0.9 1.2 0.7 CA 100% Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ y r #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) Nectarines 29 4 7 12.11 24.22 15 30 4.2 1.1 3.8 Oats/ Rye 6,133 8 18 0.13 0.29 6 13 0.7 1.0 0.7 MN MS ND TX MT MI 77% Okra 3 1 3 32.36 94.03 2 6 1.9 1.0 1.9 TX 84% Olives 32 3 5 9.61 15.42 16 26 5.3 1.0 5.3 CA 100% Onions, Dry 157 6 18 3.71 11.36 23 72 4.0 7.0 0.6 MI 100% Oranges 867 28 42 3.27 4.89 130 194 4.6 1.3 3.4 CA FL 99% Other Crops 2,515 35 43 1.39 1.70 63 156 1.8 1.3 1.4 CA MA TX NJ WA MI 75% Pasture 86,960 27 69 0.03 0.08 25 77 0.9 1.0 0.9 NC TX SC NE LA 80% Peaches 212 32 38 15.10 18.05 96 203 3.0 2.9 1.0 GA CA TX OK SC MI 68% Peanuts 1,610 48 96 2.99 5.99 53 107 1.1 1.4 0.8 GA TX NC AL VA 84% Pears 78 2 5 2.92 6.43 3 8 1.5 1.5 1.0 WA OR CA PA NY OH 73% Peas, Dry 249 6 22 2.52 8.97 6 22 1.0 1.0 1.0 WA ID TX 93% Peas, Green 386 6 28 1.59 7.13 9 40 1.5 1.0 1.5 MN OR 83% Peas, Green, Proc. 329 2 17 0.62 5.23 3 25 1.5 1.0 1.5 OR 100% Pecans 488 95 115 19.53 23.51 290 610 3.0 2.2 1.4 GA TX OK MS AR 84% Peppers, Bell 55 6 11 10.15 20.30 9 22 1.5 1.7 0.9 FL CA MI 90% Peppers, Sweet 77 10 23 12.95 29.95 14 31 1.3 1.0 1.3 CA FL KY LA IL 80% Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ y r #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) Pistachios 52 9 20 16.84 38.06 32 72 3.6 1.0 3.6 Plums 64 3 6 4.68 9.36 12 23 3.8 1.0 3.8 CA 81% Potatoes 1,421 24 38 1.70 2.68 34 50 1.4 1.7 0.8 ND WA MI ID FL NY 59% Pumpkins 36 11 20 31.21 56.11 37 66 3.2 1.6 2.0 IL PA IN OH 83% Raspberries 11 0 1 3.57 9.84 1 3 2.8 1.0 2.8 OR MI 92% Rice 2,921 33 40 1.15 1.37 41 58 1.2 1.1 1.1 TX CA 80% Safflower 113 1 7 0.98 5.96 0 3 0.4 1.0 0.4 CA 100% Sod 152 0 7 0.14 4.28 0 15 2.2 1.0 2.2 TX NH 100% Sorghum 11,280 23 47 0.21 0.41 31 62 1.3 1.2 1.1 MO KS TX LA NE MS 75% Soybeans 62,879 101 210 0.16 0.33 86 174 0.9 1.0 0.9 MN NE SD MS NC IL 60% Squash 53 6 14 11.25 26.77 8 19 1.4 1.0 1.4 NJ FL MI CA NY TX 90% Strawberries 51 8 12 16.02 23.62 24 55 2.9 2.1 1.4 CA FL NC PA 81% Sugar Beets 1,415 23 54 1.60 3.80 34 126 1.5 1.1 1.3 CA TX WA MN OR 84% Sugarcane 852 0 1 0.04 0.07 0 0 0.2 1.1 0.1 FL 100% Sunflower 2,745 11 40 0.40 1.47 8 31 0.7 1.1 0.7 SD ND 92% Sweet Corn, Fresh 233 9 17 3.84 7.12 28 52 3.1 2.5 1.3 CA MI IL 82% Sweet Corn, Proc. 544 3 21 0.49 3.81 8 63 3.0 2.9 1.1 IL 100% Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ y r #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) Sweet Potatoes 85 16 35 18.47 40.90 25 55 1.6 1.0 1.6 LA MS NC 82% Tobacco 695 10 20 1.50 2.85 18 44 1.7 1.5 1.1 NC KY SC TN IN 84% Tomatoes, Fresh 136 7 15 5.40 10.80 14 35 1.9 2.6 0.7 CA FL TX 87% Tomatoes, Proc. 329 48 88 14.47 26.86 72 135 1.5 1.3 1.2 CA 97% Walnuts 205 1 4 0.54 1.82 2 8 2.1 1.1 1.9 CA 100% Watermelons 258 33 38 12.71 14.79 16 33 0.5 1.0 0.5 FL IN MS TX GA 76% Wheat, Spring 20,799 24 48 0.11 0.23 16 32 0.7 1.0 0.6 ND MN MT 88% Wheat, Winter 45,854 50 106 0.11 0.23 44 78 0.9 1.0 0.8 KY NC TX WY OR MD 67% Woodland 62,825 31 72 0.05 0.11 26 54 0.8 1.2 0.7 PA MI FL ND OH IA 79% Total 1659.6 2464 2517.2 3926 COLUMN HEADINGS Wtd Avg = Weighted average­­ the most recent years and more reliable data are weighted more heavily. Est Max = Estimated maximum, which is estimated from available data. Average application rates are calculated from the weighted averages. NOTES ON TABLE DATA Usage data primarily covers 1987 ­ 1996. Calculations of the above numbers may not appear to agree because they are displayed as rounded to the nearest 1000 for acres treated or lb. a. i. (Therefore 0 = < 500) to two decimal percentage points for % of crop treated. Other/ Crop Groups Citrus, Other includes kumquats, limes, tangelos, and tangerines. Other Crops include ornamentals, popcorn, rapeseed/ canola, and safflower. SOURCES: EPA data, USDA, and National Center for Food and Agricultural Policy. R. E. D. Use Profile Report A. Chemical Overview Chemical Name: Carbaryl Case No: 0080 Chemical Code: 056801 B. Use Profile Type of Pesticide: Acaricide/ Insecticide and Plant regulator Mode of Action: Acetylcholine esterase inhibitor Use Sites: Terrestrial Food Crop Cucurbits ­ Cumber, Melons, Chinese okra, pumpkin, and squash Flavoring and Spice Crops ­ Dill Fruiting Vegetables ­ Eggplant and Pepper Grain Crops ­ Prosso millet Leafy and Stem Vegetables ­ Beets, Broccoli, Brussels sprouts, Cabbage, Chinese cabbage, Cauliflower, Celerey, Swiss chard, Collards, Dandelion, Endive (Escarole), Hanover Salad, Kale, Kohlrabi, Lettuce (Head, Crisphead types, Leaf types), Mustard, Parsley, Rhubarb, and Spinach Miscellaneous Fruits ­ Avocado, Olive, Pricklypear Miscellaneous Vegetables ­ Asparagus Nut Crops ­ Almond, Chestnut, Filbert (Hazelnut), Pecan, Pistachio, and Walnut (English/ black) Pome Fruits ­ Crabapple, pear, and quince Root Crop Vegetables ­ Beets, Carrot (including tops), Horseradish, Radish, Rutabaga, Salsify, and Sweet Potato Small Fruits ­ Blackberry, Blueberry, Boysenberry, Caneberries, Cranberry, Dewberry, Loganberry, Raspberry (Black, Red), and Strawberry Specialized Field Crops ­ Okra Stone Fruits ­ Apricot, Cherry, Nectarine, Peach, Plum, and Prune Terrestrial Food+ Feed Crop Citrus Fruits ­ Citrus fruits Crops Grown for Oil ­ Field corn, Flax, and Sunflower Fiber Crops ­ Flax Fruiting Vegetables ­ Tomato Grain Crops ­ Field corn, Rice, Sorghum and Wheat Groups of Agricultural Crops Which Cross Established Crop Groupings ­ Cotton, Peanuts, Peas, Sorghum, Soybeans, and Vegetables Leafy and Stem Vegetables ­ Mustard and Turnip Nut Crops ­ Almond, and Tree nuts Pome Fruits ­ Apple and Pome Fruits Root Crop Vegetables ­ Parsnip, White/ Irish potato, Salsify, and Turnip Seed and Pod Vegetables ­ Beans (Dried type), Succulent beans (Lima and Snap), Cowpea/ Blackeyed pea, Cowpea/ Sitao, Lentils, Peanuts, Peas (Dried type), Field peas, Southern peas, Succulent peas, and Soybeans (edible) Small Fruits ­ Grapes and Small fruits Specialized Field Crops ­ Pop corn, Sweet corn, and Sunflower Sugar Crops ­ Sugar beet Terrestrial Feed Crop Forage Grasses ­ Corn, Grass forage/ fodder/ hay, Millet (Proso), Pastures, Rangeland, Rice, Sorghum, and Wheat Forage Legumes and Other Nongrass Forage Crops ­ Alfalfa, Clover, Cotton, and Trefoil Grain Crops ­ Proso millet Groups of Agricultural Crops Which Cross Established Crop Groupings ­ Grasses grown for seed Terrestrial non­ food crop Agricultural Uncultivated Areas ­ Agricultural fallow/ idleland and Agricultural rights­ of way/ fencerows/ hedgerows Commercial/ Industrial/ Institutional Premises and Equipment Fiber Crops Forest Trees ­ Christmas tree plantations Groups of Agricultural Crops Which CrossEstablished Crop Groupings ­ Fruits (unspecified) Miscellaneous Fruits ­ Longan and Mango Nonagricultural Uncultivated Areas ­ Outdoor buildings/ structures, rights­ of­ way/ fencerows/ hedgerows, uncultivated areas/ soils, and recreational areas Ornamental Lawns and Turf ­ Commercial/ Industrial lawns, Golf course turf, Ornamental sod farm (turf), and recreational area lawns Specialized Field Crops ­ Tobacco Wide Area/ General Outdoor Treatments ­ Fencerows/ Hedgerows, Urban areas, and Wide area/ General outdoor treatment (Public health use) Terrestrial non­ food+ outdoor residential Nonagricultural Uncultivated Areas ­ Rights­ of­ way/ Fencerows/ Hedgerows Ornamental Herbaceous Plants Ornamental Lawns and Turf Ornamental Nonflowering Plants Ornamental Woody Shrubs and Vines Ornamental and/ or Shade Trees Wide Area/ General Outdoor Treatments ­ Fencerows/ Hedgerows Terrestrial+ Greenhouse non­ food crop Ornamental Herbaceous Plants Ornamental Woody Shrubs and Vines Ornamental and/ or Shade Trees Aquatic food crop Aquatic Sites ­ Commercial fishery water systems Grain Crops ­ Rice Small Fruits ­ Cranberry Aquatic non­ food industrial Aquatic Sites ­ Drainage systems Forestry Forest Trees ­ Forest plantings (Reforestation programs, tree farms, tree plantations, etc), forest trees (all or unspecified), maple (forest), and Shelterbelt plantings Outodoor residential Households/ Domestic Dwellings ­ Outdoor premises Ornamental Herbaceous Plants Ornamental Lawns and Turf ­ Residential lawns Pets ­ Pet living/ sleeping quarters Indoor food Poultry ­ Egg/ Meat Indoor non­ food Pets Target Pests for Single Active Ingredient: Invertebrates (insects and related organisms); Adelgid (Cooley spruce gall) Ataenius (Black turfgrass Ants (Carpenter, Fire, Imported fire) Aphids (Apple, Balsam twig, Black cherry, Blackmargined, Cooley spruce gall, Eastern spruce gall, Elm leaf, European raspberry, Filbert, Gall, Mealy plum, Rose, Rosy apple, Wooly?, Wooly apple) Appleworm (Lesser) Armyworm (Fall, True, Western yellowstriped, Yellowstriped) Bagworm Bees Beetle (Aparagus, Bean leaf, Beet leaf, Blister, Cereal leaf, Chafer, Colorado potato, Corn rootworm, Cucumber, Darkling, Darkling ground?, Elm bark, Elm leaf, Engraver, European alfalfa, Flea, Fuller rose, Green june, Ips engraver, Japanese, June, Litter, May, Mexican bean, Mountain pine, Rose, Roundheaded pine, Sap, Spruce bark?, Spruce?, Striped blister, Sunflower, Tobacco flea, Tortoise, Western pine, Whitefringed, Willow leaf) Billbugs (Bluegrass) Borer (European corn, Lesser peachtree, Limabean pod, Locust, Olive ash, Peach twig, Southwestern corn, West Indian sugarcane root) Budworm (Jack pine, Spruce, Tobacco, Western spruce) Bug (Bed, Black Grass, Boxelder, Chinch, Harlequin, Lace, Lygus, Plant, Squash, Stink, Tarnished plant) Cabbageworm (Imported) Cankerworm (Fall, Spring) Casebearer (Pecan nut) Caterpillar (Alfalfa, Eastern tent, Forest tent, Oleander, Painted lady, Puss, Range, Redhumped, Saltmarsh, Spiny elm, Spring elm, Tent, Thistle butterfly, Velvetbean, Walnut, Woolybear) Centipedes Chafer (European, Rose) Chiggers (Redbugs) Cicada (Apache, Periodical) Clipper (Strawberry) Cloverworm (Green) Cockroach (American, Australian, Brown, Smoky brown) Colaspis (Grape) Crickets (Mole, Morman, Snowy tree) Curculio (Cowpea, Plum) Cutworm (Army, Citrus, Cotton, Western bean) Earwigs (European) Earworm (Corn) Firebrats Fireworm (Cranberry, Yellowheaded) Fleahopper (Cotton) Fleas Fly (Cherry fruit, European crane, Rangeland crane) Forester (Eightspotted) Fruitworm (Cherry, Cranberry, Green, Raspberry, Sparganothis, Strawberry, Tomato) Girdler (Cranberry, Twig) Grasshoppers Grubs (White) Hornworms (Poinsettia, Sweet potato, Tobacco, Tomato) Leafcutter (Maple) Leaffolder (Grape) Leafhopper (Aster, Avocado, Cotton, Potato, Prune, Redbanded, Three cornered alfalfa, White apple) Leafminer (Alfalfa blotch, Azalea, Birch, Boxwood, Holly, Oak, Tentiform) Leafroller (Avocado, Filbert, Fruittree, Grape, Oak, Omnivorous, Redbanded, Strawberry, Variegated) Leaftier (Omnivorous) Leafworm (Cotton) Lecanium (European fruit) Lice Looper (Alfalfa, Pine, Striped grass, Western hemlock) Maggot (Apple, Blueberry) Maker (Hackberry nipplegall) Mapleworm (Greenstriped) Mealworm (Lesser) Mealybug (Apple, Cherry) Melonworm Midges (Gall) Millipedes Mites (Apple rust, Chicken, Citrus rust, Eriophyid, Fuschia gall, Fuschia?, Northern fowl, Pear rust, Pearleaf blister) Moth (Browntail, Codling, Cyprus tip, Diamondback, Douglas­ fir tussock, European pine shoot, Eyespotted bud, Grape berry, Gypsy, Holly bud, Lawn, Lucerne, Maple shoot, Nantucket pine tip, Oak, Oriental fruit, Pitch pine tip, Subtropical pine tip, Sunflower, Tussock, Western tussock) Mosquito Needleminers (Jeffrey pine, Spruce) Notcher (Little leaf) Oakworm (Orangestriped, Redhumped) Orangedog (California) Orangeworm (Navel) Pandemis (Apple) Peanutworm (Rednecked) Pearslug (California) Phylloxera (Pecan leaf?, Pecan?) Pickleworm Pillbug/ Sowbugs Pinworm (Tomato) Prominent (Saddled) Psylla (Pear) Roseslug Sawfly (European apple, Pear, Pine, Raspberry) Scale (Black, Brown soft, Calico, California red, Citricola, Citrus Snow, Forbes, Frosted, Lecanium, Olive, Oystershell, Red, San Jose, Yellow) Scorpions Shrimp (Ghost, Mud, Tadpole) Shuckworm (Hickory) Silverfish Skeletonizer (Oak, Western Grapeleaf) Skipper (Essex, Fiery) Spanworm (Elm) Spiders Spinx (Catalpa) Spittlebug (Meadow, Pecan, Pine) Springtails Sucker (Apple) Suckfly Thornbug Thrips Ticks (Amblyomma spp., Bear, Blacklegged, Brown dog, Deer, Fowl, Ixodes spp., Lone star) Tortrix (Orange) Treehoppers Wasps (Gall) Webworm (Fall, Lesser, Mimosa, Sod) Weevil (Alfalfa, Bluegrass, Chestnut nut, Citrus root, Clover head, Cotton boll, Egyptian alfalfa, Hyperodes, Pea Leaf?, Pea?, Pecan, Strawberry bud?, Strawberry?, Sugarcane rootstalk borer, Sunflower stem, Sweet potato, Yellow­ poplar) Whiteflies Worm (Filbert) Weeds Aster Blessed thistle Boxelder Plant regulator ­ abscission agen, flower inhibitor, fruit thinning, inhibit fruiting White ash Yellow poplar Formulation Types Registered (% AI): Technical Grade Material Form not identified/ solid 99.0000% Manufacturing product dust 80.0000% Emulsifiable concentrate 97.5000% End Use Product Bait/ solid 10.0400% Emulsifiable concentrate 22.5000 to 48.0000% Flowable concentrate 43.0000 to 43.4000% Granular 5.0000 to 7.0000% Liquid­ ready to use 39.7000% Pelleted/ tableted 5.0000% Wettable powder 50.0000 to 85.0000% Methods and Rates of Application: Types of Treatment: Animal bedding/ litter treatment; Animal treatment (spray); Bait application; Band treatment; Bark treatment; Basal spray treatment; Broadcast; Chemigation; Dip treatment; Directed spray; Drench; Ground spray; High volume spray (dilute); Indoor general surface treatment; Low volume spray (concentrate); Mound drench; Mound treatment; Perimeter treatment; Premise treatment; Soil drench treatment; Soil incorporated treatment by irrigation; Soil treatment; Soil/ media treatment; Spray; Surface treatment; Trunk drench; Ultra low volume Equipment: Airblast; Aircraft; Band sprayer; Chest­ mounted equipment; Compressed air sprayer; Dip tank; Drencher; Electric fogger; Fogger; Granule applicator; Ground; Hand held duster; Hand held sprayer; High pressure sprayer; High volume ground sprayer; Hose­ end sprayer; Hydraulic sprayer; Knapsack sprayer; Low pressure; Low pressure ground sprayer; Low volume ground sprayer; Mechanical sprayer; Mist blower; Mist sprayer; Not on label; Pail; Power sprayer; Pressure sprayer; Sprayer; Spreader; Sprinklercan; Sprinkler irrigation; Tank Timing: Bloom; Boot; Containerized; Cool weather (65 ­ 80 F); Delayed dormant; Dormant; Foliar; Fruit thinning; Heading; Nonbearing; Nurserystock; Petal fall; Pink; Plant bed; Popcorn; Post­ bloom; Postharvest; Prebloom; Preharvest; Preplant; Seed bed; Silk; Tassel; Transplant; When needed Use Practice Limitations: (that apply to all uses on all products) Appendix B: Carbaryl Occupational Handler Exposure Data Appendix B/ Table 1: Field Recovery Results For MRID 44658401 (Commercial Pet Groomers During Application of Adams Carbaryl Shampoo Matrix Level (concentration) Recovery Range (%) Recovery Mean (%) Recovery S. D. (%) Coefficient of Variation (%) Facial swabs Low (0. 10 µg/ ml) 97 ­ 110 106 5.2 4. 9 Medium (0. 50 µg/ ml) 96 ­ 99 97 1.5 1. 5 High (1. 0 µg/ ml) 93 ­ 98 95 1.7 1. 8 Hand Washes Low (0. 10 µg/ ml) 100 ­ 113 106 5.6 5. 3 Medium (0. 50 µg/ ml) 92 ­ 100 97 3.1 3. 2 High (1. 0 µg/ ml) 91 ­ 104 98 5 5. 1 Whole body dosimeters Low (1. 0 µg/ ml) 85 ­ 100 91 5.8 6. 4 Medium (5. 0 µg/ ml) 82 ­ 95 87 6.1 7 High (10 µg/ ml) 81 ­ 89 83 5 6 Glass fiber filter/ support pad Low (1. 0 µg/ ml) 83 ­ 100 92 7.4 8 Medium (5. 0 µg/ ml) 68 ­ 89 80 8.4 11 High (10 µg/ ml) 85 ­ 95 91 3.8 4. 2 Appendix B/ Table 2: Dermal Exposures from Whole Body Dosimeter Parts (Adjusted for Field Recovery Results) a For MRID 44658401 (Commercial Pet Groomers During Application of Adams Carbaryl Shampoo) Replicate Lower Arm (µg) Upper Arm (µg) Lower Leg (µg) Front Torso (µg) Rear Torso (µg) Total (mg) 1 7543 185 0.57 1941 1 9. 7 2 6341 157 4 389 3 6. 9 3 1382 232 0.57 43 0.57 1.4 4 2986 3.9 0. 57 65 0. 57 3. 1 5 5441 61 31 6.6 5. 9 5.5 6 1680 589 3 420 0.57 2.7 7 2457 99 1.03 38 0.57 2.6 8 2497 277 8 445 8.2 3. 2 9 1224 7.01 0.57 1.6 0. 57 1. 2 10 14947 30 1330 10 1.8 16.3 11 839 0.34 0.57 0.92 0.57 0.84 12 1730 2518 35 10 1281.6 5. 6 13 4611 12 5.4 1. 4 0.57 4.6 14 4757 29 3.4 166 2.2 5 15 1180 162 15 30 10 1.4 16 763 0.23 0.57 3.9 0. 57 0. 77 Average 3774 260 90 223 82 4.4 Geometric Mean 2647 35 3.7 30 2 3.1 Median 2477 46 3.2 34 0. 8 3.1 a Field recovery for 100% cotton union suits averaged 87%. The values in this table represent the values found in study divided by 0.87. Example: Replicate 1 Lower arm; 6562µg (actual) ÷ 0.87 = 7543µg. b Total (mg) =( Lower Arm + Upper Arm + Lower Leg + Front Torso + Back Torso) * 1mg/ 1000µg. Appendix B/ Table 3: Unit Exposures For MRID 44658401 (Commercial Pet Groomers During Application of Adams Carbaryl Shampoo ) Replicate No. ai used (mg) Whole Body Dosimeter (mg) Hand Rinses (mg) Head Exposure (mg) Total Dermal Exposure (mg) Inhalation Exposure (µg) mg ai/ lb ai handled mg ai/ hr application mg ai/ lb dog dermal inhalation dermal inhalation dermal inhalation 1 2290 9.76 0.294 0.00897 10.1 1. 96 1994 0.389 3.493 0.00068 0.207 4.04 x 10 ­5 2 684 6.918 0.175 0.00533 7.1 0. 05 4714 0.006 2.752 0 0. 623 7.63 x 10 ­7 3 916 1.462 0.134 0.0007 1.6 0. 86 793 0.426 0.521 0.00028 0.0382 2.05 x 10 ­5 4 2004 3.056 0.248 0.00631 3.31 0.57 750 0.129 1.335 0.00023 0.184 3.17 x 10 ­5 5 1640 6.367 0.124 0.00338 6.49 0.65 1795 0.18 2.107 0.00021 0.18 1.81 x 10 ­5 6 1204 2.711 0.164 0.00325 2.88 0.54 1086 0.204 0.906 0.00017 0.0847 1.59 x 10 ­5 7 659 2.603 0.082 0.0007 2.69 0.59 1852 0.406 0.918 0.0002 0.113 2.47 x 10 ­5 8 373 3.28 0.105 0.00208 3.39 0.41 4123 0.499 1.246 0.00015 0.105 1.27 x 10 ­5 9 600 1.233 0.062 0.0003 1.3 0. 05 984 0.007 0.323 0 0. 0556 3.72 x 10 ­7 10 1747 16.544 0.466 0.012 17 1.4 4423 0.364 4.387 0.00036 0.379 3.12 x 10 ­5 11 945 0.841 0.292 0.00163 1.14 0.22 548 0.106 0.36 0.0001 0.0268 5.16 x 10 ­6 12 3715 15.329 0.145 0.00806 15.5 0. 97 1889 0.118 3.822 0.00024 0.325 2.04 x 10 ­5 13 1132 4.762 0.119 0.01177 4.89 1.18 1962 0.473 0.994 0.00024 0.173 4.17 x 10 ­5 14 1148 4.961 0.141 0.00429 5.11 0.05 2020 0.003 1.481 0 0. 312 5.31 x 10 ­7 15 706 1.459 0.239 0.00254 1.7 0. 76 1093 0.489 0.561 0.00025 0.096 4.29 x 10 ­5 16 1929 0.768 0.107 0.00111 0.88 0.48 207 0.113 0.293 0.00016 0.0362 1.98 x 10 ­5 Average 1356 5.1 0. 18 4. 5 5.3 0. 67 1900 0.24 1.6 0. 0002 0.18 2.0 x 10 ­5 Geometric Mean 1148 3.4 0. 16 2. 9 3.6 0. 43 1800 0.12 1.1 0. 00096 0.13 1.1 x 10 ­5 Median 1140 3.2 0. 14 3. 3 3.4 0. 58 1800 0.19 1.1 0. 00021 0.14 2.0 x 10 ­5 Appendix C: Carbaryl Occupational Handler Risk Assessment Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Mixer/ Loader Descriptors Mixing/ Loading Dry Flowable Formulations (1a through 1f) PHED V1. 1 (May 1997 Surrogate Table) 350 and 1200 acres for aerial applications (7500 for wide area uses), 40 acres for airblast, 80 and 200 acres for groundboom in agriculture and 40 acres on turf, 5 acres for handguns on turf, and 1000 gallons for handgun applications Baseline: Hand, inhalation, and dermal data = acceptable grades. Hands = 7 replicates; Dermal = 16 to 26 replicates; and Inhalation = 23 replicates. Low confidence in hand/ dermal data because of number of hand replicates. Inhalation data are high confidence. No protection factor was needed to define the unit exposure value. PPE: As appropriate, the same dermal and inhalation data were used as for the baseline coupled with a 50% protection factor to account for an additional layer of clothing. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Hands = acceptable grades. Hands = 21 replicates. High confidence in all dermal data. Engineering Controls: A protection factor of 98% was used to calculate exposures using the baseline exposure data. Water soluble packet data (Scenario 4) could also be used to address this scenario. A protection factor has been used but the WSP rate/ acre inputs are the same as for DF formulations ( refer to Scenario 4). Loading Granular Formulations (2a/ 2b) PHED V1. 1 (May 1997 Surrogate Table) 350 and 1200 acres for aerial applications, 80 acres for agriculture and 40 acres on turf Baseline: Hands = all grades; dermal = ABC grade; inhalation = acceptable grade. Hands = 10 replicates; Dermal = 33 to 78 replicates; and inhalation = 58 replicates. Low confidence in hand/ dermal data because of number of hand replicates and quality. Inhalation data are high confidence. No protection factor was needed to define the unit exposure value. PPE: Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Hands = acceptable grades. Hands = 45 replicates. High confidence in hand data. Dermal w/ coveralls = ABC grade. Dermal w/ coveralls = 12 to 59 replicates. Low confidence in dermal data because of low number of replicates and grades. Engineering Controls: A 98 percent protection factor was applied to the baseline data to account for the use of an engineering control (e. g., closed loading system). Mixing/ Loading Liquid Formulations (3a through 3f) PHED V1. 1 (May 1997 Surrogate Table) 350 and 1200 acres for aerial applications (7500 for wide area uses), 40 acres for airblast, 80 and 200 acres for groundboom in agriculture and 40 acres on turf, 5 acres for handguns on turf, and 1000 gallons for handgun applications Baseline: Hands, dermal, and inhalation = acceptable grades. Hands = 53 replicates; Dermal = 72 to 122 replicates; and Inhalation = 85 replicates. High confidence in hand, dermal, and inhalation data. No protection factor was needed to define the unit exposures. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hands = acceptable grades. Hands = 59 replicates. High confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Hands, dermal, and inhalation = acceptable grades. Hands = 31 replicates; Dermal = 16 to 22 replicates; and Inhalation = 27 replicates. High confidence in hand, dermal, and inhalation data. Gloves were used coupled with engineering controls since empirical data without gloves were not available and back calculation of gloves to a no glove scenario is believed to give erroneously high estimates. Gloves are also required by WPS based on acute toxicity concerns. Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Mixing/ Loading Wettable Powder Formulations (4a through 4f) PHED V1. 1 (May 1997 Surrogate Table) 350 and 1200 acres for aerial applications (7500 for wide area uses), 40 acres for airblast, 80 and 200 acres for groundboom in agriculture and 40 acres on turf, 5 acres for handguns on turf, and 1000 gallons for handgun applications Baseline: Hands, dermal, and inhalation = ABC grades. Hands = 7 replicates; Dermal = 22 to 45 replicates, and Inhalation = 44 replicates. Low confidence in the dermal/ hands data due to the low number of hand replicates. Medium confidence in inhalation data. No protection factor was needed to define the unit exposure value. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hands = ABC grades. Hands = 24 replicates. Medium confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Dermal = AB grade. Hand and inhalation = all grade. Hands = 9 replicates; dermal = 6 to 15 replicates; and inhalation = 15 replicates. Low confidence in the hand, dermal, and inhalation data. No protection factor was needed to define the unit exposure value. Engineering controls are water soluble packets. Gloves were used coupled with engineering controls since empirical data were available and risk estimates for some scenarios need gloves to attain risk targets. Gloves are also required by WPS based on acute toxicity concerns Applicator Descriptors Applying Sprays with a Fixed­ wing Aircraft (5a) PHED V1. 1 (May 1997 Surrogate Table) 350 acres and 1,200 acres for agriculture and 7500 acres for wide area uses Engineering Controls: Hands = acceptable grade, dermal and inhalation = ABC grade. Hands= 34 replicates, dermal = 24 to 48 replicates, and inhalation = 23 replicates. Medium confidence in dermal and inhalation data. High confidence in hand data. No protection factor was needed to define the unit exposure value. Engineering controls are the only plausible exposure scenario for this application method as open­ cab aircraft are not available and not considered a viable application tool. Protective gloves not used. Applying Sprays with a Fixed­ wing Aircraft (5b) PHED V1. 1 (May 1997 Surrogate Table) 350 acres and 1,200 acres for agriculture Engineering Controls: Hands and inhalation = all grade, dermal = C grade. Hands= 4 replicates, dermal = 0 to 13 replicates, and inhalation = 13 replicates. Low confidence in all data. No protection factor was needed to define the unit exposure value. Engineering controls are the only plausible exposure scenario for this application method as open­ cab aircraft are not available and not considered a viable application tool. Protective gloves not used. Applying Sprays with an Airblast Sprayer (6) PHED V1. 1 (May 1997 Surrogate Table) 40 acres Baseline: Dermal, hand, and inhalation = acceptable grades. Hands = 22 replicates, dermal = 32 to 49 replicates, and inhalation = 47 replicates. High confidence in all data. No protection factor was needed to define the unit exposure value. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hands = acceptable grades. Hands = 18 replicates. High confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Hands and dermal = acceptable grade, and inhalation = ABC grade. Hands= 20 replicates; dermal = 20 to 30 replicates; and inhalation = 9 replicates. High confidence in hand and dermal data. Low confidence for inhalation data. Gloves were used coupled with engineering controls since empirical data without gloves were not available and back calculation of gloves to a no glove scenario is believed to give erroneously high (130 : g/ lb ai) estimates for a closed cab scenarios. Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Applying Sprays with a Groundboom Sprayer (7) PHED V1. 1 (May 1997 Surrogate Table) 80 and 200 acres for groundboom in agriculture and 40 acres on turf Baseline: Hand, dermal, and inhalation = acceptable grades. Hands =29 replicates, dermal = 23 to 42 replicates, and inhalation = 22 replicates. High confidence in hand, dermal, and inhalation data. No protection factors were needed to define the unit exposure values. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hands = ABC grades. Hands = 21 replicates. Medium confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Hand and dermal = ABC grade. Inhalation = acceptable grades. Hands = 16 replicates; dermal = 20 to 31 replicates; and inhalation = 16 replicates. Medium confidence in the hand and dermal data. High confidence in inhalation data. No protection factor needed to define the unit exposure value. Protective gloves not used. Applying Granulars with a Tractor Drawn Spreader (8) PHED V1. 1 (May 1997 Surrogate Table) 80 and 200 acres for groundboom in agriculture and 40 acres on turf Baseline: Hand, dermal, and inhalation = acceptable grades. Hands =5 replicates, dermal = 1 to 5 replicates, and inhalation = 5 replicates. Low confidence in hand, dermal, and inhalation data. No protection factors were required to define the unit exposure values. PPE: As appropriate, the same dermal, hand, and inhalation data are used as for the baseline coupled with a 50% protection factor to account for an additional layer of clothing, a 90% protection factor to account for the use of chemical resistant gloves. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Hand, inhalation, and dermal = acceptable grades. Hands = 17 replicates; dermal = 27 to 30 replicates; and inhalation = 37 replicates. High confidence in all data. No protection factor needed to define the unit exposure value. Protective gloves not used. Applying with Aerosol Cans (9) PHED V1. 1 (May 1997 Surrogate Table) 2 cans Baseline: Hand, dermal, and inhalation = acceptable grades. Hands = 15 replicates; dermal = 15 replicates; and inhalation = 15 replicates. High confidence in all data. No protection factor was needed to define the unit exposure values. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hands = acceptable grades. Hands = 15 replicates. High confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Applying with Trigger Pump Sprayer (10) MRID 410547­ 01 1 bottle Single Layer Clothing & Glove Scenario Monitored In Study: Hand, dermal, and inhalation = acceptable grades. Hands = 15 replicates; dermal = 15 replicates; and inhalation = 15 replicates. High confidence in all data. No protection factor was needed to define the unit exposure values. Engineering Controls: Not considered feasible for this exposure scenario. There are no data compensation issues associated with this study as there is a signed PHED data waiver. Applying with a Right of Way Sprayer (11) PHED V1. 1 (May 1997 Surrogate Table) 1,000 gallons Baseline: Hand and inhalation = acceptable grades. Dermal = ABC grades. Hands = 16 replicates; dermal = 4 to 20 replicates; and inhalation = 16 replicates. Low confidence in hand and dermal data due to low number of replicates. High confidence in inhalation data. No protection factor was needed to define the unit exposure values. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hands = acceptable grades. Hands = 4 replicates. Low confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Applying with a High Pressure Handwand (12) PHED V1. 1 (May 1997 Surrogate Table) 1,000 gallons Baseline: Hand, dermal, and inhalation = all grades. Hands = 2 replicates; dermal = 9 to 11 replicates; and inhalation = 11 replicates. Low confidence in hand, dermal, and inhalation data. No protection factor was needed to define the unit exposure values. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hands = all grades. Hands = 9 replicates. Low confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Dog Grooming With Shampoo (13) MRID 446584­ 01 ½ of 6 oz bottle Clothing (short­ sleeved tee­ shirt, smock & long pants) & No Gloves Scenario Monitored In Study: Hand, dermal, and inhalation = acceptable grades. Hands = 16 replicates; dermal = 16 replicates; and inhalation = 16 replicates. High confidence in all data. No protection factor was needed to define the unit exposure values. Engineering Controls: Not considered feasible for this exposure scenario. There are no data compensation issues associated with this study as it was sponsored by Aventis using Carbaryl. Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Dusting an Animal (14) SOPs for Residential Exposure Assessments (7/ 97) ½ of 4 lb bottle per SOPs The SOPs For Residential Exposure Assessment served as the basis for this assessment (i. e., the assumptions that were used to predict exposures from pet use products in which a percentage of the application rate is the predictor of potential dermal dose). The scenario is based on the use of a baseline clothing scenario. Calculations in which additional PPE are applied are not appropriate given the basis for the assessment. Additionally, the use of engineering controls are not considered feasible for this exposure scenario. Dispersing Granulars & Baits By Hand (15) PHED V1. 1 (May 1997 Surrogate Table) 1 acre Baseline: Values not included because barehanded data were not available and hand exposures are key to this scenario. PPE: Dermal, hand, and inhalation = ABC grades. Hands = 15 replicates, dermal = 16 replicates, and inhalation = 16 replicates. Medium confidence in all data. The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Dispersing Granulars & Baits With a Spoon (16) MRID 452507­ 01 1 acre Baseline: Values not included because barehanded data were not available and hand exposures are key to this scenario. PPE: Dermal, hand, and inhalation = acceptable grades. Hands = 10 replicates, dermal = 10 replicates, and inhalation = 10 replicates. Low confidence in all data because dernal dosimeters were unprotected and the number of replicates. Protective gloves were worn. A 50% protection factor to account for a layer of clothing was used. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. There are no data compensation issues associated with this study as it was sponsored by Aventis. Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Mixer/ Loader/ Applicator Descriptors Mixing/ Loading/ Applying Liquid Sprays w/ Low Pressure, High Volume Turfgun (17) MRID 449722­ 01 5 acres Baseline: Values back­ calculated using 90% protection factor for gloves. Non­ hand dermal data for single layer monitored (see PPE). PPE: See EPA review for data quality (Bangs, 2001), data are considered high quality. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). A 50% protection factor to account for an additional layer of clothing. Study monitored single layer clothing with gloves. Engineering Controls: Not considered feasible for this exposure scenario. There are no data compensation issues associated with this study as it was sponsored by ORETF (Aventis is a member). Turfgun, no glove data were not back calculated using a 90 percent protection factor as it is deemed unreliable. WP formulation in WSP packaging used for turfgun assessment as the unit exposures for this scenario were slightly higher than for the other scenarios and deemed representative of current products/ packaging. Mixing/ Loading/ Applying Wettable Powders with a Low Pressure Sprayer (18a) PHED V1. 1 (May 1997 Surrogate Table) 40 gallons for ornamentals and 20,000ft2 for poultry houses Baseline: The only empirical data that are available are based on the use of chemical­ resistant gloves. It is not appropriate to back­ calculate a non­ glove hand exposure level for this scenario as it is considered an overestimate of exposure because the hands are a key contributor to exposure. PPE: Dermal and inhalation= ABC grades; and hands = acceptable grades. Dermal = 16 replicates; hands = 15 replicates; and inhalation = 16 replicates. Medium confidence in inhalation, dermal, and hand data. A 50% protection factor to account for an additional layer of clothing. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Mixing/ Loading/ Applying Liquids with a Low Pressure Sprayer (18b) PHED V1. 1 (May 1997 Surrogate Table) 40 gallons for ornamentals and 20,000ft2 for poultry houses Baseline: Hands = all grades; dermal and inhalation = ABC grades. Dermal = 9 to 80 replicates; hands = 70 replicates; and inhalation = 80 replicates. Medium confidence in inhalation data. Low confidence in dermal and hand data. No protection factor was needed to define the unit exposure values. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hand = 10 replicates. Hands= ABC grades Low confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Mixing/ Loading/ Applying with a Backpack Sprayer (19) PHED V1. 1 (May 1997 Surrogate Table) 40 gallons for ornamentals and 20,000ft2 for poultry houses Baseline: Dermal and inhalation = acceptable grades. Dermal = 9 to 11 replicates and inhalation = 11 replicates. Low confidence in dermal and inhalation data. The only empirical data that are available are based on the use of chemical­ resistant gloves. It is generally not appropriate to back­ calculate a non­ glove hand exposure levels, an extrapolation has been completed for this scenario, however, because the empirical data indicate that hands are a minor contributor to overall exposure levels. PPE: Hands = C grades. Hands = 11 replicates. Low confidence in hand data. The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Loading/ Applying Granulars with a Belly Grinder (20) PHED V1. 1 (May 1997 Surrogate Table) 1 acre Baseline: Inhalation = acceptable grades; dermal and hands = ABC grades. Dermal = 29 to 45 replicates; hands = 23 replicates; and inhalation = 40 replicates. High confidence in inhalation data. Medium confidence in dermal and hand data. No protection factor was needed to define the unit exposure values. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hands = all grades. Hands = 20 replicates. Low confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Loading/ Applying granulars with a push spreader (21) PHED V1. 1 (May 1997 Surrogate Table) 5 acres Baseline: Values back­ calculated using 90% protection factor for gloves. Non hand dermal data for single layer monitored (see PPE). PPE: See EPA review for data quality (Bangs, 2001), data are considered high quality. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). A 50% protection factor to account for an additional layer of clothing. Study monitored single layer clothing with gloves. Engineering Controls: Not considered feasible for this exposure scenario. There are no data compensation issues associated with this study as it was sponsored by ORETF (Aventis is a member). Mixing/ Loading/ Applying with a Handheld Fogger (22) No Data No Data No Data Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Mixing/ Loading/ Applying with a Handheld Fogger (23) No Data No Data No Data Mixing/ Loading/ Applying with a Granular Backpack Applicator (24) MRID 451672­ 01 1 acre Clothing (coverall and apron worn on back) & Gloves Scenario Monitored In Study: High confidence in all data. No protection factor was needed to define the unit exposure values. Engineering Controls: Not considered feasible for this exposure scenario. There are no data compensation issues associated with this study as it was sponsored by Aventis using Carbaryl. Mixing/ Loading/ Applying with a Tree Injector (25) No Data No Data No Data Drench/ Dipping Forestry & Ornamentals (26) PHED V1. 1 (May 1997 Surrogate Table) 100 gallons of solution prepared Addresses only solution preparation aspects of process. This has been addressed using open mixing liquid data presented above in Scenario 3. Engineering controls are not appropriate for this scenario. Mixing/ Loading/ Applying with a Sprinkler Can (27) PHED V1. 1 (May 1997 Surrogate Table) 10 gallons Scenario assessed using hose­ end sprayer data which are believed to result in similar exposures. However, the extrapolation should be considered rangefinder in nature. Baseline: Inhalation = ABC grades; dermal = C grade; and hands = E grade. Dermal = 8 replicates; hands = 8 replicates; and inhalation = 8 replicates. Low confidence in all data. Study monitored total deposition. A 50% protection factor to account for single layer of clothing was used to define the unit exposure values. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. A 90 % protection factor was used to account for the use of protective gloves. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: Not considered feasible for this exposure scenario. Appendix C/ Table 1: Sources of Exposure Data Used In The Occupational Carbaryl Handler Exposure And Risk Calculations Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments Flagger Descriptors Flagging Aerial Spray Applications (28a) PHED V1. 1 (May 1997 Surrogate Table) 350 acres and 1,200 acres Baseline: Hands, dermal, and inhalation = acceptable grades. Dermal = 18 to 28 replicates; hands = 30 replicates; and inhalation = 28 replicates. High confidence in dermal, hand, and inhalation data. No protection factor was required to calculate unit exposures. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing. Hand = acceptable grades. Hands= 6 replicates. Low confidence in hand data. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: The same data are used as for baseline coupled with a 98% protection factor to account for the use of an engineering control (e. g., sitting in a vehicle). Flagging Aerial Spray Applications (28b) PHED V1. 1 (May 1997 Surrogate Table) 350 acres and 1,200 acres Baseline: Hands and inhalation = All grades. Dermal = ABC grades. Dermal = 16 to 20 replicates; hands = 4 replicates; and inhalation = 4 replicates. Low confidence in all data. Study monitored total deposition. A 50% protection factor to account for single layer of clothing was used to define the unit exposure values. PPE: The same dermal data are used as for baseline coupled with a 50% protection factor to account for an additional layer of clothing and a 90% protection factor to account for the use of gloves. Respirator protection factors of either 5 or 10 applied to account for the use of either dust/ mist masks or cannister type devices (e. g., organic vapor removing half face device). Engineering Controls: The same data are used as for baseline coupled with a 98% protection factor to account for the use of an engineering control (e. g., sitting in a vehicle). C All Standard Assumptions are based on an 8­ hour work day as estimated by the Agency. C All handler exposure assessments in this document are based on the "Best Available" data as defined by the PHED SOP for meeting Subdivision U Guidelines (i. e., completing exposure assessments). Best available grades are assigned to data as follows: matrices with A and B grade data (i. e., Acceptable Grade Data) and a minimum of 15 replicates; if not available, then grades A, B and C data and a minimum of 15 replicates; if not available, then all data regardless of the quality (i. e., All Grade Data) and number of replicates. High quality data with a protection factor take precedence over low quality data with no protection factor. Generic data confidence categories are assigned as follows: High = grades A and B and 15 or more replicates per body part Medium = grades A, B, and C and 15 or more replicates per body part Low = grades A, B, C, D and E or any combination of grades with less than 15 replicates. C PHED grading criteria do not reflect overall quality of the reliability of the assessment. Sources of the exposure factors should also be considered in the risk management decision. Appendix D: Carbaryl Residue Dissipation (DFR & TTR) Data Appendix E: Carbaryl Occupational Postapplication Risk Assessment Appendix F: Carbaryl Residential Handler Exposure Data Appendix F/ Table 1: Exposure Data From MRID 444399­ 01 (Carbaryl Applicator Exposure Study During Application of Sevin ® 5 Dust to Dogs By the Non­ Professional) Replicate lb ai used Inner (µg) Outer (µg) Hand (µg) Face/ Neck (µg) Total Dermal Exposure a (mg) Inhalation Exposure (µg) Upper Arm Front Torso Back Torso Upper Leg Lower Arm Lower Leg 1 0. 0034 40.7 217 122 70.7 8810 13100 5770 98.1 28 383 2 0. 016 173 445 230 130 28300 37000 12500 215 79 232 3 0. 0079 21.8 77.7 60.9 56.4 4240 1630 3890 43.5 10 252 4 0. 0042 23.3 43.9 50.9 40.8 4110 13800 5380 26.8 23 244 5 0. 0083 37.6 216 108 64.3 26200 24200 8140 180 59 149 6 0. 0025 16.4 25 38.3 9. 06 2470 541 4940 23.3 8. 1 37.4 7 0. 003 11.7 97.3 99.3 31.4 3150 2570 4490 61.6 11 66.3 8 0. 0068 41.9 111 89.5 21.8 6450 380 10500 43.4 18 170 9 0. 0068 27.2 79.4 215 31.7 3400 345 11600 65.4 16 158 10 0.012 145 648 224 278 67900 11500 11900 263 93 525 11 0.0047 20 79.4 78.1 53.2 12800 581 7300 280 21 244 12 0.022 97.4 454 435 232 44100 8310 24600 73.5 78 486 13 0.0093 50.5 85.6 64.5 42.3 7680 577 4350 31 13 173 14 0.0014 5.03 17.2 16.7 4. 92 1710 133 3870 11.9 5. 8 82.5 15 0.0085 14.8 159 129 18.6 6320 1350 5980 74 14 216 16 0.014 61.7 138 138 40.3 22000 1960 5140 41 30 509 17 0.0069 15.5 110 53 20 15600 1060 4570 33.1 21 209 18 0.0064 16.3 102 91.8 61.7 13500 651 6830 104 21 67.4 19 0.006 5.12 33.2 39.7 13.8 3830 271 9080 20.3 13 37.1 20 0.004 47.3 66.1 121 127 2720 1990 7650 41.8 13 170 Appendix F/ Table 2: Exposure Data For Hose­ End Sprayers From MRID 444598­ 01 (Mixer Loader Applicator Exposure to RP­ 2 Liquid (21%). Carbaryl Mixer/ Loader/ Applicator Exposure Study during Application of RP­ 2 Liquid (21%) Sevin ® Ready to Use Insect Spray or Sevin ® 10 Dust to Home Garden Vegetables) Rep Carbaryl Applied (lb) Inner Dosimeter (µg) Outer Dosimeter Lower Arm (µg) Outer Dosimeter Lower leg (µg) Hand (µg) Face/ Neck Wipe (µg) Total Dermal Exposure a (µg) Inhalation Exposrue (µg) 1 0. 11 19.1 71.3 571 2770 0.5 3. 43 0. 24 2 0. 076 3.0 7. 26 2548 1030 0.5 3. 59 0. 07 3 0. 045 8.8 34.1 624 291 0.5 0. 96 0. 07 4 0. 025 10.3 10.9 337 1560 0.5 1. 92 0. 07 5 0. 05 3. 0 1.97 1776 1100 17 2.90 0.07 6 0. 083 15.3 32.9 4080 2170 0.5 6. 30 0. 25 7 0. 047 3.0 3. 01 710 462 0.5 1. 18 0. 15 8 0. 052 9.8 62.5 937 618 0.5 1. 63 0. 23 9 0. 041 4.4 26 320 437 0.5 0. 79 0. 07 10 0.053 6.6 32.2 194 691 0.5 0. 92 0. 07 11 0.07 3.0 0. 5 2008 331 0.5 2. 34 0. 07 12 0.051 183.3 61.9 673 3380 0.5 4. 30 0. 21 13 0.031 3.0 7 28.6 693 0.5 0. 73 0. 07 14 0.075 3.0 44 465 3700 0.5 4. 21 0. 07 15 0.026 6.4 3. 4 130 62.6 0. 5 0.20 0.07 16 0.036 30.7 48.8 2587 4440 58 7.16 0.16 17 0.051 85.1 3037 1969 3240 0.5 8. 33 0. 07 18 0.095 3.0 23.3 422 612 0.5 1. 06 0. 07 19 0.052 10.1 158 537 385 0.5 1. 09 0. 23 20 0.025 3.0 0. 5 22.8 149 0.5 0. 18 0. 07 Appendix F/ Table 3: Exposure Data For Low Pressure Handwand Sprayers From MRID 444598­ 01 (Mixer Loader Applicator Exposure to RP­ 2 Liquid (21%). Carbaryl Mixer/ Loader/ Applicator Exposure Study during Application of RP­ 2 Liquid (21%) Sevin ® Ready to Use Insect Spray or Sevin ® 10 Dust to Home Garden Vegetables) Rep Carbaryl Applied (lb) Inner Dosimeter (µg) Outer Dosimeter Lower Arm (µg) Outer Dosimeter ­Lowel leg (µg) Hand (µg) Face/ Neck Wipe (µg) Total Dermal Exposure a (mg) 1 0. 02 3. 0 20.6 921.0 215.0 0. 5 1.16 2 0. 02 3. 0 15.8 476.0 381.0 0. 5 0.88 3 0. 02 3. 0 14.3 76.7 208.0 0. 5 0.30 4 0. 02 30.0 214.0 485.0 2100.0 9. 8 2.84 5 0. 01 3. 0 2.5 36.8 168.0 0. 5 0.21 6 0. 02 7. 9 84.4 3449.0 165.0 0. 5 3.71 7 0. 02 5. 2 7.7 85.3 235.0 0. 5 0.33 8 0. 02 18.6 41.4 876.0 205.0 0. 5 1.14 9 0. 02 3. 0 9.7 99.4 203.0 0. 5 0.32 10 0.02 10.0 5. 9 259.0 378.0 0. 5 0.65 11 0.02 3.0 2. 1 157.0 50.6 0. 5 0.21 12 0.01 3.0 69.4 64.6 451.0 0. 5 0.59 13 0.02 3.0 9. 9 247.0 1550.0 0. 5 1.81 14 0.02 3.0 5. 4 242.0 219.0 0. 5 0.47 15 0.02 7.9 3. 5 2278.0 100.0 0. 5 2.39 16 0.02 5.6 28.3 245.0 415.0 0. 5 0.69 17 0.02 4.5 0. 5 245.0 203.0 0. 5 0.45 18 0.02 3.0 2. 6 299.0 188.0 0. 5 0.49 19 0.02 16.4 5. 5 47.5 86.3 0. 5 0.16 20 0.02 17.5 328.0 255.0 118.0 0. 5 0.72 Appendix F/ Table 4: Exposure Data For Ready­ to­ use Sprayers From MRID 444598­ 01 (Mixer Loader Applicator Exposure to RP­ 2 Liquid (21%). Carbaryl Mixer/ Loader/ Applicator Exposure Study during Application of RP­ 2 Liquid (21%) Sevin ® Ready to Use Insect Spray or Sevin ® 10 Dust to Home Garden Vegetables) Rep Carbaryl Applied (lb) Inner Dosimeter (µg) Outer Dosimeter Lower Arm (µg) Outer Dosimeter Lowel leg (µg) Hand (µg) Face/ Neck Wipe (µg) Total Dermal Exposure a (mg) Inhalation Exposure (µg) 1 0. 0024 3.0 7. 43 21.6 270 0.5 0. 31 0. 66 2 0. 0022 5.5 10.5 33.7 81.9 0. 5 0.13 0.56 3 0. 0028 7.2 10.2 26.1 654 0.5 0. 70 0. 29 4 0. 0025 6.4 13.3 82.9 225 0.5 0. 33 0. 42 5 0. 002 3.0 8. 43 80.8 197 0.5 0. 29 0. 36 6 0. 0022 3.0 7. 92 41.1 150 0.5 0. 20 0. 07 7 0. 002 4.9 5. 5 22 301 0.5 0. 33 0. 36 8 0. 0022 4.3 6. 65 40.4 115 0.5 0. 17 0. 44 9 0. 0021 3.0 0. 5 1.72 44.5 0. 5 0.05 0.07 10 0.0022 3.0 0. 5 2.46 98.1 0. 5 0.11 0.07 11 0.0021 3.0 0. 5 2.3 45.1 0. 5 0.05 0.07 12 0.0022 10.0 2. 29 7. 22 198 0.5 0. 22 0. 19 13 0.0022 3.0 5. 41 3. 51 44.8 0. 5 0.05 0.07 14 0.0021 7.2 2. 46 18.4 16.5 0. 5 0.05 0.23 15 0.002 3.0 3. 84 4. 48 28.2 0. 5 0.04 0.07 16 0.0022 61.8 5. 12 6. 33 392 11.9 0. 48 0. 07 17 0.0022 5.2 2. 23 12.2 3. 67 0. 5 0.02 0.07 18 0.0022 3.0 0. 5 2.54 34.8 0. 5 0.04 0.07 19 0.0022 3.0 4. 39 17.2 67.2 0. 5 0.09 0.07 20 0.0022 3.0 2. 79 18 23.7 0. 5 0.05 0.07 Appendix F/ Table 5: Exposure Data For Dust Applications From MRID 444598­ 01 (Mixer Loader Applicator Exposure to RP­ 2 Liquid (21%). Carbaryl Mixer/ Loader/ Applicator Exposure Study during Application of RP­ 2 Liquid (21%) Sevin ® Ready to Use Insect Spray or Sevin ® 10 Dust to Home Garden Vegetables) Rep Carbaryl Applied (lb) Inner Dosimeter (µg) Outer Dosimeter Lower Arm (µg) Outer Dosimeter Lowel leg (µg) Hand (µg) Face/ Neck Wipe (µg) Total Dermal Exposure a (mg) Inhalation Exposure (µg) 1 0. 0033 126.9 296 902 884 3.23 2.22 7.5 2 0. 025 98.9 346 932 13300 23.5 14.70 15.1 3 0. 0072 57.1 112 1281 526 12.5 1. 99 9. 93 4 0. 012 96.5 453 243 719 34.4 1. 55 26.8 5 0. 012 150.0 139 282 1530 5.85 2.11 3.57 6 0. 013 38.4 309 381 488 3.62 1.22 7.94 7 0. 0045 50.4 359 83 568 3.97 1.06 21.9 8 0. 0093 26.0 1815 59.8 228 5.53 2.13 0.07 9 0. 013 86.5 230 95.4 667 15.9 1. 10 27.4 10 0.015 25.0 452 127 413 13.3 1. 03 5. 73 11 0.019 53.1 167 306 1020 7.25 1.55 40.7 12 0.012 21.6 90.9 66.9 2920 1.96 3.10 7.89 13 0.029 77.7 381 587 423 8.95 1.48 57.7 14 0.0026 44.1 227 305 3030 2.35 3.61 37.1 15 0.02 71.4 153 219 351 1.21 0.80 2.51 16 0.0086 165.7 174 624 1440 1.88 2.41 9.34 17 0.03 93.4 275 413 494 6.89 1.28 42.1 18 0.044 82.2 282 949 259 12.7 1. 59 24.9 19 0.013 171.1 1022 133 1500 23.7 2. 85 29.7 20 0.026 36.0 221 65.5 1210 2.52 1.54 6.74 Appendix F/ Table 6: Exposure Data For Hose­ End Sprayers From MRID 445185­ 01 (Carbaryl Mixer/ Loader/ Applicator Exposure Study during Application of RP­ 2 Liquid (21%) to Fruit Trees and Ornamental Plants) Rep Carbaryl Applied (lb) Inner Dosimeter (µg) Outer Dosimeter Lower Arm (µg) Outer Dosimeter Lowel leg (µg) Hand (µg) Face/ Neck Wipe (µg) Total Dermal Exposure a (mg) Inhalation Exposure (µg) 1 0. 026 4.5 15 37 128 0.5 0. 19 0. 07 2 0. 02 3. 8 133 1890 227 0.5 2. 45 0. 07 3 0. 066 17.0 995 2218 5480 3.6 8. 71 0. 07 4 0. 053 26.5 193 1230 13200 2.2 14.65 0.15 5 0. 026 3.7 337 348 952 0.5 1. 64 0. 29 6 0. 026 18.5 49 161 82 0.5 0. 31 0. 07 7 0. 02 3. 0 99 220 1060 0.5 1. 38 0. 07 8 0. 022 3.6 78 213 694 0.5 0. 99 0. 07 9 0. 021 4.6 28 87 779 0.5 0. 90 0. 07 10 0.02 4.3 298 226 460 1.9 0. 99 0. 07 11 0.035 10.4 47 119 248 0.5 0. 43 0. 08 12 0.046 5.1 23 72 130 0.5 0. 23 0. 07 13 0.042 3.0 270 181 2060 0.5 2. 52 0. 07 14 0.09 9.1 567 1824 1400 0.5 3. 80 0. 23 15 0.029 3.0 123 193 428 0.5 0. 75 0. 07 16 0.026 11.3 36 181 2850 0.5 3. 08 0. 07 17 0.062 3.0 75 878 643 0.5 1. 60 0. 07 18 0.024 21.5 251 97 1830 0.5 2. 20 0. 07 19 0.073 3.0 180 301 736 0.5 1. 22 0. 07 20 0.024 3.9 9. 4 124 521 0.5 0. 66 0. 07 Appendix F/ Table 7: Exposure Data For Low Pressure Handwand Sprayers From MRID 445185­ 01 (Carbaryl Mixer/ Loader/ Applicator Exposure Study during Application of RP­ 2 Liquid (21%) to Fruit Trees and Ornamental Plants) Rep Carbaryl Applied (lb) Inner Dosimeter (µg) Outer Dosimeter Lower Arm (µg) Outer Dosimeter Lowel leg (µg) Hand (µg) Face/ Neck Wipe (µg) Total Dermal Exposure a (mg) Inhalation Exposure (µg) 1 0. 018 3.0 5. 6 11 432 0.5 0. 45 0. 07 2 0. 015 6.7 55 467 259 0.5 0. 78 0. 07 3 0. 02 34.0 571 491 1450 20 2.57 0.07 4 0. 019 4.9 34 88 381 0.5 0. 51 0. 07 5 0. 013 5.5 133 1297 3080 0.5 4. 52 0. 07 6 0. 014 8.4 56 147 567 0.5 0. 78 0. 07 7 0. 018 7.5 906 378 825 0.5 2. 12 0. 07 8 0. 02 12.1 95 440 2970 1.2 3. 52 0. 32 9 0. 017 15.2 27 182 524 0.5 0. 75 0. 16 10 0.015 5.0 42 146 414 1.3 0. 61 0. 24 11 0.019 25.2 59 303 493 0.5 0. 88 0. 07 12 0.018 3.0 15 108 139 0.5 0. 27 0. 07 13 0.018 9.0 79 281 271 0.5 0. 64 0. 07 14 0.02 9.5 209 522 917 0.5 1. 66 0. 07 15 0.015 11.4 131 780 247 1.8 1. 17 0. 37 16 0.017 9.2 25 437 864 0.5 1. 33 0. 2 17 0.02 3.0 78 639 198 0.5 0. 92 0. 07 18 0.017 3.0 51 285 267 0.5 0. 61 0. 38 19 0.02 6.9 41 81 373 0.5 0. 50 0. 07 20 0.018 8.9 81 605 436 1.4 1. 13 0. 33 Appendix G: Carbaryl Residential Handler Risk Assessment Appendix G/ Table 1: Residential Handler Scenario Descriptions for the Use of Carbaryl Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments a Mixer/ Loader/ Applicator Descriptors Garden: Ready­ to­ use trigger sprayer (1) MRID 444598­ 01 1/ 4 to 1 bottle (1 bottle is SOP requirement, others shown for characterization) A total of 40 replicates were monitored in this study. Half of the people wore gloves and the other half did not. The clothing scenario represents short­ sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Garden: Ornamental Duster (2) MRID 444598­ 01 1/ 4 to 1 bottle (1 bottle is SOP requirement, others shown for characterization) A total of 20 replicates were monitored in this study. No individuals wore gloves. The clothing scenario represents short sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Garden: Hose­ end Sprayer (3) MRID 444598­ 01 1000 ft 2 or 100 gallons output (1000ft 2 is SOP requirement, others shown for characterization) A total of 40 replicates were monitored in this study. Half of the people wore gloves and the other half did not. The clothing scenario represents short­ sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Garden: Low Pressure Handwand Sprayer (4) MRID 444598­ 01 5 gallons or 1000 ft 2 (5 gallons is SOP requirement, others shown for characterization) A total of 40 replicates were monitored in this study. Half of the people wore gloves and the other half did not. The clothing scenario represents short­ sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Trees and Ornamentals: Low Pressure Handwand Sprayer (5) MRID 445185­ 01 5 gallons or 1000 ft 2 (5 gallons is SOP requirement, others shown for characterization) A total of 20 replicates were monitored in this study. No individuals wore gloves. The clothing scenario represents short sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Trees and Ornamentals: Hose­ end Sprayer (6) MRID 445185­ 01 100 gallons or 1000 ft 2 (1000 ft 2 is SOP requirement, others shown for characterization) A total of 20 replicates were monitored in this study. No individuals wore gloves. The clothing scenario represents short sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Mixing/ Loading/ Applying with a Backpack Sprayer (7) PHED V1. 1 (7/ 97 Residential SOP Surrogate Table) 5 gallons or 1000 ft 2 (5 gallons is SOP requirement, others shown for characterization) Inhalation and dermal = acceptable grades. Hand data = C grade. Dermal = 9 to 11 replicates, hand = 11 replicates, and inhalation = 11 replicates. Low confidence in data. Hand exposure values were back­ calculated using empirical data that were generated using chemical­ resistant gloves and a 90 percent protection factor. An additional 10x safety factor was applied to the hand exposure value because the calculated hand exposure value did not correspond to the level expected given the other dermal exposure values for the scenario (the 10x factor addition was completed based on instructions contained in the Residential SOPs). Appendix G/ Table 1: Residential Handler Scenario Descriptions for the Use of Carbaryl Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments a Lawncare: Hose­ end Sprayer (8) MRID ­44972201 1000 ft 2 for spot treatments and 20,000ft 2 for broadcast applications A total of 60 replicates were monitored in this study. Half of the subjects used ready­ to­ use packaging while the others used open pour. The values used for assessment were open pour. The clothing scenario represents short­ sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Dusting a Dog (9) MRID 444399­ 01 ½ bottle of product A total of 40 replicates were monitored in this study. Half of the people wore gloves and the other half did not. The clothing scenario represents short­ sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Dipping a Dog (10) SOPs for Residential Exposure Assessments (7/ 97) ½ bottle of product The SOPs For Residential Exposure Assessment served as the basis for this assessment (i. e., the assumptions that were used to predict exposures from pet use products in which a percentage of the application rate is the predictor of potential dermal dose). The scenario is based on the use of a residential clothing scenario (i. e., short pants, short­ sleeved shirt, no gloves, no respirator). Note that the same value is used as for the occupational handler scenarios. The refinement of the SOPs for Residential Exposure Assessment is such that furhter delineation based on clothing scenario is not appropriate (i. e., to alter value based on use of short vs. long pants and long­ sleeved vs. short­ sleeved shirts). Lawncare: Granular and Baits By Bellygrinder (11) SOPs for Residential Exposure Assessments (7/ 97) 1000 ft 2 for spot treatment Inhalation = acceptable grades. Hand and dermal data = ABC grade. Dermal = 20 to 45 replicates, hand = 23 replicates, and inhalation = 40 replicates. Medium confidence in dermal and hand data. High confidence in inhalation data. Lawncare: Granular and Baits By Push­ type Spreader (12) MRID ­44972201 20,000ft 2 for broadcast applications A total of 30 replicates were monitored in this study. The clothing scenario represents short­ sleeved shirt, short pants, and no gloves. The data are considered high quality by the Agency. There are no data compensation issues associated with this study as it was sponsored by Aventis Lawncare: Granular and Baits By Hand (13) SOPs for Residential Exposure Assessments (7/ 97) 1000 ft 2 for spot treatment Dermal, hand and inhalation data = ABC grade. Dermal = 16 replicates, hand = 16 replicates, and inhalation = 16 replicates. Medium confidence in all data. Aerosol Can (14) SOPs for Residential Exposure Assessments (7/ 97) 1 can Hand data = acceptable grades. Dermal and inhalation data = ABC grade. Dermal = 30 replicates, hand = 15 replicates, and inhalation = 30 replicates. Medium confidence in all data. Appendix G/ Table 1: Residential Handler Scenario Descriptions for the Use of Carbaryl Exposure Scenario (Number) Data Source Standard Assumptions (8­ hr work day) Comments a Flea Collar (15) SOPs for Residential Exposure Assessments (7/ 97) 1 collar The SOPs For Residential Exposure Assessment served as the basis for this assessment (i. e., the assumptions that were used to predict exposures from pet use products in which a percentage of the application rate is the predictor of potential dermal dose). The scenario is based on the use of a residential clothing scenario (i. e., short pants, short­ sleeved shirt, no gloves, no respirator). Note that the same value is used as for the occupational handler scenarios. The refinement of the SOPs for Residential Exposure Assessment is such that furhter delineation based on clothing scenario is not appropriate (i. e., to alter value based on use of short vs. long pants and long­ sleeved vs. short­ sleeved shirts). Sprinkler Can (16) MRID 445185­ 01 5 gallons Data from hose­ end sprayer applications to trees and ornamentals was used to assess this scenario. The results should be considered as rangefinder in nature to account for the extrapolation completed for this assessment. Ornamental Paint On (17) SOPs for Residential Exposure Assessments (7/ 97) 1 gallon Hand data = acceptable grade. Dermal and inhalation data = C grade. Dermal = 14 to 15 replicates, hand = 15 replicates, and inhalation = 15 replicates. Low to medium confidence in all data. a All Standard Assumptions are based on an 8­ hour work day as estimated by HED. BEAD data were not available. bAll handler exposure assessments in this document are based on the "Best Available" data as defined by the PHED SOP for meeting Subdivision U Guidelines (i. e., completing exposure assessments). Best available grades are assigned to data as follows: matrices with A and B grade data (i. e., Acceptable Grade Data) and a minimum of 15 replicates; if not available, then grades A, B and C data and a minimum of 15 replicates; if not available, then all data regardless of the quality (i. e., All Grade Data) and number of replicates. High quality data with a protection factor take precedence over low quality data with no protection factor. Generic data confidence categories are assigned as follows: High = grades A and B and 15 or more replicates per body part Medium = grades A, B, and C and 15 or more replicates per body part Low = grades A, B, C, D and E or any combination of grades with less than 15 replicates. c PHED grading criteria do not reflect overall quality of the reliability of the assessment. Sources of the exposure factors should also be considered in the risk management decision. Appendix H: Carbaryl Residential Postapplication Risk Assessment For Turf Uses Appendix I: Carbaryl Residential Postapplication Risk Assessment For Garden/ Ornamental Uses Appendix J: Carbaryl Residential Postapplication Risk Assessment For Pet Uses Appendix K: Determination of Deposition Factors For Carbaryl Mosquito Control Uses Background Information: Carbaryl has been historically used for the control of insect pests such as mosquitoes and black flies in a manner that has employed the use of Ultra­ low Volume (ULV) application methods over wide areas. As the reregistration process has progressed, the labels for these types of applications have been reviewed and the Aventis Corporation has submitted a draft label for the Sevin XLR (4 lb ai/ gallon) product which has been used to develop the risk assessment for these uses. Aventis is interested in maintaining this use pattern even though the marketshare for carbaryl in this area has declined in recent years due to the use of the synthetic pyrethroids and other chemistries. According to the Sevin XLR label, applications can be made using ground, aerial or handheld equipment suitable for fogging urban environments (e. g., backpack or handheld foggers). ULV type applications or thermal fogging applications are allowable based on the label. The label indicates that the optimal droplet size is 8 to 30 µm by mass median diameter (MMD) or volume median diameter (VMD) calculations for ground fogger applications. For aerial applications, the droplet spectra that is specified has a calculated VMD of less than 50 µm and no more than 5 percent of the droplets should be larger than 80 µm. The label presents a range of application rates from 0.016 to 1.0 lb ai/ acre (i. e., 0.016, 0.15, and 1.0 lb ai/ acre). These use rates have not been linked to specific pests or pest pressures on the label. Applications can be made using undiluted material or with a 1: 1 or 1: 2 dilution rate. Agricultural Engineering Considerations: With few notable exceptions such as public health scenarios (e. g., mosquito control), the general intent during most pesticide applications is to confine the deposition of applied chemicals to specific target areas such as agricultural fields. Economic concerns, health concerns, environmental concerns, and efficacy are the generally recognized rationale for limiting off­ target deposition. Pesticide applicators can control deposition patterns through the use of specific types of equipment and by controlling application parameters. Several application parameters can potentially impact deposition patterns of liquid­ form pesticides in the environment during application (e. g., nozzle size, application pressure, vehicle configuration and speed, meteorological conditions including environmental stability, and physical­ chemical characteristics of the formulation). As indicated above, ULV mosquito control applications serve as the basis for this assessment. The general intent of these types of applications is antithetical to most pesticide applications in that spray drift is generally not inhibited but promoted in order to broaden the effective treatment area and ensure that the resulting droplets stay aloft for as long as possible. In fact, the efficacy of mosquito adulticide compounds is based on droplets contacting in­ flight mosquitos. As a result, there are significant agricultural engineering differences that were considered by The Agency in this assessment. These include: C Release heights for mosquito control aerial ULV applications are typically 100 to 500 feet (or even higher) as opposed to most typical agricultural aerial applications where the release height is generally as low as the pilot can go (i. e., often 10 feet or less). Release height can significantly impact spray drift (i. e., the higher the release, the longer to time of impact with target area, and the more potential for drift). A release height of 300 feet was used in this assessment (i. e., the upper limit application height allowed in the AgDRIFT model). C Nozzle configurations are such that extremely small droplets are released as opposed to typical aerial applications (i. e., Sevin XLR label specifies VM of 50 µm while the values for most agricultural applications are 100 µm or more). C Larger aircraft are generally used to make malaria control applications. For example, Lee County Florida, one of the largest Florida mosquito abatement districts, has a fleet of Douglas DC3s and Huey Helicopters. The DC3 is a much larger aircraft than the common agricultural application fixed­ wing aircraft (e. g., Air Tractor AT401). These differences are significant when predicting deposition and were addressed in the Agency calculation of deposition after an aerial ULV application. The DC3 was used as the basis for all AgDRIFT calculations completed by The Agency. Predictive Tools and Data: The Agency has used state­ of­ the­ art tools in order to calculate deposition rates resulting from ground­ based and aerial ULV applications as well as to calculate the postapplication dermal exposures that result from entry into areas previously treated with carbaryl using these techniques. The Agency used AgDrift V2.01 to predict the amount of residues that would deposit in residential areas after aerial ULV application, published data were used to predict deposition after ground ULV applications, and the latest residential exposure assessment methods were used to calculate the risks associated with these residues. The first aspect of this exposure/ risk assessment required the calculation of realistic deposition rates from the aerial and ground­ based ULV applications of carbaryl (i. e., addressed in this appendix ­ residential exposure methods are discussed in detail in Section 3 of the document). The Agency could have taken a very simplistic approach of assigning the application rate as the deposition after an application. However, The Agency did not utilize this approach given the current state of knowledge pertaining to spray drift and recent industry and agency efforts in this area (i. e., this approach would generally be considered as unrealistic given the intent of mosquito control applications). There are a number of predictive tools and open literature articles that pertain to this technical area. Given that ground­ based and aerial ULV applications are allowable, models and data were identified to support a human health exposure/ risk assessment for each scenario. [Note: The Agency recognizes that there are potential issues with the selection and use of these models in this assessment. As such, the use of each model for completing this exposure/ risk assessment is appropriately characterized (see below).] Aerial ULV: In order to calculate deposition from aerial ULV applications, The Agency used AgDRIFT (V 2.01) which is the model that was developed as a result of the efforts of the Spray Drift Task Force (SDTF). The SDTF is a coalition of pesticide registrants whose primary objectives were to develop a comprehensive database of off­ target drift information in support of pesticide registrations and an appropriate model system. This model was selected based on the consensus of several experts in the spray drift area because it represents the current state­ of­ the­ art. The Agency discussed the issue of model selection with several experts in the spray drift community prior to selecting AgDRIFT (e. g., Sandra L. Bird, U. S. EPA; Steven G. Perry, U. S. EPA; Milton E. Teske, Continuum Dynamics; Pat Skyler, U. S. Forest Service; Arnet Jones, U. S. EPA; and Harold Thistle, U. S. Forest Service). The Agency considered using the USDA Forest Service Cramer­ BarryGrim Model (commonly referred to as FSCBG). FSCBG was developed through support from the U. S. Forest Service, in cooperation with the U. S. Army, and has been in existence for over 20 years in various iterations. Actual support and development of FSCBG was completed by Continuum Dynamics, Inc. located in Princeton, New Jersey under the technical direction of Milton E. Teske. However, it was decided that AgDRIFT should be used because it is based on essentially the same algorithms as FSCBG (personal communication with Milton E. Teske of Contiuum Dynamics), it has undergone extensive validation by the SDTF, and it is very user­ friendly compared to FSCBG. AgDRIFT is a Microsoft Windows­ based personal computer program that is provided to the U. S. Environmental Protection Agency's Office of Pesticide Programs as a product of the Cooperative Research and Development Agreement (CRADA) between EPA's Office of Research and Development and the SDTF. AgDRIFT predicts the motion of spray material released from aircraft, including the mean position of the material and the position variance about the mean as a result of turbulent fluctuations. AgDRIFT enhancements include a significant solution speed increase, an in­ memory computation of deposition and flux as the solution proceeds, and extensive validation based on 180 separate aerial treatments performed during field trials in 1992 and 1993 by the SDTF. Ground ULV: In contrast to the aerial ULV scenario, the data available to predict deposition patterns and resulting exposures from ground­ based ULV malaria applications are limited. In fact, The Agency utilized two published journal articles and a preliminary model developed for the Environmental Fate and Effects Division of OPP by EPA's Office of Research and Development as the basis of this effort. These documents include: Mass Recovery of Malathion in Simulated Open Field Mosquito Adulticide Tests: N. S. Tietze, P. G. Hester, and K. R. Shaffer; Archives of Environmental Contamination and Toxicology; 26: 473­ 477 (1994). [Note: This document was used as the primary source of deposition rates resulting from ground­ based ULV mosquito applications.] Downwind Drift and Deposition of Malathion on Human Targets From Ground Ultra­ Low Volume Mosquito Sprays: J. C. Moore, J. C. Dukes, J. R. Clark, J. Malone, C. F. Hallmon, and P. G. Hester; Journal of the American Mosquito Control Association; Vol. 9, No. 2 (June, 1993).[ Note: This document was used as the primary source of deposition rates resulting from ground­ based ULV mosquito applications and as a confirmatory source of exposure data.] Modeling of Deposition From Mosquito Adulticide Applications: S. G. Perry and W. B. Petersen of EPA/ ORD for Arnet Jones of EPA/ OPP (February 7, 1995). [Note: This is an internal document that has not been peer reviewed. It was used only for confirmatory purposes in this exposure/ risk assessment.] Determination of Deposition Rates: Deposition rates were determined for both aerial and ground­ based ULV application methods as a percentage of the nominal application rate (i. e., how much of the target application rate actually deposited on outdoor surfaces such as turf). The application rates used to complete the assessment are the range specified above. As indicated above, AgDRIFT V 2.01 was used to calculate the deposition rate from aerial ULV applications. The following inputs were used as the basis of the AgDRIFT calculations: C AgDRIFT Model Tier: 3. C Droplet Size Distribution: Dv0.1 = 25.59 µm; Dv0.5 = 51.0 µm; Dv0.9 = 74.27 µm; and <141 µm = 100 percent (developed to reflect droplet spectrum requirements of Sevin XLR label). [Note: The droplet distribution was developed based on the Sevin label. No proprietary SDTF data were used in the completion of this assessment.] C Spray Material: User­ defined option (oil option). Inputs include: nonvolatile rate 0.5 lb per acre, specific gravity 1.2 (calculated based on approximately 10 pounds per gallon), spray rate 0.25 gallons/ acre, active ingredient application rate (0.5 lb ai/ acre), and evaporation rate (1 µm 2 /deg C/ sec). [Note: Several of these parameters do not exactly coincide with the Sevin XLR label but were used because the Sevin XLR label inputs exceeded the allowable input parameters. These differences are not expected to significantly effect the AgDRIFT results because a nonvolatile oil was selected, hence the critical input is the active ingredient application rate. Additionally, no proprietary SDTF physical property data were used in the completion of this assessment. ] C Aircraft: User­ defined option (fixed­ wing option). Inputs include: Douglas DC3, wingspan: 94.6 ft (semispan 47.28 ft), typical application airspeed: 228 mph, weight: 21397 pounds, planform area: 999 ft 2 , propeller RPM: 2550, propeller radius: 5.81 feet, engine vertical distance: ­4.003 feet, and engine forward distance: 20.01 feet. [Note: DC3­ specific inputs were obtained from the FSCBG (V4) aircraft library.] C Nozzles: User­ defined option. Inputs include number of nozzles: 60, vertical distance of nozzles from wing: ­2.66 feet, horizontal distance from wing: ­0.82 feet, and horizontal distance limit: 75 percent. C Meteorology: Inputs were not changed from Tier 3 recommendations of wind speed: 2 mph, wind direction: ­90 degrees (perpendicular to flight path), temperature: 86° F, and relative humidity: 50 percent. C Control: Inputs were altered from the Tier 3 recommendations. The parameters that were used included a spray release height of 300 feet, 20 spray lines (aircraft passes) in each application event, a swath width of 500 feet, and a swath displacement based on the aircraft centerline. C Advanced Settings: Inputs were not changed from Tier 3 recommendations of wind speed height (2 meters), maximum compute time (600 seconds), maximum downwind distance (795 meters), vortex decay rate (0.56 m/ s), aircraft drag coefficient (0.1), propeller efficiency (0.8), and ambient pressure (1013 mb). AgDRIFT is capable of producing a variety of useful outputs. The key for The Agency in this assessment was to determine from the model what percentage of the application volume remained aloft and what percentage of the resulting droplets deposited on the surfaces in the treatment area as well as downwind from the treatment area. AgDRIFT is generally intended to calculate deposition rates in areas that are downwind from the treatment area (i. e., presented from the border of the treatment area to areas of interest downwind). The Agency has used the values at the border of the treatment area to represent the deposition rate within the treated area. It is clear from the results that from the edge of the treatment area to 2000 feet downwind, approximately 9.5 percent of the theoretical application is deposited. This value is intuitively consistent with what one might suspect would occur considering the agricultural engineering parameters associated with mosquito applications (see graph below). As indicated above, two published journal articles served as the basis for predicting deposition rates, as a percentage of the application rate, after ground­ based ULV application for mosquito control (i. e., Tietze, et al, 1994 and Moore, et al, 1993). Both of these studies were completed using ULV formulations of malathion (91 and 95 percent). The Agency anticipates that the "behavior" of these formulations in the referenced studies would not be significantly different from the Sevin XLR formulation because the physical­ chemical properties of the malathion formulations and the nature of the application would be expected to be similar (i. e., the Agency believes the malathion formulations to be acceptable surrogates for Baytex in this analysis). In the study conducted by Moore, et al both human exposure and deposition was quantified over 5 separate application events. A 91 percent formulation of malathion was applied in April and May of 1989 in the early evening (a time of day for relative atmospheric stability). A Leco HD ULV cold aerosol generator (Lowndes Engineering Company, Valdosta Georgia) was used to make each application. The application parameters included a fluid flow rate of 4.3 fluid ounces per minute, a vehicle groundspeed of 10 mph, and a nominal application rate of 0.05 lb ai/ acre (i. e., equates to a deposition rate of 0.51 µg/ cm 2 ). Deposition was monitored at three locations downwind from the treatment area (i. e., 15.2m, 30.4m, and 91.2m). For the events considered in the deposition calculations, "average amounts of malathion deposited on ground level at 15.2, 30.4, and 91.2 m were not significantly different." The percentage of the application rate reported to have deposited ranged from 1 to 14 percent. The mean deposition value for all measurements was 4.3 percent (n= 35, CV= 98). In the study conducted by Tietze, et al only deposition was quantified over 6 separate application events (i. e., one event was not included in deposition calculations "due to negative air stability"). The application parameters were similar to that used by Moore et al. A 95 percent formulation of malathion was applied from May to August of 1993. A Leco 1600 ULV cold aerosol generator (Lowndes Engineering Company, Valdosta Georgia) was also used to make each application. The application parameters included a fluid flow rate of 4.3 fluid ounces per minute, a vehicle groundspeed of 10 mph, and a nominal application rate of 0.057 lb ai/ acre (i. e., equates to a deposition rate of 0.58 µg/ cm 2 ). Deposition was monitored at four locations downwind from the treatment area (i. e., 5 m, 25 m, 100 m and 500 m). For the events considered in the deposition calculations, "malathion mass deposited differed significantly between the 500 m site and the three closer sites (df = 3; F­ value = 3.42; P< 0.05)." The percentage of the application rate reported to have deposited (not including 500 m samples which were much less) ranged up to 5.8 percent. The mean deposition value for all measurements was 3.8 percent. Considering the data that are available in the Tietze et al and Moore et al papers, an off­ target deposition rate of 5 percent was used by The Agency to evaluate ground­ based ULV applications. A value slightly higher than the mean values for both studies was selected because of the variability in the data and the limited number of datapoints. It should be noted that this value is also consistent with the draft modeling assessment for ground­ ULV approaches completed by S. T. Perry and W. B. Petersen of EPA's Office of Research and Development (i. e., within a factor of 5). Perry and Petersen used "the INPUFF Lagrangian puff model" as the basis for their assessment (Petersen and Lavdas, 1986: INPUFF 2.0 ­ A Multiple Source Gaussian Puff Dispersion Algorithm, User's Guide, EPA/ 600/ 8­ 86/ 024). Depending on the scenario selected from this document, deposition rates ranged from approximately 2.5 percent deposition 450 m downwind to 15 to 20 percent deposition immediately adjacent to the treatment zone. The following deposition rates presented as a percentage of the application rate served as the basis of the postapplication exposure calculations completed by The Agency: C Ground­ based ULV = 5 percent of application rate, and C Aerial ULV = 9.5 percent of application rate. Appendix L: Carbaryl Residential Postapplication Risk Assessment For Mosquito Control Appendix M: Carbaryl Residential Postapplication Risk Assessment For Oyster Bed Uses

epa

2024-06-07T20:31:42.166576

regulations

EPA-HQ-OPP-2002-0138-0006

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES May 30, 2002 MEMORANDUM SUBJECT: Carbaryl. List A Reregistration Case 0080. Chemical No. 056801. Revised Product and Residue Chemistry Chapters for the Reregistration Eligibility Decision. DP Barcode: D283328. FROM: Felecia Fort, Chemist Reregistration Branch 1 Health Effects Division (7509C) THRU: Whang Phang, Ph. D., Branch Senior Scientist Reregistration Branch 1 Health Effects Division (7509C) TO: Jeff Dawson, Chemist Health Effects Division( 7509C) and Anthony Britten, Chemical Review Manager Special Review and Reregistration Division (7508C) Attached are the Revised Product and Residue Chemistry Chapters for the Carbaryl Reregistration Eligibility Decision Document (RED). The chapters were revised to incorporate comments submitted by the registrant. These revisions include changes to the requirements for label amendments, changes to label acceptance dates, and changes to the food/ feed use patterns table. The chapters were also changed to reflect uses that are not being supported by the registrant or have been cancelled. Product Chemistry Most pertinent data requirements are satisfied for the Aventis 99% T, except that data are required for UV/ visible absorption (OPPTS 830.7050). For the Aventis 97.5% and 80% FIs, and the Drexel 50% FI, additional data are required concerning product identity and composition, discussion of formation of impurities, certified limits, enforcement analytical method, oxidation/ reduction, explodability, storage stability, corrosion characteristics, and density (OPPTS 830.1550, 1670, 1750, 1800, 6314, 6316, 6317, 6320, and 7000). Data requirements for the Drexel and Platte 99% Ts, and AgrEvo 97.5% FI, which are repackaged from EPA­ registered products, will be satisfied by data for the source products. All product­ specific product chemistry data are required for the Sureco 80% FI, Amvac 46% FI, and AgrEvo 1% FI. Provided that the registrants submit the data required in the attached data summary tables for the carbaryl MPs, and 2 either certify that the suppliers of beginning materials and the manufacturing processes for the carbaryl MPs have not changed since the last comprehensive product chemistry review or submit complete updated product chemistry data packages, HED has no objections to the reregistration of carbaryl with respect to product chemistry data requirements. Residue Chemistry The residue chemistry database is essentially complete. The reregistration requirements for plant and livestock metabolism are fulfilled. Acceptable metabolism studies depicting the qualitative nature of the residues in lettuce, radish, soybean, ruminants and poultry have been submitted and evaluated. In addition, adequate magnitude of the residue data are available on the following crops: alfalfa, almond, asparagus, beans (dried and succulent), blueberry, broccoli, cabbage, celery, cherry, citrus fruits, clover, corn (sweet and field), cucurbits (cantaloupes, cucumbers and squash), cranberry, flax, grape, head and leaf lettuce, mustard greens, okra, peanut, peas (dried and succulent), pecan, pepper, pistachio, pome fruits, potato, prickly pear cactus, raspberry, rice, sorghum, soybean, spinach, stone fruits, strawberry, sunflower, sweet potato, tobacco, tomato, and walnut. The following data gaps remain outstanding. ° A review of the labels and supporting residue data indicate that several label amendments are required. Details are provided in the attached chapter. ° The requirement for acceptable enforcement methods which determine residues of concern in plant and livestock commodities remains outstanding. ° The requirements for storage stability data are not satisfied for purposes of reregistration. Additional data are required depicting the storage stability of carbaryl per se in an oilseed, processed commodities of an oily crop, and a dried fruit stored for up to 10 months. In addition, the registrant is relying on earlier magnitude of the residue studies that are not supported by the existing storage stability data; therefore, additional storage stability data are required. The required data must reflect storage intervals of 18 months for alfalfa commodities, 15 months for potatoes, 22 months for wheat commodities, and 33 months for rangeland grass. In addition, if the registrant wishes to rely on the previously submitted sugar beet processing study, information pertaining to sample conditions and intervals for the study must be submitted. ° For the purpose of reregistration, the requirements for storage stability data for carbaryl residues in livestock commodities are partially satisfied. Additional information on the storage intervals prior to analysis for metabolite residues in the cattle feeding study is required. ° Separate tolerances on many commodities need to be reassigned concomitant with establishing tolerances for the appropriate crop group and subgroup. The recommended changes are summarized in Table C under "Tolerances Needed Under 40 CFR §180.169( a), crop group/ subgroup tolerances." 3 ° The data submitted are not adequate to support the use of granular (G) formulations of carbaryl on leafy vegetables. Residues of carbaryl found in leaf lettuce were not consistent. Both samples of lettuce from the 10% G treatment had substantially higher residues (37.01 and 47.22 ppm) than one of the samples treated with the FlC (23.25 ppm). Additionally, all residues were significantly above the current tolerance of 10 ppm. and all residue data submitted in support of the tolerance in lettuce (< 8.85 ppm). No explanation for the higher residues was given by the registrant. The registrant may elect to repeat the side by side trial on leaf lettuce again or submit a rationale for the results of the leaf lettuce study. ° Data are required depicting residues of carbaryl in/ on grass forage harvested immediately (0­ day) following the last of two applications of carbaryl (WP or FlC) at 1.5 lb ai/ A to pasture. A total of 12 field trials are required in areas throughout the U. S. ° Adequate data are available to reassess the tolerances for residues of carbaryl in/ on dried beans, cowpeas, lentils and peas with pods. These data support the establishment of crop subgroup tolerances for edible­ podded legume vegetables (6A), and for dried, shelled pea and bean except soybean (6C). However, additional residue data are required if the registrant seeks tolerances for residues in/ on succulent, shelled pea and bean commodities. A total of 12 tests, six tests each on a succulent, shelled cultivar of bean and garden pea, are required to support a tolerance for residues in/ on the succulent, shelled pea and bean crop subgroup (6B). The registrant is referred to OPPTS GLN 860.1500 for the number and distribution of tests required. ° Adequate data are available to reassess the tolerance for wheat forage and straw. However, the Agency now considers wheat hay a significant RAC for feed purposes (OPPTS GLN 860.1000 Table 1.). A full set of 20 field trials as specified in OPPTS GLN 860.1500 are required depicting carbaryl residues in/ on wheat hay. When all the field trials are complete, PHIs and tolerances for hay based on the field trial data should be proposed. Data on wheat hay will be translatable to proso millet hay. ° The registrant intends to support a tolerance for residues of carbaryl in/ on imported pineapples (Aventis personal communication with C. Olinger, 9/ 24/ 98 SMART meeting). Residue data are required depicting residues in/ on pineapples following application of carbaryl at the maximum use rate and minimum PHI. Five trials must be submitted, three from Costa Rica and two from Mexico. ° The registrant does not intend to support carbaryl uses on avocados, barley, maple sap, oats, rye, and sweet sorghum; however, IR­ 4 has indicated (Correspondence from K. Dorschner, IR­ 4 Project, 9/ 15/ 94) that they may fulfill the residue data requirements for some of these commodities. These data have not been submitted. cc: List B Rereg. File RDI: WPhang 11/ 7/ 00, WJHazel 10/ 7 /2000 7509C: FFort: RRB1: CM2: Rm 722H: 703 305­ 7478: 11/ 03/ 2000 CARBARYL Chemical ID No. 056801; Case 0080 Product Chemistry Chapter of the Reregistration Eligibility Decision (RED) Document O O N H CH 3 CARBARYL REREGISTRATION ELIGIBILITY DECISION: PRODUCT CHEMISTRY CONSIDERATIONS Chemical ID No. 056801; Case No. 0080 DESCRIPTION OF CHEMICAL Carbaryl [1­ naphthyl N­ methylcarbamate] is a broad­ spectrum insecticide used for control of various insects on numerous varieties of fruits, nuts, and field and vegetable crops. Empirical Formula: C12H11NO2 Molecular Weight: 201.2 CAS Registry No.: 63­ 25­ 2 Chemical ID No.: 056801 IDENTIFICATION OF ACTIVE INGREDIENT Carbaryl is a white to light tan solid with a melting point of 142 C, vapor pressure of <0.005 mm Hg at 26 C, specific gravity of 1.23 at 20 C, and octanol/ water partition coefficient (Koc) of 217. Carbaryl is soluble in water (40 ppm at 25 C) and in organic solvents including dimethyl formamide ( # 45 g/ 100 mL); acetone, cyclohexanone, and isophorone ( # 25 g/ 100 mL); methylethyl ketone ( # 20 g/ 100 mL); dichloromethane ( # 15 g/ 100 mL); ethanol and ethyl acetate ( # 10 g/ 100 mL); mixed aromatic solvents and xylene ( # 3 g/ 100 mL); and kerosene ( # 1 g/ 100 mL). Carbaryl hydrolyzes rapidly in alkaline solutions. MANUFACTURING­ USE PRODUCTS A search of the Reference Files System (REFS) conducted 10/ 25/ 00 identified 10 carbaryl manufacturing­ use products (MPs) registered under Chemical ID No. 056801; the registered carbaryl MPs are listed below in Table 1. Only the registered MPs listed below are subject to a reregistration eligibility decision. Table 1. Registered Carbaryl Manufacturing­ Use Products. 3 Table 2. Product chemistry data requirements specified in the Carbaryl FRSTR. Product OPPTS 830 Guidelines Outstanding 99% T (EPA Reg. No. 264­ 324) 830.1600, 1620, 1670, 1700, 1750, 1800, 6313, 7000, 7370, and 7950 97.5% T (EPA Reg. No. 264­ 325) 830.1670, 1750, 1800, 6314, 6316, 6317, 6320, and 7000 80% FI (EPA Reg. No. 264­ 328) 830.1670, 1750, 1800, 6314, 6316, 6317, 6320, and 7000 99% T (EPA Reg. No. 19713­ 75) All Group A and B Guidelines 50% FI (EPA Reg. No. 19713­ 369) a 830.1670, 1750, 1800, 6314, 6316, 6317, 6320, and 7000 97.5% FI (EPA Reg. No. 4816­ 270) None; data requirements to be satisfied by the source product. 46% FI (EPA Reg. No. 5481­ 190) All Group A and B Guidelines. a Based on data submitted by Aventis. The current status of the product chemistry data requirements for the carbaryl manufacturing­ use products is presented in the attached data summary tables. Refer to these tables for a listing of the outstanding product chemistry data requirements. CONCLUSIONS All pertinent product chemistry data requirements are satisfied for the Aventis 99% T, except that data are required for UV/ visible absorption (OPPTS 830.7050). For the Aventis 97.5% and 80% FIs, and the Drexel 50% FI, additional data are required concerning product identity and composition, discussion of formation of impurities, certified limits, enforcement analytical method, oxidation/ reduction, explodability, storage stability corrosion characteristics, and density (OPPTS 830.1550, 1670, 1750, 1800, 6314, 6316, 6317, 6320, and 7000). Data requirements for the Drexel and Platte 99% Ts, and AgrEvo 97.5% FI, which are repackaged from EPA­ registered products, will be satisfied by data for the source products. All productspecific product chemistry data are required for the Sureco 80% FI, Amvac 46% FI, and AgrEvo 1% FI. Provided that the registrants submit the data required in the attached data summary tables for the carbaryl MPs, and either certify that the suppliers of beginning materials and the manufacturing processes for the carbaryl MPs have not changed since the last comprehensive product chemistry review or submit complete updated product chemistry data packages, HED has no objections to the reregistration of carbaryl with respect to product chemistry data requirements. AGENCY MEMORANDA CITED IN THIS DOCUMENT CBRS No( s).: 8724 DP Barcode( s): D169720 Subject: Rhone­ Poulenc Ag Company: Response to the Carbaryl Reregistration Standard: Residue and Product Chemistry Comments From: R. Perfetti 2 Formulation EPA Reg. No. Registrant 99% T 264­ 324 Aventis Ag Company (formerly Union Carbide) 97.5% FI a 264­ 325 80% FI 264­ 328 99% T b 19713­ 75 Drexel Chemical Company 50% FI c 19713­ 369 99% T b 34704­ 707 Platte Chemical Company Inc. 97.5% FI b 4816­ 270 AgrEvo Environmental Health (formerly Fairfield American) 1% FI 4816­ 407 80% FI 769­ 971 Sureco Inc. 46% FI 5481­ 190 Amvac Chemical Corporation a Although REFS identifies this product as a technical (T), it is appropriately identified as an formulation intermediate (FI) because it is formulated from a registered technical product. b Repackaged from an EPA­ registered product; confirmed for the Drexel 99% T (EPA Reg. No. 19713­ 75) subsequent to the FRSTR. c Transferred from Aventis (EPA Reg. No. 264­ 327; 7/ 15/ 92). REGULATORY BACKGROUND The Carbaryl Reregistration Standard dated 6/ 11/ 82 and Guidance Document dated 3/ 30/ 84 required additional generic and product­ specific product chemistry data for the registered carbaryl MPs. The Carbaryl (FRSTR) Reregistration Standard dated 5/ 3/ 88 reviewed data submitted in response to the Guidance Document and summarized the outstanding data requirements for the reregistration of carbaryl. Additional data requirements listed in the FRSTR are presented in Table 2. The FRSTR did not address the AgrEvo 1% FI (EPA Reg. No. 4816­ 407), which was registered 3/ 31/ 72; the Platte 99% T (EPA Reg. No. 34704­ 707) and Sureco 80% FI (EPA Reg. No. 769­ 971) were registered subsequent to issuance of the FRSTR. 4 To: W. Burnam and L. Rossi Dated: 11/ 1/ 91 MRID( s): 41982601 CBRS No( s).: 10083 DP Barcode( s): D179698 Subject: Rhone­ Poulenc Ag Company: Response to the Carbaryl Reregistration Standard: Nitrosamine & Stability Considerations. From: K. Dockter To: L. Propst/ J. Edwards Dated: 7/ 14/ 92 MRID( s): 42318501 CBRS No( s).: 11101 DP Barcode( s): D186160 Subject: Response to the Carbaryl Reregistration Standard: Product Chemistry From: R. Perfetti To: L. Rossi and E. Saito Dated: 1/ 29/ 93 MRID( s): None CBRS No( s).: 11201 DP Barcode( s): D186515 Subject: Response to the Carbaryl Reregistration Standard: Product Chemistry. From: R. Perfetti To: L. Rossi and E. Saito Dated: 4/ 21/ 93 MRID( s): 42583901 and 42583902 5 CBRS No( s).: 12225 DP Barcode( s): D193013 Subject: Carbaryl Reregistration: List A Chemical No. 056801; Case No. 0080. Rhone­ Poulenc Response to the Carbaryl Product Chemistry Data Requirements Regarding Dissociation Constant and pH (Guideline Nos. 63­ 10 and 63­ 12). From: F. Toghrol To: L. Rossi/ L. Propst Dated: 1/ 26/ 94 MRID( s): 42832401 CBRS No( s).: 13127 DP Barcode( s): D198578 Subject: Carbaryl. Rhone­ Poulenc 1/ 4/ 94 Response [62­ 3 data for EPA Reg. 264­ 324] to 5/ 13/ 93 Agency Letter [RE: 5/ 3/ 88 FRSTR] Rereg. Case 0080. From: K. Dockter To: J. Loranger Dated: 4/ 29/ 94 MRID( s): 43075801 CBRS No( s).: 15442 DP Barcode( s): D214535 Subject: Carbaryl (056801) Reregistration Case No. 0080, Drexel Request for Product Chemistry Generic Data Exemption (GDE), New Confidential Statement of Formula. From: S. Hummel To: J. Loranger/ L. Propst Dated: 5/ 8/ 95 MRID( s): None 6 PRODUCT CHEMISTRY CITATIONS Bibliographic citations include only MRIDs containing data which fulfill data requirements. References (cited): 00151776 Union Carbide Agricultural Products Co., Inc. (1984) The Name, Chemical Identity and Composition of the Pesticide Chemical Sevin. Unpublished compilation. 336 p. 41982601 McDaniel, R.; Weiler, D. (1987) Vapor Pressure Determination of Carbaryl: Final Report: Lab Project Number: 40196. Unpublished study prepared by Rhone­ Poulenc Ag Co. 35 p. 42318501 Siemann, L. (1992) Product Chemistry on Technical Grade Carbaryl in Support of Registration: Analysis for Nitrosoamines and Stability Study: [Interim Report]: Lab Project Number: 6489­ F. Unpublished study prepared by Midwest Research Institute. 26 p. 42583901 Helfant, L. (1992) Sevin Brand 99% Technical Carbaryl Insecticide: Product Identity and Composition Series 61: Lab Project Number: AC­ 92­ 014: 41330. Unpublished study prepared by Rhone­ Poulenc Ag Co. 42 p. 42583902 Siemann, L. (1992) Product Chemistry on Technical Grade Carbaryl in Support of Registration Analysis for Nitrosoamines and Stability Study: Lab Project Number: 6489­ F. Unpublished study prepared by Midwest Research Institute. 149 p. 42832401 Siemann, L. (1993) Carbaryl Product Chemistry: Lab Project Number: 3424­ F. Unpublished study prepared by Midwest Research Institute. 21 p. 43075801 Siemann, L. (1993) Method Validation for Analysis of Carbaryl: Lab Project Number: 3521/ F. Unpublished study prepared by Midwest Research Institute. 127 p. 7 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: Aventis Ag Company Product( s): 99% T (EPA Reg No. 264­ 324) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition Y 00151776, 42583901 3 830.1600 Description of materials used to produce the product Y 00151776, 42583901 3 830.1620 Description of production process Y 00151776, 42583901 3 830.1670 Discussion of formation of impurities Y 00151776, 42583901 3 830.1700 Preliminary analysis Y 00151776, 42318501 4 , 42583902 3 830.1750 Certified limits Y 00151776, 42583901 3 830.1800 Enforcement analytical method Y 00151776, 43075801 5 830.6302 Color Y 00151776 830.6303 Physical state Y 00151776 830.6304 Odor Y 00151776 830.6313 Stability to normal and elevated temperature, metals, and metal ions Y 00151776, 42318501 4 830.6314 Oxidation/ reduction: chemical incompatibility Y 00151776 830.6315 Flammability N/ A 6 830.6316 Explodability Y 00151776 830.6317 Storage stability Y 00151776 830.6319 Miscibility N/ A 6 830.6320 Corrosion characteristics Y 00151776 830.7000 pH Y 42832401 7 830.7050 UV/ visible absorption N 8 830.7100 Viscosity N/ A 6 830.7200 Melting point/ melting range Y 00151776 830.7220 Boiling point/ boiling range N/ A 6 830.7300 Density/ relative density/ bulk density Y 00151776 830.7370 Dissociation constants in water Y 42832401 7 830.7550 Partition coefficient (n­ octanol/ water), shake flask method Y 00151776 830.7840 Water solubility: column elution method; shake flask method Y 00151776 830.7950 Vapor pressure Y 00151776, 41982601 9 1 Y = Yes; N = No; N/ A = Not Applicable. Aventis indicated (CBRS No. 11101, D186160, 1/ 29/ 93, R. Perfetti) that the alternate formulation for which data were required in the FRSTR is no longer produced. 2 MRID 00151776 was reviewed initially under a HED Memorandum from W. T. Chin dated 9/ 18/ 85 and reevaluated in the Carbaryl (FRSTR) Reregistration Standard dated 5/ 3/ 88; remaining references were reviewed as noted. 3 CBRS No. 11201, D186515, 4/ 21/ 93, R. Perfetti. 4 CBRS No. 10083, D179698, 7/ 14/ 92, K. Dockter. 5 CBRS No. 13127, D198578, 4/ 29/ 94, K. Dockter. 6 Data are not required because the T/ TGAI is a solid at room temperature. 7 CBRS No. 12225, D193013, 1/ 26/ 94, F. Toghrol. 8 The OPPTS Series 830, Product Properties Test Guidelines require data pertaining to UV/ visible absorption for the PAI. 9 CBRS No. 8724, D169720, 11/ 1/ 91, R. Perfetti. 8 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: Aventis Ag Company Product( s): 97.5% FI (EPA Reg. No. 264­ 325) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition N 3 00151776 830.1600 Description of materials used to produce the product Y 00151776 830.1650 Description of formulation process Y 00151776 830.1670 Discussion of formation of impurities N 4 00151776 830.1700 Preliminary analysis N/ A 5 830.1750 Certified limits N 3 00151776 830.1800 Enforcement analytical method N 6 00151776 830.6302 Color Y 00151776 830.6303 Physical state Y 00151776 830.6304 Odor Y 00151776 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 5 830.6314 Oxidation/ reduction: chemical incompatibility N 830.6315 Flammability N/ A 7 830.6316 Explodability N 830.6317 Storage stability N 830.6319 Miscibility N/ A 7 830.6320 Corrosion characteristics N 830.7000 pH N 830.7050 UV/ visible absorption N/ A 5 830.7100 Viscosity N/ A 7 830.7200 Melting point/ melting range N/ A 5 830.7220 Boiling point/ boiling range N/ A 5 830.7300 Density/ relative density/ bulk density Y 00151776 830.7370 Dissociation constants in water N/ A 5 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 5 830.7840 Water solubility: column elution method; shake flask method N/ A 5 830.7950 Vapor pressure N/ A 5 1 Y = Yes; N = No; N/ A = Not Applicable. Although REFS identifies this product as a T, it is appropriately identified as an FI because it is formulated from a registered technical product. 2 MRID 00151776 was reviewed initially under a HED Memorandum from W. T. Chin dated 9/ 18/ 85 and reevaluated in the Carbaryl (FRSTR) Reregistration Standard dated 5/ 3/ 88. 3 Product identity, nominal concentrations and proposed certified limits must be submitted on EPA Form 8570­ 4. 4 A discussion must be submitted concerning the possible formation of impurities associated with the inert ingredients in the MP and the potential for formation of nitrosamines in the formulation process or in storage. 5 Data requirements for the TGAI will be satisfied by data for the technical source product. 6 Supporting validation data must be submitted for the enforcement method used to quantitate the active ingredient in the formulated product. 7 Data are not required because the MP is a solid at room temperature. 9 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: Aventis Ag Company Product( s): 80% FI (EPA Reg. No. 264­ 328) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition N 3 00151776 830.1600 Description of materials used to produce the product Y 00151776 830.1650 Description of formulation process Y 00151776 830.1670 Discussion of formation of impurities N 4 00151776 830.1700 Preliminary analysis N/ A 5 830.1750 Certified limits N 3 00151776 830.1800 Enforcement analytical method N 6 00151776 830.6302 Color Y 00151776 830.6303 Physical state Y 00151776 830.6304 Odor Y 00151776 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 5 830.6314 Oxidation/ reduction: chemical incompatibility N 830.6315 Flammability N/ A 7 830.6316 Explodability N 830.6317 Storage stability N 830.6319 Miscibility N/ A 7 830.6320 Corrosion characteristics N 830.7000 pH N 830.7050 UV/ visible absorption N/ A 5 830.7100 Viscosity N/ A 7 830.7200 Melting point/ melting range N/ A 5 830.7220 Boiling point/ boiling range N/ A 5 830.7300 Density/ relative density/ bulk density Y 00151776 830.7370 Dissociation constants in water N/ A 5 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 5 830.7840 Water solubility: column elution method; shake flask method N/ A 5 830.7950 Vapor pressure N/ A 5 1 Y = Yes; N = No; N/ A = Not Applicable. 2 MRID 00151776 was reviewed initially under a HED Memorandum from W. T. Chin dated 9/ 18/ 85 and reevaluated in the Carbaryl (FRSTR) Reregistration Standard dated 5/ 3/ 88. 3 Product identity, nominal concentrations and proposed certified limits must be submitted on EPA Form 8570­ 4. 4 A discussion must be submitted of the possible formation of impurities associated with the inert ingredients in the MP and the potential for formation of nitrosamines in the formulation process or in storage. 5 Data requirements for the TGAI will be satisfied by data for the technical source product. 6 Supporting validation data must be submitted for the enforcement method used to quantitate the active ingredient in the formulated product. 7 Data are not required because the MP is a solid at room temperature. 10 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: Drexel Chemical Company Product( s): 99% T (EPA Reg No. 19713­ 75) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition Y CSF date not specified CSF dated 8/ 7/ 95 830.1600 Description of materials used to produce the product N/ A 830.1620 Description of production process N/ A 830.1670 Discussion of formation of impurities N/ A 830.1700 Preliminary analysis N/ A 830.1750 Certified limits N/ A 830.1800 Enforcement analytical method N/ A 830.6302 Color N/ A 830.6303 Physical state N/ A 830.6304 Odor N/ A 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 830.6314 Oxidation/ reduction: chemical incompatibility N/ A 830.6315 Flammability N/ A 830.6316 Explodability N/ A 830.6317 Storage stability N/ A 830.6319 Miscibility N/ A 830.6320 Corrosion characteristics N/ A 830.7000 pH N/ A 830.7050 UV/ visible absorption N/ A 830.7100 Viscosity N/ A 830.7200 Melting point/ melting range N/ A 830.7220 Boiling point/ boiling range N/ A 830.7300 Density/ relative density/ bulk density N/ A 830.7370 Dissociation constants in water N/ A 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 830.7840 Water solubility: column elution method; shake flask method N/ A 830.7950 Vapor pressure N/ A 1 Y = Yes; N = No; N/ A = Not Applicable. 2 The CSF (date not specified) reviewed under CBRS No. 15442, D214535, 5/ 8/ 95, S. Hummel, and an updated CSF dated 8/ 7/ 95 (from the product jacket), confirm that this product is repackaged from an EPA­ registered product; all data requirements will be fulfilled by data for the source product. 11 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: Drexel Chemical Company Product( s): 50% FI (EPA Reg. No. 19713­ 369) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition N 3 00151776 830.1600 Description of materials used to produce the product Y 00151776 830.1650 Description of formulation process Y 00151776 830.1670 Discussion of formation of impurities N 4 00151776 830.1700 Preliminary analysis N/ A 5 830.1750 Certified limits N 3 00151776 830.1800 Enforcement analytical method N 6 00151776 830.6302 Color Y 00151776 830.6303 Physical state Y 00151776 830.6304 Odor Y 00151776 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 5 830.6314 Oxidation/ reduction: chemical incompatibility N 830.6315 Flammability N/ A 7 830.6316 Explodability N 830.6317 Storage stability N 830.6319 Miscibility N/ A 7 830.6320 Corrosion characteristics N 830.7000 pH N 830.7050 UV/ visible absorption N/ A 5 830.7100 Viscosity N/ A 7 830.7200 Melting point/ melting range N/ A 5 830.7220 Boiling point/ boiling range N/ A 5 830.7300 Density/ relative density/ bulk density Y 00151776 830.7370 Dissociation constants in water N/ A 5 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 5 830.7840 Water solubility: column elution method; shake flask method N/ A 5 830.7950 Vapor pressure N/ A 5 1 Y = Yes; N = No; N/ A = Not Applicable. This product was transferred from Aventis (EPA Reg. No. 264­ 327); the data summary table includes data submitted by Aventis. Drexel must confirm that the manufacturing process and site have not changed since the product transfer; otherwise, all product chemistry data will be required. 2 MRID 00151776 was reviewed initially under a HED Memorandum from W. T. Chin dated 9/ 18/ 85 and reevaluated in the Carbaryl (FRSTR) Reregistration Standard dated 5/ 3/ 88. 3 Product identity, nominal concentrations and proposed certified limits must be submitted on EPA Form 8570­ 4. 4 A discussion must be submitted of the possible formation of impurities associated with the inert ingredients in the MP and the potential for formation of nitrosamines in the formulation process or in storage. 5 Data requirements for the TGAI will be satisfied by data for the technical source product. 6 Supporting validation data must be submitted for the enforcement method used to quantitate the active ingredient in the formulated product. 7 Data are not required because the MP is a solid at room temperature. 12 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: Platte Chemical Company Product( s): 99% T (EPA Reg No. 34704­ 707) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition Y CSF dated 4/ 12/ 91 830.1600 Description of materials used to produce the product N/ A 830.1620 Description of production process N/ A 830.1670 Discussion of formation of impurities N/ A 830.1700 Preliminary analysis N/ A 830.1750 Certified limits N/ A 830.1800 Enforcement analytical method N/ A 830.6302 Color N/ A 830.6303 Physical state N/ A 830.6304 Odor N/ A 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 830.6314 Oxidation/ reduction: chemical incompatibility N/ A 830.6315 Flammability N/ A 830.6316 Explodability N/ A 830.6317 Storage stability N/ A 830.6319 Miscibility N/ A 830.6320 Corrosion characteristics N/ A 830.7000 pH N/ A 830.7050 UV/ visible absorption N/ A 830.7100 Viscosity N/ A 830.7200 Melting point/ melting range N/ A 830.7220 Boiling point/ boiling range N/ A 830.7300 Density/ relative density/ bulk density N/ A 830.7370 Dissociation constants in water N/ A 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 830.7840 Water solubility: column elution method; shake flask method N/ A 830.7950 Vapor pressure N/ A 1 Y = Yes; N = No; N/ A = Not Applicable. 2 The CSF dated 4/ 12/ 91 (from the product jacket) confirms that this product is repackaged from an EPA­ registered product; all data requirements will be fulfilled by data for the source product. We note that an updated CSF should be submitted reflecting the nominal concentration of the active ingredient in the product. 13 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: AgrEvo Environmental Health Product( s): 97.5% T (EPA Reg No. 4816­ 270) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition Y CSF dated 7/ 24/ 91 830.1600 Description of materials used to produce the product N/ A 830.1620 Description of production process N/ A 830.1670 Discussion of formation of impurities N/ A 830.1700 Preliminary analysis N/ A 830.1750 Certified limits N/ A 830.1800 Enforcement analytical method N/ A 830.6302 Color N/ A 830.6303 Physical state N/ A 830.6304 Odor N/ A 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 830.6314 Oxidation/ reduction: chemical incompatibility N/ A 830.6315 Flammability N/ A 830.6316 Explodability N/ A 830.6317 Storage stability N/ A 830.6319 Miscibility N/ A 830.6320 Corrosion characteristics N/ A 830.7000 pH N/ A 830.7050 UV/ visible absorption N/ A 830.7100 Viscosity N/ A 830.7200 Melting point/ melting range N/ A 830.7220 Boiling point/ boiling range N/ A 830.7300 Density/ relative density/ bulk density N/ A 830.7370 Dissociation constants in water N/ A 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 830.7840 Water solubility: column elution method; shake flask method N/ A 830.7950 Vapor pressure N/ A 1 Y = Yes; N = No; N/ A = Not Applicable. 2 The CSF dated 7/ 24/ 91 (from the product jacket) confirms that this product is repackaged from an EPA­ registered product; all data requirements will be fulfilled by data for the source product. We note that an updated CSF should be submitted reflecting the nominal concentration of the active ingredient in the product. 14 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: AgrEvo Environmental Health Product( s): 1% FI (EPA Reg No. 4816­ 407) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition N CSF dated 7/ 24/ 91 830.1600 Description of materials used to produce the product N 830.1650 Description of formulation process N 830.1670 Discussion of formation of impurities N 830.1700 Preliminary analysis N/ A 3 830.1750 Certified limits N 830.1800 Enforcement analytical method N 830.6302 Color N 830.6303 Physical state N 830.6304 Odor N 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 3 830.6314 Oxidation/ reduction: chemical incompatibility N 830.6315 Flammability N 830.6316 Explodability N 830.6317 Storage stability N 830.6319 Miscibility N 830.6320 Corrosion characteristics N 830.7000 pH N 830.7050 UV/ visible absorption N/ A 3 830.7100 Viscosity N 830.7200 Melting point/ melting range N/ A 3 830.7220 Boiling point/ boiling range N/ A 3 830.7300 Density/ relative density/ bulk density N 830.7370 Dissociation constants in water N/ A 3 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 3 830.7840 Water solubility: column elution method; shake flask method N/ A 3 830.7950 Vapor pressure N/ A 3 1 Y = Yes; N = No; N/ A = Not Applicable. 2 The CSF dated 7/ 24/ 91 (from the product jacket) confirms that this product is formulated from an EPA­ registered product. 3 TGAI data requirements will be satisfied by data for the technical source product. 15 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: Sureco Inc. Product( s): 80% FI (EPA Reg No. 769­ 971) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition N CSF dated 9/ 23/ 94 830.1600 Description of materials used to produce the product N 830.1650 Description of formulation process N 830.1670 Discussion of formation of impurities N 830.1700 Preliminary analysis N/ A 3 830.1750 Certified limits N 830.1800 Enforcement analytical method N 830.6302 Color N 830.6303 Physical state N 830.6304 Odor N 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 3 830.6314 Oxidation/ reduction: chemical incompatibility N 830.6315 Flammability N 830.6316 Explodability N 830.6317 Storage stability N 830.6319 Miscibility N 830.6320 Corrosion characteristics N 830.7000 pH N 830.7050 UV/ visible absorption N/ A 3 830.7100 Viscosity N 830.7200 Melting point/ melting range N/ A 3 830.7220 Boiling point/ boiling range N/ A 3 830.7300 Density/ relative density/ bulk density N 830.7370 Dissociation constants in water N/ A 3 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 3 830.7840 Water solubility: column elution method; shake flask method N/ A 3 830.7950 Vapor pressure N/ A 3 1 Y = Yes; N = No; N/ A = Not Applicable. A letter from L. Howard, Aventis, to D. Edwards, EPA, dated 9/ 14/ 94 authorizes use of Aventis data to satisfy data requirements for this product; however, until a determination concerning substantial similarity for the two products has been made, all product chemistry data requirements remain outstanding. 2 The CSF available from the product jacket confirms that this product is formulated from an EPA­ registered product. 3 TGAI data requirements will be satisfied by data for the technical source product. 16 Case No. 0080 Chemical No. 056801 Case Name: Carbaryl Registrant: Amvac Chemical Corporation Product( s): 46% FI (EPA Reg No. 5481­ 190) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition N CSF dated 5/ 18/ 84 830.1600 Description of materials used to produce the product N 830.1650 Description of formulation process N 830.1670 Discussion of formation of impurities N 830.1700 Preliminary analysis N/ A 3 830.1750 Certified limits N 830.1800 Enforcement analytical method N 830.6302 Color N 830.6303 Physical state N 830.6304 Odor N 830.6313 Stability to normal and elevated temperature, metals, and metal ions N/ A 3 830.6314 Oxidation/ reduction: chemical incompatibility N 830.6315 Flammability N 830.6316 Explodability N 830.6317 Storage stability N 830.6319 Miscibility N 830.6320 Corrosion characteristics N 830.7000 pH N 830.7050 UV/ visible absorption N/ A 3 830.7100 Viscosity N 830.7200 Melting point/ melting range N/ A 3 830.7220 Boiling point/ boiling range N/ A 3 830.7300 Density/ relative density/ bulk density N 830.7370 Dissociation constants in water N/ A 3 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 3 830.7840 Water solubility: column elution method; shake flask method N/ A 3 830.7950 Vapor pressure N/ A 3 1 Y = Yes; N = No; N/ A = Not Applicable. 2 The CSF dated 5/ 18/ 84 (from the product jacket) confirms that this product is manufactured from an EPAregistered product. 3 TGAI data requirements will be satisfied by data for the technical source product. CARBARYL Chemical ID No. 056801; Case 0080 Residue Chemistry Chapter of the Reregistration Eligibility Decision (RED) Document CARBARYL REREGISTRATION ELIGIBILITY DECISION RESIDUE CHEMISTRY CONSIDERATIONS PC Code 056801; Case 0080 TABLE OF CONTENTS page INTRODUCTION ............................................................. 1 REGULATORY BACKGROUND ................................................ 1 SUMMARY OF SCIENCE FINDINGS ............................................ 2 GLN 860.1300: Nature of the Residue ­ Plants ................................. 4 GLN 860.1300: Nature of the Residue ­ Livestock ............................... 5 GLN 860.1340: Residue Analytical Methods ................................... 5 GLN 860.1360: Multiresidue Methods ........................................ 6 GLN 860.1380: Storage Stability Data ­ Plants ................................. 7 GLN 860.1380: Storage Stability Data ­ Livestock .............................. 8 GLN 860.1500: Crop Field Trials ............................................ 8 GLN 860.1520: Processed Food/ Feed ....................................... 11 GLN 860.1480: Meat, Milk, Poultry, Eggs .................................... 12 GLN 860.1400: Water, Fish, and Irrigated Crops ............................... 13 GLN 860.1460: Food Handling ............................................ 14 GLNs 860.1850 and 860.1900: Confined/ Field Accumulation in Rotational Crops .... 14 FOOD/ FEED USE PATTERN .................................................. 15 TOLERANCE REASSESSMENT SUMMARY .................................... 78 Tolerances Listed Under 40 CFR §180.169( a), (b), (c), (d), and (e) ................. 80 Tolerance Listed Under 40 CFR §180.319 .................................... 86 Tolerance Listed Under 40 CFR §186.550 .................................... 86 Tolerances Needed Under 40 CFR §180.169( a) ................................ 86 CODEX HARMONIZATION................................................... 89 AGENCY MEMORANDA RELEVANT TO REREGISTRATION ..................... 94 MASTER RECORD IDENTIFICATION NUMBERS................................ 98 O O N H CH 3 CARBARYL REREGISTRATION ELIGIBILITY DECISION RESIDUE CHEMISTRY CONSIDERATIONS PC Code No. 056801; Case 0080 INTRODUCTION Carbaryl (1­ naphthyl N­ methylcarbamate) is a carbamate insecticide registered for use on a variety of field, fruit, and vegetable crops. The reregistration of carbaryl in the United States is being supported by the Aventis Crop Science (basic producer); the Interregional Research Project No. 4 (IR­ 4) is additionally supporting the reregistration of carbaryl use on a few selected minor crops. Carbaryl products are marketed under trade names such as Sevin® and Sevimol®. Registered carbaryl end­ use formulations include flowable concentrates (FlC), granulars (G), pelleted/ tableted (P/ T), ready­ to­ use (RTU), and wettable powders (WP). Depending on the crop, these formulations may be applied as dormant, delayed dormant, prebloom, foliar (broadcast, banded, and directed spray), post­ harvest treatment (dip), soil (broadcast and banded), premise treatment, and direct animal treatment using ground or aerial equipment. Carbaryl may be applied on agricultural and residential use sites. REGULATORY BACKGROUND Carbaryl was the subject of a Reregistration Standard Guidance Document dated 3/ 30/ 84; the Residue Chemistry Science Chapter of the Guidance Document was dated 3/ 15/ 83. The Residue Chemistry Chapter of the Carbaryl (FRSTR) Reregistration Standard was issued on 5/ 3/ 88. A Data Call­ In (DCI) Notice for carbaryl was also issued 4/ 91. These documents summarized the regulatory conclusions based on available residue chemistry data, and specified the additional data required for reregistration purposes. Several data submissions have been received and evaluated since the FRSTR. The information contained in this document outlines the Residue Chemistry Science Assessments with respect to the reregistration of carbaryl. Tolerances for residues of carbaryl are currently expressed in terms of carbaryl (1­ naphthyl Nmethylcarbamate including its hydrolysis product 1­ naphthol, calculated as carbaryl, for most raw crop commodities [40 CFR §180.169( a)]. The established tolerances for residues in/ on pineapples, pome fruits, avocados, and fresh dill are expressed in terms of carbaryl per se [40 CFR §180.169( d) and (e)]. Tolerances for residues in livestock commodities are expressed as 2 carbaryl, including its metabolites 1­ naphthol (naphthyl sulfate), 5,6­ dihydrodihydroxy carbaryl, and 5,6­ dihydrodihydroxy naphthol, calculated as carbaryl [40 CFR §180.169( b) and (c)]. A tolerance for residues in pineapple bran is expressed in terms of carbaryl per se [40 CFR §186.550]. An interim tolerance has been established for carbaryl and its 1­ naphthol metabolite in eggs [40 CFR §180.319]. Since the FRSTR was issued, the Agency has updated the list of raw agricultural and processed commodities and feedstuffs derived from crops (Table 1, OPPTS 860.1000). As a result of changes to Table 1, additional carbaryl residue data are now required for some commodities; these data requirements have been incorporated into this document. These new data requirements will be imposed at the issuance of the Carbaryl RED but should not delay on the reregistration eligibility decisions for carbaryl. The need for revisions to dietary exposure/ risk assessments will be determined upon receipt of the required residue chemistry data. SUMMARY OF SCIENCE FINDINGS GLN 860.1200: Directions for Use A REFS search, conducted on 1/ 5/ 2000, identified 15 carbaryl end­ use products (EPs) registered under FIFRA Section 3 to the basic producer, Aventis Ag Company, with registered uses on food/ feed crops. These EPs, including the associated Special Local Need (SLN) registrations under FIFRA Section 24 (c), are listed in Table A1. 3 Table A1. Carbaryl EPs with Food/ Feed Uses Registered to Aventis Ag Company. EPA Reg. No. Label Acceptance Date 1 Formulation Product Name 234­ 312 6/ 99 10.04% P/ T Sevin® brand 10% Bait Carbaryl Insecticide 264­ 314 6/ 99 50% WP Sevin® brand 50W Carbaryl Insecticide 264­ 315 6/ 99 85% WP Sevin® brand 85 Sprayable Carbaryl Insecticide 264­ 316 2 1/ 00 80% WP Sevin® brand 80S Carbaryl Insecticide 264­ 320 6/ 99 5% P/ T Sevin® brand 5% Bait Carbaryl Insecticide 264­ 321 6/ 99 4 lb/ gal FlC Sevimol® brand Carbaryl Insecticide 264­ 333 2/ 01 4 lb/ gal FlC Sevin® brand XLR Carbaryl Insecticide 264­ 334 2/ 99 2 lb/ gal FlC Sevin® brand RP2 Carbaryl Insecticide 264­ 335 10/ 00 4 lb/ gal FlC Sevin® brand RP4 Carbaryl Insecticide 264­ 349 3 1/ 00 4 lb/ gal FlC Sevin® brand 4F Carbaryl Insecticide 264­ 422 4/ 97 4 lb/ gal RTU Sevin® brand 4­ Oil ULV Carbaryl Insecticide 264­ 427 9/ 96 3.2 lb/ gal RTU Sevin® brand 4­ Oil 41A Carbaryl Insecticide 264­ 429 3/ 99 7% G Sevin® brand Granular Carbaryl Insecticide For Commercial Use Only 264­ 430 3/ 99 6 7% G Sevin® brand Granular Carbaryl Insecticide For Outdoor Home Use 264­ 526 4/ 00 80% WP Sevin® brand 80 WSP Carbaryl Insecticide 1 Date of the most recently EPA­ approved label submitted by the basic producer which corresponds to the most recently EPA­ approved label date found in REFs, unless specified otherwise. 2 Including SLN Nos. CA810059, FL890036, and WA900013. 3 Including SLN No. FL890037. A review of the labels listed above and supporting residue data indicate that the following label amendments are required: Based on acceptable residue data on okra from IR­ 4, the registrant should amend use directions on FlC and WP labels to specify a maximum of four applications per season at 1.5 lb ai/ A/ application at a minimum retreatment interval (RTI) of 6 days and a minimum PHI of 3 days. Use directions for oysters on the 80% WP label (SLN WA900013) concerning the PHI should be amended to read "treatment is allowed only on beds from which no oysters will be harvested within one year of application." A comprehensive summary of the registered food/ feed use patterns of carbaryl, based on the product labels registered to Aventis, is presented in Table A2. A tabular summary of the residue chemistry science assessments for reregistration of carbaryl is presented in Table B. The conclusions listed in Table B regarding the reregistration eligibility of carbaryl food/ feed uses are based on the use patterns registered by the basic producer, Aventis. When end­ use product DCIs are developed (e. g., at issuance of the RED), all end­ use product labels (e. g., MAI labels, SLNs, 4 and products subject to the generic data exemption) should be amended such that they are consistent with the basic producer's labels. GLN 860.1300: Nature of the Residue ­ Plants The reregistration requirements for plant metabolism are fulfilled. Acceptable metabolism studies depicting the qualitative nature of the residues in lettuce, radish, and soybean have been submitted and evaluated. In these studies (all conducted at ­ 1x rates), surface residues on radish tops, lettuce, and soybean forage accounted for 38­ 67% of the total radioactive residues (TRR), and virtually all of these residues were unconjugated carbaryl. Unconjugated carbaryl ranged from 36­ 95% of the TRR in all commodities of radish, lettuce, and soybean, with the exception of soybean seed, in which the parent accounted for only 4% of the TRR. Other unconjugated residues, including N­( hydroxymethyl) carbaryl (N­ OH­ Me carbaryl), 1­ naphthol, and 5,6­ dihydro­ dihydroxy­ 1­ naphthol, were present in minor amounts ( # 3.4% of the TRR). Conjugated carbaryl accounted for # 2.8% of the TRR in the tested commodities. Other conjugates detected in plants included a malonylglycoside conjugate of 1­ naphthol comprising 26% of the TRR in soybeans; a hexose conjugate of N­ OH­ Me carbaryl accounting for 17% and 12.2% of the TRR in soybeans and soybean hay; and several minor conjugates of desmethyl carbaryl, 5­ hydroxycarbaryl, and 4­ hydroxycarbaryl, each at # 2.7% of the TRR. Based on the available metabolism data, the HED Metabolism Committee (S. Hummel, 2/ 8/ 96) determined that tolerances for crop commodities should be expressed as residues of carbaryl per se. The carbaryl metabolite, N­ hydroxymethyl carbaryl does not need to be regulated because it is expected to have considerably less potential as a cholinesterase inhibitor (based on in vitro studies). As noted above, conjugated carbaryl does not contribute significantly to the TRR, and is not of concern. GLN 860.1300: Nature of the Residue ­ Livestock The reregistration requirements for livestock metabolism are fulfilled. Acceptable metabolism studies depicting the qualitative nature of the residues in ruminants and poultry have been submitted and evaluated. The metabolic pathways for carbaryl in plants and livestocks are similar, but are more extensive in livestocks. In the ruminant metabolism study, lactating cows were orally dosed with 1­ naphthyl­[ 14 C] carbaryl at dietary levels of 10­ 100 ppm for 14 days. The high­ dose group represents approximately a 0.8x feeding level based on current tolerance levels. The Metabolism Assessment Review Committee (6/ 17/ 99) concluded that tolerances for ruminant meat and milk should be expressed as residues of free and conjugated forms of carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, and 5­ methoxy­ 6­ hydroxy carbaryl. The tolerance expression should be modified to reflect these changes. 5 Currently, no tolerances are needed for residues of carbaryl in/ on poultry; the presently registered uses of carbaryl are classified as Category 3 of 40 CFR §180.6( a) with respect to the need for tolerances in poultry and eggs i. e., there is no reasonable expectation of finite residues. GLN 860.1340: Residue Analytical Methods The available methods for tolerance enforcement (PAM, Volume II, Methods I through IV, A, and B) measure total combined residues of carbaryl and 1­ naphthol, calculated as carbaryl. The requirement for acceptable enforcement methods which determine residues of carbaryl per se in plant and livestock commodities remains outstanding. Athough some analytical methods determine the combined residue of carbaryl and 1­ naphthol, it should be noted that 1­ napthol is a very minor part of the residue; therefore, the plant commodity tolerances, which are based on carbaryl only, are not greatly exaggerated. The registrant has proposed as an enforcement method HPLC Method CACR­ 0194, which quantifies carbaryl per se in plant matrices. This method has undergone successful independent laboratory validation (ILV) using samples of representative plant commodities (oily and non­ oily matrices), and has also been successfully radiovalidated using samples from plant metabolism studies. The method should be submitted to the Agency for method validation. Residue data on most crop plants and processed commodities have been collected using the above HPLC method with only minor modifications involving changes in solvents and cleanup procedures. Method CACR­ 1212, a modification of CACR­ 0194, has also been used to generate data on residues of carbaryl per se in some of the recent residue studies. The two methods are identical except that with method CACR­ 1212 residues are extracted with ethyl acetate instead of DCM, and cleanup procedures use deactivated rather than activated Florisil. The carbaryl­ HPLCalfalfa method, described in the FRSTR, was used to generate data for earlier residue studies. This method does not distinguish between carbaryl and 1­ naphthol; however, the Agency concluded (DP Barcode D194407, S. Hummel, 2/ 25/ 94) that the contribution of residues of 1­ naphthol is insignificant relative to residues of carbaryl per se. The registrant must also propose an enforcement method for determining residues of free and conjugated forms of carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, and 5­ methoxy­ 6­ hydroxy carbaryl in livestock commodities. An adequate HPLC data collection method (Aventis File No. 45186) used to determine residues of carbaryl (free and conjugated) and its metabolites in livestock commodities is available, and has undergone a successful ILV. The method is similar to method CARDC­ 1286 which was described in a recent Agency review (C. Olinger, 12/ 13/ 99). Once the modified method has been submitted, the Agency will initiate a method validation. GLN 860.1360: Multiresidue Methods The FDA PESTDATA database indicates that residues of carbaryl per se are completely recovered using FDA Multiresidue Protocols A and D (PAM I Sections 242.2 and 232.4). No data are available concerning the recovery of carbaryl by Protocol E (PAM I Section 211.1 and 211.2). These PAM I methods are not expected to recover conjugated carbaryl residues. 6 GLN 860.1380: Storage Stability Data ­ Plants The requirements for storage stability data are not satisfied for purposes of reregistration. Additional data are required depicting the storage stability of carbaryl per se in an oilseed, processed commodities of an oily crop, and a dried fruit stored for up to 10 months. In addition, the registrant is relying on earlier magnitude of the residue studies that are not supported by the existing storage stability data; therefore, additional storage stability data are required. The required data must reflect storage intervals of 18 months for alfalfa commodities, 15 months for potatoes, 22 months for wheat commodities, and 33 months for rangeland grass. In addition, if the registrant wishes to rely on the previously submitted sugar beet processing study, information pertaining to sample conditions and intervals for the study must be submitted. Adequate storage stability data have been submitted indicating that residues of carbaryl are relatively stable under frozen storage conditions (­ 20 C) for up to 12 months in/ on pearled barley and barley flour, head lettuce, potatoes, tomatoes and tomato processed commodities, and wheat forage, hay, and straw. Residue decline was observed in tomato dry pomace after 3 months storage ( ­ 30­ 40%), and barley grain and peanut hulls after 3 months of storage ( ­ 50% and 40%, respectively; these commodities are no longer considered to be significant livestock feed items. In a separate study, carbaryl residues were shown to be stable in/ on wheat grain stored at ­20 C for up to 7 months. Adequate storage stability data have been submitted indicating that weathered residues of carbaryl per se are stable at ­20 C for at least 15 months in/ on apple fruit, juice, and wet and dry pomace; 13 months in/ on grapes; 12 months in/ on processed raisins; 11 months in/ on almond nutmeat and hulls, and dry bean hay; and 10 months in/ on dry bean vines. GLN 860.1380: Storage Stability Data ­ Livestock For the purpose of reregistration, the requirements for storage stability data for carbaryl residues in livestock commodities are partially satisfied. Additional information on the storage intervals prior to analysis for metabolite residues in the cattle feeding study is required. Samples from the feeding study were analyzed for carbaryl per se within the interval of known stability of free carbaryl residues. The storage stability studies conducted to date indicate that residues of unconjugated carbaryl and metabolites are less stable than conjugated residues. A storage stability study submitted in conjunction with the ruminant feeding study indicated that residues of carbaryl per se are relatively stable in frozen storage for up to 3 months in milk, fat, and muscle and up to 1 month in kidney. Residues of carbaryl per se in liver declined ­ 69% after 2 weeks of storage and continued to decline over the 3­ month storage interval (94% decline). Tissue and milk samples from the ruminant feeding study were stored frozen for # 21 days (9 days for liver) prior to carbaryl analysis. The data indicate that conjugated carbaryl­ related residues are relatively stable in frozen storage for up to 158 days in muscle, 173 days in liver, 196 days in kidney, 215 days in fat, and 7 248 days in milk. A method equivalency study using samples from the feeding study adequately demonstrated that unconjugated residues are not a significant portion of carbaryl residues in liver. GLN 860.1500: Crop Field Trials Aventis CropScience submitted data to support the use of granular (G) formulations for postemergence applications to several food/ feed crops. HED (DP Barcode D240441, C. Olinger, 1/ 22/ 98) required the registrant to conduct one side­ by­ side trial comparing a granular formulation and a spray formulation for each crop group and miscellaneous crop. To these uses, Aventis CropScience submitted data comparing carbaryl residues in/ on asparagus, cabbage, sweet corn, leaf lettuce, black­ eyed peas, squash, strawberries, tomatoes, and turnips following multiple applications of either a 4 lb/ gal flowable concentrate (FlC) or 10% granular (G) formulation in side­ by­ side tests. A total of nine side­ by­ side tests using a 10% G and 4 lb/ gal FlC were conducted on crops representing major field crop groups and miscellaneous commodities (asparagus, cabbage, sweet corn, peas, squash, strawberry, tomato and turnip). The tests were conducted at the maximum label rate specified on the label for the 4 lb/ gal FlC (EPA Reg No. 264­ 333) and were conducted in a major growing region for each crop. Carbaryl residues resulting from application of the 10% G formulation were substantially lower than from the FlC formulation in/ on 9 of the 14 commodities analyzed (asparagus, cabbage w/ o wrapper leaves, sweet corn forage, pea hay and dried seeds, squash, strawberries, tomatoes and turnip tops) and were similar in 2 other commodities (sweet corn K+ CWHR and fodder). Although residues of the 10% G formulation were higher than residues from the side by side trial for cabbage (w/ wrapper leaves) and turnip root, the residues were similar or lower than residues found in the residue field trials submitted to the Agency in support of tolerances in/ on turnip and cabbage. The data submitted are not adequate to support the use of granular (G) formulations of carbaryl on leafy vegetables. Residues of carbaryl found in leaf lettuce were not consistent. Both samples of lettuce from the 10% G treatment had substantially higher residues (37.01 and 47.22 ppm) than one of the samples treated with the FlC (23.25 ppm). Additionally, all residues were significantly above the current tolerance of 10 ppm. and all residue data submitted in support of the tolerance in lettuce (< 8.85 ppm). No explanation for the higher residues was given by the registrant. The registrant may elect to repeat the side by side trial on leaf lettuce again or submit a rationale for the results of the leaf lettuce study. In addition, conclusions regarding the adequacy of the data for alfalfa, apples, potatoes, wheat processed commodities, grasses, and soybean processed commodities are contingent upon receipt and acceptance of adequate supporting storage stability data. For the purpose of reregistration, adequate magnitude of the residue data are available on the following crops: alfalfa, almond, asparagus, bananas, beans (dried and succulent), blueberry, broccoli, cabbage, celery, cherry, citrus fruits, clover, corn (sweet and field), cucurbits (cantaloupes, cucumbers and squash), cranberry, flax, grape, okra, peanut, peas (dried and 8 succulent), pecan, pepper, pistachio, pome fruits, potato, prickly pear cactus, raspberry, rice, sorghum, soybean, spinach, stone fruits, strawberry, sunflower, sweet potato, tobacco, tomato, and walnut. Adequate field trial data depicting carbaryl residues following applications made according to the maximum or proposed use patterns have been submitted for these commodities. Geographic representation is adequate and a sufficient number of trials reflecting representative formulation classes were conducted. Carbaryl residues were <LOQ in/ on sweet potato, sugar beets, corn grain, flax seed, and peanuts. Quantifiable residues were detected in all other RACs. For a given crop, residue levels were quite variable overall, probably owing to climactic variations, but were generally consistent within any specific field trial location. In addition to the required field trial data, an adequate [ 14 C]­ carbaryl tobacco pyrolysis study has been conducted. Adequate data are available to reassess the tolerances for residues of carbaryl in/ on sugar beet roots and tops provided that use directions on five currently approved labels are modified to allow a maximum of two applications per season at 1.5 lb ai/ A/ application and a PHI of 28 days. The registrant has proposed (Letter from Aventis to J. Loranger, 6/ 1/ 94) amending all EP labels to conform to these requirements, and the Greybeard Committee (1/ 9/ 97) has granted a waiver from the requirement of additional field trials provided that the labels are amended. Alternatively, residue data are required depicting residues of carbaryl per se in/ on sugar beet roots and tops harvested 28 days following four applications totaling 4.0 lb ai/ A (1x the maximum seasonal rate). A total of 12 tests should be conducted in the following areas: Region 5 (5 tests), Regions 7, 8, and 9 (one test each), and Regions 10 and 11 (2 tests each). Adequate residue data on representative Brassica and leafy vegetables are available to support uses on other vegetable commodities with the same carbaryl use pattern: Adequate data on broccoli will be translated to support the uses on Brussels sprouts, cauliflower, and kohlrabi; data on spinach will support tolerances on dandelion and parsley; and residue data on lettuce will be translated to endive. The available data from alfalfa will be translated to support uses on birdsfoot trefoil. The following data on grasses are available for risk assessment/ reregistration purposes: Residue data from rangeland grass field trials support the current tolerance of 100 ppm in/ on grass forage. Data on pasture hay harvested at the 14­ day PHI indicate that the tolerance on grass hay should be lowered to 15 ppm. The registrant has provided data on pasture grass forage harvested at a PHI of 14 days. For postemergence applications to grasses, the Agency currently considers feeding restrictions and PHIs greater than zero days impractical for forage of pasture and rangeland grasses. Grass forage tolerances are set using residue data from a 0­ day post­ treatment interval. However, reasonable PHIs are allowed for the cutting of grass hay. Adequate data are available to reassess the tolerances for residues of carbaryl in/ on dried beans, cowpeas, lentils and peas with pods. These data support the establishment of crop subgroup 9 tolerances for edible­ podded legume vegetables (6A), and for dried, shelled pea and bean except soybean (6C). However, additional residue data are required if the registrant seeks tolerances for residues in/ on succulent, shelled pea and bean commodities. A total of 12 tests, six tests each on a succulent, shelled cultivar of bean and garden pea, are required to support a tolerance for residues in/ on the succulent, shelled pea and bean crop subgroup (6B). The registrant is referred to OPPTS GLN 860.1500 for the required number and distribution of tests. Data are available to reassess the tolerances for residues in/ on soybean forage and hay. To establish a tolerance for residues in/ on the foliage of legume vegetables except soybeans crop subgroup (7A), the guidelines state that three field trials each are required on any cultivar of bean and field pea. Although data from forage and hay of field pea are not available, data from seven field trials depicting residues in/ on bean forage (vines) and hay are adequate to satisfy the guidelines for a tolerance on the crop subgroup 7A. The use patterns are the same for forage and hay of peas and beans. Adequate data are available to reassess the tolerance for wheat forage and straw. However, the Agency now considers wheat hay to be a livestock feed item. (OPPTS GLN 860.1000 Table 1.). A full set of 20 field trials as specified in OPPTS GLN 860.1500 is required depicting carbaryl residues in/ on wheat hay. When all the field trials are complete, PHIs and tolerances for hay based on the field trial data should be proposed. Data on wheat hay will be translatable to proso millet hay. The registrant intends to support a tolerance for residues of carbaryl in/ on imported pineapples (Aventis personal communication with C. Olinger, 9/ 24/ 98 SMART meeting). Residue data are required depicting residues in/ on pineapples following application of carbaryl at the maximum use rate and minimum PHI. Five trials must be submitted, three from Costa Rica and two from Mexico. The registrant does not intend to support carbaryl uses on avocados, barley, maple sap, oats, rye, and sweet sorghum; however, IR­ 4 has indicated (Correspondence from K. Dorschner, IR­ 4 Project, 9/ 15/ 94) that they may fulfill the residue data requirements for some of these commodities. These data have not been submitted. GLN 860.1520: Processed Food/ Feed Pending adequate resolution of the outstanding storage stability issues noted above, the reregistration requirements for magnitude of the residue data in processed food/ feed commodities are fulfilled for citrus fruits, corn, flaxseed, grape, olive, peanut, plum, pome fruits, rice, sorghum, soybean, sugar beet, sunflower, potato, tomato, and wheat. Based on the available processing studies, tolerances are required for residues in citrus fruit oil, raisins, wet apple pomace, and rice hulls only. In a tomato processing study, carbaryl residues concentrated by 2x in puree. However, when this concentration factor is applied the HAFT residues of 2.45 ppm for tomatoes, the resulting value is 10 lower than the reassessed tolerance (5.0 ppm) for residues in/ on fruiting vegetables. Therefore, a separate tolerance for residues in puree is not required. In an apple processing study, carbaryl residues concentrated in wet apple pomace by 1.3x. Based on this concentration factor and the current HAFT residues of 10.6 ppm in/ on apples, an appropriate tolerance for carbaryl residues in wet apple pomace is 15.0 ppm. Residues did not concentrate in apple juice. Data from the citrus fruit processing study indicate that residues of carbaryl concentrate in citrus oil by 2.4x. Based on this concentration factor and the current HAFT residues of 8.09 ppm in/ on citrus fruit, an appropriate tolerance for carbaryl residues in citrus oil is 20.0 ppm. Residues did not concentrate in dried pulp or juice. Data from adequate grape processing studies indicate that residues of carbaryl do not concentrate in grape juice; however, carbaryl residues concentrate by 1.4x in raisins. Based on the current HAFT residues of 7.94 ppm in/ on grapes, carbaryl residues in raisins could be expected to reach 11.1 ppm. A 12.0 ppm tolerance for carbaryl residues in raisins should be established. Residues did not concentrate in dried pulp or juice. A rice processing study indicated that residues of carbaryl do not concentrate in polished rice or bran, but concentrate in rice hulls by 2.4x. Based on this concentration factor and the current HAFT residues of 11.0 ppm in/ on rice grain, residues in rice hulls could be expected to reach 26.4 ppm; therefore, an appropriate tolerance for carbaryl residues in rice hulls is 30.0 ppm. Data from a wheat processing study indicate that carbaryl residues in/ on wheat aspirated grain fractions are 11.8x higher than in/ on wheat grain. Based upon HAFT residues of 0.27 ppm, residues of carbaryl may be expected to reach 3.2 ppm in wheat aspirated grain fractions. Adequate soybean aspirated grain fraction data are available and indicate that residues of carbaryl in/ on soybean aspirated grain fractions are 5.6x higher than in soybean seed. Based on HAFT residues of 0.15 ppm, residues of carbaryl may be expected to reach 0.8 ppm in soybean aspirated grain fractions. For grain sorghum, the concentration factor between the aspirated grain fractions and the whole grain samples was 7.4x. Based on HAFT residues of 9.55 ppm, residues of carbaryl could be expected to reach 70.2 ppm in sorghum aspirated grain fractions. As carbaryl residues were nondetectable (< 0.02 ppm) in/ on all samples of field corn grain from field trials conducted at the maximum labeled use rate (8.0 lb ai/ A, MRID 44058001), no carbaryl residue data on aspirated grain fractions derived from field corn grain are required. Based on these data, a tolerance of 70 ppm should be established for residues of carbaryl per se in/ on aspirated grain fractions. GLN 860.1480: Meat, Milk, Poultry, Eggs The reregistration data requirements for magnitude of the residue in livestock commodities are fulfilled. 11 The presently registered uses of carbaryl are classified as Category 3 of 40 CFR §180.6( a) with respect to the need for tolerances in poultry and eggs i. e., there is no reasonable expectation of finite residues. Based upon the established or reassessed tolerances for carbaryl residues in/ on livestock feed items, the calculated maximum theoretical dietary burdens for livestock are presented below: Calculation of maximum dietary burdens of livestock for carbaryl. Feed Commodity % Dry Matter a % Diet a Tolerance (ppm) b Dietary Contribution (ppm) c Beef and Dairy cattle grass, forage 25 60 100.0 240.00 cowpea seed 88 20 5.0 1. 1 Aspirated grain fraction 85 20 70.0 16.0 TOTAL BURDEN 100 257.1 Swine sorghum grain N/ A 85 10.0 8. 5 cowpea forage N/ A 15 60.0 9. 0 TOTAL BURDEN 100 17.5 a Table 1 (August 1996). b Current or reassessed tolerance from Table C. c Contribution = [tolerance / % DM (if cattle)] X % diet). An adequate ruminant feeding study is available reflecting the dosing of dairy cattle for 28 days at levels equivalent to 114, 342, and 1140/ 570 ppm in the diet (the high­ dose level was reduced to 570 ppm on Day 5 due to toxic effects observed in study animals). These dosing levels represent 0.4x, 1.3x, and 4.4/ 2.2x the theoretical dietary burden for cattle, and 6.5x, 19.5x, and 65.1/ 32.6x the theoretical dietary burden for swine. The calculation of the maximum dietary is tentative because data remain outstanding for pasture grass forage. Based upon the results of this study, tolerances for residues of carbaryl per se in livestock (excluding swine) commodities should be reassessed as follows: 1.0 ppm for milk, 0.5 ppm for fat, 1.0 ppm for meat, and 3.0 ppm for meat byproducts. Using the results of the feeding study to reassess tolerances for swine, tolerances for residues of carbaryl per se in swine commodities should be reassessed as follows: 0.05 ppm for fat, 0.1 ppm for meat, and 0.5 ppm for meat byproducts. GLN 860.1400: Water, Fish, and Irrigated Crops Adequate residue data are available to support the use of carbaryl on oyster beds in WA. No residue data are required for catfish or crayfish from the use of carbaryl on rice since this use is prohibited on the carbaryl labels. 12 GLN 860.1460: Food Handling Carbaryl is presently not registered for use in food­ handling establishments; therefore, no residue chemistry data are required under this guideline topic. GLNs 860.1850 and 860.1900: Confined/ Field Accumulation in Rotational Crops An adequate confined rotational crop study is available, and no additional rotational crop studies are required. The current label restriction against rotating crops for which carbaryl is not registered is adequate. 13 (continued; footnotes follow) Table A2. Food/ Feed Use Patterns on EP Labels Subject to Reregistration for Carbaryl (Case 0080). 1 Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 Food/ Feed Crop Uses Alfalfa Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal Fl/ C [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 1 per cutting 1.5 lb/ A per cutting 7 Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 14 (continued; footnotes follow) Almond, chestnut, filbert, pecan, walnut Foliar, dormant/ delayed dormant Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 5.0 lb/ A 4 15.0 lb/ A 14 A maximum of four applications may be made (including dormant/ delayed dormant applications) with a minimum 7­ day retreatment interval. For almonds only, dormant/ delayed dormant applications may be made in combination with dormant oil. Foliar application Ground 50% WP [CA830007] 80% WP [CA830007] 1.0 lb/ 100 gal NS NS 1 (for nut crops) Use limited to CA for nut crops. Applications may be made at 7­ day retreatment intervals or as needed. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 15 (continued; footnotes follow) Apricot, cherry, nectarine, peach, plum/ prune Foliar and dormant/ delayed dormant Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 3.0 lb/ A 4.0 lb/ A (CA only) 5.0 lb/ A (dormant/ delayed only) 3 (foliar) and 1 (dormant/ delayed dormant) 14.0 lb/ A 3 (except CA) 1 (CA only) A maximum of three foliar applications and one dormant/ delayed dormant application may be made with a minimum 7­ day retreatment interval (14 days in CA). A maximum seasonal rate of 14.0 lb ai/ A (5.0 lb ai/ A during dormant/ delayed dormant period and 9.0 lb ai/ A during production season) has been established. Foliar application Ground 50% WP [CA830007] 80% WP [CA830007] 1.0 lb/ 100 gal NS NS 3 Use limited to CA. Applications may be made at 7­ day retreatment intervals or as needed. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 16 (continued; footnotes follow) Asparagus Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 3 6.0 lb/ A 3.0 lb/ A for 5% P/ T only 1 A maximum of three applications may be made prior to harvest or a maximum of five applications may be made per crop with a minimum 3­ day retreatment interval. Postharvest Ground or aerial 2 10.0 lb/ A Not applicable (NA) Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 17 (continued; footnotes follow) Asparagus (continued) Postharvest (to fern or brush growth) Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 4.0 lb/ A 5 10.0 lb/ A NA A maximum of five applications may be made per crop (spears and ferns combined) with a minimum 7­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 1 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Avocado Foliar application Ground 50% WP [CA830007] 80% WP [CA830007] 1.0 lb/ 100 gal 5 NS 5 Use limited to CA. Applications may be made at 7­ day retreatment intervals or as needed. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 18 (continued; footnotes follow) Bean, cowpea, pea Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 1.5 lb/ A 4 6. 0 lb/ A 3 A maximum of four applications may be made with a minimum 7­ day retreatment interval. Bean, fresh and dried (Phaseolus species including snap, navy, and kidney), cowpea, lentil, pea, fresh and dried (pisum species), soybean Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 4 6. 0 lb/ A 3 (fresh beans) 14 (forage) 21 (dried beans, or hay) A maximum of four applications may be made with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 19 (continued; footnotes follow) Beet, garden, roots, carrot, horseradish, radish, parsnip, rutabaga, salsify Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 6 6. 0 lb/ A 7 A maximum of six applications may be made with a minimum 7­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 7 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 20 (continued; footnotes follow) Beet, garden, tops Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 2.0 lb/ A 5 6. 0 lb/ A 14 A maximum of five applications may be made with a minimum 7­ day retreatment interval. Beet, sugar Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 2.0 lb/ A 4 4. 0 lb/ A 28 (roots and forage) A maximum of four applications may be made with a minimum 14­ day retreatment interval. 50% WP [264­ 314] 4 lb/ gal FlC [264­ 321] [264­ 335] 1.5 lb/ A 4 4.0 lb/ A 3.0 lb/ A (FlC) 28 (roots and forage) A maximum of four applications may be made with a minimum 14­ day retreatment interval. 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 333] [264­ 349] 1.5 lb/ A 2 4.0 lb/ A 3.0 lb/ A (FlC) 28 (roots and forage) A maximum of two applications may be made with a minimum 14­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 21 (continued; footnotes follow) Blueberry Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 5 10.0 lb/ A 7 A maximum of five applications may be made with a minimum 7­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 0.05 lb/ 1,000 sq. ft 4 NS 7 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 22 (continued; footnotes follow) Broccoli, Brussels sprouts, cabbage, cauliflower, Chinese cabbage, collards, kale, kohlrabi, mustard greens Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 4 6. 0 lb/ A 3 14 (Chinese Cabbage, collards, kale and mustard greens) A maximum of four applications may be made with a minimum 7­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 3 14 (Chinese Cabbage, collards, kale and mustard greens) Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Brussels sprouts (see broccoli) Cabbage (see broccoli) Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 23 (continued; footnotes follow) Caneberry Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 5 10.0 lb/ A 7 A maximum of five applications may be made with a minimum 7­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 7 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Carrot (see beet, garden) Cauliflower (see broccoli) Celery, dandelion Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 24 (continued; footnotes follow) Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 5 6. 0 lb/ A 14 A maximum of five applications may be made with a minimum 7­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 14 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 25 (continued; footnotes follow) Cherry (see apricot) Chestnut (see almond) Chinese cabbage (see broccoli) Citrus fruits Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 7.5 lb/ A 8 16.0 lb/ A 5 A maximum of eight applications may be made with a minimum 14­ day retreatment interval. 16.0 lb/ A 1 16.0 lb/ A 5 Use limited to CA for control of California red scale and yellow scale. Foliar application Ground 50% WP [CA83007] 80% WP [CA83007] 1.0 lb/ 100 gal NS NS 5 Use limited to CA. Applications may be made at 7­ day retreatment intervals or as needed. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 26 (continued; footnotes follow) Citrus fruits (continued) Foliar application Ground or aerial 80% WP [FL890036] 4 lb/ gal FlC [FL890037] 10.0 lb/ A NS NS 5 Use limited to FL. Applications may be made as a dilute or concentrate spray using ground equipment or in a minimum of 10 gal/ A by air. Applications may be made as needed. Clover Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 1 per cutting 1.5 lb/ A per cutting 7 Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 27 (continued; footnotes follow) Collards Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 4 6.0 lb/ A 6.1 lb/ A for the 2 and 4 lb/ gal FlC (EPA Reg. Nos. 264­ 334 and 264­ 335) 14 See "Broccoli." Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 14 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 28 (continued; footnotes follow) Corn, field and pop Broadcast foliar, banded Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 4 8. 0 lb/ A 14 (forage and silage) 48 (grain and fodder) A maximum of four applications may be made with a minimum 14­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 29 (continued; footnotes follow) Corn, sweet Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 8 16.0 lb/ A 2 (ears) 14 (forage) 48 (fodder) A maximum of eight applications may be made with a minimum 3­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 2 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 30 (continued; footnotes follow) Cotton Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 1.5 lb/ A 4 6. 0 lb/ A 14 (forage) 28 (seed) A maximum of four applications may be made with a minimum 7­ day retreatment interval. Band and/ or directed spray Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 4 6. 0 lb/ A 14 (forage) 28 (seed) Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 31 (continued; footnotes follow) Cowpea (see bean) Cranberry Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 5 10.0 lb/ A 7 See "Blueberry." Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 32 (continued; footnotes follow) Cucumber, melon, pumpkin, squash Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.0 lb/ A 6 6. 0 lb/ A 3 A maximum of six applications may be made with a minimum 7­ day retreatment interval. P/ T formulations not used on pumpkins Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 33 (continued; footnotes follow) Dandelion (see celery) Eggplant (see tomato) Endive (see lettuce) Filbert (see almond) Flax Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 2 3. 0 lb/ A 42 (seed and straw) Use prohibited in CA. A maximum of two applications may be made with a minimum 14­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 34 (continued; footnotes follow) Grape Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 5 10.0 lb/ A 7 See "Blueberry." Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 7 See "Blueberry." Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 35 (continued; footnotes follow) Grasses (grown for seed) Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 2 3. 0 lb/ A 14 A maximum of two applications may be made with a minimum 14­ day retreatment interval. Horseradish (see beet, garden) Kale (see broccoli) Kohlrabi (see broccoli) Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 36 (continued; footnotes follow) Lentil (see bean) Lettuce, head and leaf; endive Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 5 6. 0 lb/ A 14 See "Beet, garden, top" or "Celery." Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 14 See "Celery." Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 37 (continued; footnotes follow) Melon (see cucumber) Millet, proso Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 2 3. 0 lb/ A 7 (forage) 21 (grain and straw) A maximum of two applications may be made with a minimum 14­ day retreatment interval. Use of the 50%, 80%, and 85% WP (EPA Reg. Nos. 264­ 314, 264­ 315, 264­ 316, and 264­ 526) and the 4 lb/ gal FlC (EPA Reg. Nos. 264­ 321, 264­ 333, 264­ 335, and 264­ 349) formulations is prohibited in CA. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 38 (continued; footnotes follow) Mustard greens Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 4 6.0 lb/ A 6.1 lb/ A for the 2 and 4 lb/ gal FlC (EPA Reg. Nos. 264­ 334 and 264­ 335) 14 See "Broccoli." Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 14 A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 39 (continued; footnotes follow) Nectarine (see apricot) Olive Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 7.5 lb/ A 2 15.0 lb/ A 14 A maximum of two applications may be made with a minimum 14­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 40 (continued; footnotes follow) Parsley (see lettuce) Parsnip (see beet, garden) Pastures Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 2 3. 0 lb/ A 14 A maximum of two applications may be made with a minimum 14­ day retreatment interval. Cereal grain bait application Ground or aerial 4 lb/ gal FlC [264­ 333] 0.5 lb/ A 1 NS 0 Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 41 (continued; footnotes follow) Peach (see apricot) Peanut Broadcast foliar, banded Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 1.0 lb/ A 5 8. 0 lb/ A 14 A maximum of five applications may be made with a minimum 7­ day retreatment interval. 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 5 8. 0 lb/ A 14 A maximum of five applications may be made with a minimum 7­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 14 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 42 (continued; footnotes follow) Pea (see bean) Pea, fresh and dried (Pisum species) and Southern pea (see bean) Pecan (see almond) Pepper (see tomato) Pistachio Dormant/ delayed dormant and foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 5.0 lb/ A 4 15.0 lb/ A 14 A maximum of four applications may be made (including dormant/ delayed dormant applications) with a minimum 7­ day retreatment interval. Dormant/ delayed dormant applications may be made in combination with dormant oil. Foliar application Aerial 80% WP [CA810059] 6.0 lb/ A 1 NS 14 Use limited to CA. Application may be made in a minimum of 20 gal/ A. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 43 (continued; footnotes follow) Plum/ Prune (see apricot) Pome fruits (including apples, pears, loquats, crabapples, oriental pears, and quince) Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 3.0 lb/ A 8 15.0 lb/ A 3 A maximum of eight applications may be made (including thinning sprays on apples) with a minimum 14­ day retreatment interval. Application of the 80% WP (EPA Reg. Nos. 264­ 316 and 264­ 526) and 4 lb/ gal FlC (EPA Reg. Nos. 264­ 333, 264­ 335, and 264­ 349) formulations to quince are prohibited. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 44 (continued; footnotes follow) Pome fruits (including apples, pears, loquats, crabapples, oriental pears, and quince)( continued) Postbloom (for fruit thinning) Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 3.0 lb/ A 8 15.0 lb/ A 3 Use limited to apples. A maximum of eight applications may be made (including thinning sprays on apples) with a minimum 14­ day retreatment interval. Postbloom (for fruit thinning) Ground 4 lb/ gal FlC [NC960003] [OH960003] [OR950006] [PA960002] [VA950001] [WA940021] 3.0 lb/ A NS 6.0 lb/ A for NC960003 NS Use limited to NC, OH, OR, PA, VA, and WA. Applications may be made after 80 to 100% petal fall and 9 mm fruit size. Postbloom (for fruit thinning) Ground 50% WP [NC820007] 1.0 lb/ 100 gal (dilute) [250­ 600 gal finished spray/ A] NS NS NS Tank mix use with plant regulator ethephon limited to NC. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 45 (continued; footnotes follow) Pome fruits (including apples, pears, loquats, crabapples, oriental pears, and quince)( continued) Foliar application Ground 50% WP [CA83007] 80% WP [CA83007] 1.0 lb/ 100 gal 5 (for loquats) NS 1 (for apples and pears) 5 (for loquats) Use limited to CA. Applications may be made at 7­ day retreatment intervals or as needed. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 46 (continued; footnotes follow) Potato Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 6 6. 0 lb/ A 7 See "Beet, garden, roots." Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 47 (continued; footnotes follow) Potato (continued) Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 7 See "Beet, garden, roots." Pumpkin (see cucumber) Radish (see beet, garden) Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 48 (continued; footnotes follow) Rangeland Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 3.2 lb/ gal RTU [264­ 427] 3 4 lb/ gal RTU [264­ 422] 1.0 lb/ A 1 1. 0 lb/ A 0 A maximum of one application may be made per year. Cereal grain bait application Ground or aerial 4 lb/ gal FlC [264­ 333] 4 lb/ gal RTU [264­ 422] 0.5 lb/ A 1 NS 0 Rhubarb Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 49 (continued; footnotes follow) Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 14 See "Celery." Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 50 (continued; footnotes follow) Rice Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 2 4. 0 lb/ A 14 (grain and straw) A maximum of two applications may be made with a minimum 7­ day retreatment interval. CA only: for control of tadpole shrimp; max number applications and RTI not specified. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 51 (continued; footnotes follow) Rutabaga (see beet, garden) Salsify (see beet, garden) Sorghum, grain Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 4 6. 0 lb/ A 21 (grain and fodder) 14 (forage and silage) A maximum of four applications may be made with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 52 (continued; footnotes follow) Soybean (see bean) Spinach (see lettuce) Squash (see cucumber) Strawberry Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 5 10.0 lb/ A 7 A maximum of five applications may be made with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 53 (continued; footnotes follow) Strawberry (continued) Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 7 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Sunflower Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 2 3. 0 lb/ A 30 (forage) 60 (seed) Use in CA is prohibited. A maximum of two applications may be made with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 54 (continued; footnotes follow) Sweet potato Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 8 8. 0 lb/ A 7 A maximum of eight applications may be made with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 55 (continued; footnotes follow) Sweet potato (continued) Dip treatment Preplant 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 8.0 lb/ 100 gal NS 1. 2 lb/ A NA Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.3 lb/ A 4 NS 7 Use prohibited in CA. A maximum of four applications may be made per year with a minimum 7­ day retreatment interval. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 56 (continued; footnotes follow) Swiss chard (see lettuce) Tobacco Broadcast foliar (plant bed and field) Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 4 8. 0 lb/ A 0 A maximum of four applications may be made with a minimum 7­ day retreatment interval. Applications may be made in a minimum of 10 gal of finished spray/ A. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 57 (continued; footnotes follow) Tomato, pepper, eggplant Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 2 lb/ gal FlC [264­ 334] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 2.0 lb/ A 7 8. 0 lb/ A 3 A maximum of seven applications may be made with a minimum 7­ day retreatment interval. Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 3 Use prohibited in CA. A maximum of 4 applications may be made per year with a minimum 7­ day RTI. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 58 (continued; footnotes follow) Trefoil, birdsfoot Broadcast foliar Ground or aerial 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 1 per cutting 1.5 lb/ A per cutting 7 Turnip, roots Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 2.0 lb/ A 6 6. 0 lb/ A 7 See "Beet, garden, roots." Soil broadcast Before, during, or after the growing season Ground 7% G [264­ 429] [264­ 430] 2.2 lb/ A 4 NS 7 See "Beet, garden, root." Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 59 (continued; footnotes follow) Turnip, tops Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 2.0 lb/ A 5 6. 0 lb/ A 14 See "Beet, garden, top." Walnut (see almond) Wheat Broadcast foliar Ground or aerial 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 1.5 lb/ A 2 3. 0 lb/ A 7 (forage) 21 (grain and straw) A maximum of two applications may be made with a minimum 14­ day retreatment interval. Use of the 50%, 80%, and 85% WP (EPA Reg. Nos. 264­ 314, 264­ 315, 264­ 316, and 264­ 526) and 4 lb/ gal FlC (EPA Reg. Nos. 264­ 321, 264­ 333, 264­ 335, and 264­ 349) formulations is prohibited in CA. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 60 (continued; footnotes follow) Livestock Uses Poultry treatment (chickens, ducks, geese, game birds, pigeons, and turkeys) Direct animal treatment Electric fog machine 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 349] 5 oz/ 1 gal [1. 5 gal finished spray per 1,000 hens] NS NS 7­ day pre slaughter interval Applications may be repeated in 4 weeks if necessary. Direct animal treatment Compressed air sprayer 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 333] [264­ 335] [264­ 349] 3.2 oz/ 5 gal [1 gal finished spray per 100 hens] NS NS 7­ day pre slaughter interval Applications may be repeated in 4 weeks if necessary. Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 61 (continued; footnotes follow) Poultry houses (chickens, ducks, geese, gamebirds, pigeons, and turkeys) Premise treatment Spreader or sprayer 5% P/ T [264­ 320] 10.04% P/ T [264­ 312] 2.4 oz/ 1,000 sq. ft NS NS NA Applications may be made uniformly to the floor or litter area. A 7­ day preslaughter interval (PSI) has been established for poultry, game birds and their premises. 50% WP [264­ 314] 80% WP [264­ 316] [264­ 526] 85% WP [264­ 315] 4 lb/ gal FlC [264­ 321] [264­ 335] [246­ 349] 4­ 50 lb/ 100 gal [1­ 2 gal of spray mixture per 1,000 sq. ft] NS NS NA Applications may be made to the wall, litter, or roost area. A 7­ day PSI has been established for birds and their premises. Premise treatment Sprayer or duster 80% WP [264­ 316] [264­ 526] 1.0 lb/ 1,000 sq. ft NS NS NA Applications may be made as a dilute spray or as a dry dust to floor surface, walls, cracks, posts, and crevices. A 7­ day PSI has been established for birds and their premises. 4 lb/ gal FlC [264­ 333] [264­ 335] [264­ 349] 0.54­ 0.55 lb/ 1,000 sq. ft NS NS NA Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Maximum Single Application Rate, ai Maximum Number of Applications Per Season Maximum Seasonal Rate, ai Preharvest Interval, Days Use Directions and Limitations 2 62 Fish and Shellfish Uses Oyster beds Application to dewatered oyster beds Ground or aerial 80% WP [WA900013] 10.0 lb/ A NS NS 365 Application is for control of ghost shrimp and mud shrimp. Application must be made and completed within 30 minutes after low tide to prevent direct contamination of water. Use is limited to areas greater than 200 feet from channels and sloughs. For aerial application, a 200­ foot buffer zone is required between the treatment area and the nearest shellfish to be harvested. A 50­ foot buffer zone is required if treatment is by hand spray. Treatment is allowed only on ground with no oysters within one year of harvest are present. 1 The following labels list a drench spot application to fire ant mounds in rangeland or pastures: Epa Reg. Nos. 264­ 314, ­315, ­316, ­321, ­349, and ­526. EPA Reg. Nos. 264­ 334 and ­335 permit drench spot treatment for fire ants on all labeled crops/ sites. The labeled rate for fire ant spot treatment is 6.7­ 10.6 g/ gal. Granular spot treatment with EPA Reg. Nos. 264­ 429 and ­430 may also be made at 6g/ ant mound. 2 A restriction against planting rotational food and feed crops not listed on the label or other carbaryl labels in carbaryl treated soil is specified on the labels for the following products: EPA Reg. Nos. 264­ 312, 264­ 314, 264­ 315, 264­ 316, 264­ 320, 264­ 321, 264­ 333, 264­ 334, 264­ 335, 264­ 349, 264­ 422, 264­ 427, 264­ 429, and 264­ 526. Irrigation restrictions: (i) Use in irrigation systems prohibited for EPA Reg. No. 264­ 422, ­427; (ii) use of reclaimed irrigation water on upland crops for which no carbaryl tolerances established prohibited for EPA Reg. Nos. 264­ 312, ­314, ­315, ­320, ­321, ­333, ­334, ­335, ­349, ­422, ­427; (iii) may be applied through sprinkler irrigation systems including center pivot and solid set ­ use of all other types prohibited EPA Reg. Nos. 264­ 312, ­314, ­315, ­316, ­321, ­333, ­349, ­526). 12­ Hour RTI for EPA Reg. Nos. 264­ 312, ­314, ­315, ­316, ­320, ­321, ­333, ­335, ­349, ­422, ­427, ­526). 3 The 3.2 lb/ gal RTU (EPA Reg. No. 264­ 427) product label lists the application rates in quarts of product per acre for non cropland and rangeland; however, to make this product label consistent with the other products the application rates should be expressed as fluid ounces per acre. (continued; footnotes follow) 63 Table B. Residue Chemistry Science Assessments for Reregistration of Carbaryl. GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 860.1200: Directions for Use N/ A = Not Applicable Yes 3 860.1300: Plant Metabolism N/ A No 00049135 00053897 00116083 00118342 00124353 00124968 00125170 43249101 4 43249102 4 43249103 4 860.1300: Livestock Metabolism N/ A No 5 00015669 00053897 00080417 00080679 00080680 00080681 00080682 00080683 00080686 00080689 00080690 00091952 00095927 00118346 00118347 00118365 00118368 00118371 00118375 00118376 00118377 00139664 43324601 6,7 860.1340: Residue Analytical Methods ­Plant commodities N/ A Yes 8 00080417 00080680 00098504 00107017 00118342 00118346 00118366 00118367 00118368 00118370 00118372 00118373 00118377 00124334 00124361 00145884 00147760 00154626 00156736 00159326 05001852 05004154 05004934 05008728 05010424 05014156 05014889 05016141 05018884 05019959 40255702 40408601 43672701 9 43672702 9 43786805 10 44155401 11 ­Livestock commodities N/ A Yes 12 00061103 00080417 00080680 00118346 00118366 00118367 00118368 00118370 00118372 00118373 00118375 00118376 05001852 05004154 05008728 05010424 05014156 05014889 05016141 05018884 05019959 44286901 13 44286902 13 44286903 13 860.1360: Multiresidue Methods N/ A No 860.1380: Storage Stability Data ­Plant commodities N/ A Yes 14 00163007 00163009 00163014 40408601 43850902 15 44068401 16 44123101 17 44250301 16 44412501 18 Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 (continued; footnotes follow) 64 ­Livestock commodities N/ A No 44250901 13 44381901 13 860.1500: Crop Field Trials Root and Tuber Vegetables Group ­Beet, garden, roots 5 [§ 180.169( a)] No 00089868 43813601 10 ­Beet, sugar, roots None established No 00089868 00163007 40376001 19 40376002 20 ­Carrot 10 [§ 180.169( a)] No 00090325 43813601 10 ­Horseradish 5 [§ 180.169( a)] No 00089868 43813601 10 ­Parsnips 5 [§ 180.169( a)] No 00089868 43813601 10 ­Potato 0. 2 [§ 180.169( a)] No 00107017 00134421 40512501 20 ­Radishes 5 [§ 180.169( a)] No 00089868 43813601 10 ­Salsify, roots 5 [§ 180.169( a)] No 00089868 43813601 10 ­Turnip, roots 5 [§ 180.169( a)] No 00089868 43813601 10 ­Sweet potato 0.2 [§ 180.169( a)] No 00107017 43702002 21 Leaves of Root and Tuber Vegetables Group ­Beet, garden, tops 12 [§ 180.169( a)] No 00089868 43813601 10 ­Beet, sugar, tops 100 [§ 180.169( a)] No 19 00089868 ­Salsify, tops 10 [§ 180.169( a)] No 00089868 43813601 10 ­Turnip, tops 12 [§ 180.169( a)] No 00089868 43813601 10 Leafy Vegetables (except Brassica) Vegetables Group ­Celery 10 [§ 180.169( a)] No 00124337 43677401 22 ­Dandelions 12 [§ 180.169( a)] No 22 00089868 43677401 22 ­Endive 10 [§ 180.169( a)] No 23 00089868 43677401 22 Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 (continued; footnotes follow) 65 ­Lettuce 10 [§ 180.169( a)] No 00089868 00090162 43677401 22 ­Parsley 12 [§ 180.169( a)] No 23 00089868 43677401 22 ­Spinach 12 [§ 180.169( a)] No 00089868 43677401 22,24 ­Swiss chard 12 [§ 180.169( a)] No 00089868 43677401 22 Brassica (Cole) Vegetables Group ­Broccoli 10 [§ 180.169( a)] No 00090325 43721001 22 44019701 25 ­Brussels sprouts 10 [§ 180.169( a)] No 26 00090325 43721001 22 ­Cabbage 10 [§ 180.169( a)] No 00090325 43786806 10 ­ Cauliflower 10 [§ 180.169( a)] No 27 00090325 43721001 22 ­ Chinese cabbage 10 [§ 180.169( a)] No 00089868 43794903 10 ­ Collards 12 [§ 180.169( a)] No 00089868 43794903 10 ­Kale 12 [§ 180.169( a)] No 00089868 43794903 10 ­ Kohlrabi 10 [§ 180.169( a)] No 27 00090325 43721001 22 ­Mustard greens 12 [§ 180.169( a)] No 00089868 43794903 10 Legume Vegetables Group ­Bean, fresh and dried 10 [§ 180.169( a)] No 00089679 00089680 00089681 00082424 00089837 00090113 00163014 00124334 43786804 10 43984701 27 ­Cowpeas 5 [§ 180.169( a)] No 00089837 43694103 22 ­Lentils 10 [§ 180.169( a)] No 00089837 00124334 43694103 22 ­Peas (with pods) 10 [§ 180.169( a)] No 00090113 00124334 43703102 22 ­Soybeans 5 [§ 180.169( a)] No 00089837 43694102 22 Foliage of Legume Vegetables Group Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 (continued; footnotes follow) 66 ­Bean, forage and hay 100, forage 100, hay [§ 180.169( a)] No 28 00082424 00089679 00089680 00089681 00089837 00125090 ­Cowpea, forage and hay 100, forage 100, hay [§ 180.169( a)] No 00089837 43786804 10 ­Pea, vines 100 [§ 180.169( a)] No 00089837 00124334 43786804 10 ­Soybean, forage and hay 100, forage 100, hay [§ 180.169( a)] No 00089837 43694102 22 Fruiting Vegetables (Except Cucurbits) Group ­Eggplant 10 [§ 180.169( a)] No 00089600 43686701 22 43996101 28 ­Pepper 10 [§ 180.169( a)] No 00089600 43686701 22 ­Tomato 10 [§ 180.169( a)] No 00089600 00159326 43996101 28 Cucurbit Vegetables Group ­Cucumber 10 [§ 180.169( a)] No 00089376 43786802 10 ­Melon 10 [§ 180.169( a)] No 00090325 43786802 10 ­Pumpkin 10 [§ 180.169( a)] No 00090325 43786802 10 ­Squash, summer 10 [§ 180.169( a)] No 00089376 43786802 10 ­Squash, winter 10 [§ 180.169( a)] No 00090325 43786802 10 Citrus Fruits Group ­Citrus 10 [§ 180.169( a)] No 00090204 00090320 00163008 43802101 15 44211801 29 Pome Fruits Group ­Pome fruits 10 [§ 180.169( d)] No 00080419 00082420 00082423 00083311 00083312 00089455 00089679 00089680 00159327 44072901 11 Stone Fruits Group ­Apricot 10 [§ 180.169( a)] No 00090160 43793202 15 44284701 30 Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 (continued; footnotes follow) 67 ­Cherry 10 [§ 180.169( a)] No 00089348 00124345 43793202 15 44284701 30 ­Nectarine 10 [§ 180.169( a)] No 00090160 43793202 15 44284701 30 ­Peach 10 [§ 180.169( a)] No 00082422 43793202 15 44284701 30 ­Plum (fresh prune) 10 [§ 180.169( a)] No 00089348 00124345 43793202 15 44284701 30 Berries Group ­Blackberry 12 [§ 180.169( a)] No 00089868 43698201 22 ­Blueberry 10 [§ 180.169( a)] No 00090161 43694101 22 ­Boysenberry 12 [§ 180.169( a)] No 00089868 43698201 22 ­Dewberry 12 [§ 180.169( a)] No 00089868 43698201 22 ­Loganberry 12 [§ 180.169( a)] No 00089868 43698201 22 ­Raspberry 12 [§ 180.169( a)] No 00089868 43698201 22 Tree Nuts Group ­Almond, nutmeat and hulls 1, almonds; 40, almonds, hulls [§ 180.169( a)] No 00108985 00140447 43786801 15 ­Chestnut 1 [§ 180.169( a)] No 43786801 15 43802102 15 ­Filbert 1 [§ 180.169( a)] No 00090156 43786801 15 43802102 15 ­Pecan 1 [§ 180.169( a)] No 00123219 43802102 15 ­Walnut 1 [§ 180.169( a)] No 00108985 00140447 43818901 15 Cereal Grains Group ­Barley, grain 0 [§ 180.169( a)] No 30 ­Corn, field and pop 5, fresh (including sweet) K+ CWHR [§ 180.169( a)] No 00089420 00125090 00125107 00163009 44058001 16 Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 (continued; footnotes follow) 68 ­Corn, sweet 5, fresh (including sweet) K+ CWHR [§ 180.169( a)] No 00089378 00089420 00125090 00125107 44058101 11 ­Millet, proso, grain 3 [§ 180.169( a)] No 31 00074368 43975601 15 ­Oats, grain 0 [§ 180.169( a)] No 30 ­Rice, grain 5 [§ 180.169( a)] No 00089837 00125138 43802103 15 ­Rye, grain 0 [§ 180.169( a)] No 30 ­Sorghum, grain 10 [§ 180.169( a)] No 43794901 10 ­Wheat, grain 3 [§ 180.169( a)] No 00015669 00115284 00136415 41594301 32 43975601 15 Forage, Fodder, and Straw of Cereal Grains Group ­Barley, forage and straw 100, green fodder 100, straw [§ 180.169( a)] No 30 ­Corn, fodder and forage 100, fodder 100, forage [§ 180.169( a)] No 00089378 00089420 00125090 00125107 44058001 33 44058101 11 ­Millet, proso, straw 100 [§ 180.169( a)] No 31 00074368 43975601 15 ­Oats, forage and straw 100, green fodder 100, straw [§ 180.169( a)] No 30 ­Rice, straw 100, straw [§ 180.169( a)] No 00089837 00125138 43802103 15 ­Rye, forage 100, green fodder 100, straw [§ 180.169( a)] No 30 ­Sorghum, forage 100, forage [§ 180.169( a)] No 00159329 43794901 10 ­Wheat, forage and straw 100, green fodder 100, straw [§ 180.169( a)] Yes 34 00015669 00115284 00136415 Grass Forage, Fodder, and Hay Group ­Pastures 100, grass; 100, hay [§ 180.169( a)] Yes 35 00089837 00125121 00125123 00125555 00163006 43716601 22 ­Rangeland 100, grass; 100, hay [§ 180.169( a)] No 00089837 00125121 00125123 00125555 00163006 44065901 34 Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 (continued; footnotes follow) 69 Non­ grass Livestock Feeds (Forage, Fodder, Straw, and Hay) Group ­Alfalfa, forage and hay 100, fresh; 100, hay [§ 180.169( a)] No 00089837 00125121 00125123 00159325 ­Birdsfoot trefoil, forage and hay 100, fresh; 100, hay [§ 180.169( a)] No 00089837 00125121 00125123 00159325 ­Clover, forage and hay 100, fresh; 100, hay [§ 180.169( a)] No 00089837 00125121 00125123 43694105 22 Herbs and Spices Group ­Dill, fresh 0.2 [§ 180.169( e)] No PP# 7E3543 36 Miscellaneous Commodities ­Aspirated grain fractions None No 37 43794902 10 43813602 10 ­Asparagus 10 [§ 180.169( a)] No 00083527 00140449 43654201 10 ­Avocado 10 [§ 180.169( e)] No 30 ­Banana 10 [§ 180.169( a)] No 44798401 39 ­Cranberry 10 [§ 180.169( a)] No 00090161 43697604 22 ­Cotton, seed and forage 5, cottonseed 100, cotton forage [§ 180.169( a)] No (Revoke) 38 00089837 00124343 00125099 40881307 ­Flax, seed and straw 5, seed; 100, straw [§ 180.169( a)] No 00074366 00074367 43982801 15 ­Grapes 10 [§ 180.169( a)] No 00089418 00089458 00125084 43793201 15 ­Maple, sap 0.5 [§ 180.169( a)] No 30 ­Okra 10 [§ 180.169( a)] No 00090229 44123101 17 ­Olives 10 [§ 180.169( a)] No 40 00090281 43702001 22 44321301 18 ­Peanuts, nut and hay 5, peanut; 100, hay [§ 180.169( a)] No 00089837 43703101 22 ­Pineapple 2. 0 [§ 180.169( d)] Yes 39 PP# 5F3208 ­Pistachio nuts 1 [§ 180.169( a)] No 00124335 43703103 22 ­Prickly pear cactus 12, fruit; 12, pads [§ 180.169( a)] No 00103288 44145201 17 Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 (continued; footnotes follow) 70 ­Strawberry 10 [§ 180.169( a)] No 00089348 43698202 22 ­Sunflower 1, seeds [§ 180.169( a)] No 00058927 00058928 43786803 10 ­Tobacco None established No 44114301 40 860.1520: Processed Food/ Feed ­Beet, sugar None established No 00163017 ­Citrus fruits None established No 43694104 22 ­Corn, field None established No 00163018 43915201 15 ­Cottonseed None established No 43850901 15 ­Flaxseed None established No 00074366 00074367 ­Grapes None established No 00163010 00163011 43697601 22 43697602 22 ­Olives None established No 43698203 22 ­Peanut None established No 00163012 44046101 26 ­Pineapple 20, bran [§ 186.550] No PP# 5F3208 41 ­Plum None established No 00159328 ­Pome fruits None established No 43702003 22 ­Potato None established No 00159324 43697603 22 ­Rice None established No 00163013 43813603 10 ­Sorghum None established No 00163015 43813604 10 ­Soybean None established No 00163016 43794902 10 ­Sunflower None established No 43845205 15 ­Tomato None established No 43686702 22 ­Wheat None established No 43813602 10 860.1480: Meat, Milk, Poultry, Eggs ­Milk and the Fat, Meat, and Meat Byproducts of Cattle, Goats, Hogs, Horses, and Sheep 0.1, fat, meat, and meat byproducts; 1, kidney and liver [§ 180.169( b)] No 00015669 00061106 00080417 00080419 00080420 00089380 00089836 00089837 00118342 00118346 00118367 00118368 00118370 00118372 00118373 00118374 00118378 40881302 40881312 40881313 40881314 44250901 13 44381901 13 Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 (continued; footnotes follow) 71 ­Fat, Meat, and Meat Byproducts of Poultry 5.0 Fat and meat [§ 180.169( b)] No 00061103 00080420 00080680 00118375 00118376 00124367 00125571 00135678 00135680 40881308 40881309 ­Eggs 0.5 [§ 180.319] No Table B (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? 1 References 2 72 1. Reassessed tolerances for leafy vegetables remain tentative until granular data required to support the reregistration of carbaryl are submitted. The registrant should conduct one side­ by­ side trial comparing a granular formulation and a spray formulation. If the residues resulting from use of the granular formulation for all crops are the same or less than the spray formulation, then no additional granular data would be required. 2. Bolded references were reviewed in the Residue Chemistry Chapter of the Carbaryl Reregistration Standard dated 3/ 15/ 83 or the Interim Residue Chemistry Chapter of the Carbaryl Reregistration Standard dated 3/ 30/ 84. Italicized references were reviewed in the Residue Chemistry Chapter of the Carbaryl (FRSTR) Reregistration Standard dated 5/ 3/ 88. All other references were reviewed as noted. 3. Label revisions are required for several crops in order to reflect the parameters of use patterns for which residue data are available. Details of the required label amendments are presented in the Directions for Use section. 4. DP Barcode D204197, 11/ 28/ 95, S. Hummel. 5. No tolerances are needed for residues of carbaryl in/ on poultry; the presently registered uses of carbaryl are classified as Category 3 of 40 CFR §180.6( a) with respect to the need for tolerances in poultry and eggs i. e., there is no reasonable expectation of finite residues. 6. CB No. 14249, DP Barcode D206777, 11/ 28/ 95, S. Hummel. 7. DP Barcode D255855, C. Olinger, 5/ 16/ 99 and 6/ 17/ 99. 8. The proposed HPLC enforcement method for carbaryl per se in plants (Method CACR­ 0194) should be submitted to the Agency for validation. 9. DP Barcode D216544, S. Hummel, 1/ 22/ 96. 10. DP Barcodes D216242, D219527, D219596, and D220287, T. Morton, 9/ 17/ 98. 11. DP Barcodes D230246, D230406, and D231533, M. Perry, 5/ 26/ 98. 12. HPLC Method Aventis File No. 45186, which has successfully undergone an ILV should be submitted to the Agency for validation 13. DP Barcodes D236574, D236421, and D240469, C. Olinger, 12/ 15/ 99. 860.1400: Water, Fish, and Irrigated. Crops ­Oysters 0.25 [§ 180.169( a)] No PP# 1E2554 42 860.1460: Food Handling Establishments N/ A N/ A 860.1850: Confined Rotational Crops N/ A No 43651701 43 860.1900: Field Rotational Crops None established No Table B (continued). 73 14. Additional data are required depicting the storage stability of carbaryl per se in processed commodities of an oily crop for up to 10 months. The maximum storage interval for processed commodities of an oily crop was ­ 10 months (soybean processed commodities). In addition, the registrant is relying on earlier magnitude of the residue studies which are not supported by the existing storage stability data. Unless the registrant can demonstrate that samples from studies reflecting the use patterns the registrant wishes to support were not stored longer than 12 months, additional storage stability data are required. The required data must reflect storage intervals of 18 months for alfalfa commodities, 15 months for potatoes, 22 months for wheat commodities, and 33 months for rangeland grass. In addition, if the registrant wishes to rely on the previously submitted sugar beet processing study, information pertaining to sample conditions and intervals for the study must be submitted. 15. DP Barcodes D218865, D219999, D220949, D221158, D223008, D219971, D220601, D220948, D221313, D225204, and D225576, F. Suhre, 9/ 13/ 96. 16. DP Barcodes D228656 and D235113, C. Olinger, 11/ 09/ 99. 17. DP Barcodes D230900 and D231134, M. Perry, 5/ 22/ 98 18. DP Barcode D240998 and D237653, C. Olinger, 4/ 9/ 98. 19. CB No.: 3027, DP Barcode: none, M. Nelson, 3/ 28/ 88. 20. CB No.: 3510, DP Barcode: none, M. Kovacs, 4/ 25/ 88. 21. DP Barcodes D217179, D217172, D217177, D217631, D217704, and D217705, F. Suhre, 10/ 7/ 96. 22. Data for spinach will be translated to dandelion and parsley. 23. Data on lettuce will translate to endive. 24. DP Barcode D234692, C. Olinger, 9/ 11/ 97. 25. DP Barcodes D227765 and D227009, M. Perry, 5/ 12/ 98. 26. Data on broccoli will be translated to Brussels sprouts, cauliflower, and kohlrabi. 27. DP Barcodes D225659 and D226582, F. Suhre, 8/ 21/ 96. 28. Data are no longer required as cowpea is the only bean crop considered for livestock feeding. 29. DP Barcodes D236422 and D236485, C. Olinger, 11/ 9/ 99. 30. The registrant does not intend to support carbaryl uses on avocados, barley, maple trees, oats, rye, and sweet sorghum; however, IR­ 4 has indicated (Correspondence from K. Dorschner, IR­ 4 Project, 9/ 15/ 94) that they may submit residue data to support reregistration for some of these commodities. These data have not been submitted. 31. Acceptable residue data on wheat will be translated to support the use on proso millet. 32. CB No. 6972, H. Fonouni, 10/ 5/ 90. 33. DP Barcodes D228260 and D228652, C. Olinger, 11/ 9/ 99. 34. Adequate data are available to reassess the tolerance for wheat forage and straw. However, the Agency now considers wheat hay a significant livestock feed item (OPPTS GLN 860.1000 Table 1.). A full set of 20 field trials as specified in OPPTS GLN 860.1500 are required depicting carbaryl residues in/ on wheat hay. When all the field trials are complete, PHIs and tolerances for hay based on the field trial data should be proposed. Data on wheat hay will be translatable to proso millet hay. Table B (continued). 74 35. Data are required depicting residues of carbaryl in/ on grass forage harvested immediately (0­ day) following the last of two applications of carbaryl (WP or FlC) at 1.5 lb ai/ A to pasture. A total of 12 field trials are required in areas throughout the U. S. The following data on grasses are available for risk assessment/ reregistration purposes: Residue data from rangeland field trials support the current tolerance of 100 ppm in/ on grass forage; as noted above, data are still needed on pasture grass forage before the tolerance can be reassessed . Data on pasture hay harvested at the 14­ day PHI indicate that the tolerance on grass hay should be lowered to 15 ppm. 36. CB No. 3357, DP Barcode: none, M. Nelson, 2/ 25/ 88. 37. Based on available data, a tolerance of 70 ppm should be established for residues of carbaryl per se in/ on aspirated grain fractions. 38. The use of carbaryl products on cotton has been cnaceled. 39. The registrant intends to support a tolerance for residues in/ on imported pineapple. Five residue field trials must be submitted, three from Costa Rica and two from Mexico. DP Barcode D255348, 11/ 2000, C. Olinger. 40. DP Barcode D230407, T. Morton, 9/ 29/ 98. 41. DP Barcode D215259, S. Hummel, 5/ 31/ 95. 42. Residues resulting from the registered use of carbaryl on oyster beds in WA are not likely to exceed the established tolerance (DP Barcode D204888, J Garbus, 8/ 5/ 94). 43. DP Barcode D215844, 9/ 10/ 98, C. Olinger. 75 TOLERANCE REASSESSMENT SUMMARY The HED Metabolism Committee has concluded that the U. S. tolerance expression for plant commodities should be amended to include only carbaryl per se (S. Hummel, 2/ 8/ 96). Accordingly, the tolerance definition for carbaryl should be amended to include only parent carbaryl. The tolerance expression for livestock commodities should be amended to include free and conjugated residues of carbaryl, 5,6­ dihydro5,6 dihydroxy carbaryl, and 5­ methoxy­ 6­ hydroxy carbaryl. In addition, the tolerances listed separately under 40 CFR §180.169 (a through e) should be pooled into three listings, one for plant commodity tolerances with national registrations, one for livestock commodities, and the third for tolerances with regional registrations. The food additive tolerance for residues in pineapple bran should be revoked as this is no longer a regulated commodity (40 CFR §186.550). Some analytical methods determine the combined residue of carbaryl and 1­ naphthol. It should be noted that 1­ napthol is a very minor part of the residue; therefore, the plant commodity tolerances, which are based on carbaryl only, are not greatly exaggerated. A summary of carbaryl tolerance reassessments and recommended modifications in commodity definitions are presented in Table C. Tolerances Listed Under 40 CFR §180.169( a), (b), (c), (d), and (e): As noted above, conclusions pertaining to leafy vegetables crops which retain post­ emergence granular uses are tentative pending submission of bridging residue data reflecting use of a representative G formulation or revision of the labels for the G formulations. In addition, supporting storage stability data are still required for several crop commodities. Aventis has proposed and/ or the available data support the establishment of tolerances for residues in/ on the following crop groups and subgroups: Brassica leafy greens; bushberry; caneberry; cucurbit vegetables; dried, shelled pea and bean (except soybean); edible­ podded legume vegetables; foliage of legume vegetables except soybeans; fruiting vegetables (excluding cucurbits); leaf petioles; leaves of root and tuber vegetables (excluding sugar beet); root and tuber vegetables (excluding sugar beet roots and sweet potatoes); stone fruits; and tree nuts (excluding walnuts). As a result, separate tolerances on many commodities need to be revoked concomitant with establishing tolerances for the appropriate crop group and subgroup. The recommended changes are summarized in Table C under "Tolerances Needed Under 40 CFR §180.169( a), crop group/ subgroup tolerances." Residue data are required on pasture grass forage before the tolerance for residues in/ on grass forage can be reassessed. Additional data are required on pineapple before the tolerance can be reassessed. Five trials must be submitted, three from Costa Rica and two from Mexico. The registrant is not supporting carbaryl uses on avocados, barley, maple sap, oats, and rye, and with the exception of avocados, these uses have been removed from the labels. IR­ 4 has indicated (Correspondence from K. Dorschner, IR­ 4 Project, 9/ 15/ 94) that they may be willing to submit residue data for some of these commodities; however, data have not been submitted. The tolerances for bean forage and hay should be revoked because they are no longer considered significant livestock feed items. 76 Data from a ruminant feeding study were used as the basis for reassessing tolerances for residues in livestock commodities. For tolerances on commodities of cattle, goats, horses and sheep, the available data support the current tolerances of 0.1 ppm for residues of carbaryl in meat, but indicate that the tolerances for fat are too low and should be increased to 0.2 ppm; the established tolerance for residues in milk should be lowered to 0.1 ppm. Separate tolerances for residues in kidney and liver (1.0 ppm) and meat byproducts excluding kidney and liver (0.1 ppm) should be revoked, and a separate tolerance for residues in meat byproducts should be established at 3.0 ppm. For swine commodities, the available data indicate the established tolerances for carbaryl residues in hog meat and fat (0.1 ppm) are too high and should be set at 0.02 ppm (the method limit of quantitation). Separate tolerances for residues in hog kidney and liver (1.0 ppm each) and meat byproducts excluding kidney and liver (0.1 ppm) should be revoked, and a separate tolerance for residues in hog meat byproducts established at 0.5 ppm. The available residue data support the establishment of separate tolerances for residues in/ on various crop groups and subgroups. As a result, separate tolerances on many commodities need to be revoked concomitant with establishing new tolerances for residues in/ on the appropriate crop groups and subgroups. The recommended changes are summarized in Table C under "Tolerances Needed Under 40 CFR §180.169( a), crop group/ subgroup tolerances." New tolerances are also needed for carbaryl residues in/ on the following RACs: aspirated grain fractions, proso millet hay, sorghum stover, sugar beet roots, and wheat hay. At the present time, sufficient data are only available to determine an appropriate tolerance for residues in/ on aspirated grain fractions (70 ppm), sugar beet roots (0.5 ppm) and sorghum stover (30.0 ppm). Additional residue data are required before appropriate tolerances can be determined for residues in/ on the remaining commodities; data on wheat hay will be translatable to proso millet hay. Separate tolerances are also required for residues in the following processed food/ feed items: wet apple pomace (15.0 ppm), citrus fruit oil (20.0 ppm), raisins (12.0 ppm), and rice hulls (30.0 ppm). For livestock commodities, the residue data support establishing new tolerances for residues in meat byproducts of swine (0.5 ppm) and cattle, goats, and sheep (3.0 ppm); separate tolerances for residues in kidney and liver (1.0 ppm), and meat byproducts excluding kidney and liver (0.1 ppm) should be reassigned. 77 (continued; footnotes follow) Table C. Tolerance Reassessment Summary for Carbaryl. Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] Tolerance Listed Under 40 CFR §180.169( a) Alfalfa 100.0 50.0 Residue data indicate that the tolerance should be lowered to 50.0 ppm. Alfalfa, Hay 100.0 75.0 Residue data indicate that the tolerance should be lowered to 75.0 ppm. Almonds 1.0 Reassign Tolerance should be reassignd concomitant with establishing a 0.1 ppm tolerance on the nuts, tree crop group (excluding walnuts). Almond, hulls 40.0 50.0 Residue data indicate that the tolerance should be increased. Apricots 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the fruit, stone crop group. Asparagus 10.0 15.0 Residue data indicate that the tolerance should be increased. Banana 10.0 5 Barley, fodder, green 100.0 Revoke The registrant does not intend to support carbaryl uses on barley. Barley, grain 0.0 Barley, straw 100.0 Beans 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance for ediblepodded legume vegetables ( crop subgroup 6A), and a 1.0 ppm tolerance for dried, shelled pea and bean (except soybean) (crop subgroup 6C). Beans, forage 100.0 Revoke Tolerance should be revoked. Bean forage and hay are no longer considered significant livestock feed items. Beans, hay 100.0 Beets, garden, roots 5.0 Reassign Tolerance should be reassigned concomitant with establishing a 2.0 ppm tolerance on the vegetables, root and tuber crop group (excluding sugar beets and sweet potatoes). Beets, garden, tops 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 75.0 ppm tolerance on the leaves of vegetables, root and tuber group (excluding sugar beets tops). Beets, sugar, tops 100.0 25.0 The available data indicate that the tolerance should be lowered. Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 78 (continued; footnotes follow) Blackberries 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 12.0 ppm tolerance on the caneberry crop subgroup. Blueberries 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 3.0 ppm tolerance on the bushberry crop subgroup. Boysenberries 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 12.0 ppm tolerance on the caneberry crop subgroup. Broccoli 10.0 10.0 Brussels sprouts 10.0 10.0 Data on broccoli will translate to Brussels sprouts. Cabbage 10.0 21.0 The residue data indicate that the tolerance should be increased to 21.0 ppm. Cabbage, chinese 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the vegetable, Brassica leafy group. Carrots 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 2.0 ppm tolerance on the vegetables, root and tuber group (excluding sugar beets and sweet potatoes). Cauliflower 10.0 10.0 Data on broccoli will translate to cauliflower. Celery 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 3.0 ppm tolerance on the leaf petioles crop subgroup. Cherries 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the fruit, stone group . Chestnuts 1.0 Reassign Tolerance should be reassignd concomitant with establishing a 0.1 ppm tolerance on the nut, tree group (excluding walnuts). Citrus fruits 10.0 10.0 Fruit, citrus, group Clover 100.0 50.0 Residue data indicate that the tolerance should be lowered to 50.0 ppm. Clover, hay 100.0 70.0 Residue data indicate that the tolerance should be lowered to 70.0 ppm. Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 79 (continued; footnotes follow) Collards 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the vegetables, Brassica, leafy, group . Corn (inc. sweet) (K+ CWHR) 5.0 0.10 Corn, sweet (K+ CWHR); residue data indicate that a separate tolerance on sweet corn (K+ CWHR) should be established at 0.1 ppm. 0.02 Corn, grain, field and pop; residue data indicate that a separate tolerance should be established for corn, grain at 0.02 ppm. Corn, fodder 100.0 20.0 Corn, stover (field and pop). Residue data indicate that the tolerance for field and pop corn stover should be lowered to 20.0 ppm. 215.0 Corn, sweet, stover. Residue data indicate that the tolerance for sweet corn stover should be increased. Corn, forage 100.0 30.0 Corn, field, forage. Residue data indicate that the tolerance for field corn forage should be lowered to 30.0 ppm. 185.0 Corn, sweet, forage. Residue data indicate that the tolerance for field corn forage should be increased. Cotton, forage 100.0 Revoke No longer considered a significant feed item. Cotton, seed 5.0 Revoke The use on cotton has been cancelled. Cranberries 10.0 3.0 Residue data indicate that the tolerance should be lowered to 3.0 ppm. Cucumbers 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 3.0 ppm tolerance on the vegetable, cucurbit, group. Dandelions 12.0 22.0 Residue data on spinach are translatable to dandelion. The residue data on spinach indicate that the tolerance must be increased. Dewberry 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 12.0 ppm tolerance on the caneberry crop subgroup. Eggplant 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 5.0 ppm tolerance on the vegetables, fruiting, group (excluding cucurbits). Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 80 (continued; footnotes follow) Endive (escarole) 10.0 10.0 Residue data on lettuce are translatable to endive. Filberts (hazelnuts) 1.0 Reassign Tolerance should be reassignd concomitant with establishing a 0.1 ppm tolerance on the nuts, tree, group (excluding walnuts). Flax, seed 5.0 0.50 Residue data support lowering the tolerance. Flax, straw 100.0 Revoke No longer considered a RAC of flax. Grapes 10.0 10.0 Grasses 100.0 TBD Grass, forage. Residue data on rangeland grass forage harvested at a 0­ day PGI support the current tolerance of 100 ppm; data on pasture grass forage harvested at 0­ day PGI are needed. Grasses, hay 100.0 15.0 Residue data on pasture hay indicate that the tolerance should be lowered to 15.0 ppm. Horseradish 5.0 Reassign Tolerance should be reassignd concomitant with establishing a 2.0 ppm tolerance on the vegetable, root and tuber, group (excluding sugar beets and sweet potatoes). Kale 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the vegetable, Brassica, leafy, group. Kohlrabi 10.0 10.0 Residue data on broccoli are translatable to kohlrabi. Lentils 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 1.0 ppm tolerance on the pea and bean, dried shelled, except soybean group (6C). Lettuce 10.0 10.0 Loganberries 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 12.0 ppm tolerance on the caneberry crop subgroup. Maple sap 0.50 Revoke The registrant is not supporting this use Melons 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 3.0 ppm tolerance on the vegetable, cucurbit, group. Millet, proso, grain 3.0 1.0 Residue data for wheat grain indicate that the tolerance should be lowered to 1.0 ppm Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 81 (continued; footnotes follow) Millet, proso, straw 100.0 20.0 Adequate residue data on wheat straw are translatable to proso millet straw; the residue data support lowering the tolerance. Mustard, greens 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the vegetable, Brassica, leafy, group. Nectarines 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the fruit, stone, group. Oats, fodder, green 100.0 Revoke The registrant does not intend to support carbaryl uses on oats Oats, grain 0.0 Oats, straw 100.0 Okra 10.0 4.0 The available data indicate that the tolerance should be lowered. Olives 10.0 10.0 Oysters 0.25 0.25 Parsley 12.0 22.0 Residue data on spinach are translatable to parsley; the data indicate that the tolerance on parsley should be increased. Parsnips 5.0 Reassign Tolerance should be reassignd concomitant with establishing a 2.0 ppm tolerance on the vegetable, root and tuber, group (excluding sugar beets and sweet potatoes). Peaches 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the fruit, stone, group. Peanuts 5.0 0.05 The available data indicate that the tolerance should be lowered. Peanuts, hay 100.0 20.0 Residue data support a lower tolerance. Peas, cowpeas 5.0 Reassign Tolerance should be reassignd concomitant with establishing a 1.0 ppm tolerance for dried, shelled pea and bean (except soybean) group. Peas, cowpeas, Forage 100.0 Reassign Tolerances should be reassignd concomitant with establishing a 60.0 ppm tolerance for vegetable, foliage of legume, group. Peas, cowpeas, Hay 100.0 Peas, vines 100.0 Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 82 (continued; footnotes follow) Peas, with pods 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance for vegetable, legume, edible­ podded subgroup (crop subgroup 6A). Pecans 1.0 Reassign Tolerance should be reassignd concomitant with establishing a 0.1 ppm tolerance on the nuts, tree, group (excluding walnuts). Peppers 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 5.0 ppm tolerance on the vegetable, fruiting group (excluding cucurbits) crop group. Pistachio 1.0 0.10 Residue data indicate that the tolerance should be lowered. Plums (fresh prunes) 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 10.0 ppm tolerance on the fruit, stone, group. Potatoes 0.20 Reassign Tolerance should be reassignd concomitant with establishing a 2.0 ppm tolerance on the vegetable, root and tuber, group (excluding sugar beets and sweet potatoes). Prickly pear cactus, fruit 12.0 5.0 Residue data indicate that the tolerance should be decreased. Prickly pear cactus, pads 12.0 12.0 Pumpkins 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 3.0 ppm tolerance on the vegetable, cucurbit, group. Radishes 5.0 Reassign Tolerance should be reassignd concomitant with establishing a 2.0 ppm tolerance on the vegetable, root and tuber, group (excluding sugar beets and sweet potatoes). Raspberry 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 12.0 ppm tolerance on the caneberry crop subgroup. Rice 5.0 15.0 Rice, grain; the residue data indicate that the tolerance should be increased. Rice, straw 100.0 60.0 Residue data support lowering the tolerance to 60.0 ppm. Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 83 (continued; footnotes follow) Rutabagas 5.0 Reassign Tolerance should be reassignd concomitant with establishing a 2.0 ppm tolerance on the vegetable, root and tuber, group (excluding sugar beets and sweet potatoes). Rye, fodder, green 100.0 Revoke The registrant does not intend to support carbaryl uses on rye Rye, grain 0.0 Rye, straw 100.0 Salsify, roots 5.0 Reassign Tolerance should be reassignd concomitant with establishing a 2.0 ppm tolerance on the vegetable, root and tuber, group (excluding sugar beets and sweet potatoes). Salsify, tops 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 75.0 ppm tolerance on the leaves of vegetables, root and tuber vegetables, group (excluding sugar beets tops). Sorghum grain, forage 100.0 30.0 Residue data indicate that the tolerance should be lowered. Sorghum grain, grain 10.0 10.0 Soybean 5.0 0.50 Residue data support lowering the tolerance to 0.5 ppm. Soybean, forage 100.0 15.0 Residue data support lowering the tolerance to 15.0 ppm. Soybean, hay 100.0 15.0 Residue data support lowering the tolerance to 15.0 ppm. Spinach 12.0 22.0 Residue data on spinach indicate that a higher tolerance is required. Squash, summer 10.0 Reassign Tolerances should be reassignd concomitant with establishing a 3.0 ppm tolerance on the vegetable, cucurbit group . Squash, winter 10.0 Strawberries 10.0 4.0 Residue data indicate that the tolerance should be lowered to 4.0 ppm. Sunflower, seed 1.0 0.50 Residue data indicate that the tolerance should be lowered to 0.5 ppm. Sweet potatoes 0.20 0.20 potato, sweet Swiss chard 12.0 Reassign The tolerance should be reassignd concomitant with establishing a 3.0 ppm tolerance on the leaf petioles crop subgroup. Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 84 (continued; footnotes follow) Tomatoes 10.0 Reassign Tolerance should be reassignd concomitant with establishing a 5.0 ppm tolerance on the vegetables, fruiting group( excluding cucurbits). Trefoil, birdsfoot, forage 100.0 15.0 Residue data on alfalfa forage will translate to trefoil, forage. Trefoil, birdsfoot, hay 100.0 25.0 Residue data on alfalfa hay will translate to trefoil, hay. Turnips, roots 5.0 Reassign Tolerance should be reassignd concomitant with establishing a 2.0 ppm tolerance on the vegetable, root and tuber, group (excluding sugar beets and sweet potatoes). Turnips, tops 12.0 Reassign Tolerance should be reassignd concomitant with establishing a 75.0 ppm tolerance on the leaves of vegetables, root and tuber, group (excluding sugar beets tops). Walnuts 1.0 1.0 Wheat, fodder, green 100.0 30.0 The available data indicate that the tolerance should be lowered. Wheat, forage Wheat, grain 3.0 1.0 Residue data indicate that the tolerance should be lowered. Wheat, straw 100.0 20.0 The available data indicate that the tolerance should be lowered. Tolerance Listed Under 40 CFR §180.169( b) Cattle, goats, horses and sheep, fat 0.10 0.50 Residue data support increasing the tolerance Hog, fat 0.10 0.05 Residue data support lowering the tolerance Cattle, goats, horses, and sheep, meat 0.10 1.0 Hog, meat 0.10 0.10 Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 85 (continued; footnotes follow) Cattle, goats, horses and sheep, kidney & Liver 1.0 Reassign Tolerances should be reassignd concomitant with establishing a 3.0 ppm tolerance for meat byproducts of cattle, goats, horses, and sheep. Cattle, goats, horses, and sheep, mbyp (exc. kidney & liver) 0.10 Hog, kidney & Liver 1.0 Reassign Tolerances should be reassignd concomitant with establishing a 0.5 ppm tolerance for hog meat byproducts Hog, mbyp (exc. kidney & liver) 0.10 Poultry, fat and meat 5.0 Revoke A Category 3 Tolerance Listed Under 40 CFR §180.169( c) Milk 0.30 1.0 Should be moved to 40 CFR §180.169( b) Tolerance Listed Under 40 CFR §180.169( d) Pineapple 2.0 TBD Residue data are required Pome fruits 10.0 12.0 The residue data indicate that the tolerance should be increased. Tolerance Listed Under 40 CFR §180.169( e) Avocados 10.0 Revoke The registrant is not supporting this use. Dill (fresh) 0.20 0.20 Interim Tolerance Listed Under 40 CFR §180.319 Eggs 0.50 Revoke Category 3. 0Tolerance Listed Under 40 CFR §186.550 Pineapple, bran, wet and dry 20.0 Revoke No longer considered a significant processed commodity. Tolerances Needed Under 40 CFR §180.169( a) Separate plant commodities Apple, wet pomace None 15.0 Residue data support establishing a 15.0 ppm tolerance on wet apple pomace. Aspirated grain fractions None 70 The available data indicate that a tolerance of 70 ppm should be established for residues in/ on aspirated grain fractions. Beet, sugar, roots None 0.50 The available data indicate that a tolerance of 0.5 ppm should be established for residues in/ on sugar beet roots. Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 86 (continued; footnotes follow) Citrus, fruit, oil None 20.0 Residue data support establishing a 20.0 ppm tolerance on citrus fruit oil. Cotton, gin byproducts None TBD Residue data are required. Grapes, raisins None 12.0 Residue data support establishing a 12.0 ppm tolerance on raisin. Millet, proso, hay None TBD Residue data are required. Residue data required on wheat hay may be translatable to proso millet hay. Rice, hulls None 30.0 Residue data support establishing a 30.0 ppm tolerance for residues in/ on rice hulls. Sorghum, stover None 30.0 Residue data support establishing a 30.0 ppm on sorghu grain, stover. Wheat, hay None TBD Residue data are required. Livestock commodities Cattle, goats, horses and sheep, meat byproducts None 3.0 Concomitant with reassigning separate tolerances for residues in kidney and liver and meat byproducts (excluding kidney and liver), separate 3.0 ppm tolerances are required on meat byproducts of cattle, goats, horses, and sheep. Hog, meat byproducts None 0.50 Residue data support establishing a 0.5 ppm tolerance on meat byproducts of hog; the separate tolerances for residues in kidney and liver and meat byproducts (excluding kidney and liver) of hog should be reassigned. Croup group/ subgroups Brassica leafy greens None 10.0 Concomitant with reassigning separate tolerances on Chinese cabbage, collards, kale, and mustard greens, a 10.0 ppm tolerance on the vegetable, Brassica, leafy, group crop subgroup should be established. Bushberry None 3.0 Residue data support establishing a 3.0 ppm tolerance on the bushberry crop subgroup; the separate tolerance on blueberry should be reassigned. Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 87 (continued; footnotes follow) Caneberry None 12.0 Concomitant with reassigning separate tolerances on blackberry, boysenberry, dewberry, loganberry, and raspberry, a 12.0 ppm tolerance on the caneberry crop subgroup should be established. Cucurbit Vegetables None 3.0 Residue data support establishing a 3.0 ppm tolerance on the vegetable, cucurbit groups crop group; separate tolerances on cucumbers, melons, pumpkins, and summer and winter squash should be reassigned. Dried, shelled pea and bean (except soybean) None 1.0 Concomitant with reassigning separate tolerances on beans, cowpeas, and lentils, a 1.0 ppm tolerance should be established on the dried, shelled pea and bean (except soybean) crop subgroup (6C). Edible­ podded legume vegetables None 10.0 Concomitant with reassigning separate tolerances on peas (with pods), a 10.0 ppm tolerance should be established on the edible­ podded legume vegetables crop subgroup (6A). Foliage of legume vegetables except soybeans None 60.0 Concomitant with reassigning separate tolerances on cowpea forage and hay, and pea vines, a 60.0 ppm tolerance should be established on the foliage of legume vegetables except soybeans crop subgroup. Fruiting vegetables (excluding cucurbits) None 5.0 Residue data support establishing a 5.0 ppm tolerance on the vegetables, fruiting group( excluding cucurbits) crop group; separate tolerances on eggplants, peppers, and tomatoes should be reassigned. Leaf petioles None 3.0 Residue data support establishing a 3.0 ppm tolerance on the leaf petioles crop subgroup; the separate tolerances on celery and swiss chard should be reassigned. Leaves of root and tuber vegetables (excluding sugar beet) None 75.0 Concomitant with reassigning separate tolerances on garden beet, salsify, and turnip tops, a 75.0 ppm tolerance on the leaves of root and tuber vegetables crop group (excluding sugar beet tops) should be established. Table C (continued). Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Comments [Correct Commodity Definition] 88 Root and tuber vegetables (excluding sugar beet roots and sweet potatoes) None 2.0 Concomitant with reassigning separate tolerances on garden beet roots, carrots, horseradish, potatoes, parsnips, radishes, rutabagas, salsify roots, and turnip roots, a 2.0 ppm tolerance on the root and tuber vegetables crop group (excluding sugar beet roots and sweet potatoes) should be established. Stone fruits None 10.0 Concomitant with reassigning separate tolerances on apricots, cherries, nectarines, peaches, and plums (fresh prunes), a 10.0 ppm tolerance on the fruit, stone, group should be established. Tree nuts (excluding walnuts) None 0.10 Concomitant with reassigning separate tolerances on almonds, chestnuts, filberts, and pecans, a 0.1 ppm tolerance on the nuts, tree, group (excluding walnuts) should be established. 1 TBD = To be determined. Reassessment of tolerance( s) cannot be made at this time because additional data are required. 89 CODEX HARMONIZATION The Codex Alimentarius Commission has established maximum residue limits (MRLs) for carbaryl residues in/ on various plant and livestock commodities (see Guide to Codex Maximum Limits For Pesticide Residues, Part A. 1, 1995). The Codex MRLs and U. S. tolerances are not compatible because the U. S. tolerance expression includes parent carbaryl and its metabolite 1­ naphthol for most raw crop commodities [40 CFR §180.169( a)]; tolerances for residues in livestock commodities are expressed as carbaryl and its metabolites 1­ naphthol, 5,6­ dihydrodihydroxy carbaryl, and 5,6­ dihydrodihydroxy naphthol [40 CFR §180.169( b)]. Only the established tolerances for residues in/ on pineapples, pome fruits, avocados, and fresh dill are expressed in terms of carbaryl per se. However, the HED Metabolism Committee (MARC) determined that the U. S. tolerance expression for plant comodities be amended to include only carbaryl per se (S. Hummel, 2/ 8/ 96). Once the U. S. tolerance definition is amended, it will be compatible with the definition for Codex MRLs. The MARC has recommended that the tolerance expression for livestock commodities include the free and conjugated forms of carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, and 5­ methoxy­ 6­ hydroxy carbaryl. The Codex MRLs and U. S. tolerances cannot be made compatible for livestock commodities with respect to the tolerance definition. A comparison of the Codex MRLs and the corresponding reassessed U. S. tolerances is presented in Table D. The following conclusions can be made regarding efforts to harmonize the U. S. tolerances with the Codex MRLs: Once the U. S. tolerance definition is amended to include only carbaryl per se, U. S. tolerances and Codex MRLs would be compatible for the following crops and commodities: apricot, beetroot, carrot, cherries, cowpea (dry), cucumber, egg plant, hay or fodder (dry) of grasses, leafy vegetables, melons (except watermelon), nectarine, olives, parsnip, peppers, plums (including prunes), pumpkins, radish, tomato, and winter squash. Based upon the use patterns registered in the U. S. and the available residue data, compatibility of U. S. tolerances and Codex MRLs is not currently possible for the following crops/ commodities: Alfalfa forage, apple, asparagus, blackberries, cabbage, milk, meat of cattle, goats, and sheep, citrus fruits, clover, common bean, cranberry, dewberries (including boysenberry and loganberry), grapes, maize forage, okra, pea vines, peanut (whole and fodder), pear, peas (podded and succulent), potato, raspberries, sorghum forage, soya bean (dry), soya bean forage, strawberry, sugar beet, sugar beet tops, sweet corn (kernels), and tree nuts. 90 (continued; footnotes follow) Table D. Codex MRLs for carbaryl and applicable U. S. tolerances for carbaryl. Codex Reassessed U. S. Tolerance ( ppm) 2 Comments Commodity, As Defined MRL (mg/ kg) 1 Step Alfalfa forage (green) 100 CXL 15.0 U. S residue data support the lower reassessed tolerance Apple 5 CXL 12.0 Tolerance to be established for pome fruits crop group; U. S. residue data indicate that the tolerance cannot be lowered. Apricot 10 CXL 10.0 Tolerance to be established for fruit, stone, group Asparagus 10 CXL 15.0 U. S residue data support the higher reassessed tolerance Banana 5 CXL 5 Barley 5 (Po) CXL None Not registered for use in the U. S. Bean forage (green) 100 CXL None No longer regulated as a feed item in the U. S. Beetroot 2 CXL 2.0 Tolerance to be established on the root and tuber vegetables crop group (excluding sugar beets and sweet potatoes) which includes garden beet roots. Blackberries 10 CXL 12.0 Tolerance to be established for caneberry crop subgroup; U. S. residue data indicate that the tolerance cannot be lowered. Blueberries 7 CXL 4.0 Tolerance to be established for bushberry crop subgroup; U. S. residue data support the lower reassessed tolerance. Cabbages, head 5 CXL 21.0 U. S residue data support the higher reassessed tolerance Carrot 2 CXL 2.0 Tolerance to be established on the root and tuber vegetables crop group (excluding sugar beets and sweet potatoes). Cattle meat 0.2 CXL 1.0 U. S tolerance expression includes metabolites not included in Codex MRL expression, resulting in a higher numerical level. Cherries 10 CXL 10.0 Tolerance to be established for fruit, stone, group Table D (continued). Codex Reassessed U. S. Tolerance ( ppm) 2 Comments Commodity, As Defined MRL (mg/ kg) 1 Step 91 (continued; footnotes follow) Citrus fruits 7 CXL 10.0 Tolerance to be established for citrus fruits crop group; U. S. residue data indicate that the tolerance cannot be lowered. Clover 100 fresh wt CXL 50.0 U. S residue data support the lower reassessed tolerance Common bean (pods and or immature seeds) 5 CXL Tolerance to be established for edible10.0 podded legume vegetables ( crop subgroup 6A); U. S. residue data indicate that the tolerance cannot be lowered. TBD Data are not available for succulent, shelled pea and beans Cotton seed 1 CXL Revoke Uses in the U. S. are cancelled. Cowpea (dry) 1 CXL 1.0 Tolerance to be established for dried, shelled pea and bean (except soybean) crop subgroup. Cranberry 7 CXL 3.0 U. S residue data support the lower reassessed tolerance Cucumber 3 CXL 3.0 Tolerance to be established for vegetable, cucurbit groups crop group Dewberries (including boysenberry and loganberry) 10 CXL 12.0 Tolerance to be established for caneberry crop subgroup; U. S. residue data indicate that the tolerance cannot be lowered. Egg plant 5 CXL 5.0 Tolerance to be established for vegetables, fruiting group( excluding cucurbits) crop group Eggs 0.5 CXL None Dermal and poutry house uses cancelled in the U. S. Category 3 of 40 CFR §180.6( a) exists for U. S. Goat meat 0.2 CXL 1.0 U. S tolerance expression includes metabolites not included in Codex MRL expression, resulting in a higher numerical level. Grapes 5 CXL 10.0 U. S residue data support the higher reassessed tolerance Table D (continued). Codex Reassessed U. S. Tolerance ( ppm) 2 Comments Commodity, As Defined MRL (mg/ kg) 1 Step 92 (continued; footnotes follow) Hay or fodder (dry) of grasses 100 CXL 100.0 Kiwifruit 10 CXL None Not registered for use in the U. S. Leafy vegetables 10 CXL 3.0 and 10.0 Tolerances to be established on the Vegetable, Brassica, leafy, group and leaf petioles crop subgroups, 10.0 and 3.0 ppm, respectively, together with separate tolerances on broccoli, Brussels sprouts, cauliflower, endive, and kohlrabi 21.0 U. S residue data on spinach support the higher reassessed tolerance Maize forage (fresh wt) 100 CXL 30.0 U. S residue data on field corn forage support the lower reassessed tolerance 185.0 U. S residue data on sweet corn forage support the higher reassessed tolerance Melons, except watermelon 3 CXL 3.0 Tolerance to be established for vegetable, cucurbit groups crop group Milk products 0.1(*) CXL None A U. S. tolerance is not established on milk products Milks 0.1 (*) CXL 1.0 U. S tolerance expression includes metabolites not included in Codex MRL expression, resulting in a higher numerical level. Nectarine 10 CXL 10.0 Tolerance established for fruit, stone, group Nuts (whole in shell) except peanut, whole and tree nuts 10 CXL 0.1 Tolerance to be established for tree nuts, except walnuts crop group Oats 5 (Po) CXL None Not registered for use in the U. S. Okra 10 CXL 4.0 U. S residue data support the lower reassessed tolerance Olives 10 CXL 10.0 Olives, processed 1 CXL None U. S residue data do not support a separate tolerance for olive processed commodities Table D (continued). Codex Reassessed U. S. Tolerance ( ppm) 2 Comments Commodity, As Defined MRL (mg/ kg) 1 Step 93 (continued; footnotes follow) Parsnip 2 CXL 2.0 Tolerance to be established on the vegetables, root and tuber, group (excluding sugar beets and sweet potatoes). Pea vines (green) (Fresh wt) 100 CXL TBD Residue data are required (preferably on Austrian winter pea) Peanut fodder 100 CXL 20.0 Tolerance established for peanut hay; U. S. residue data support the lower reassessed tolerance. Peanut, whole 2 CXL 0.05 U. S. residue data support the lower reassessed tolerance. Pear 5 CXL 12.0 Tolerance to be established for pome fruits crop group; U. S. residue data indicate that the tolerance cannot be lowered. Peas (pods and succulent = immature seeds) 5 CXL Tolerance to be established for edible10.0 podded legume vegetables ( crop subgroup 6A); U. S. residue data indicate that the tolerance cannot be lowered. TBD Data are not available for succulent, shelled pea and beans Peppers 5 CXL 5.0 Tolerance to be established for vegetables, fruiting group( excluding cucurbits) crop group Plums (including prunes) 10 CXL 10.0 Tolerance to be established for fruit, stone, group Potato 0.2 CXL 2.0 Tolerance to be established on the root and tuber vegetables crop group (excluding sugar beets and sweet potatoes); U. S. residue data indicate that the tolerance cannot be lowered. Poultry meat 0.5 (V) CXL None Dermal and poutry house uses cancelled in the U. S. Category 3 of 40 CFR §180.6( a) exists for U. S. Poultry skin 5 CXL None Pumpkins 3 CXL 3.0 Tolerance to be established for vegetable, cucurbit groups crop group Table D (continued). Codex Reassessed U. S. Tolerance ( ppm) 2 Comments Commodity, As Defined MRL (mg/ kg) 1 Step 94 (continued; footnotes follow) Radish 2 CXL 2.0 Tolerance to be established on the root and tuber vegetables crop group (excluding sugar beets and sweet potatoes). Raspberries, red and black 10 CXL 12.0 Tolerance to be established for caneberry crop subgroup; U. S. residue data indicate that the tolerance cannot be lowered. Rice 5 (PoP) CXL 15.0 Not registered for postharvest use on rice and rye in the U. S. Rice, husked 5 (Po) CXL None Rye 5 (Po) CXL None Sheep meat 0.2 CXL 1.0 U. S tolerance expression includes metabolites not included in Codex MRL expression, resulting in a higher numerical level. Sorghum 10 (Po) CXL None Not registered for this use in the U. S. Sorghum forage (green) (fresh wt) 100 CXL 30.0 U. S residue data support the lower reassessed tolerance Soya bean (dry) 1 CXL 0.5 U. S residue data support the lower reassessed tolerance Soya bean forage (green) (fresh wt) 100 CXL 15.0 U. S residue data support the lower reassessed tolerance Squash, summer 3 CXL 3.0 Tolerance to be established for vegetable, cucurbit groups crop group Strawberry 7 CXL 4.0 U. S residue data support the lower reassessed tolerance Sugar beet 0.2 CXL 0.5 U. S residue data support the higher reassessed tolerance Sugar beet leaves or tops 100 CXL 25.0 U. S residue data support the lower reassessed tolerance Swede 2 CXL 2.0 Tolerance to be established on the root and tuber vegetables crop group (excluding sugar beets and sweet potatoes). Table D (continued). Codex Reassessed U. S. Tolerance ( ppm) 2 Comments Commodity, As Defined MRL (mg/ kg) 1 Step 95 Sweet corn (kernels) 1 CXL 0.1 U. S residue data support the lower reassessed tolerance for sweet corn (K+ CWHR) Tomato 5 CXL 5.0 Tolerance to be established for vegetables, fruiting group( excluding cucurbits) crop group Tree nuts 1 CXL 0.1 Tolerance to be established for nuts, tree, group (excluding walnuts); U. S residue data support the lower reassessed tolerance 1.0 Tolerance established for walnuts Wheat 5 (Po) CXL 1.0 Not registered for postharvest use on wheat in the U. S. Wheat bran, unprocessed 20 (PoP) CXL None Wheat flour 0.2( PoP ) CXL None Wheat wholemeal 2 CXL None A separate tolerance on processed commodities of wheat is not needed Winter squash 3 CXL 3.0 Tolerance to be established for vegetable, cucurbit groups crop group 1 An asterisk (*) signifies that the MRL was established at or about the limit of detection. A "Po" or "PoP" following the MRL indicate that the MRL was established based on postharvest uses. 2 Recommendations for compatibility are based on conclusions following reassessment of U. S. tolerances (see Table C). 96 AGENCY MEMORANDA RELEVANT TO REREGISTRATION Date DP Barcode CB No. From To MRID Nos. Subject 2/ 25/ 88 None 3357 M. Nelson H. Jamerson and Toxicology Branch None PP# 7E3543 ­ Carbaryl in or on Dill Amendment of 1/ 18/ 88. 3/ 28/ 88 None 3027 M. Nelson D. Edwards and Toxicology Branch 40376001, 40376002 PP# 7F3490 ­ Carbaryl in or on Sugar Beet Roots ­ Amendment of 10/ 6/ 87. 4/ 25/ 88 None 3510 M. Kovacs H. Jamerson and Toxicology Branch 40512501 PP# 2E2667 ­ Carbaryl in or on Potatoes Amendment Dated January 27, 1988. 10/ 5/ 90 None 6972 H. Fonouni W. Boodee 41594301 Carbaryl in/ on Wheat, Amended Use Registration No. 264­ 333. 4/ 9/ 92 D176240 9659 R. Perfetti W. Burnam and L. Rossi None Aventis Ag Company: Response to the Carbaryl Reregistration Standard: Residue Chemistry Comments. 12/ 2/ 93 D193129 12374 S. Hummel J. Loranger/ L. Propst and D. Utterback None Carbaryl (056801) Anticipated Residues for Carcinogenic Dietary Risk Assessment. 2/ 25/ 94 D194407 12405 S. Hummel J. Loranger/ L. Propost and D. Utterback 42883101­ 42883104 Carbaryl (056801; Case No. 0080) Field Trial Protocols, Waiver Requests Date DP Barcode CB No. From To MRID Nos. Subject 97 8/ 5/ 94 D204888 13984 J. Garbus D. Edwards and R. Kumar None WA­ 90­ 0013: Special Local Need Label [24( c)] for Carbaryl (SEVIN 80S) for Use in Washington State on Oyster Beds 5/ 22/ 95 D213142 15275 S. Hummel J. Loranger/ L. Propst None Carbaryl (056801) Reregistration Case No. 0080 DCI for Field Trials on Onions, Barley, Oats, and Rye; and Sweet Sorghum Processing Data 5/ 31/ 95 D215259 15565 S. Hummel Files None Carbaryl (056801) Reregistration Case No. 0080 Analysis of Pineapple Bran Feed Additive Tolerance with Respect to the DES Proviso 11/ 28/ 9 5 D204197 13831 S. Hummel J. Loranger 43249101­ 43249103 Carbaryl (056801) Reregistration Case No. 0080 Metabolism in Lettuce, Radish, and Soybeans GLN 171­ 4( a). 11/ 28/ 9 5 D206777 14249 S. Hummel J. Loranger 43324601 Carbaryl (056801) Reregistration Case No. 0080 Metabolism in Poultry GLN 171­ 4( b). 1/ 19/ 96 D221978 16669 S. Hummel HED Metabolism Committee None Carbaryl (056801) Reregistration Case No. 0080 Issues to be presented to HED Metabolism Committee on 1/ 25/ 96 1/ 22/ 96 D216544 15757 S. Hummel J. Loranger 43672701 43672702 Carbaryl (056801) Reregistration Case No. 0080 Plant Analytical Methods GLN 171­ 4( c), Independent Laboratory Validation of Proposed Enforcement Method 2/ 8/ 96 D221979 16670 S. Hummel HED Metabolism Committee None Carbaryl (056801) Reregistration Case No. 0080 HED Metabolism Committee Decision; Meeting on 1/ 25/ 96. Date DP Barcode CB No. From To MRID Nos. Subject 98 3/ 15/ 96 D211172 16516 S. Hummel J. Loranger None Carbaryl (056801) Reregistration Case No. 0080 Metabolism in Lettuce, Radish, and Soybeans GLN 171­ 4( a) Corrected Study Pages for MRIDs 43249101 and 43249103 (Update to CB 13831, DP Barcode D204197). 8/ 21/ 96 D225659, D226582 17209, 17243 F. Suhre J. Loranger 43984701, 43996101 Carbaryl (056801) Reregistration Case No. 0080 Magnitude of the Residue in Succulent Bean and Tomato; GLN 171­ 4( k) 9/ 13/ 96 D218865, D219999, D220949, D221158, D223008, D219971, D220601, D220948, D221313, D225204, D225576 16140, 16364, 16555, 16559, 16887, 16329, 16460, 16556, 16584, 17127, 17147 F. Suhre P. Deschamp 43786801, 43793201, 43793202, 43802101­ 43802103, 43818901, 43845205, 43850901, 43850902, 43915201, 43975601, 43982801 Carbaryl (056801) Reregistration Case No. 0080 Magnitude of the Residue Studies (GLN 171­ 4( k)) on Several Crops; Processing Studies (GLN 171­ 4( l)) on Field Corn, Cottonseed, and Sunflower; Storage Stability Studies (GLN 171­ 4( e)) for Representative Crops. 10/ 7/ 96 D217179, D217172, D217177, D217631, D217704, D217705 15829, 15830, 15832, 15897, 15946, 15952 F. Suhre P. Deschamp 43677401, 43686701, 43686702, 43694101­ 43694105, 43697601­ 43697604, 43698201­ 43698203, 43702001­ 43702003, 43703101­ 43703103, 43716601, 43721001 Carbaryl (056801) Reregistration Case No. 0080 Magnitude of the Residue (GLN 171­ 4( k)) and Processing (GLN 171­ 4( l)) studies on numerous crops. 9/ 11/ 97 D234692 None C. Olinger J. Loranger None Carbaryl: Over­ Tolerance Residues on Spinach; Chemical No. 56801. Date DP Barcode CB No. From To MRID Nos. Subject 99 1/ 22/ 98 D240441 None C. Olinger K. Boyle None Carbaryl: Request for Waiver of Field Trials Using Granular Formulation; Chemical No. 56801 4/ 9/ 98 D240998, D237653 None C. Olinger V. Dobozy 44321301 and 44412501 Reregistration of Carbaryl: Olive Field Trial and Wheat Storage Stability; Chemical No. 56801. 5/ 12/ 98 D227765, D227009 17424 17444 M. Perry J. Loranger 44019701, 44046101 Carbaryl. Aventis Ag Company. Reregistration Case No. 0080. Peanut Processing Study and Amended Report to Broccoli Field Trial Study. 5/ 22/ 98 D230900, D231134 17626 and 17655 M. Perry J. Loranger 44123101, 44145201 Carbaryl. PC Code 056801. Reregistration Case No. 0080. IR­ 4 Submission of Okra and Prickly Pear Magnitude of the Residue Studies (GLN 860.1500) 5/ 26/ 98 D230246, D230406, D231533 17610, 17606, and 17689 M. Perry J. Loranger 44058101, 44072901, and 44155401 Carbaryl. PC Code 056801. Reregistration Case No. 0080. Magnitude of the Residue Data in/ on Sweet Corn and Pome Fruits and ILV Data on Enforcement Method for Oily Crops. 9/ 10/ 98 D215844 None C. Olinger V. Dobozy 43651701 Reregistration of Carbaryl: Confined Rotational Crop Study; Chemical No. 56801. 9/ 29/ 98 D230407 None T. Morton K. Boyle 44114301 Carbaryl Reregistration ­ Evaluation of tobacco pyrolysis study to satisfy GLN 860.1500. 9/ 17/ 98 D206443 14130 T. Morton K. Boyle None Carbaryl (056801); Reregistration Case No. 0080) Review of Revised Labels for EPA Reg. No. 264­ 315 and 264­ 321. Date DP Barcode CB No. From To MRID Nos. Subject 100 9/ 17/ 98 D216242, D219527, D219596, and D220287 15690, 16235, 16266, and 16384 T. Morton K. Boyle 43654201, 43786802­ 43786806, 43794901­ 43794903, 43813601­ 43813604 Carbaryl: PC Code 56801, Case No. 0080. Residue Analytical Methods, and Magnitude of the Residue in/ on Asparagus; Beans (dry); Cabbage; Cucurbits; Mustard Greens; Root and Tuber Vegetables including Beets, Carrots, and Turnips; Sorghum; Sunflowers; and Processed Commodities of Rice; Sorghum; Soybeans; and Wheat. 5/ 6/ 99 D255855 None C. Olinger G. Kramer None Metabolism of Carbaryl in Dairy Cattle; Briefing Memorandum for HED Metabolism Assessment Review Committee; Chemical No. 56801 6/ 17/ 99 D255855 None C. Olinger G. Kramer None Metabolism of Carbaryl in Dairy Cattle; HED Metabolism Assessment Review Committee Decision Memorandum; Chemical No. 56801 11/ 9/ 99 D228656 and D235113 None C. Olinger V. Dobozy 44068401, 44250301 Reregistration of Carbaryl: Storage Stability Studies; Chemical No. 56801 11/ 9/ 99 D228260 and D228652 None C. Olinger V. Dobozy 44321301, 44412501 Reregistration of Carbaryl: Field Corn and Rangeland Grass Field Trial Studies; Chemical No. 56801 11/ 9/ 99 D236422 and D236485 None C. Olinger V. Dobozy 44321301, 44412501 Reregistration of Carbaryl: Stone Fruit and Orange Field Trial Studies; Chemical No. 56801 12/ 15/ 9 9 D236574, D236421, D240469 None C. Olinger V. Dobozy 44250901, 44286901­ 44286903, 44381901 Reregistration of Carbaryl: Livestock Analytical Method, Storage Stability, and Magnitude of Residue Studies; Chemical No. 56801 Date DP Barcode CB No. From To MRID Nos. Subject 101 10/ 2000 D266186 None F. Fort V. Dobozy 45115402, 45115403, 45115404, 45115405, 45115406, 45115407, 45115408, 45115409, 45189102 Reregistration of Carbaryl: Magnitude of the Residue in/ on Various Cops Resulting from Ground Applications of Liquid and Granular Formulations, Chemical No. 56801 102 MASTER RECORD IDENTIFICATION NUMBERS [Note: references for MRIDs 05001852­ 05019959, representing published material, were unavailable for citation] 00015669 Knaak, J. B.; Tallant, M. J.; Bartley, W. J.; et al. (1965) The metabolism of Carbaryl in the rat, guinea pig, and man. Journal of Agricultural and Agricultural and Food Chemistry 13( 6): 537­ 543. (Also in unpublished submission received Sep 26, 1974 under 5G1553; submitted by Ciba­ Geigy Corp., Greensboro, N. C.; CDL: 094221­ C) 00049135 Kuhr, R. J.; Casida, J. E. (1966?) Persistent Glycosides of Metabolites of Methylcarbamate Insecticide Chemicals Formed by Hydroxylation in Bean Plants: Report No. 19547. (Unpublished study received Jul 15, 1976 under 3125­ EX­ 135; prepared by Univ. of California­­ Berkeley, Div. of Entomology, submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 226512­ G) 00053897 Union Carbide Corporation (1975) Introduction: [Carbaryl]. (Reports by various sources; unpublished study including published data, received Oct 14, 1976 under 7F1878; CDL: 095306­ B) 00058927 Union Carbide Corporation (1977) Determination of Carbaryl Residues in Sunflowers. Method dated May 1977. (Unpublished study received Jan 7, 1980 under 5E1564; submitted by Interregional Research Project No. 4, New Brunswick, N. J.; CDL: 099745­ B) 00058928 Interregional Research Project Number 4 (1978) Carbaryl: Residue Tolerance Petition­ Sunflowers. (Reports by various sources; unpublished study received on unknown date under 5E1564; CDL: 099745­ C) 00061103 Johnson, D. P.; Critchfield, F. E.; Arthur, B. W. (1963) Determination of Sevin insecticide and its metabolites in poultry tissues and eggs. Journal of Agricultural and Food Chemistry 11( 1): 77­ 80. (Also In unpublished submission received 1963 under unknown ad­ min. no.; submitted by Union Carbide Corp., Arlington, Va.; CDL: 129334­ D) 00061106 Claborn, H. V.; Roberts, R. H.; Mann, H. D.; et al. (1963) Residues in body tissues of livestock sprayed with Sevin or given Sevin in the diet. Journal of Agricultural and Food Chemistry 11( 1): 74­ 76. (Also In unpublished submission received 1963 under unknown admin. no.; submitted by Union Carbide Corp., Arlington, Va.; CDL: 129334­ H) 00074366 Interregional Research Project Number 4 (1979) Carbaryl: Residue Tolerance Petition­­ Flax. (Compilation; unpublished study received Apr 7, 1981 under 1E2498; CDL: 099997­ A) 00074367 McBride, D. K. (1979) Carbaryl (Sevin) Residue Trial­­ Flax (PR# 1084). (Unpublished study received Apr 7, 1981 under 1E2498, prepared by North Dakota State Univ. of Agriculture and Applied Science, submitted by Interregional Research Project No. 4, New Brunswick, N. J.; CDL: 099997­ C) 00074368 Interregional Research Project Number 4 (1979) Carbaryl: Residue Tolerance Petition­­ Millet: Summary. (Compilation; unpublished study received Apr 7, 1981 under 1E2497; CDL: 099998­ A) 103 00080419 Annand, A. M.; Robinson, D. H. (1965) Residues of Sevin in Tissues of Cattle Dipped at Various Frequencies in Sevin Cattle Dip: Report No. 230/ 102/ 2. (Unpublished study received Jun 1, 1966 under 7E0518; submitted by Union Carbide Corp., South Charleston, W. Va.; CDL: 090613­ F) 00080420 Claborn, H. V.; Roberts, R. H.; Mann, H. D.; et al. (1963) Residues in body tissues of livestock sprayed with Sevin or given Sevin in the diet. Journal of Agricultural and Food Chemistry II( 1): 74­ 76. (Also in unpublished submission received Jun 1, 1966 under 7E0518; submitted by Union Carbide Corp., South Charleston, W. Va.; CDL: 090613­ G) 00080679 Union Carbide Corporation (1971) Metabolism of Carbaryl in Animals: Summary. Summary of studies 091048­ R, 091048­ S, 091048­ U, 091048­ V and 091048­ AB. (Unpublished study received Dec 22, 1971 under 2F1220; CDL: 091048­ O) 00080680 Andrawes, N. R.; Chancey, E. L.; Crabtree, R. J.; et al. (1971) Fate of Naphthyl­ 1­ 14 C Carbaryl in Laying Chickens. (Unpublished study received Dec 22, 1971 under 2F1220; submitted by Union Carbide Corp., Arlington, Va.; CDL: 091048­ P) 00080681 Baron, R. L.; Locke, R. K. (1970) Utilization of cell culture techniques in carbaryl metabolism studies. Bulletin of Environmental Contamination & Toxicology 5( 4): 287­ 291. (Also in unpublished submission received Dec 22, 1971 under 2F1220; submitted by Union Carbide Corp., Arlington, Va.; CDL: 091048­ Q) 00080682 Bartley, W. J. (1970) Sevin Metabolism Studies: The Identification of a New Metabolite of Sevin in Milk: Project No. 111A12, File No. 14750. (Unpublished study received Dec 22, 1971 under 2F1220; submitted by Union Carbide Corp., Arlington, Va.; CDL: 091048­ R) 00080683 Bartley, W. J. (1971) Sevin Metabolism Studies: The Identification of 3,4­ Dihydro­ 3,4­ dihydroxy­ 1­ naphthyl Methylcarbamate in Milk­­ a New Sevin Metabolite: Project No. 111A12, File No. 15133. (Unpublished study received Dec 22, 1971 under 2F1220; submitted by Union Carbide Corp., Arlington, Va.; CDL: 091048­ S) 00080686 Dorough, H. W. (1971) Carbaryl Residues in Milk and Meat of Dairy Animals. (Unpublished study received Dec 22, 1971 under 2F1220; prepared by Univ. of Kentucky, Dept. of Entomology, submitted by Union Carbide Corp., Arlington, Va.; CDL: 091048­ V) 00080689 Pekas, J. C. (1971) Intestinal metabolism and transport of Naphthyl N­ methylcarbamate in vitro (rat). American Journal of Physiology 220( 6): 2008­ 2012. (Also in unpublished submission received Dec 22, 1971 under 2F1220; submitted by Union Carbide Corp., Arlington, Va.; CDL: 091048­ Y) 00080690 Pekas, J. C.; Paulson, G. D. (1970) Intestinal hydrolysis and conjugation of a pesticidal carbamate in vitro. Science 170: 77­ 78. (Also in unpublished submission received Dec 22, 1971 under 2F1220; submitted by Union Carbide Corp., Arlington, Va.; CDL: 091048­ Z) 00082420 Union Carbide & Carbon Corporation (1958) Summary: [Results of Residue Determinations on Apples with Sevin]. (Compilation; unpublished study received Oct 15, 1958 under PP0193; CDL: 092469­ J) 104 00082422 Union Carbide & Carbon Corporation (1958) Summary: [Residues of Sevin on Peaches]. (Unpublished study received Oct 15, 1958 under PP0193; CDL: 092469­ L) 00082423 Carbide and Carbon Chemicals Company (1957) Alpha­ Naphthyl N­ Methyl Carbamate (Experimental Insecticide Sevin): Determination of Residues in Apples. Method 30­ U1A15­ 4 dated Feb 20, 1957. (Unpublished study received Oct 15, 1958 under PP0193; CDL: 092469­ M) 00082424 Union Carbide & Carbon Corporation (1958) Summary: [Results of Residue Determinations on Beans]. (Unpublished study, including letter dated Sep 15, 1958 from C. E. Herald to J. W. Keays, received Oct 15, 1958 under PP0193; CDL: 092469­ O) 00083311 Union Carbide & Chem. (1957) Summary: [Evidence of Residues of Sevin on Apples]. (Compilation; unpublished study received Nov 14, 1957 under PP0155; CDL: 090181­ D) 00083312 Whitehurst, W. E.; Johnson, J. B. (1957) alpha­ Naphthyl N­ Methyl­ carbamate: Determination of Residues in Apples: File No. 300­ U1A15; 1543­ I1. Interim rept. Method dated Feb 26, 1957. (Unpublished study received Nov 14, 1957 under PP0155; submitted by Union Carbide & Chem., New York, N. Y.; CDL: 090181­ E) 00083527 Union Carbide Corporation (19??) Sevin Residues in Asparagus: Summary and Discussion. (Unpublished study received Oct 2, 1961 under PP0333; CDL: 092615­ C) 00089348 Union Carbide & Carbon Corporation (1959) Summary: [Sevin Residue­ Plums]. (Compilation; unpublished study received Aug 21, 1959 under PP0222; CDL: 090250­ A) 00089376 Union Carbide & Carbon Corporation (1959) The Results of Tests on the Amount of Residue Remaining on Cucumbers and Summer Squash Including a Description of the Analytical Method Used: [Sevin]. (Compilation; unpublished study received Dec 7, 1959 under PP0236; CDL: 090264­ A) 00089378 Union Carbide & Carbon Corporation (1960) Results of Tests To Determine Sevin Residues in Corn (Kernels Only and Kernel plus Cob with Husk Removed) and in Corn Fodder and Forage. (Compilation; unpublished study received Jan 5, 1960 under PP0243; CDL: 090270­ A) 00089380 Whitehurst, W. E.; Bishop, E. T,; Critchfield, F. E. (1960) Sevin Insecticide: A Study of the Metabolic Fate in Dairy Cows: Project No. 328B. Final rept. (Unpublished study received Jan 5, 1960 under PP0243; submitted by Union Carbide & Carbon Corp., New York, N. Y.; CDL: 090270­ C) 00089418 Union Carbide & Carbon Corporation (1958) Summary: [Sevin and 1­ Naphthol Residue Analyses]. Includes method no. 30­ U1A15­ 7 dated Jul 9, 1958. (Compilation; unpublished study received Dec 19, 1958 under PP0203; CDL: 090231­ A) 00089420 Union Carbide & Carbon Corporation (1958) Summary: [Sevin and 1­ Naphthol Residue Analyses]. Includes method no. 30­ U1A15­ 7 dated Jul 9, 1958. (Compilation; unpublished study received Dec 19, 1958 under PP0203; CDL: 090231­ C) 00089455 Union Carbide & Carbon Corporation (1957) Summary: [Residues of Sevin on Pears]. (Compilation; unpublished study received Jan 31, 1958 under PP0165; CDL: 090191­ A) 105 00089458 Union Carbide & Carbon Corporation (1957) Summary: [Analyses for Sevin Residues on Grapes]. Includes method 30­ U1A15­ 4 dated Feb 20, 1957. (Compilation; unpublished study received Feb 24, 1958 under PP0169; CDL: 090196­ A) 00089600 Union Carbide & Carbon Corporation (1959) The Results of Tests on the Amount of Residue Remaining on Tomatoes, Eggplants and Peppers Including a Description of the Analytical Method Used: [Sevin]. Includes method 30­ U1A15­ 7 dated Jul 9, 1958. (Compilation; unpublished study received Oct 30, 1959 under PP0228; CDL: 090257­ A) 00089679 Union Carbide & Carbon Corporation (1957) Summary: [Residues of Sevin on Beans]. (Compilation; unpublished study received Feb 6, 1958 under PP0167; CDL: 090193­ A) 00089680 Carbide and Carbon Chemicals Company (1957) Alpha­ Naphthyl N­ Methyl Carbamate (Experimental Insecticide Sevin): Determination of Residues in Apples. Method 30­ U1A15­ 4 dated Feb 20, 1957. (Unpublished study received Feb 6, 1958 under PP0167; CDL: 090193­ B) 00089681 Swango, W. H.; Herald, C. E.; Massie, J. L.; et al. (1957) Insecticide Sevin: Determination on Green Beans: File No. 307­ U­ 1A15. Final rept. (Unpublished study received Feb 6, 1958 under PP0167; submitted by Union Carbide & Carbon Corp., New York, N. Y.; CDL: 090193­ C) 00089836 U. S. Agricultural Research Service (1960) Residues in Animal Tissues following Dermal Application and Feeding with Sevin: Special Report K­ 64. (Unpublished study; CDL: 090343­ B) 00089837 Union Carbide Corporation (1961) Results of Tests To Determine Residues of Sevin in (1) the Green Forage and/ or Cured Hay or Crop Refuse of Alfalfa, Bean, Clovers, Cotton, Cowpea, Grasses, Peanut, Rice, Sorghum, Soybean, Sugarbeet, and (2) in Sorghum Grain, Cowpeas, Peanuts, Rice and Soybean. (Compilation; unpublished study received Mar 10, 1961 under PP0302; CDL: 090343­ C) 00089868 Union Carbide Chemicals Company (1962) Results of Tests To Determine Sevin Residues in Spinach Group, Lettuce Group, Blackberry Group and Root Crops. (Compilation; unpublished study received on unknown date under PP0368; CDL: 090397­ B) 00090113 Union Carbide Chemicals Company (1961) Sevin Residues in Garden Peas and Pea Vines. (Unpublished study received Nov 12, 1962 under PP0387; CDL: 090419­ A) 00090156 Union Carbide Corporation (1960) Sevin for Use on Filberts: Insect Control and Residue Data: April 1960. (Compilation; unpublished study received Oct 7, 1960 under PP0277; CDL: 090299­ B) 00090160 Union Carbide & Carbon Corporation (1960) Sevin Residues in Apricots and Nectarines. (Compilation; unpublished study received Nov 25, 1960 under PP0281; CDL: 090303­ A) 00090161 Union Carbide & Carbon Corporation (1960) Sevin Residues in Cranberries and Blueberries. (Compilation; unpublished study received Nov 25, 1960 under PP0281; CDL: 090303­ B) 00090162 Union Carbide & Carbon Corporation (1960) Sevin Residues on Lettuce. (Compilation; unpublished study received Nov 25, 1960 under PP0281; CDL: 090303­ C) 106 00090204 Union Carbide & Carbon Corporation (1961) Summary­­ Sevin Residues on Citrus. (Compilation; unpublished study received May 5, 1961 under PP0313; CDL: 090331­ A) 00090229 Union Carbide Corporation (1961) The Results of Tests on the Amount of Residue Remaining on Okra Including a Description of the Analytical Method Used: [Sevin]. (Unpublished study received Feb 10, 1961 under PP0296; CDL: 090316­ A) 00090281 Union Carbide Corporation (1961) Sevin Residues in Olives. (Compilation; unpublished study received Nov 20, 1961 under PP0337; CDL: 090367­ A) 00090320 Union Carbide Corporation (1961) Summary­­ Sevin Residue in Citrus. (Compilation; unpublished study received Aug 4, 1961 under PP0327; CDL: 090354­ A) 00090325 Union Carbide Corporation (1961) Results of Tests To Determine Sevin Residues in Cabbage; Broccoli, Brussels Sprouts, Cauliflower and Kohlrabi, Melons, Pumpkins and Winter Squash, and Carrots. (Compilation; unpublished study received Jun 14, 1961under PP0318; CDL: 090346­ A) 00091952 Oonnithan, E. S.; Casida, J. E. (1968) Oxidation of methyl­ and dimethylcarbamate insecticide chemicals by microsomal enzymes and anticholinesterase activity of the metabolites. Journal of Agricultural and Food Chemistry 16( 1): 28044. (Also in unpublished submission received Jun 9, 1971 under 3125­ EX­ 118; submitted by Mobay Chemical Corp., Kansas City, Mo.; CDL: 126996­ E) 00095927 Dorough, H. W. (1970) Metabolism of insecticidal methylcarbamates in animals. Journal of Agricultural and Food Chemistry 18( 6): 1015­ 1022. (Also In unpublished submission received Jan 18, 1971 under 9F0843; submitted by Shell Chemical Co., Washington, D. C.; CDL: 093138­ AC) 00098504 Interregional Research Project Number 4 (1980) Summary of Residue Data for Carbaryl in or on Potatoes from Postharvest Treatment. (Compilation; unpublished study received Apr 7, 1982 under 2E2667; CDL: 070770­ A) 00103288 Interregional Research Project No. 4 (1981) The Results of Tests on the Amount of Carbaryl Residues Remaining in or on Prickley Pear Cactus Including a Description of the Analytical Method Used. (Compilation; unpublished study received Jun 17, 1982 under 2E2712; CDL: 070930­ A) 00107017 Union Carbide (1965) The Results of Analyses on the Amount of Residue Remaining on or in Irish Potatoes and Sweet Potatoes: [Sevin]. (Compilation; unpublished study received Sep 19, 1966 under 7F0537; CDL: 090655­ A) 00108985 Prudich, J.; Herald, C.; Zweig, G. (1961) Summary: [Residue Determinations for Sevin on Walnuts and Almonds]. (Unpublished study received Aug 17, 1961 under PP0329; prepared in cooperation with Univ. of California­­ Berkeley, submitted by Union Carbide Corp., New York, NY; CDL: 090356­ A) 00115284 Union Carbide Corp. (1977) The Results of Tests on the Amount of Residue Remaining Including a Description of the Analytical Method Used: [Sevin]. (Compilation; unpublished study received Dec 23, 1977 under 1016­ EX­ 39; CDL: 096707­ A) 107 00116083 Union Carbide Corp. (1971) The Results of Tests on the Amount of Residue Remaining Including a Description of the Methods Used: [Sevin Carbaryl]. (Compilation; unpublished study received Jul 17, 1972 under 2F1220; CDL: 091049­ A) 00118342 Union Carbide Corp. (1969) [Study: Carbaryl Residue in Milk, Oysters, and Selected Crops]. (Compilation; unpublished study received May 15, 1970 under 0F0902; CDL: 091556­ E) 00118346 Knaak, J.; Tallant, M.; Kozbelt, S.; et al. (1968) The metabolism of carbaryl in man, monkey, pig, and sheep. J. Agr. Food Chem. 16( 3): 465­ 470. 16( 3): 465­ 470. (Also in unpublished submission received May 15, 1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ J) 00118347 Knaak, J.; Sullivan, L. (1967) Metabolism of carbaryl in the dog. J. Agr. Food Chem. 15( 6): 1125. (Also in unpublished submission received May 15, 1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ K) 00118365 Union Carbide Corp. (1969) Metabolism of Carbaryl in Animals: Summary. (Unpublished study received May 15, 1970 under 0F0902; CDL: 091556­ AD) 00118366 Baron, R. (1968) Radioactive lactose in skim milk following administration of carbonyl­ 14Ccarbaryl to a lactating cow. Journal of the Assoc. Off. Anal. Chem. 51( 5): 1046­ 1049. (Also In unpublished submission received May 15, 1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AE) 00118367 Baron, R.; Palmer, N.; Ross, R.; et al. (1968) Distribution of radioactivity in milk resulting from oral administration of 14C­ labelled carbaryl. Journal of the Assoc. Off. Anal. Chem. 51 (1): 32­ 34. (Also In unpublished submission received May 15,1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AF) 00118368 Baron, R.; Sphon, J.; Chen, J.; et al. (1969) Confirmatory isolation and identification of a metabolite of carbaryl in urine and milk. Journal of Agricultural and Food Chemistry 17( 4): 883­ 887. (Also In unpublished submission received May 15, 1970 under0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AG) 00118370 Dorough, H. (1967) Carbaryl­ C14 metabolism in a lactating cow. Agricultural and Food Chemistry 15( 2): 261­ 266. (Also In unpublished submission received May 15, 1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AI) 00118371 Dorough, H. (1969) Continuous Feeding of Sevin­ naphthyl­ C14 to Lactating Cows. Progress rept., Jun 17, 1969. (Unpublished study received May 15, 1970 under 0F0902; prepared by Univ. of Kentucky, Dept. of Entomology, submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AJ) 00118372 Dorough, H.; Casida, J. (1964) Nature of certain carbamate metabolites of the insecticide Sevin. Agricultural and Food Chemistry 12( 4): 294­ 304. (Also In unpublished submission received May 15, 1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AK) 108 00118373 Dorough, H.; Leeling, N.; Casida, J. (1963) Nonhydrolic pathway in metabolism of Nmethylcarbamate insecticides. Science 140( Apr 12): 170­ 171. (Also In unpublished submission received May 15, 1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AL) 00118374 Dorough, H.; Wiggins, O. (1969) Nature of the water­ soluble metabolites of carbaryl in bean plants and their fate in rats. Journal of Economic Entomology 62( 1): 49­ 53. (Also In unpublished submission received May 15, 1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AM) 00118375 Paulson, G.; Feil, V. (1969) The Fate of a Single Oral Dose of Carbaryl ... in the Chicken. (Unpublished study received May 15, 1970 under 0F0902; prepared by U. S. Agricultural Research Service, Metabolism and Radiation Research Laboratory, Animal Husbandry Research Div., submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AO) 00118376 Paulson, G.; Zaylskie, R.; Zehr, M.; et al. (1969) Metabolites of Carbaryl ... in Chicken Urine. (Unpublished study received May 15, 1970 under 0F0902; prepared by U. S. Agricultural Research Service, Metabolism and Radiation Research Laboratory, Animal Husbandry Research Div. and Entomology Research Div., submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AP) 00118377 Sullivan, L. (1969) 5,6­ Dihydro­ 5,6­ dihydroxycarbaryl Glucuronide as a Significant Metabolite of Carbaryl in the Rat: Special Report 32­ 100. (Unpublished study received May 15, 1970 under 0F0902; prepared by Mellon Institute, submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AQ) 00118378 Whitehurst, W.; Bishop, E.; Critchfield, F.; et al. (1963) The metabolism of Sevin in dairy cows. Agricultural and Food Chemistry 11( 2): 167­ 169. (Also In unpublished submission received May 15, 1970 under 0F0902; submitted by Union Carbide Corp., New York, NY; CDL: 091556­ AR) 00123219 Interregional Research Project No. 4 (1972) The Results of Tests on the Amount of Carbaryl Residues Remaining on or in Pecans, Including a Description of the Analytical Method Used. (Compilation; unpublished study received Oct 18, 1972 under 3E1324; CDL: 093553­ A) 00124334 Union Carbide Corp. (1977) The Results of Tests on the Amount of Carbaryl Residues Remaining in or on Lentils and Lentil Forage and Hay, Including a Description of the Analytical Method Used. (Compilation; unpublished study received Sep 13, 1978 under1016­ 68; CDL: 097397­ A) 00124335 Interregional Research Project No. 4 (1978) The Results of Tests on the Amount of Carbaryl Residues Remaining in or on Pistachios. (Compilation; unpublished study received Nov 21, 1978 under 9E2153; CDL: 097652­ A) 00124337 Interregional Research Project No. 4 (1965) Results of Tests Concerning the Amount of Carbaryl Residue Remaining in or on Celery, Including a Description of the Analytical Method Used. (Compilation; unpublished study received Mar 11, 1977 under7E1935; CDL: 097769­ A) 00124343 Herald, C.; Wene, G. (1959) Residue Analyses for Sevin on Cotton Seed Crop and Variety: Reference T­ 797­ 142. (Unpublished study received on unknown date under PP0212; submitted by Union Carbide Agricultural Products Co., Inc., Research Triangle Park, NC; CDL: 098737­ A) 109 00124345 Union Carbide Agricultural Products Co., Inc. (1959) [Residues: Sevin]. (Compilation; unpublished study received 1959 under PP0222; CD: 098753­ A) 00124353 Herrett, R.; Bagley, W.; Kramer, J. (1966) Insecticide Sevin: Uptake and Distribution in Corn: 855­ 31047­ 8019. (Unpublished study received Oct 5, 1966 under unknown admin. no.; submitted by Union Carbide Corp., Research Triangle Park, NC; CDL: 121177­ A) 00124361 Gutenmann, W.; Lisk, D. (1964) Gas Chromatographic Residue Determination of Sevin as Brominated 1­ Naphthyl Acetate. (Unpublished study received 1964 under unknown admin. no.; prepared by Cornell Univ., Dept. of Entomology, submitted by ?; CDL: 121435­ A) 00124367 Union Carbide Corp. (1963) Summary of Sevin and 1­ Naphthol Residues in Poultry, Meat and Eggs: Hens Treated by Dust­ bath­ box Method. (Unpublished study received Mar 13, 1963 under unknown admin. no.; CDL: 121450­ A) 00124968 Abdel­ Wahab, A.; Kuhr, R.; Casida, J. (1966) Fate of C14­ carbonyl­ labeled aryl methylcarbamate insecticide chemicals in and on bean plants. J. Agr. Food Chem. 14( 3): 290­ 297. (Submitter 18274; also In unpublished submission received Jul 15, 1976under 3125­ EX­ 135; submitted by Mobay Chemical Corp., Kansas City, MO; CDL: 227756­ E) 00125084 Union Carbide Agricultural Products Co., Inc. (19??) [Sevin Residues in Leaves and Other Subjects]. (Compilation; unpublished study received Feb 24, 1958 under PP0169; CDL: 092447­ A) 00125090 Union Carbide Agricultural Products Co., Inc. (1959) [Study of the Residue of Sevin in Milk, Fruit and Vegetables]. (Compilation; unpublished study received Feb 17, 1959; Jan 22, 1959 under PP0193; CDL: 092470­ A) 00125099 Union Carbide Agricultural Products Co., Inc. (1959) The Results of Tests on the Amount of Residue Remaining, Including a Description of the Analytical Method Used: [Sevin]. (Compilation; unpublished study received Mar 3, 1959; Jul 9, 1959; Jun 8,1959 under PP0212; CDL: 092490­ A) 00125107 Union Carbide Agricultural Products Co., Inc. (1960) [Residues: Sevin]. (Compilation; unpublished study received 1960 under PP0243; CDL: 092520­ A) 00125121 Union Carbide Agricultural Products Co., Inc. (1960) The Results of Tests on the Amount of Residue Remaining on Alfalfa, Grass Forage, Sorghum Forage and Sorghum Grain, Including a Description of the Analytical Methods Used: [Sevin]. (Compilation; unpublished study received 1960 under PP0263; CDL: 092540­ A) 00125123 Union Carbide Agricultural Products Co., Inc. (1960) [Residues: Sevin]. (Compilation; unpublished study received Nov 28, 1960 under PP0263; CDL: 092541­ A) 00125138 Union Carbide Agricultural Products Co., Inc. (1961) [Residues: Sevin]. (Compilation; unpublished study received Mar 14, 1960 under PP0302; CDL: 092582­ A) 00125170 Union Carbide Agricultural Products Co., Inc. (1974) The Results of Tests on the Amount of Residues Remaining, Including a Description of the Methods Used: [Carbaryl]. (Compilation; unpublished study received 1974 under 2F1220; CDL: 094079­ L) 110 00125555 Union Carbide Agricultural Products Co., Inc. (1963) [Sevin: Residues in Wheat and Other Crops]. (Compilation; unpublished study received May 3, 1963 under PP0405; CDL: 092693­ C) 00125571 Union Carbide Agricultural Products Co., Inc. (1963) The Results of Analyses on the Amount of [Carbaryl] Residue Remaining on or in Eggs. (Compilation; unpublished study received Sep 24, 1966 under 7F0538; CDL: 092826­ B) 00134421 Union Carbide Corp. (1958) Sevin Insecticide Residues in Potatoes. (Compilation; unpublished study received Dec 22, 1958 under unknown admin. no.; CDL: 121475­ A) 00135678 Union Carbide Agricultural Products Co., Inc. (1961) [Residue: Sevin in Poultry Meat]. (Compilation; unpublished study received 1961 under PP0311; CDL: 092591­ B) 00135680 Union Carbide Agricultural Products Co., Inc. (1961) [Residue: Sevin in Poultry Products]. (Compilation; unpublished study received Mar 23, 1961 under PP0311; CDL: 092592­ B) 00136415 Romine, R. (1979) Residue Data Transmittal: [Carbaryl in or on Wheat]. (Unpublished study received Aug 9, 1979 under 264­ 316; submitted by Union Carbide Agricultural Products Co., Inc., Research Triangle Park, NC; CDL: 098950­ A) 00139664 Dorough, H. (1971) Carbaryl Residues in Milk and Meat of Dairy Animals. (Unpublished study received Dec 1, 1971 under 2F1220; prepared by Univ. of Kentucky, Dept. of Entomology, submitted by Union Carbide Agricultural Products Co., Inc., Research Triangle Park, NC; CDL: 111825­ W) 00140447 Union Carbide Agricultural Products Co., Inc. (1962) [Residue: Sevin in Almonds and Filberts]. (Compilation; unpublished study received 1962 under PP0329; CDL: 092611­ A) 00140449 Union Carbide Agricultural Products Co., Inc. (1961) [Residue: Sevin on Asparagus]. (Compilation; unpublished study received 1961 under PP0333; CDL: 092616­ B) 00145884 Interregional Research Project No. 4 (1984) The Results of Tests on the Amount of Carbaryl Residues Remaining in or on Loquats Including a Description of the Analytical Method Used. Unpublished study. 30 p. 00147760 Interregional Research Project No. 4. (1984) The Results of Tests on the Amount of Carbaryl Residues Remaining in or on Avocado Including a Description of the Analytical Method Used. Unpublished compilation. 27 p. 00154626 Union Carbide Agricultural Products Co., Inc. (1984) Results of Tests on the Amount of Residue Remaining Including a Description of the Analytical Method Used: Carbaryl on or in Pineapples . Unpublished compilation. 26 p. 00156736 Union Carbide Agricultural Products Co. (1985) Sevin (Carbaryl) Residues in Pineapple Products. Unpublished compilation. 29 p. 00159324 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Potato Processing Study: Project No. 801R11: File No. 34477. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 20 p. 111 00159325 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Alfalfa Processing Study: Project No. 801R11: File No. 34398. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 11 p. 00159326 Davis, C.; Thomas, S. (1986) Sevin Brand Carbaryl Insecticide: Tomato Processing Study: Project No. 801R11: File No. 34397. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 13 p. 00159327 Davis, C.; Thomas, S. (1986) Sevin Brand Carbaryl Insecticide: Apple Processing Study: Project No. 801R11: File No. 34443. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 13 p. 00159328 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Prune Processing Study: Project No. 801R11: File No. 34438. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 8 p. 00159329 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Sweet Sorghum Processing Study: Project No. 801R11: File No. 34413. Unpublished study prepared by Union Carbide Agricultural Products Co. Inc. 13 p. 00163006 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Magnitude of Carbaryl Residues on Rangeland and Pasture Grasses: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. in cooperation with Hazleton Laboratories, Inc. 78 p. 00163007 Thomas, S. (1986) Sevin Brand Carbaryl Insecticide: Magnitude of Carbaryl Residues in Sugar Beet Roots: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. in cooperation with Hazleton Laboratories America, Inc. 28 p. 00163008 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Citrus Processing Study: Residue Data in Grapefruits, Oranges, and Lemons: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. in cooperation with Univ. of Florida, Citrus Research and Education Center. 46 p. 00163009 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Field Corn Processing Study: Residue Data: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. in cooperation with Texas A& M University, Food Protein Center and US Dept. of Agriculture, Northern Regional Research Center. 22 p. 00163010 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Grape Processing Study: Residue Data: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. in cooperation with Agricultural Chemicals Development Services, Inc. 13 p. 00163011 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Magnitude of Carbaryl Residues in Raisins and Raisin Waste: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 15 p. 00163012 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Peanut Processing Study: Residue Data: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. in cooperation with Texas A& M Univ., Food Protein Center. 18 p. 112 00163013 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Rice Processing prepared bu Union Carbide Agricultural Products Co., Inc. in cooperation with Univ. of Arkansas, Dept. of Entomology. 15 p. 00163014 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Magnitude of Carbaryl Residues in Snap Bean Cannery Waste: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 19 p. 00163015 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Grain Sorghum Processing Study: Project No. 801R11: File No. 34847. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 12 p. 00163016 Davis, C.; Thomas, S. (1986) Sevin Brand Carbaryl Insecticide: Soybean Processing Study: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. in cooperation with Texas A& M Univ., Food Protein Center. 17 p. 00163017 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Sugar Beet Processing Study: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 16 p. 00163018 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Magnitude of Carbaryl Residues in Sweet Corn Cannery Waste: Project No. 801R11. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 19 p. 05008444 Baron, R. L. (1978) Terminal residues of carbamate insecticides. Pure and Applied Chemistry 50( 5): 505­ 509. 40255702 Davis, C. (1986) Sevin Brand Carbaryl Insecticide: Magnitude of Carbaryl Residues in Sweet Corn Cannery Waste: Project No.: 801R11: File No.: 34830. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 21 p. 40376001 Davis, C.; Thomas, S. (1985) Sevin Brand Carbaryl Insecticide: Method of Analysis for Carbaryl in Alfalfa (Modified to Include Sugar Beets): Laboratory Project ID: 801R11; File No: 33769. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. 17 p. 40376002 Davis, C. (1987) Data in Support of Sugar Beet Root: Residue Data Submitted as Part of Pesticide Petition # 7F3490. Unpublished compilation prepared by Aventis Ag Co. 42 p. 40408601 Davis, C.; Thomas, S. (1987) Carbaryl Insecticide: Magnitude of the Residue Crop Field Trials: Barley: Project No. 801R11 and File No. 40092. Unpublished study prepared by Union Carbide Agricultural Products Co., Inc. in cooperation with Hazleton Laboratories America, Inc. 136 p. 40512501 Sorensen, K.; Sheets, T.; Markle, G. (1987) Carbaryl­­ Magnitude of Residues on Potato (Post Harvest): Project No. 402. Unpublished study prepared by North Carolina State Univ. 31 p. 40881302 Butler, L.; McDonough, L. (1970) Specific glc method for determining residues of carbaryl by electron capture detection after derivative formation. Journal of the AOAC 53( 3): 494­ 499. 40881307 Pablo, F.; Bello, F. (19??) Carbaryl and monocrotophos residues in cottonseeds, oil and cake. Phillipine Entomologist (?): 301­ 309. 113 40881308 Nir, I.; Weisenberg, E.; Hadani, A.; et al. (1966) Studies of the toxicity, excretion and residues of sevin in poultry p. 719­ 728. 40881309 McCay, C.; Arthur, B. (1962) Sevin residues in poultry products. Journal of Economic Entomology 55( 6): 936­ 938. 40881312 Johnson, D. (1963) Determination of Sevin insecticides residues in fruits and vegetables. Journal of the AOAC 46( 2): 233­ 237. 40881313 Johnson, D. (1964) Determination of sevin insecticide residues in fruits and vegetables. Journal of the AOAC 47( 2): 282­ 287. 40881314 Miskus, R.; Gordon, H.; George, D. (1959) Colorimetric determination of 1­ naphthyl nmethylcarbamte in agricultural crops. Agricultural and Food Chemistry 7(?): 612­ 614. 41594301 Lee, R. (1990) Carbaryl Insecticide: Wheat: Residues ­Examination of Residue Levels in/ on Forage, Straw and Grain at Selected PreHarvest Intervals: Lab Project Number: S86­ 054­ 02: 40533. Unpublished study prepared by Aventis Ag Co. 79 p. 43249101 Harsy, S. (1994) Metabolic Fate and Distribution of (carbon 14)­ Carbaryl in Lettuce: Final Report: Lab Project Number: HWI 6224­ 188: EC­ 92­ 231. Unpublished study prepared by Hazleton Wisconsin, Inc. 125 p. 43249102 Harsy, S. (1994) Metabolic Fate and Distribution of (carbon 14)­ Carbaryl in Radishes: Final Report: Lab Project Number: HWI 6224­ 186: EC­ 92­ 232. Unpublished study prepared by Hazleton Wisconsin, Inc. 164 p. 43249103 Harsy, S. (1994) Metabolic Fate and Distribution of (carbon 14)­ Carbaryl in Soybeans: Final Report: Lab Project Number: HWI 6224­ 190: EC­ 92­ 233. Unpublished study prepared by Hazleton Wisconsin, Inc. 178 p. 43324601 Struble, C. (1994) Nature of the Residue of (carbon 14)­­ Carbaryl in Laying Hens: Final Report: Lab Project Number: HWI 6224­ 183: EC­ 92­ 223. Unpublished study prepared by Hazleton Wisconsin, Inc. 157 p. 43651701 Harsy, S. (1995) (Carbon­ 14) Carbaryl Accumulation in Confined Rotational Crops (Screenhouse Study): Lab Project Number: HWI 6224­ 192: EC­ 94­ 284. Unpublished study prepared by Hazleton Wisconsin, Inc. 180 p. 43654201 Chancey, E. (1995) Sevin XLR Plus: Carbaryl Residues in/ on Asparagus Raw Agricultural Commodities: Final Study Report: Lab Project Number: 44695: US94S20R: 94­ 0143. Unpublished study prepared by Aventis Ag Co. 239 p. 43672701 Thiem, D. (1995) Method Validation for Aventis Ag Company Method No. CACR­ 0194 Revised March 27, 1995: Carbaryl General Method for the Determination of Residue in Crop Samples by High Performance Liquid Chromatography: Final Report: Lab Project Number: 44754: 1247. Unpublished study prepared by Colorado Analytical Research & Development Corp. 353 p. 114 43672702 Humble, G.; Herzig, R. (1995) Independent Laboratory Confirmation of the Tolerance Enforcement Method by EPA Notice 88­ 5 for Carbaryl: General Method for the Determination of Residues in Crop Samples by High Performance Liquid Chromatography: Final Report: Lab Project Number: RES9544: 44778: 8765. Unpublished study prepared by Agvise Labs, Inc. 120 p. 43677401 Tew, E.; Koktavy, K. (1995) Sevin XLR PLUS: Magnitude of Carbaryl Residues in Leafy Vegetables (Celery, Head Lettuce, Leaf Lettuce, and Spinach): Lab Project Number: US94S04R: 44749. Unpublished study prepared by Research Designed for Agriculture; Ag Consulting Inc.; Agsearch Co. 608 p. 43686701 Ely, C. (1995) Carbaryl: Magnitude of Carbaryl Residues in Bell Peppers Following Treatment with SEVIN XLR PLUS: Final Report: Lab Project Number: 94­ 0059: 44758: US94S14R. Unpublished study prepared by EN­ CAS Analytical Labs. 262 p. 43686702 Lee, R. (1995) SEVIN XLR PLUS: Carbaryl Tomato Processing (Magnitude of Residues): Final Report: Lab Project Number: 44759: US94S01R: 94­ 0001. Unpublished study prepared by Aventis Ag Co. 228 p. 43694101 Mede, K. (1995) CARBARYL: Magnitude of Residues in/ on Blueberries Resulting from Ground Application of SEVIN XLR PLUS (1994): Final Report: Lab Project Number: 94­ 0177: 94­ 0178: 94­ 0179. Unpublished study prepared by Enviro­ Bio­ Tech and Aventis. 216 p. 43694102 Robinson, P. (1995) Carbaryl: Magnitude of Carbaryl Residue in/ on Soybeans: Final Report: Lab Project Number: US94S41R: 44740: 94­ 0248. Unpublished study prepared by Agri Business Group, Inc. 459 p. 43694103 Robinson, P. (1995) Carbaryl: Magnitude of Carbaryl Residue in/ on Dried Peas: Final Report: Lab Project Number: US94S39R: 44737: 94­ 0232. Unpublished study prepared by Agri Business Group, Inc. 291 p. 43694104 Robinson, P. (1995) SEVIN XLR PLUS: Carbaryl Citrus Processing (Orange): Final Report: Lab Project Number: 94­ 0095: US94S10R: 44734. Unpublished study prepared by Agri Business Group, Inc. 248 p. 43694105 Singer, G. (1995) Carbaryl: Magnitude of Residues in/ on Clover Forage and Clover Hay Resulting from a Ground Application of SEVIN XLR PLUS: Final Report: Lab Project Number: 94­ 0321: 94­ 0322: 94­ 0323. Unpublished study prepared by American Agricultural Services, Inc. 488 p. 43697601 Robinson, P. (1995) Sevin XLR PLUS: Carbaryl: Grape Processing (Raisins): Final Report: Lab Project Number: US94S13R: 44733: 94­ 0098. Unpublished study prepared by Agri Business Group, Inc. 468 p. 43697602 Robinson, P. (1995) Sevin XLR PLUS: Carbaryl: Grape Processing (Juice): Final Report: Lab Project Number: US94S12R: 44732: 94­ 0097. Unpublished study prepared by Agri Business Group, Inc. 312 p. 115 43697603 Robinson, P. (1995) Carbaryl: Magnitude of Carbaryl Residue in Processed Potato Fractions Following Field Treatment with Sevin XLR Plus: Final Report: Lab Project Number: US94S21R: 44742: 94­ 149. Unpublished study prepared by Agri Business Group, Inc. 319 p. 43697604 Mede, K. (1995) Carbaryl: Magnitude of Residue in/ on Cranberries Resulting from Ground Applications of Sevin XLR Plus (1994): Final Report: Lab Project Number: US94S28R: 44780: 94­ 0181. Unpublished study prepared by Aventis Ag Co. and Enviro­ Bio­ Tech, Ltd. 216 p. 43698201 Lee, R. (1995) Carbaryl: Magnitude of Residues in/ on Caneberries Resulting from Ground Applications of Sevin XLR Plus (1994): Final Report: Lab Project Number: US94S18R: 44760: 94­ 0173. Unpublished study prepared by Aventis Ag Co. 220 p. 43698202 Mede, K. (1995) Carbaryl: Magnitude of Residues in/ on Strawberries Resulting from Ground Applications of Sevin XLR Plus (1994): Final Report: Lab Project Number: US94S30R: 44765: 94­ 0195. Unpublished study prepared by Aventis Ag Co. and Enviro­ Bio­ Test, Ltd. 216 p. 43698203 Robinson, P. (1995) Determination of the Magnitude of Residues in Olive Oil Processed from Olives Treated with Sevin XLR Plus Brand of Carbaryl Insecticide: Final Report: Lab Project Number: US94S02R: 44731: 94­ 002. Unpublished study prepared by Agri Business Group, Inc. 263 p. 43702001 Macy, L.; Lee, R. (1995) Carbaryl: Determination of the Magnitude of Residues on Olives Treated with Foliar Applications of SEVIN XLR Plus Brand of Carbaryl Insecticide: Final Report: Lab Project Number: US94S09R: 44791: 94­ 0091. Unpublished study prepared by Colorado Analytical Research & Development Corp. and Aventis Ag Co. 288 p. 43702002 Kowite, W. (1995) Carbaryl: Magnitude of Residues in Sweet Potato RAC Resulting from Applications of SEVIN XLR Plus Insecticide (1994): Final Report: Lab Project Number: US94S16R: 44794: 94­ 0117. Unpublished study prepared by Colorado Analytical Research & Development Corp. and Aventis Ag Co. 367 p. 43702003 Cappy, J. (1995) Carbaryl: Magnitude of Carbaryl Residues in/ on Apples and Processed Fractions of Apples: Final Report: Lab Project Number: US94S11R: 44773: 94­ 0096. Unpublished study prepared by Enviro­ Bio­ Tech, Ltd. and Aventis Ag Co. 263 p. 43703101 Kowite, W. (1995) Carbaryl: Magnitude of Residues in Peanuts RAC Resulting From Application of Sevin XLR PLUS Insecticide (1994): Final Report: Lab Project Number: US94S22R: 44795: 94­ 0150. Unpublished study prepared by Enviro­ Bio­ Tech, Ltd. 332 p. 43703102 Robinson, P. (1995) Carbaryl: Magnitude of Carbaryl Residue In/ On Fresh Peas: Final Report: Lab Project Number: US94S40R: 44738: 94­ 0240. Unpublished study prepared by Aventis Ag Co. 332 p. 43703103 Macy, L. (1995) Carbaryl: Determination of the Magnitude of Residues on Pistachios Treated with Foliar Applications of SEVIN XLR PLUS of Carbaryl Insecticide: Final Report: Lab Project Number: US94S23R: 44792: 94­ 0158. Unpublished study prepared by Enviro­ Bio­ Tech, Ltd. 246 p. 43716601 Singer, G. (1995) Carbaryl: Magnitude of Residues in/ on Pasture Forage and Pasture Hay Resulting From Ground Applications of the SEVIN XLR PLUS: Final Report: Lab Project Number: 94S43R: 44654: 94­ 0329. Unpublished study prepared by American Agricultural Services, Inc. 670 p. 116 43721001 Macy, L. (1995) Carbaryl: Magnitude of Residues in/ on Broccoli Resulting from Ground Applications of Sevin XLR Plus (1993): Final Study Report: Lab Project Number: US94S05R: 44799: 94­ 0051. Unpublished study prepared by Aventis Ag Co. and Colorado Analytical & Development Corp. 301 p. 43786801 Macy, L. (1995) Carbaryl: Determination of the Magnitude of Residues on Almonds Treated with Foliar Applications of SEVIN XLR Brand of Carbaryl Insecticide: Final Report: Lab Project Number: US94S19R: 94­ 0199: 94­ 0200. Unpublished study prepared by Aventis Ag Co. and Enviro­ Bio­ Tech, Ltd. 279 p. 43786802 Lee, R. (1995) SEVIN XLR PLUS: Magnitude of Carbaryl Residues in/ on Cucurbit Vegetable Raw Agricultural Commodities: Final Report: Lab Project Number: 44870: US94S15R: 94­ 0060. Unpublished study prepared by EN­ CAS Analytical Labs. 552 p. 43786803 Robinson, P. (1995) Determination of the Magnitude of Residues in Sunflower Seeds and Forage Treated with Foliar Applications of SEVIN XLR PLUS Brand of Carbaryl Insecticide: Final Report: Lab Project Number: 44741: US94S44R: 94­ 0220. Unpublished study prepared by Agri Business Group. 311 p. 43786804 Robinson, P.; Cappy, J. (1995) Carbaryl: Magnitude of Carbaryl Residue in/ on Dried Beans: Final Report: Lab Project Number: ML 95­ 0514­ RHP: 44736: US94S38R. Unpublished study prepared by Agri Business Group. 341 p. 43786805 Pittman, J. (1995) Radiovalidation of the Method No. CARC­ 0194 Revised March 27, 1995: "Carbaryl Method for the Determination of Residue in Crop Samples by High Performance Liquid Chromatography": Final Report: Lab Project Number: EC­ 95­ 308: 6295: 44789. Unpublished study prepared by Aventis Ag Co. 107 p. 43786806 Mede, K. (1995) Carbaryl: Magnitude of Residues in/ on Cabbage Resulting from Application of SEVIN XLR PLUS (1993): Final Report: Lab Project Number: US94S06R: 94­ 0059: 94­ 0060. Unpublished study prepared by Colorado Analytical Research & Development Corp. 326 p. 43793201 Tew, E. (1995) Carbaryl: Magnitude of Residues in/ on Grapes Resulting from Ground Applications of Sevin XLR Plus (1994): Final Study Report: Lab Project Number: 44856: US94S29R: ML94­ 0509­ RHP. Unpublished study prepared by Aventis Ag Co. 349 p. 43793202 Ely, C. (1995) Carbaryl: Magnitude of Residues in Stone Fruit (Cherry, Peach, and Plum) RAC Resulting from Applications of Sevin XLR Plus (1994): Final Study Report: Lab Project Number: 44822: US94S17R: 94­ 0123. Unpublished study prepared by Aventis Ag Co. and McKenzie Labs, Inc. 495 p. 43794901 Robinson, P. (1995) Carbaryl: Magnitude of Carbaryl Residues in/ on Sorghum: Final Report: Lab Project Number: US94S42R: 44739: 94/ 0070. Unpublished study prepared by Agri Business Group. 592 p. 43794902 Cappy, J. (1995) Carbaryl: Magnitude of Carbaryl Residues in/ on Soybean and Processed Fractions of Soybean: Final Report: Lab Project Number: US94S33R: 44880: 1258/ US94S33R. Unpublished study prepared by Colorado Analytical & Development Corp. 296 p. 117 43794903 Mede, K. (1995) Carbaryl: Magnitude of Residues in/ on Mustard Green Resulting from Ground Applications of Sevin XLR Plus (1993): Final Report: Lab Project Number: US94S07R: 44872: 1230/ US94S07R. Unpublished study prepared by Colorado Analytical & Development Corp. 291 p. 43802101 Hovis, A. (1995) Sevin XLR Plus: Magnitude of Carbaryl Residues in Citrus (Orange, Grapefruit, Lemon): Final Report: Lab Project Number: 44860: US94S08R: 94­ 0075. Unpublished study prepared by Aventis Ag Co. and Enviro­ Bio­ Tech, Ltd. 407 p. 43802102 Macy, L. (1995) Carbaryl: Determination of the Magnitude of Residues on Pecans Treated with Foliar Applications of Sevin XLR Plus Brand of Carbaryl Insecticide: Final Report: Lab Project Number: 44871: US94S32R: 94­ 0209. Unpublished study prepared by Aventis Ag Co. and EN­ CAS Analytical Labs. 303 p. 43802103 Mede, K. (1995) Carbaryl: Magnitude of the Residues in/ on Rice Resulting from Foliar Applications of Sevin XLR Plus (1994): Final Report: Lab Project Number: 44853: US94S24R: 94­ 0163. Unpublished study prepared by Aventis Ag Co. and EN­ CAS Analytical Labs. 498 p. 43813601 Kowite, W. (1995) Carbaryl: Magnitude of Residues in Root and Tuber Crops (Garden Beets, Carrots, and Turnips) RAC Resulting from Application of Sevin XLR Plus Insecticide (1994): Final Report: Lab Project Number: US94S03R: 44883: 94­ 0003 CA. Unpublished study prepared by Colorado Analytical Research & Development Corp. and Aventis Ag Co. 854 p. 43813602 Cappy, J. (1995) Carbaryl: Magnitude of Carbaryl Residues in/ on Wheat and Processed Fractions of Wheat: Final Report: Lab Project Number: US94S36R: 44884: 94­ 0218. Unpublished study prepared by Enviro­ Bio­ Tech, Ltd. and Aventis Ag Co. 267 43813603 Macy, L. (1995) Carbaryl: Magnitude of Residues in Processed Rice Fractions Resulting from Applications of Sevin XLR Plus (1994): Final Report: Lab Project Number: US94S26R: 44889: RP­ 04­ 95. Unpublished study prepared by Enviro­ Bio­ Tech, Ltd. and Aventis Ag Co. 187 p. 43813604 Cappy, J. (1995) Carbaryl: Magnitude of Carbaryl Residues in/ on Grain Sorghum and Processed Fractions of Grain Sorghum: Final Report: Lab Project Number: US94S35R: 44892: 94­ 0217. Unpublished study prepared by Aventis Ag Co. and Colorado Analytical Research & Development Corp. 270 p. 43818901 Macy, L. (1995) Carbaryl: Determination of the Magnitude of Residues on Walnuts Treated with Foliar Applications of SEVIN XLR Plus Brand of Carbaryl Insecticide: Final Report: Lab Project Number: US94A31R: 94­ 0204: 94­ 0205. Unpublished study prepared by EN­ CAS Analytical Labs. 295 p. 43845205 Robinson, P. (1995) Determination of the Magnitude of Residues in Sunflower Seed Processed Fractions Treated with Foliar Applications of SEVIN XLR Plus Brand Carbaryl Insecticide: Final Report: Lab Project Number: 44735: US94S37R: 94­ 0219. Unpublished study prepared by Agri Business Group. 484 p. 43850901 Lee, R. (1995) Sevin XLR Plus: Magnitude of Carbaryl Residue in/ on Cottonseed and Processed Fractions of Cottonseed: Final Report: Lab Project Number: US94S25R: 44875: 94­ 0162. Unpublished study prepared by Aventis Ag Co. 390 p. 118 43850902 Shults, J. (1995) Storage Stability of Carbaryl on Frozen Raw Agricultural Commodity Substrates and Selected Processing Fractions: Final Report: Lab Project Number: US94S47R: U:\ RHONE\ 94S47RFR. DOC. Unpublished study prepared by McKenzie Labs, Inc. 276 p. 43915201 Cappy, J. (1995) Carbaryl: Magnitude of Carbaryl Residue in/ on Field Corn and Processed Fractions of Field Corn: Final Report: Lab Project Number: US94S34R: 44944: 1272. Unpublished study prepared by Rhone­ Poulenc Ag Co. 309 p. 43975601 Ely, C. (1996) SEVIN XLR PLUS: Magnitude of Carbaryl Residues in/ on Wheat Grain: Final Report: Lab Project Number: US95S10R: 45031: 95­ 0126. Unpublished study prepared by Aventis Ag Co. 315 p. 43982801 Lee, R. (1996) Determination of the Magnitude of Residues on Flax Seed and Straw Treated with Foliar Applications of SEVIN XLR Plus Brand of Carbaryl Insecticide: Final Study Report: Lab Project Number: US95S12R: 45045: 1278. Unpublished study prepared by Agvise Laboratories; Agri Business Group; and Colorado Analytical Research and Development. 240 p. 43984701 Hovis, A. (1996) Sevin XLR Plus: Magnitude of Carbaryl Residues in/ on Succulent Beans: Final Report: Lab Project Number: US95S14R: 45044: 95­ 0258. Unpublished study prepared by McKenzie Labs, Inc.; Agri Business Group, Inc.; and Aventis Ag Co. 273 p. 43996101 Macy, L. (1996) Magnitude of Residues in/ on Tomatoes Resulting from Foliar Applications of Sevin XLR Plus (1995): Final Report: Lab Project Number: US95S05R: 95­ 0149: 95­ 0150. Unpublished study prepared by McKenzie Laboratories. 323 p. 44019701 Macy, L. (1995) Carbaryl: Magnitude of Residues in/ on Broccoli Resulting from Ground Applications of Sevin XLR Plus (1993): Amended Final Report: Lab Project Number: US94SO5R: 44799: 1231/ US94SO5R. Unpublished study prepared by Colorado Analytical Research and Development Corporation: Aventis Ag Co.: and Agvise Lab. 303 p. 44046101 Chancey, E. (1996) Carbaryl Residues in Processed Peanut Fractions: Final Study Report: Lab Project Number: US95S03R: 45070: 95­ 0161. Unpublished study prepared by Texas A& M University Food Protein R& D Center and Colorado Analytical R& D Corp. 234 p. 44058001 Chancey, E. (1996) Sevin XLR Plus: Magnitude of Carbaryl Residues in/ on Field Corn Raw Agricultural Commodities: Final Report: Lab Project Number: US95S01R: 45068: 95­ 0117. Unpublished study prepared by Colorado Analytical Research and Development Corp. and Aventis Ag Co. 356 p. 44058101 Kowite, W. (1996) Carbaryl: Magnitude of Residues in or on Sweet Corn RAC Resulting from Application of Sevin XLR Plus Insecticide (1995): Final Report: Lab Project Number: US95S13R: 45099: 95­ 0195. Unpublished study prepared by Aventis Ag Co. 303 p. Relates to L0000109. 44065901 Norris, F. (1996) Carbaryl: Magnitude of Residues in/ on Rangeland Forage Resulting from an Aerial Application of Sevin 4­ Oil ULV: Lab Project Number: US95S02R: 45095: 95­ 0037. Unpublished study prepared by Diamond Ag Research; Midwest Research, Inc.; and Agvise Labs., Inc. 270 p. 44068401 Norris, F. (1996) Carbaryl: Freezer Storage Stability of Carbaryl in/ on Selected Agricultural Commodities: Lab Project Number: US95S15R: 45112: ML95­ 0570­ RHP. Unpublished study prepared 119 by Colorado Analytical Research & Development Corp.; Enviro­ Bio­ Tech, Ltd.; Morse Laboratories, Inc. 433 p. 44072901 Mede, K. (1996) Carbaryl: Magnitude of Residues in/ on Pome Fruit Resulting from Foliar Applications of SEVIN XLR Plus (1995): Final Report: Lab Project Number: US95S06R: 45101: 95­ 0141. Unpublished study prepared by McKenzie Labs. 293 p. (Relates to L0000110). 44114301 O'Neal, S.; Bentley, W. (1996) Identification of the Pyrolysis Products of (carbon 14) Carbaryl in Cigarette Smoke: (Final Report): Lab Project Number: 984: 1912: EC­ 95­ 326. Unpublished study prepared by PTRL East, Inc. 128 p. 44123101 Dorschner, K. (1996) Carbaryl: Magnitude of the Residue on Okra Fruit (Pods): (Final Report): Lab Project Number: 05772: PR 05772: 5772.95­ FL25. Unpublished study prepared by North Carolina State University; University of Florida; and USDA/ ARS SARL. 436 p. 44145201 Dorschner, K. (1996) Carbaryl: Magnitude of the Residue on Prickly Pear Cactus Fruit and Pads: Lab Project Number: 5146: 05146: PR 05146. Unpublished study prepared by Herbicide Science Agriculture Foundation and Food and Environmental Toxicology Lab., University of Florida. 261 p. 44155401 Nandihalli, U. (1996) Independent Laboratory Validation of a Method for the Determination of Residues of Carbaryl in Crop Samples: Final Report: Lab Project Number: CHW 6224­ 233: 45151: 11642. Unpublished study prepared by Corning Hazleton, Inc. 71 p. 44211801 Ely, C. (1997) Sevin XLR Plus: Magnitude of Carbaryl Residues in/ on Oranges Grown in EPA Region 10: Final Report: Lab Project Number: US95S11R: 45202: 1282. Unpublished study prepared by Aventis Ag Co. 299 p. (Relates to L0000142). 44250301 Hunt, T. (1997) Sample Storage Intervals and Conditions Data to Support MRIDs 42883102, 42883103, 42883104: (Magnitude of Residues of Carbaryl): Final Report: Lab Project Number: 45268. Unpublished study prepared by Aventis Ag Co. 17 p. 44250901 Lee, R. (1997) Carbaryl: Magnitude of Residues in Milk and Tissues of Lactating Dairy Cows: Final Report: Lab Project Number: 96S06298: 45266: 96139B. Unpublished study prepared by Southwest Bio­ Labs, Inc.; Colorado Analytical Research and Development; and Aventis Ag Co. 1270 p. (Relates toL0000170). {OPPTS 860.1480}. 44284701 Macy, L. (1997) Sevin 80WSP: Magnitude of Carbaryl Residues in/ on Stone Fruit (Cherry, Peach, and Plum) RAC in California: Final Report: Lab Project Number: 96S10562: 45306: 10562­ 01. Unpublished study prepared by Aventis Ag Co. 372 p. 44286901 Ibrahim, A. (1997) Carbaryl­­ Validation of Method of Analysis for Free and Conjugated Carbaryl, 5,6­ Dihydro­ 5,6­ dihydroxy Carbaryl and 5­ Methoxy­ 6­ hydroxy Carbaryl in Egg, Milk, Poultry, and Animal Tissues: Final Report: Lab Project Number: EC­ 96­ 349: 45319: 45186. Unpublished study prepared by Aventis Ag Co. 300 p. {OPPTS 860.1340} 120 44286902 Curti, J.; Keller, G. (1997) Independent Laboratory Validation of a Method for the Determination of Free and Conjugated Carbaryl, 5,6­ Dihydro­ 5,6­ dihydroxy Carbaryl, and 5­ Methoxy­ 6­ hydroxy Carbaryl in Egg, Milk, and Beef Liver: Final Report, : Lab Project Number: 6224­ 237: EC­ 97­ 365. Unpublished study prepared by Covance Labs, Inc. 155 p.{ OPPTS 860.1340} 44286903 Ibrahim, A. (1997) Method of Analysis for the Determination of Free and Conjugated Carbaryl, 5,6­ Dihydro­ 5,6­ dihydroxy Carbaryl, and 5­ Methoxy­ 6­ hydroxy Carbaryl and Egg, Milk, Poultry and Animal Tissues: Revised: Lab Project Number: 45321. Unpublished study prepared by Aventis Ag Co. 40 p. 44303101 Lee, R. (1997) Carbaryl and Its Metabolites: Magnitude of Residues in Milk and Tissues of Lactating Dairy Cows: Storage Stability (Interim Report): Lab Project Number: 96S12035: 1292: 45132. Unpublished study prepared by Colorado Analytical Research and Development Corp. 448 p. 44321301 Mede, K. (1997) Carbaryl: Magnitude of Residues in/ on Olives Resulting from Foliar Applications of Sevin 80WSP (1996): Final Report: Lab Project Number: 96S10561: 45324: 10561­ 01. Unpublished study prepared by Aventis Ag Co. 179 p. 44381901 Lee, R. (1997) Carbaryl and Its Metabolites: Magnitude of Residues in Milk and Tissues of Lactating Dairy Cows Storage Stability: Final Study Report: Lab Project Number: 45402: 96S12035: Aventis 1292. Unpublished study prepared by Colorado Analytical Research and Development, Inc. 466 p. {OPPTS 860.1380} 44412501 Ely, C. (1997) Sevin XLR Plus: Magnitude of Carbaryl Residues in/ on Wheat Grain: Amended Report: Lab Project Number: US95S10R: 45031: 95­ 0126. Unpublished study prepared by Colorado Analytical Research & Development Corp. and Agvise Labs. 359 p. {OPPTS 860.1500}

epa

2024-06-07T20:31:42.228980

regulations

EPA-HQ-OPP-2002-0138-0007

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES April 28, 2002 MEMORANDUM SUBJECT: Carbaryl. (Chemical ID No. 056801/ List A Reregistration Case No. 0080). Revised Dietary Exposure Analysis for the HED Revised Human Health Risk Assessment. No MRID# DP Barcode D281419. FROM: Felecia A. Fort, Chemist Reregistration Branch I Health Effects Division (7509C) THRU: Sheila Piper, Chemist and William Cutchin, Chemist Dietary Exposure Science Advisory Council and Whang Phang, Ph. D., Branch Senior Scientist Reregistration Branch I Health Effects Division (7509C) TO: Jeffrey Dawson, Chemist Reregistration Branch I Health Effects Division (7509C) and Anthony Britten, Chemical Review Manager Special Review and Reregistration Division (7508C) The Health Effects Division (HED) has revised the acute, chronic and cancer dietary risk analysis for the carbamate insecticide carbaryl in association with the human health risk assessment for the Reregistration Eligibility Decision Document (RED). These revisions were made to include processing factors submitted by the registrant; to exclude commodities that are no longer supported and to incorporate revised acute and chronic Population Adjusted Doses (PADs) and Q1 * (cancer) that were selected by the HIARC and CARC, respectively. Additionally, in response to comments from the registrant, the dietary assessments include both the 1989­ 1992 and the 1994­ 1996 consumption data (CSFII). Carbaryl is used on commodities in numerous crop groups in agricultural and home settings. A 2 highly refined exposure assessment is needed for the RED. Detailed usage information, monitoring data, and field trial data are described in appendices to this review. Acute and chronic assessments are required as well as cancer assessments using the Q1 * approach. CONCLUSIONS/ SUMMARY This is a Tier 3/ 4 assessment, which is the most highly refined assessment that can be conducted at this time. Changes in the acute and chronic dietary PADs as well as the addition of processing factors resulted in significantly lower risk estimates. HED has provided revised anticipated residues (ARs) for carbaryl based on USDA Pesticide Data Program (PDP) and Food and Drug Administration (FDA) monitoring data and field trial data for the commodities listed in Table 1a of Attachment 1. In addition, separate acute assessments were conducted incorporating the results of the Carbamate Market Basket Survey (CMBS) (Table 1b, Attachment 1). At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has not been completely approved for use in dietary risk assessments. Assessments which include these data are presented in this document for comparison. When quality assurance procedures have been completed, HED will examine the database for appropriateness of inclusion into dietary risk assessments for the carbamate pesticides monitored in the study. Chronic Chronic dietary risk estimates less than 100% of the cPAD are considered by HED to be not of concern. Estimated chronic dietary exposures for all population subgroups consumed <1% of the cPAD and consequently are below HED's level of concern. Cancer The cancer dietary exposure assessment was conducted using the Q 1 * approach. The Q1* for carbaryl is 8.75 X 10 ­4. . Risks estimates above 1 x 10 ­6 are considered to be of concern. Results indicate a maximum lifetime risk of 2.8 X 10 ­8 for the general US population. Acute Estimated acute dietary exposure at the 99.9th percentile of exposure exceeds HED's level of concern for some population subgroups when CMBS data are not used and are not of concern when the CMBS results are incorporated. The acute dietary assessment when CMBS data are not used resulted in risk estimates greater than 100% of the acute Population Adjusted Dose (aPAD) for all infants (< 1 years old) and children (1­ 6 years old) at the 99.9th percentile of exposure. The highest exposed subpopulation incorporating all commodities using PDP and FDA monitoring data was all infants which consumed 133% of the aPAD. When CMBS data was incorporated, highest exposed subpopulation was children (1­ 6 years old) at 73% of the aPAD. Although this exposure assessment is the most refined carbaryl assessment performed by HED to date, there are several uncertainties associated with this assessment which are noted in the Characterization/ Uncertainties section of this document. 3 Revisions Made to the Carbaryl Dietary Assessment This revised carbaryl dietary assessment included changes made as a result of registrant comments and additional data that were submitted to the Agency. Uses deleted The following uses which are no longer being supported by the registrant were deleted from the dietary assessment: dermal use on poultry and in poultry houses, and the uses on barley, oats, rye, and cottonseed. Processing, cooking and washing factors The registrant also submitted processing, cooking and washing factors which were incorporated into the dietary assessment (Table 1). Some washing factors such as those provided for broccoli, cauliflower, grapes, orchard fruit, spinach, but were not used when PDP or CMBS data were used since the residues reflect commodities that have been washed before analysis. Additionally, canning and cooking factors for green beans, tomatoes, and spinach were not used since processed PDP data were already available and used in the assessment. Table 1. Processing Factors (bolded commodities denotes change from prior assessment) Commodity Type Factor Used for Apple Juice Drying 0.37 2.58 Pear juice apple, pear, dried Cabbage Cooking Washing 0.1 0.25 cabbage, Brussels sprouts, kohlrabi, cooked cabbage, Brussels sprouts, kohlrabi, washed Grapefruit Peel 1.13 Grapefruit peel Lemon Peel 1.16 Lemon peel Orange Peel 1.27 Orange peel Corn Grain oil 0.25 Corn oil Grapes unprocessed raisins processed raisins 2.17 1.37 Grapes ­ raisins Olive oil 0.81 Olive­ oil Okra Cooking Cooking/ steaming Washing 0.66 0.18 0.28 Okra Peas Cooking/ boiling Washing 0.15 0.30 Peas ­ cooked Peanuts oil 0.29 Peanut oil Pineapple flesh 0. 54 Pineapple peeled fruit Pineapple juice Plums dried washed 0.15 0.26 Plums( prunes) Plums fresh Commodity Type Factor Used for 4 Potatoes dried fried baked boiled 0.4 0.04 1.2 2.5 Potatoes, dried Potatoes, fried Potatoes, baked Potatoes, boiled Rice polished bran 0.03 0.4 Rice, white Rice, bran Soybean oil 0.005 Soybean oil Sugarbeets sugar molasses 0.04 0.04 Sugarbeets Sugarbeets molasses Sunflowers oil 0.03 Sunflowers oil Tomatoes puree juice dry 0.65 0.52 0.52 Tomatoes puree, paste, catsup Tomatoes juice Tomatoes, dried Wheat Flour Germ Bran 0.10 0.65 1.03 Wheat flour Wheat germ Wheat Bran Almonds The dietary assessment for almond nutmeat erroneously used the almond hulls residue information. The anticipated residues were recalculated using the data shown in Table 2 and resulted in the following residue distribution files and chronic AR. Residue Distribution File for Acute Assessment Almonds ­ FT 15 samples RDF # 68 Almonds ­ FT 4% CT Totalz= 360 Totalnz= 15 0.0614 0.0704 0.0786 0.0822 0.0826 0.0932 0.0304 0.0358 0.0380 0.0704 0.0800 0.0840 0.01 0.0300 0.0384 Chronic AR = 0.059 ppm Table 2 . Residues of carbaryl in/ on almond nutmeats harvested 14 days following three applications of the 4 lb/ gal FlC formulation at ­ 5.0 lb ai/ A/ application ( 15.0 lb ai/ A/ season). 5 RAC Test Location (county, state) Total Application Rate (lb ai/ A) Carbaryl Residues (ppm) a Almond nutmeats Butte, CA 14.9 0. 0614, 0.0704, 0.0786 Fresno, CA 14.9 0. 0822, 0.0826, 0.0932 Fresno, CA 14.9 0. 0304, 0.0358, 0.0380 Stanislaus, CA 15.8 0. 0704, 0.0800, 0.0840 Madera, CA 15.2 <0.02, 0.0300, 0.0384 Peaches Single Serving Peach PDP Data from the year 2000 were used for non­ blended peach food forms where HED previously used data that had been decomposited (Allender method). The resultant RDF file is shown below. Five hundred and thirty­ four samples were analyzed; carbaryl was detected in 79 of those samples. Peaches (not blended) PDP Single Serving 2000 534 samples/ 79 detects 18% CT ­ 15% detected Residues ranged from 0.01 ­ 2.7 ppm RDF # 60 Peaches ­ PDP single serving 18% CT ­ 15% detected Totalz= 438 Totalnz= 79 17, 0.003 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.011 0.022 0.025 0.026 0.03 0.031 0.031 0.041 0.042 0.046 0.049 0.051 0.052 0.054 0.057 0.06 0.065 0.071 0.073 0.083 0.087 0.094 0.1 0.11 0.11 0.12 0.13 0.14 0.14 0.15 0.15 0.15 0.15 0.15 0.16 0.16 0.18 0.2 0.21 0.24 0.25 0.29 0.34 0.37 0.41 0.49 0.5 0.51 0.54 0.56 0.58 0.59 0.76 0.94 0.94 1.2 1.5 2.7 Toxicology Information The HED Hazard Identification Assessment Review Committee (HIARC) on February 19, 6 2002 reevaluated the toxicology data base of carbaryl and selected toxicology endpoints for chronic and acute dietary as well as occupational exposure risk assessments. The selected toxicological endpoints and the doses for risk assessment and additional relevant details are summarized in Table 3. On November 7, 2001, the CARC reconsidered the cancer classification of carbaryl. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC classified carbaryl into the category "Likely to be carcinogenic to humans" and recommended a low dose linear extrapolation approach using all dose levels for the quantification of human cancer risk based on the most potent vascular tumors in mice. The HED FQPA Safety Factor Committee (C. Christensen, 2/ 25/ 02) determined that when assessing acute and chronic dietary exposures, the safety factor should be reduced to1x for all population subgroups. Table 3: Carbaryl Toxicity Endpoints EXPOSURE SCENARIO Old RfD PAD New DOSE (mg/ kg/ day) New RfD PAD ENDPOINT STUDY Acute Dietary (all populations) aRfD = 0.03 mg/ kg aPAD = 0.003 mg/ kg/ day NOAEL= 1 mg/ kg UF = 100 FQPA SF = 1 aRfD = 0.01 mg/ kg aPAD = 0.01 mg/ kg/ day Alterations in FOB parameters after a single dose to maternal animals Acute neurotoxicity study ­ rat Chronic Dietary (all populations) cRfD = 0.01 mg/ kg/ day cPAD = 0.001 mg/ kg/ day NOAEL = 3.1 mg/ kg/ day UF = 300 FQPA SF = 1 cRfD = 0.01 mg/ kg/ day cPAD = 0.01 mg/ kg/ day Decrease in brain cholinesterase in females Chronic toxicity ­ dog Cancer Q1* = 1.19 x 10 ­2 [mg/ kg/ day] ­1 n/ a Q1* = 8.75 x 10 ­4 [mg/ kg/ day] ­1 Carbaryl was classified as "likely to be carcinogenic to humans" based on an increased incidence of hemangiosarcomas in male mice Carcinogenicity ­ mice DEEM™ Program and Consumption Information Carbaryl acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model (DEEM™) software Version 7.76, which incorporates consumption data from USDA's 7 Continuing Surveys of Food Intake by Individuals (CSFII), 1989­ 1992. The 1989­ 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive days, and therefore represent more than 30,000 unique "person days" of data. Foods "as consumed" (e. g., apple pie) are linked to raw agricultural commodities and their food forms (e. g., apples­ cooked/ canned or wheat­ flour) by recipe translation files internal to the DEEM software. Consumption data are averaged for the entire US population and within population subgroups for chronic exposure assessment, but are retained as individual consumption events for acute exposure assessment. As requested by the registrant, separate assessments which shows the results using the newer 1994 ­1998 consumption data were conducted. For chronic exposure and risk assessment, an estimate of the residue level in each food or food­ form (e. g., orange or orange­ juice) on the commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms on the commodity residue list to arrive at the total estimated exposure. Exposure estimates are expressed in mg/ kg body weight/ day and as a percent of the cPAD. This procedure is performed for each population subgroup. For acute exposure assessments, individual one­ day food consumption data are used on an individual­ byindividual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic (Tier 1 or Tier 2) exposure assessment, or "matched" in multiple random pairings with residue values and then summed in a probabilistic (Tier 3/ 4) assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user (i. e., those who reported eating relevant commodities/ food forms) and a per­ capita (i. e., those who reported eating the relevant commodities as well as those who did not) basis. In accordance with HED policy, per capita exposure and risk are reported for all tiers of analysis. However, for tiers 1 and 2, significant differences in user vs. per capita exposure and risk are identified and noted in the risk assessment. HED notes that there is a degree of uncertainty in extrapolating exposures for certain population subgroups from the general U. S. population which may not be sufficiently represented in the consumption surveys, (e. g., nursing and non­ nursing infants or Hispanic females). Therefore, risks estimated for these population subgroups were included in representative populations having sufficient numbers of survey respondents (e. g., all infants or females, 13­ 50 years). Usage Information BEAD provided information (F. Hernandez, 7/ 21/ 98, Attachment 9) on the percent crop treated (% CT). For the chronic analysis, the weighted average %CT was incorporated; for the acute analysis, the estimated maximum %CT was used when appropriate. In acute analyses (except blended commodities) the adjustment for %CT is incorporated in the residue distribution files (RDFs) via addition of zero residue values corresponding to the % of crop not treated. For blended/ not further processed commodities where monitoring data are available, the entire distribution of monitoring data with no futher adjustment for %CT were used. For blended/ processed commodities where monitoring data are available and for all blended commodities where field trial data were used, %CT is incorporated into a point estimate. For the chronic analyses, the %CT is listed as Adjustment Factor 2 in the DEEM analysis. 8 Use of usage information for assessments incorporating the CMBS are described below. Residue Data Tolerances for residues of carbaryl are currently expressed in terms of carbaryl (1­ naphthyl Nmethylcarbamate including its hydrolysis product 1­ naphthol, calculated as carbaryl, for most raw crop commodities [40 CFR §180.169( a)]. The established tolerances for residues in/ on pineapples, pome fruits, avocados, and fresh dill are expressed in terms of carbaryl per se [40 CFR §180.169( d) and (e)]. Tolerances for residues in livestock commodities are expressed as carbaryl, including its metabolites 1­ naphthol (naphthyl sulfate), 5,6­ dihydrodihydroxy carbaryl, and 5,6­ dihydrodihydroxy naphthol, calculated as carbaryl [40 CFR §180.169( b) and (c)]. A tolerance for residues in pineapple bran is expressed in terms of carbaryl per se [40 CFR §186.550]. An interim tolerance has been established for carbaryl and its 1­ naphthol metabolite in eggs [40 CFR §180.319]. For the purpose of reregistration, adequate magnitude of the residue data are available on the following crops: alfalfa, almond, asparagus, beans (dried and succulent), blueberry, broccoli, cabbage, celery, cherry, citrus fruits, clover, corn (sweet and field), cucurbits (cantaloupes, cucumbers and squash), cranberry, flax, grape, head and leaf lettuce, mustard greens, okra, peanut, peas (dried and succulent), pecan, pepper, pistachio, pome fruits, potato, prickly pear cactus, raspberry, rice, sorghum, soybean, spinach, stone fruits, strawberry, sunflower, sweet potato, tobacco, tomato, and walnut. Tolerances of 2 ppm and 10 ppm have been established for residues of carbaryl in pineapples and bananas, respectively. The registrant intends to support the tolerances for residues of carbaryl in/ on these commodities as import tolerances. Adequate field trial data depicting carbaryl residues following applications made according to the maximum or proposed use patterns have been submitted for these commodities. Geographical representation is adequate and a sufficient number of trials reflecting representative formulation classes were conducted. Carbaryl residues were <LOQ in/ on sweet potato, sugar beets, corn grain, flax seed, and peanuts. Quantifiable residues were detected in all other raw agricultural commodities (RACs). For a given crop, residue levels were quite variable overall, probably owing to climactic variations, but were generally consistent within any specific field trial location. Anticipated residue estimates are presented in Table 1a of Attachment 1 of this document. In general PDP data were used if available. Alternatively, FDA surveillance monitoring data from the years 1992­ 98 were used if sufficient samples were available. Finally, data from crop field trials were used if there were insufficient PDP or FDA monitoring data. Adequate PDP monitoring data are available for the following commodities: potatoes, carrots, sweet potato, celery, spinach, lettuce (head), broccoli, succulent peas (processed) , succulent beans, soybean, tomatoes, cantaloupe, winter squash, orange, orange juice, apple, apple juice, pear, peach, wheat, sweet corn, banana, grape, grape juice and milk. FDA monitoring data were used for the commodities, lettuce (leaf), cabbage, eggplant, succulent peas (fresh), non­ bell pepper, bell pepper, cucumber, watermelon, summer squash, cherries, raspberry, blueberry, asparagus, cranberry, pineapple, and strawberry. Monitoring data were translated to similar crops when possible, generally according to the HED SOP 99.3 "Translation of Monitoring Data". See Table 1a of Attachment 1 for translations. Monitoring data from the years 1994 through 1998 (PDP) and the years 1992 through 1998 (FDA) were considered. Field trial data were used for the commodities, garden beets, turnips, mustards, dried beans, dried peas, 9 almonds, pecans, walnuts, field corn grain, rice, flax seed, okra, olive, peanuts, pistachio, sugar beets, and sunflower. For oysters and dill (fresh), tolerances of 2 ppm and 0.2 ppm, respectively was used in the assessment. These data are summarized in Attachment 1 below. One half the weighted average of the limits of detection (LOD) will be used in the dietary assessment for all treated non­ detectable (ND) residues. Detectable residues from composite monitoring data for nonblended food forms were used to generate residue values in single units using the methods described in the H. Allender paper dated 5/ 26/ 99 "Statistical methods for Use of Composite Data in Acute Dietary Risk Assessment." The "decomposited" residues were then included in residue distribution files (RDF) for the probabilistic analysis. Biological and Economic Analysis Division (BEAD)­ supplied %CT which were incorporated into the anticipated residue or residue distribution file when appropriate. Carbamate Market Basket Survey (CMBS) A separate dietary assessment was conducted utilizing the CMBS results. These data are currently under review by the Agency and have not been approved for use in dietary assessments. The CMBS Task Force conducted a year long, national survey of carbamate residues on selected food commodities purchased at grocery stores. Residue data from a market basket survey are considered close approximations to residues potentially found at most `dinner plates' and is generally considered the most appropriate survey type for use in pesticide risk and exposure assessment. The CMBS collected up to 400 single­ serve samples of 8 different crops (apple, banana, broccoli, grape, lettuce, orange, peach and tomato). These data are used in the acute dietary analysis directly via RDFs incorporating %CT for all food forms considered to be partially or not blended. For blended commodities, the entire distribution of data with no further adjustment for %CT was done. If CMBS data were not available, then PDP or FDA monitoring or field trial data were used. CMBS data were translated to similar commodities when feasible (Table 1b, Attachment 1); however, if PDP monitoring data were available for the processed commodity, then CMBS data were not translated (i. e., PDP orange juice data were used instead of CMBS data for oranges). The RDFs are shown in Attachment 1 of this document. Processing Factors Most of the carbaryl processing factors (see Table 1) were obtained from processing studies submitted by the registrant either in response to the preliminary dietary risk assessment or those compiled in a memo entitled "Carbaryl Anticipated Residues for Carcinogenic Dietary Risk Assessment", S. Hummel, 12/ 3/ 93. The rice processing factors were from a review by Thurston Morton (D216242, 9/ 17/ 98). Default processing factors were maintained for all commodities not included in Table 1 in this document. Results This is a Tier 3/ 4 assessment, which is the most highly refined assessment that can be conducted at this time. Processing factors have been incorporated to the fullest extent possible. A sensitivity analysis, setting all non­ detectable residue values to zero was conducted to test the relative contribution of 1/ 2 LOD residues to the dietary risk. These results are based on 1989 to 92 consumption data. When the assessments were done using the 1994 ­1998 consumption data, no significant differences in dietary exposure were found. 10 HED has provided revised anticipated residues (ARs) for carbaryl based on USDA PDP and FDA monitoring data, field trial data, and CMBS data for the commodities listed in Table 1a and 1b of Attachment 1. Chronic Chronic dietary risk estimates less than 100% of the cPAD are not of concern. Carbaryl estimated dietary exposure to the general US population and all population subgroups consumed <1% of the cPAD and are therefore not of concern. (Table 4 and Attachment 2). Cancer The cancer dietary exposure assessment was conducted using the Q 1 * approach. The Q1* for carbaryl is 8.75 X 10 ­4. . Risks estimates above 1 x 10 ­6 are considered to be of concern. Results indicate a maximum lifetime risk of 2.8 x 10 ­8 for the general U. S. population. (Table 4 and Attachment 2). 1 aPAD/ cPAD = acute/ chronic Population Adjusted Dose = Acute or Chronic RfD FQPA Safety Factor 11 Table 4. Results of the Carbaryl Chronic and Cancer Dietary Analyses. Chronic Pop. Subgroup 1989­ 92 1994­ 1998 Exposure (mg/ kg/ day) % cPAD Exposure (mg/ kg/ day) % cPAD Gen. Population 0.000032 <1 0.000035 <1 All Infants 0.000054 <1 0.000059 <1 Children 1 ­ 6 years 0. 000057 <1 0.000074 <1 Children 7 ­ 12 years 0. 000036 <1 0.000034 <1 Females 13 ­ 50 years 0. 000026 <1 0.000028 <1 Males 13­ 19 years 0. 000022 <1 0.000026 <1 Males 20+ years 0. 000031 <1 0.000032 <1 Seniors 55+ 0.000031 <1 0.000030 <1 Cancer Exposure (mg/ kg/ day) Lifetime risk Gen. Population 0.000032 2.8 x 10 ­8 0.000035 3.04 X 10 ­8 Acute The acute dietary assessment resulted in risk estimates greater than 100% of the acute Population Adjusted Dose (aPAD) for the population subgroups, all infants and children (1 to 6 years old) at the 99.9th percentile of exposure (Table 5). The highest exposed subpopulation using PDP and FDA monitoring data was all infants at 133% of the aPAD. When CMBS data are incorporated, the acute risk estimates are below the Agency's level of concern (< 100% aPAD 1 ) at the 99.9 th exposure percentile for the general U. S. population (46% of the aPAD) and all population subgroups (Table 6). The acute dietary exposure estimates for the highest exposed population subgroups, all infants (< 1 years old) and children are 73% of the aPAD. Peaches and apples were found to be the most significant contributor to the risk estimate. (Attachments 3, 6, 7 and 8). Characterization/ Uncertainties of the Risk Estimates ° No detectable residues were found in/ on several commodities: carrots, chicory, flax seed, horseradish, parsnip, salsify, potato, celery, canned spinach, head lettuce, leaf lettuce, rhubarb, sugarbeets, Swiss chard, Brussels sprouts, cabbage, kohlrabi, soybean, corn, banana, peanuts, meat, meat fat, and milk. Sensitivity analyses conducted by eliminating crops where no detectable residues were found showed that risk estimates were not significantly affected by assuming zero 12 in place of 1/ 2 LOD on samples reported as ND. (Attachments 5). ° The consumption database used in the dietary exposure analysis, CSFII 1989­ 1992, has a limited number of individuals for the age group infants less than one year old. The USDA has conducted the Supplemental Children's Survey (approximately 5000 children) which will be available for use in the near future. ° The results of the Critical Exposure Contribution analysis showed that peaches and apples comprised a large percentage of the residues found in the tail end of acute exposure (Attachments 4) for children and infants, respectively. ° Detectable residues from composite monitoring data for non­ blended food forms were used to generate residue values in single units using the methods described in the H. Allender paper dated 5/ 26/ 99 "Statistical methods for Use of Composite Data in Acute Dietary Risk Assessment." The "decomposited" residues were then included in residue distribution files (RDF) for the probabilistic analysis. Although there is a statistical basis for using these data, some degree of uncertainty can be associated with this method. 13 Table 5. Results of the Carbaryl Acute Dietary Analyses (Market Survey Data Not Included) All Commodities (1989­ 92 Consumption Data) Pop. Subgroup 99.9 th Percentile 99 th Percentile 95 th Percentile Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Gen. Population 0.005989 60 0.001381 14 0.000505 5 All Infants 0.013251 133 0.003683 37 0.000864 9 Children 1 ­ 6 0. 010974 110 0.002552 26 0.001309 13 Children 7 ­ 12 0.008721 87 0.001644 16 0.000722 7 Females 13 ­ 50 0.004444 44 0.000918 9 0. 000318 3 Males 13­ 19 yrs 0. 003596 36 0.000899 9 0. 000428 4 Males 20+ yrs 0. 004223 42 0.000929 9 0. 000318 3 Seniors 55+ yrs 0.005789 58 0.001068 11 0.000307 3 All Commodities (1994­ 98 Consumption Data) Pop. Subgroup 99.9 th Percentile 99 th Percentile 95 th Percentile Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Gen. Population 0.006150 62 0.001467 15 0.000508 5 All Infants 0.013420 134 0.004027 40 0.000922 9 Children 1 ­ 6 0. 013812 138 0.003282 33 0.001460 15 Children 7 ­ 12 0.007073 71 0.001473 15 0.000685 7 Females 13 ­ 50 0.004794 48 0.000997 10 0.000322 3 Males 13­ 19 yrs 0. 005181 52 0.000929 9 0. 000420 4 Males 20+ yrs 0. 003940 39 0.000922 9 0. 000336 3 Seniors 55+ yrs 0.005442 54 0.001003 10 0.000313 3 14 Table 6. Results of the Carbaryl Acute Dietary Analyses (Market Basket Survey Data Included) All Commodities (1989­ 92 Consumption Data) Pop. Subgroup 99.9 th Percentile 99 th Percentile 95 th Percentile Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Gen. Population 0.004623 46 0.001241 12 0.000462 5 All Infants 0.007272 73 0.002875 29 0.000593 6 Children 1 ­ 6 0. 007344 73 0.002280 23 0.001241 12 Children 7 ­ 12 0.006238 62 0.001345 13 0.000680 7 Females 13 ­ 50 0.003546 35 0.000858 9 0. 000299 3 Males 13­ 19 yrs 0. 002723 27 0.000815 8 0. 000409 4 Males 20+ yrs 0. 003423 34 0.000836 8 0. 000297 3 Seniors 55+ yrs 0.004810 48 0.000905 9 0. 000275 3 All Commodities (1994­ 98 Consumption data) Pop. Subgroup 99.9 th Percentile 99 th Percentile 95 th Percentile Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Gen. Population 0.004865 49 0.001303 13 0.000465 5 All Infants 0.008091 81 0.002630 26 0.000650 7 Children 1 ­ 6 0. 009481 95 0.002799 28 0.001348 13 Children 7 ­ 12 0.004921 49 0.001214 12 0.000643 6 Females 13 ­ 50 0.004224 42 0.000878 9 0. 000298 3 Males 13­ 19 yrs 0. 004515 45 0.000867 9 0. 000402 4 Males 20+ yrs 0. 003359 34 0.000831 8 0. 000311 3 Seniors 55+ yrs 0.004649 46 0.000819 8 0. 000279 3 15 Table 7. Results of the Carbaryl Sensitivity Analyses. Acute ­ All Commodities at the 99.9th percentile of exposure (Market Basket Survey Data Not Included) Pop. Subgroup All commodities Eliminating Peaches Eliminating Apples Eliminating Commodities with No Detectable Residues Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Gen. Population 0.005989 60 0.005451 55 0.004943 49 0.005870 59 All Infants 0.013251 133 0.007188 72 0.011784 118 0.012965 130 Children 1 ­ 6 0. 010974 110 0.010164 102 0.008201 82 0.0010765 108 Children 7 ­ 12 0.008721 87 0.008243 82 0.006867 69 0.008555 86 Females 13 ­ 50 0.004444 44 0.004262 43 0.003890 39 0.004434 44 Males 13­ 19 yrs 0. 003596 36 0.003535 35 0.003014 30 0.003802 38 Males 20+ yrs 0. 004223 42 0.003949 39 0.003575 36 0.004178 42 Seniors 55+ yrs 0.005789 58 0.005456 55 0.005094 51 0.005703 57 16 Atttachments Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities Attachment 3: Acute Dietary Exposure Analysis : All Commodities Attachment 4: Acute ­ Critical Exposure Contribution Analysis Attachment 5: Acute Dietary Exposure Analysis : Excluding all Commodities with No detects Attachment 6: Acute Dietary Exposure Analysis : Excluding Peaches Attachment 7: Acute Dietary Exposure Analysis : Excluding Apples Attachment 8: Acute Dietary Exposure Analysis : Market Basket Survey ­ All Commodities Attachment 9: Quantitative Usage Analysis (QUA) Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 17 Table 1a: Summary of Anticipated Residues for Carbaryl (Market Basket Data not included) Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max Crop Group 1: Root and Tuber vegetable Beets, garden (roots) 11­ Uncooked 14­ Boiled 2 garden beets FT 0.024 RDF #1 NB 17 27 Beets, garden (roots) 31­ Canned: NFS 32­ Canned: Cooked 51­ Cured: NFS (smoked/ pickled/ 2 garden beets FT 0.024 RDF #1 PB 17 27 Carrots 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 2 carrots PDP 0. 0116 RDF # 2 NB 4 6 Carrots 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 44­ Frozen: Boiled 2 carrots PDP 0.0116 RDF #2 PB 4 6 Horseradish 12­ Cooked: NFS 14­ Boiled 2 carrots PDP 0. 0116 RDF #3 NB 1 3 2 Horseradish 34­ Canned: Boiled 51­ Cured: NFS (smoked/ pickled/ 2 carrots PDP 0. 0116 RDF #3 PB 1 3 2 Parsnips 14­ Boiled 2 carrots PDP 0. 0116 RDF #3 NB 1 3 2 Potatoes/ white­ dry 12­ Cooked: NFS 14­ Boiled 15­ Fried 31­ Canned: NFS 34­ Canned: Boiled 42­ Frozen: Cooked 2 potato PDP 0. 0119 PE = 0.00036 B 2 3 Potatoes/ white­ peel only 13­ Baked 15­ Fried 2 potato PDP 0. 0119 RDF # 4 NB 2 3 Potatoes/ white­ peeled 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 2 potato PDP 0.0119 RDF # 4 NB 2 3 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 18 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 43­ Frozen: Baked 45­ Frozen: Fried 0.0119 RDF # 4 PB 2 3 Potatoes// white­ unspecified 31­ Canned: NFS 0. 0119 RDF # 4 PB 2 3 Potatoes/ white­ whole 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 2 potato PDP 0.0119 RDF # 4 NB 2 3 31­ Canned: NFS 0. 0119 RDF # 4 PB 2 3 Radishes 11­ Uncooked 12­ Cooked: NFS 2 garden beets FT 0.024 RDF #5 PB 1 3 2 Radish, Chinese 12­ Cooked: NFS Radishes­ oriental 2 garden beets FT 0.024 RDF #5 NB 1 3 2 Rutabagas Rutabagas­ roots 2 turnips FT 0.121 RDF # 6 NB 1 3 2 Salsify (roots) Salsify( oyster plant) 2 carrot PDP 0. 0116 RDF #3 NB 1 3 2 Sugar Beets (inc. molasses 98­ Refined 0.5 sugar beets FT 0.01 0.0004 B 2 4 Sweet potatoes 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 0.2 sweet potato PDP 0. 0065 RDF #7 NB 18 41 32­ Canned: Cooked 34­ Canned: Boiled sweet potato PDP 0. 0065 RDF #7 PB 18 41 Turnips, roots 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 2 turnips FT 0.121 RDF # 6 NB 1 3 2 Crop Group 2: Leaves of Root and Tuber Vegetables Beets, garden (tops) 11­ Uncooked 14­ Boiled 75 garden beets FT 10.14 RDF #8 PB 17 27 Radish ­ Tops Radishes­ tops 75 garden beets FT 10.14 RDF #9 PB 1 3 2 Rutabaga ­ Tops 12­ Cooked: NFS 75 Turnip tops FT 15.3 RDF #10 PB 1 3 2 Turnips, tops 14­ Boiled 32­ Canned: Cooked 44­ Frozen: Boiled 75 turnip tops FT 15.3 RDF #10 PB 1 3 2 Crop Group 4: Leafy Vegetables (except Brassica Vegetables) Celery 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 3 Celery PDP 0. 0152 RDF # 11 NB 3 6 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 19 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 3 Celery PDP 0. 0152 RDF # 11 PB 3 6 Celery Juice 31­ Canned: NFS 3 Celery PDP 0. 0152 RDF # 11 PB 3 6 Dandelions 11­ Uncooked 22 Spinach PDP 0. 0082 RDF # 12 PB 1 3 2 Endive (escarole) 11­ Uncooked 12­ Cooked: NFS 10 Leaf Lettuce FDA 0.001 RDF # 15 PB 1 3 2 Lettuce ­ head 11­ Uncooked 10 Lettuce PDP 0. 0169 RDF #14 NB 3 8 Lettuce ­ leaf 11­ Uncooked 10 Leaf Lettuce FDA 0. 001 RDF # 15 PB 1 3 2 Lettuce (unspecified) 31­ Canned: NFS 10 Lettuce ­ PDP 0. 0169 RDF #14 PB 3 8 Parsley 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 22 Spinach PDP 0. 0082 RDF # 12 PB 1 3 2 Rhubarb 12­ Cooked: NFS 13­ Baked 3 Celery PDP 0. 015 RDF #16 NB 1 3 2 43­ Frozen: Baked 3 Celery PDP 0. 015 RDF #16 PB 1 3 2 Spinach 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 42­ Frozen: Cooked 44­ Frozen: Boiled 22 Spinach PDP 0. 0082 RDF # 12 PB 1 3 2 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 22 Canned Spinach PDP 0. 006 RDF #13 PB 1 3 2 Swiss chard 11­ Uncooked 14­ Boiled 3 Celery PDP 0. 015 RDF # 16 NB 1 3 2 Crop Group 5: Brassica Leafy vegetables Broccoli 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 10 Broccoli PDP 0. 013 RDF #17 NB 4 9 32­ Canned: Cooked 42­ Frozen: Cooked 44­ Frozen: Boiled 10 Broccoli PDP 0. 013 RDF # 17 PB 4 9 Brussels Sprouts 14­ Boiled 42­ Frozen: Cooked 10 Cabbage FDA 0. 001 RDF #18 PB 33 67 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 20 Cabbage 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 21 Cabbage FDA 0. 001 RDF # 19 NB 2 4 31­ Canned: NFS 32­ Canned: Cooked 51­ Cured: NFS (smoked/ pickled/ 21 Cabbage FDA 0. 001 RDF # 19 PB 2 4 Cauliflower 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 15­ Fried 10 Broccoli PDP 0. 013 RDF # 20 NB 2 4 42­ Frozen: Cooked 10 Broccoli PDP 0. 012 RDF #20 PB 2 4 Collards 42­ Frozen: Cooked 10 Mustard FT 2.78 RDF # 21 PB 4 10 Kale 12­ Cooked: NFS 14­ Boiled 32­ Canned: Cooked 10 Mustard FT 2.78 RDF # 22 PB 1 3 2 Kohlrabi 14­ Boiled 10 Cabbage FDA 0. 001 RDF # 23 NB 1 3 2 Mustard greens 14­ Boiled 10 Mustard FT 2.78 RDF # 22 PB 1 3 2 Crop Group 6: Legume Vegetables (Succulent or Dried) Beans­ dry­ black­ eyed peas/ cowpea 14­ Boiled 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ broadbeans 14­ Boiled 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ garbanzo/ chick pea 12­ Cooked: NFS 14­ Boiled 15­ Fried 32­ Canned: Cooked 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ great northern 32­ Canned: Cooked 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ hyacinth 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ kidney 12­ Cooked: NFS 13­ Baked 14­ Boiled 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ lima 14­ Boiled 32­ Canned: Cooked 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ navy (pea) 32­ Canned: Cooked 34­ Canned: Boiled 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ other 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 34­ Canned: Boiled 1 Dried Beans FT 0.067 0.002 B 1 3 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 21 Beans­ dry­ pigeon beans 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ dry­ pinto 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 32­ Canned: Cooked 42­ Frozen: Cooked 1 Dried Beans FT 0.067 0.002 B 1 3 Beans­ broadbeans 10 Succulent Beans PDP .0.023 RDF # 24 PB 14 21 Beans­ succulent­ green 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 10 Succulent Beans PDP .0.023 RDF # 24 PB 14 21 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 44­ Frozen: Boiled 51­ Cured: NFS (smoked/ pickled/ 10 Processed Succulent Beans PDP 0.012 RDF #25 PB 10 16 Beans­ succulent­ hyacinth 10 Succulent Beans PDP 0. 023 RDF # 24 PB 14 21 Beans­ succulent­ lima 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 32­ Canned: Cooked 42­ Frozen: Cooked 44­ Frozen: Boiled 10 Processed Succulent Beans PDP 0.012 RDF #26 PB 13 30 Beans­ succulent­ other 34­ Canned: Boiled 10 Processed Succulent Beans PDP 0.012 RDF #25 PB 10 16 Beans­ yellow/ wax 14­ Boiled 10 Succulent Beans PDP 0. 023 RDF # 24 PB 14 21 32 Canned: Cooked 42­ Frozen: Cooked 10 Processed Succulent Beans PDP 0.012 RDF #25 PB 10 16 Beans­ unspecified 10 Succulent Beans PDP 0. 0.023 RDF # 24 PB 14 21 Lentils 14­ Boiled 1 Dried Beans FT 0.067 0.002 B 1 3 Mung Bean (SPROUTS) 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 15­ Fried 1 Dried Beans FT 0.067 0.002 B 1 3 Peas­ succulent/ black­ eyed/ cowpea 12­ Cooked: NFS 14­ Boiled 10 Peas ­ FDA 0. 13 RDF # 27 PB 2 7 32­ Canned: Cooked 42­ Frozen: Cooked 10 Peas ­ PDP 0. 0127 RDF # 28 PB 1 5 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 22 Peas (garden)­ green 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 10 Peas ­ FDA 0. 13 RDF # 27 PB 2 7 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 44­ Frozen: Boiled 45­ Frozen: Fried 10 Peas ­ PDP 0. 0127 RDF # 28 PB 1 5 Snowpeas 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 15­ Fried 10 Peas FDA 0. 13 RDF #27 PB 1 5 42­ Frozen: Cooked 10 Peas PDP 0. 0127 RDF # 28 PB Peas (garden)­ dry 12­ Cooked: NFS 14­ Boiled 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 1 Dry Peas ­ FT 0.146 0.013 B 3 9 Soybeans­ other 0. 5 Soybeans ­ PDP 0.0015 0.000015 B 1 1 Soybeans­ flour (defatted) 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 34­ Canned: Boiled 42­ Frozen: Cooked 98­ Refined 0.5 Soybeans ­ PDP 0. 0015 0.000015 B 1 1 Soybeans­ flour (full fat) 12­ Cooked: NFS 13­ Baked 14­ Boiled 34­ Canned: Boiled 42­ Frozen: Cooked 0.5 Soybeans ­ PDP 0. 0015 0.000015 B 1 1 Soybeans­ flour (low fat) 12­ Cooked: NFS 13­ Baked 15­ Fried 31­ Canned: NFS 0.5 Soybeans ­ PDP 0. 0015 0.000015 B 1 1 Soybeans­ mature seeds dry 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 41­ Frozen: NFS 0.5 Soybeans ­ PDP 0. 0015 0.000015 B 1 1 Soybeans­ oil 98­ Refined 0.5 Soybeans ­ PDP 0. 0015 0.000015 B 1 1 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 23 Soybeans­ protein isolate 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 41­ Frozen: NFS 42­ Frozen: Cooked 51­ Cured: NFS (smoked/ pickled/ 0.5 Soybeans ­ PDP 0. 0015 0.000015 B 1 1 Soybeans­ sprouted seeds 14­ Boiled 0.5 Soybeans ­ PDP 0. 0015 0.000015 B 1 1 Crop Group 8: Fruiting Vegetables (except Cucurbits) Group Eggplants 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 5 Sweet pepper­ FDA 0.005 RDF # 29 NB 9 21 Peppers­ chilli incl jalapeno 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 5 Hot Pepper ­ FDA 0. 108 RDF # 30 NB 1 3 2 Peppers­ chilli incl jalapeno 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 42­ Frozen: Cooked 51­ Cured: NFS (smoked/ pickled/ 52­ Cured: Cooked( smokd/ pickld/ 60­ Canned: Cured 5 Hot Pepper ­ FDA 0. 108 RDF # 30 PB 1 3 2 Peppers­ sweet( garden) 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 5 Sweet Pepper ­ FDA 0. 02 RDF # 31 NB 13 30 Peppers­ sweet( garden) 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 51­ Cured: NFS (smoked/ pickled/ 5 Sweet Pepper ­ FDA 0. 02 RDF # 31 PB 13 30 Peppers ­ Other 11­ Uncooked 5 Hot Pepper ­ FDA 0. 108 RDF # 30 NB 1 3 2 Pimiento 12­ Cooked: NFS 14­ Boiled 5 Hot Pepper ­ FDA 0. 108 RDF # 30 NB 1 3 2 31­ Canned: NFS 60­ Canned: Cured 5 Hot Pepper ­ FDA 0. 108 RDF # 30 NB 1 3 2 Paprika 12­ Cooked: NFS 5 Hot Pepper ­ FDA 0. 108 RDF # 30 NB 1 3 2 Tomato ­Catsup 34­ Canned: Boiled 5 Tomato PDP 0. 0044 RDF # 32 PB 15 27 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 24 Tomatoes­ dried 12­ Cooked: NFS 15­ Fried 5 Tomato PDP 0. 0044 RDF # 32 PB 15 27 Tomatoes­ juice 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 5 Tomato PDP 0. 0044 RDF # 32 PB 15 27 Tomatoes­ paste 14­ Boiled 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 42­ Frozen: Cooked 5 Tomato PDP 0. 0044 RDF # 32 PB 15 27 Tomatoes­ puree 12­ Cooked: NFS 14­ Boiled 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 42­ Frozen: Cooked 5 Tomato PDP 0. 0044 RDF # 32 PB 15 27 Tomatoes­ whole 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 5 Tomato PDP 0. 0044 RDF # 33 NB 5 11 Tomatoes­ whole 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 42­ Frozen: Cooked 5 Tomato PDP 0. 0044 RDF # 32 PB 15 27 Crop Group 9: Cucurbit Vegetables Cucumbers 11­ Uncooked 3 Cucumbers­ FDA 0. 0033 RDF # 34 NB 14 32 34­ Canned: Boiled 60­ Canned: Cured 3 Cucumbers­ FDA 0.0033 RDF #34 PB 14 32 Bitter melon 12­ Cooked: NFS 3 Cantaloupe ­ PDP 0. 0056 RDF #35 NB 1 3 2 Melons­ cantaloupes­ juice 3 Cantaloupe ­ PDP 0. 0056 RDF # 36 PB 7 9 Melons­ cantaloupes­ pulp 11­ Uncooked 3 Cantaloupe ­ PDP 0. 0056 RDF # 36 NB 7 9 Melons ­ Casaba 11­ Uncooked 3 Cantaloupe ­ PDP 0. 0056 RDF # 35 NB 1 2a Melons ­ Crenshaw 3 Cantaloupe ­ PDP 0. 0056 RDF # 35 NB 1 2a Melons­ honeydew 11­ Uncooked 3 Cantaloupe ­ PDP 0. 0056 RDF # 37 NB 19 44 Melons­ persian 3 Cantaloupe ­ PDP 0. 0056 RDF #35 NB 1 3 2 Watermelon 11­ Uncooked 3 Watermelon ­ FDA 0. 0019 RDF #38 NB 13 15 Watermelon­ juice 3 Watermelon ­ FDA 0. 0019 RDF #38 PB 13 15 Wintermelon 14­ Boiled 3 Cantaloupe ­ PDP 0. 0056 RDF #35 NB 1 3 2 Casabas 11­ Uncooked 3 Cantaloupe ­ PDP 0. 0056 RDF #35 NB 1 3 2 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 25 Pumpkins 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 3 Winter Squash PDP 0. 006 RDF # 39 NB 31 56 33­ Canned: Baked 34­ Canned: Boiled 3 Winter Squash PDP 0. 006 RDF # 39 PB 31 56 Squash, winter (includes spaghetti squash) 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 3 Winter Squash ­ PDP 0. 006 RDF # 40 NB 11 27 Squash, summer 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 3 Summer Squash FDA 0. 016 RDF # 41 NB 11 27 34­ Canned: Boiled 42­ Frozen: Cooked 51­ Cured: NFS (smoked/ pickled/ 3 Summer Squash FDA 0. 016 RDF # 41 PB 11 27 Crop Group 10: Citrus Fruits Citrus citron 13­ Baked 14­ Boiled 10 Orange ­ PDP 0. 013 RDF #42 PB 1 3 2 Grapefruit peel 10 Orange ­ PDP 0. 013 RDF #42 PB 4 6 Grapefruit­ juice 11­ Uncooked 31­ Canned: NFS 10 Orange juice ­ PDP 0. 006 RDF #43 PB 4 6 Grapefruit­ juice­ concentrate 41­ Frozen: NFS 10 Orange juice ­ PDP 0. 006 RDF #43 PB 4 6 Grapefruit­ peeled fruit 11­ Uncooked 12­ Cooked: NFS 10 Orange ­ PDP Decomposited 0.013 RDF #45 NB 4 6 Grapefruit­ peeled fruit 31­ Canned: NFS 10 Orange ­ PDP 0. 006 RDF #42 PB 4 6 Kumquats 10 Orange ­ PDP 0. 013 RDF #42 PB 1 3 2 Lemons­ juice 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 41­ Frozen: NFS 42­ Frozen: Cooked 10 Orange juice ­ PDP 0. 006 RDF #44 PB 3 7 Lemons­ juice­ concentrate 12­ Cooked: NFS 13­ Baked 14­ Boiled 31­ Canned: NFS 34­ Canned: Boiled 41­ Frozen: NFS 10 Orange juice­ PDP 0. 006 RDF #44 PB 3 7 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 26 Lemons­ peel 11­ Uncooked 13­ Baked 14­ Boiled 31­ Canned: NFS 34­ Canned: Boiled 41­ Frozen: NFS 10 Orange ­ PDP 0. 013 RDF #42 PB 3 7 Lemons­ peeled fruit 11­ Uncooked 12­ Cooked: NFS 10 Orange ­ PDP Decomposited 0.013 RDF #45 NB 3 7 Lemons­ peeled fruit 31­ Canned: NFS 10 Orange ­ PDP 0. 013 RDF #42 PB 3 7 Limes­ juice 11­ Uncooked 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 41­ Frozen: NFS 10 Orange juice ­ PDP 0. 006 RDF #46 PB 1 3 2 Limes­ juice­ concentrate 12­ Cooked: NFS 41­ Frozen: NFS 10 Orange juice ­ PDP 0. 006 RDF #46 PB 1 3 2 Limes­ peel 13­ Baked 14­ Boiled 10 Orange ­ PDP 0. 013 RDF #42 PB 1 3 2 Limes­ peeled fruit 11­ Uncooked 10 Orange ­ PDP Decomposited 0.013 RDF #45 NB 1 3 2 Oranges­ juice 11­ Uncooked 12­ Cooked: NFS 31­ Canned: NFS 41­ Frozen: NFS 10 Orange juice­ PDP 0. 006 RDF #47 PB 3 5 Oranges­ juice­ concentrate 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 31­ Canned: NFS 41­ Frozen: NFS 42­ Frozen: Cooked 10 Orange juice ­ PDP 0. 006 RDF #47 PB 3 5 Oranges­ peel 11­ Uncooked 12­ Cooked: NFS 31­ Canned: NFS 41­ Frozen: NFS 10 Orange ­ PDP 0. 013 RDF #42 PB 3 5 Oranges­ peeled fruit 11­ Uncooked 12­ Cooked: NFS 10 Orange ­ PDP Decomposited 0.013 RDF #45 NB 3 5 Oranges­ peeled fruit 31­ Canned: NFS 10 Orange ­ PDP 0. 013 RDF #42 PB 3 5 Tangelos 10 Orange ­ PDP Decomposited 0.013 RDF #45 NB 1 3 2 Tangerine 11­ Uncooked 10 Orange ­ PDP Decomposited 0.013 RDF #45 NB 1 3 2 31­ Canned: NFS 41­ Frozen: NFS 10 Orange ­ PDP 0. 013 RDF #42 PB 1 3 2 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 27 Tangerines­ juice 11­ Uncooked 31­ Canned: NFS 41­ Frozen: NFS 10 Orange juice ­ PDP 0. 006 RDF #46 PB 1 3 2 Tangerines­ juiceconcentrate 10 Orange juice­ PDP 0. 006 RDF #46 PB 1 3 2 Crop Group 11: Pome Fruits Group Apples 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 12 Apple PDP Decomposited 0.03 RDF # 48 NB 23 31 18­ Dried 12 Apple PDP 0. 03 0. 009 B 23 31 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 42­ Frozen: Cooked 12 Apple PDP 0. 03 RDF #49 PB 23 31 Apples­ dried 13­ Baked 14­ Boiled 18­ Dried 42­ Frozen: Cooked 12 Apple PDP 0. 03 RDF #49 PB 23 31 Apples­ juice/ cider 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 31­ Canned: NFS 41­ Frozen: NFS 12 Apple juice PDP 0. 010 RDF #50 PB 23 31 Apples­ juice­ concentrate 12­ Cooked: NFS 13­ Baked 31­ Canned: NFS 41­ Frozen: NFS 12 Apple juice PDP 0. 010 RDF #50 PB 23 31 Pears 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 12 Pear PDP Decomposite 0.0098 RDF #51 NB 3 6 31­ Canned: NFS 12 Pear PDP 0. 0098 RDF #52 PB 3 6 Pears­ dried 13­ Baked 14­ Boiled 18­ Dried 12 Pear PDP 0. 0098 RDF #52 PB 3 6 Pears­ juice 11­ Uncooked 12­ Cooked: NFS 13­ Baked 31­ Canned: NFS 33­ Canned: Baked 41­ Frozen: NFS 42­ Frozen: Cooked 12 Pear PDP 0. 0098 RDF #52 PB 3 6 Quinces 12 Pear PDP 0. 0098 RDF #53 NB 1 3 2 Loquat 12 Pear PDP 0. 0098 RDF #53 NB 1 3 2 Crabapples 31­ Canned: NFS 12 Apple PDP 0. 033 RDF #54 PB 1 3 2 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 28 Crop Group 12: Stone Fruits Group Apricot juice 11­ Uncooked 12­ Cooked: NFS 31­ Canned: NFS 42­ Frozen: Cooked 10 Peaches PDP 0. 07 RDF # 55 PB 1 3 2 Apricots 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 10 Peaches PDP 0. 07 RDF # 56 NB 1 3 2 31­ Canned: NFS 34­ Canned: Boiled 10 Peaches PDP 0. 07 RDF # 55 PB 1 3 2 Apricots­ dried 13­ Baked 14­ Boiled 18­ Dried 10 Peaches PDP 0. 07 RDF # 55 PB 1 3 2 Cherries 11­ Uncooked 10 Cherries FDA 0. 127 RDF #57 PB 25 36 12­ Cooked: NFS 13­ Baked 14­ Boiled 31­ Canned: NFS 33­ Canned: Baked 41­ Frozen: NFS 10 Cherries FDA 0. 127 RDF #58 PB 12 24 Cherries­ dried 10 Cherries FDA 0. 127 RDF #57 PB 25 36 Cherries­ juice 13­ Baked 14­ Boiled 31­ Canned: NFS 41­ Frozen: NFS 10 Cherries FDA 0. 127 RDF #58 PB 12 24 Nectarines 11­ Uncooked 10 Peaches PDP 0. 07 RDF #59 NB 12 24 Peaches 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 10 Peaches PDP 0. 07 RDF #60 NB 15 18 31­ Canned: NFS 41­ Frozen: NFS 10 Peaches PDP 0. 07 RDF #61 PB 15 18 Peaches­ dried 14­ Boiled 18­ Dried 10 Peaches PDP 0. 07 RDF #61 PB 15 18 Peaches­ juice 11­ Uncooked 31­ Canned: NFS 10 Peaches PDP 0. 07 RDF #61 PB 15 18 Plums (damsons) 11­ Uncooked 12­ Cooked: NFS 10 Peaches PDP 0. 07 RDF # 96 NB 5 9 31­ Canned: NFS 42­ Frozen: Cooked 51­ Cured: NFS (smoked/ pickled/ 10 Peaches PDP 0. 07 RDF # 62 PB 5 9 Plums/ prune­ juice 11­ Uncooked 31­ Canned: NFS 10 Peaches PDP 0. 07 RDF # 62 PB 5 9 Plums­ prunes (dried) 13­ Baked 14­ Boiled 18­ Dried 31­ Canned: NFS 10 Peaches PDP 0. 07 RDF # 62 PB 5 9 Crop Group 13: Berries Group Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 29 Blackberries 11­ Uncooked 13­ Baked 14­ Boiled 31­ Canned: NFS 34­ Canned: Boiled 41­ Frozen: NFS 12 Raspberry FDA 0. 09 RDF # 63 PB 28 44 Blackberries­ juice 11­ Uncooked 31­ Canned: NFS 12 Raspberry FDA 0. 09 RDF #63 PB 28 44 Blueberries 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 41­ Frozen: NFS 3 Blueberry FDA 0. 09 RDF # 64 PB 22 45 Boysenberries 31­ Canned: NFS 34­ Canned: Boiled 41­ Frozen: NFS 12 Raspberry FDA 0. 09 RDF #65 PB 1 3 2 Currant 11­ Uncooked 3 Blueberry FDA 0. 09 RDF #66 PB 1 3 2 Dewberries Dewberries 12 Raspberry FDA 0. 09 RDF #65 PB 1 3 2 Elderberry Elderberries 3 Blueberry FDA 0. 09 RDF #66 PB 1 3 2 Gooseberry Gooseberries 3 Blueberry FDA 0. 09 RDF #66 PB 1 3 2 Huckleberry Huckleberries 3 Blueberry FDA 0. 09 RDF #66 PB 1 3 2 Loganberries Loganberries 12 Raspberry FDA 0. 09 RDF #65 PB 1 3 2 Raspberries 11­ Uncooked 13­ Baked 14­ Boiled 31­ Canned: NFS 34­ Canned: Boiled 41­ Frozen: NFS 12 Raspberry FDA 0. 09 RDF #67 PB 4 10 Youngberries 12 Raspberry FDA 0. 09 RDF #65 PB 1 3 2 Crop Group 14: Tree Nuts Almonds 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 18­ Dried 41­ Frozen: NFS 0.1 Almond FT 0.059 RDF #68 PB 2 4 Chestnuts 14­ Boiled 12­ Cooked: NFS 13­ Baked 0.1 Almond FT 0.059 RDF #69 PB 1 3 2 Filberts (hazelnuts) 11­ Uncooked 13­ Baked 14­ Boiled 0.1 Pecan FT 0.022 RDF #70 PB 4 12 Pecans 11­ Uncooked 13­ Baked 14­ Boiled 0.1 Pecan FT 0.022 RDF #71 PB 20 24 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 30 Walnuts 11­ Uncooked 12­ Cooked: NFS 13­ Baked 1.0 Walnut FT 0.27 RDF #72 PB 1 2 Walnut oil 1. 0 Walnut FT 0.27 0.0054 B 1 2 Crop Group 15: Cereal Grains Corn, fresh (including sweet) K + CWHR 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 0.1 Corn PDP 0. 0085 RDF # 73 NB 1 1 32­ Canned: Cooked 34­ Canned: Boiled 35­ Canned: Fried 42­ Frozen: Cooked 0.1 Corn PDP 0. 0085 RDF # 73 PB 1 1 Corn grain­ endosperm 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 41­ Frozen: NFS 42­ Frozen: Cooked 43­ Frozen: Baked 45­ Frozen: Fried 99­ Alcohol/ Fermented/ Distilled 0.02 Corn FT 0.01 0.0001 B 11 Corn grain­ oil 98­ Refined 0.02 Corn FT 0.01 0.0001 B 11 Corn grain­ bran 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 0.02 Corn FT 0.01 0.0001 B 11 Corn grain/ sugar­ molasses 12­ Cooked: NFS 41­ Frozen: NFS 0.02 Corn FT 0.01 0.0001 B 11 Corn grain/ sugar/ hfcs 98­ Refined 0.02 Corn FT 0.01 0.0001 B 11 Corn, popcorn 12­ Cooked: NFS 13­ Baked 0.02 Corn FT 0.01 0.0001 B 11 Millet, proso, grain 13­ Baked 1 Wheat PDP 0. 0015 0.000015 B 1 1 Rice­ milled (white) 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 32­ Canned: Cooked 34­ Canned: Boiled 42­ Frozen: Cooked 99­ Alcohol/ Fermented/ Distilled 15 Rice FT 7.4 0. 074 B 1 1 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 31 Rice­ bran 11­ Uncooked 12­ Cooked: NFS 13­ Baked 15­ Fried 31­ Canned: NFS 15 Rice FT 7.4 0. 074 B 1 1 Rice­ rough (brown) 12­ Cooked: NFS 13­ Baked 14­ Boiled 99­ Alcohol/ Fermented/ Distilled 15 Rice FT 7.4 0. 074 B 1 1 Sorghum, grain 14­ Boiled 10 Wheat PDP 0. 0015 0.000015 B 1 1 Wheat­ flour 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 31­ Canned: NFS 32­ Canned: Cooked 33­ Canned: Baked 34­ Canned: Boiled 41­ Frozen: NFS 42­ Frozen: Cooked 43­ Frozen: Baked 45­ Frozen: Fried 52­ Cured: Cooked( smokd/ pickld/ 1 Wheat PDP 0. 0015 0.000015 B 1 1 Wheat­ bran 11­ Uncooked 12­ Cooked: NFS 13­ Baked 1 Wheat PDP 0. 0015 0.000015 B 1 1 Wheat­ germ 12­ Cooked: NFS 13­ Baked 14­ Boiled 1 Wheat PDP 0. 0015 0.000015 B 1 1 Wheat­ germ oil 13­ Baked 1 Wheat PDP 0. 0015 0.000015 B 1 1 Wheat­ rough 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 1 Wheat PDP 0. 0015 0.000015 B 1 1 Crop Group 19: Herbs ans Spices Dill (fresh) 13­ Baked 14­ Boiled 0.2 Tolerance 0.2 0. 004 B 1 3 2 Miscellaneous Commodities Asparagus 11­ Uncooked 14­ Boiled 15 Asparagus FDA 0. 0032 RDF # 74 NB 43 87 32­ Canned: Cooked 42­ Frozen: Cooked 15 Asparagus FDA 0. 0032 RDF # 74 PB 43 87 Bananas Imports only 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried TBD Bananas ­ PDP 0. 01 RDF # 75 NB 100 100 31­ Canned: NFS 32­ Canned: Cooked TBD Bananas ­ PDP 0. 01 RDF # 75 PB 100 100 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 32 Bananas­ dried 13­ Baked 15­ Fried 18­ Dried 32­ Canned: Cooked TBD Bananas ­ PDP 0. 01 RDF # 75 PB 100 100 Bananas­ juice 11­ Uncooked 31­ Canned: NFS TBD Bananas ­ PDP 0. 01 RDF # 75 PB 100 100 Plantains­ dried TBD Bananas ­ PDP 0. 01 RDF # 75 PB 100 100 Plantains­ green 15­ Fried TBD Bananas ­ PDP 0. 01 RDF # 75 NB 100 100 Plantains­ ripe 11­ Uncooked 14­ Boiled 15­ Fried TBD Bananas ­ PDP 0. 01 RDF # 75 NB 100 100 Cranberries 11­ Uncooked 12­ Cooked: NFS 13­ Baked 18­ Dried 31­ Canned: NFS 42­ Frozen: Cooked 3 Cranberries FDA 0.001 RDF # 76 PB 39 84 Cranberries­ juice 11­ Uncooked 12­ Cooked: NFS 31­ Canned: NFS 3 Cranberries FDA 0. 001 RDF # 76 PB 39 84 Cranberries­ concentrate 31 Canned: NFS 3 Cranberries FDA 0. 001 RDF #76 PB 39 84 Flax, seed Refined 0. 5 Flax seed FT 0.01 0.0001 B 1 1 Grapes 11­ Uncooked 12­ Cooked: NFS 31­ Canned: NFS 41­ Frozen: NFS 10 Grapes PDP 0. 016 RDF # 77 PB 8 12 Grapes­ juice 11­ Uncooked 12­ Cooked: NFS 14­ Boiled 31­ Canned: NFS 34­ Canned: Boiled 41­ Frozen: NFS 10 Grapes juice PDP 0. 010 RDF # 78 PB 8 12 Grapes­ juice­ concentrate 12­ Cooked: NFS 13­ Baked 14­ Boiled 31­ Canned: NFS 41­ Frozen: NFS 10 Grapes juice PDP 0. 010 RDF # 78 PB 8 12 Grapes­ leaves 14­ Boiled 10 Grapes PDP 0. 016 RDF # 77 PB 8 12 Grapes­ raisins 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 18­ Dried 42­ Frozen: Cooked 10 Grapes PDP 0. 016 RDF # 77 PB 8 12 Grapes­ wine and sherry 99­ Alcohol/ Fermented/ Distilled 10 Grapes PDP 0. 016 RDF # 77 PB 8 12 Okra 12­ Cooked: NFS 14­ Boiled 15­ Fried 4 Okra FT 1.0 RDF # 79 NB 32 94 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max 33 32­ Canned: Cooked 42­ Frozen: Cooked 44­ Frozen: Boiled 4 Oka FT 1.0 RDF #79 PB 32 94 Olives 60­ Canned: Cured 10 Olive FT 3.85 RDF # 80 PB 1 3 2 Olive oil 98­ Refined 10 Olive FT 3.85 0.077 B 1 3 2 Peanuts­ butter 13­ Baked 14­ Boiled 0.05 Peanuts FT 0.01 0.0006 B 3 6 Peanuts­ hulled 12­ Cooked: NFS 13­ Baked 14­ Boiled 15­ Fried 41­ Frozen: NFS 0.05 Peanuts FT 0.01 0.0006 B 3 6 Peanuts­ oil 98­ Refined 0.05 Peanuts FT 0.01 0.0006 B 3 6 Pineapples­ dried Imports only 18­ Dried TBD Pineapple FDA 0. 053 RDF # 82 RDF # 95 RDF #97 PB 1 3 2 Pineapples­ juice Imports only 11­ Uncooked 12­ Cooked: NFS 31­ Canned: NFS 42­ Frozen: Cooked TBD Pineapple FDA 0. 053 RDF # 82 RDF # 95 RDF #97 PB 1 3 2 Pineapples­ juice­ concentrate Imports only 12­ Cooked: NFS 31­ Canned: NFS 33­ Canned: Baked 41­ Frozen: NFS TBD Pineapple FDA 0. 053 RDF # 82 RDF # 95 RDF #97 PB 1 3 2 Pineapples­ peeled fruit Imports only 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled TBD Pineapple FDA 0. 053 RDF # 81 RDF # 95 RDF #97 NB 1 3 2 Pineapples­ peeled fruit Imports only 31­ Canned: NFS 33­ Canned: Baked 41­ Frozen: NFS TBD Pineapple FDA 0. 053 RDF # 82 RDF # 95 RDF #97 PB 1 3 2 Pistachio nuts 11­ Uncooked 12­ Cooked: NFS 13­ Baked 0.1 Pistachio FT 0.03 RDF # 83 PB 17 38 Prickly pear cactus, pads Cactus pads (nopal) 12 not in DEEM Prickly pear cactus, fruit 5 not in DEEM Strawberries 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 31­ Canned: NFS 34­ Canned: Boiled 41­ Frozen: NFS 4 Strawberry FDA 0. 0638 RDF # 84 PB 16 24 Strawberries­ juice 11­ Uncooked 12­ Cooked: NFS 13­ Baked 14­ Boiled 31­ Canned: NFS 4 Strawberry FDA 0. 0638 RDF # 84 PB 16 24 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files Commodity DEEM Food Form Reassessed Tolerance, ppm 1 Data Source 2 Anticipated Residue (ppm) or RDF # Blended Classification % CT Chronic Acute Avg Max Sunflower­ oil 98­ Refined 0.5 Sunflower ­FT 0. 042 0.0004 B 1 1 Sunflower­ seeds 11­ Uncooked 13­ Baked 0.5 Sunflower ­ FT 0.042 RDF # 85 PB 1 1 Fish Oysters 2 Tolerance ­­­ ­­­­ ­­­­­ 1. See Carbaryl Product and Residue Chemistry Chapters for the Reregistration Eligibility Decision. DP Barcode: D238151. 2. PDP = USDA Pesticide Data Program; FDA = FDA Surveillance Program Data; FT = field trial data; P = processing. 3. Reported in the QUA as "Other Crops" Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 35 Table 1b: Summary of Market Basket Survey Data Commodity DEEM Food Form Market Basket Survey Commodity Used RDF # %CT Likely Max Citrus Fruit Citrus citron All food forms Orange RDF #100 2 Grapefruit All food forms except juice RDF #101 6 Kumquats All food forms RDF #100 2 Lemons All food forms except juice RDF #103 7 Limes All food forms except juice RDF #100 2 Oranges All food forms except juice RDF #45 5 Tangelos All food forms RDF #100 2 Tangerine All food forms except juice RDF #100 2 Pome Fruit Apples All food forms except juice and apples, dried Apple RDF # 48 31 18­ Dried RDF # 108 31 Pear All food forms RDF #105 6 Quinces All food forms RDF #107 2 Loquat All food forms RDF #107 2 Crabapples All food forms RDF #107 2 Stone Fruits Apricot All food forms Peach RDF # 98 2 Nectarines All food forms RDF #104 24 Peaches All food forms RDF #60 18 Plums (damsons) All food forms RDF # 106 9 Brassica Vegetables Broccoli All food forms Broccoli RDF #17 9 Cauliflower All food forms RDF # 99 4 Leafy Vegetables Lettuce ­ head 11­ Uncooked Lettuce RDF #14 8 Lettuce ­ leaf 11­ Uncooked RDF #102 2 Lettuce (unspecified) 31­ Canned: NFS RDF #102 8 Fruiting Vegetables Tomato All food forms Tomato RDF # 33 27 Miscellaneous Crops Bananas All food forms Bananas RDF # 75 100 Plantains All food forms RDF # 75 100 Grapes All food forms except juice Grapes RDF # 77 12 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 36 Table 2. Residue Distribution Files Garden Beets (roots) Field Trial data 24 samples RDF #1 Garden Beets (roots) 27% CT Totalz= 65 Totalnz= 24 0.01 0.01 0.02 0.03 0.07 0.07 0.01 0.03 0.03 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.05 0.05 0.06 0.01 0.02 0.03 Sugarbeet (roots) Blended Field trial data Information from 12/ 2/ 93 AR memo (S. Hummel, D193129, 12/ 3/ 93) 4% CT Average Residue = 0.01 ppm Acute AR = 0.0004 Carrots ­ PDP 1994 ­ 1996 1888 samples/ 0 detects 1/ 2 LOD = 0.0116 ppm RDF #2 Carrots PDP 1994­ 96 6% CT Totalz= 94 Totalnz= 6 0.0116 0.0116 0.0116 0.0116 0.0116 0.0116 Chicory, Horseradish, Parsnip, Salsify (Carrots ­ PDP) 1994 ­ 1996 1888 samples/ 0 detects 1/ 2 LOD = 0.0116 ppm RDF #3 Chic, Horse, Parsnip, Salsify (Carrots PDP) 1994­ 96 2% CT Totalz= 98 Totalnz= 2 0.0116 0.0116 Chronic AR = 0.024 ppm Chronic AR = 0.01 ppm Chronic AR = 0.0116 ppm Chronic AR = 0.0116 ppm Potatoes ­ PDP 1994­ 1995 1401 samples/ 0 detects 1/ 2 LOD = 0.0119 ppm RDF #4 Potatoes PDP 1994­ 95 3% CT Totalz= 97 Totalnz= 3 0.0119 0.0119 0.0119 For dried potatoes (blended) ­ acute AR = 0.00036 Radishes (Garden Beets (roots) Field Trial data 24 samples RDF #5 Radishes (Garden Beets (roots)) 2% CT Totalz= 1176 Totalnz= 24 0.01 0.01 0.02 0.03 0.07 0.07 0.01 0.03 0.03 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.05 0.05 0.06 0.01 0.02 0.03 Turnips translate to rutabagas Field Trial Data 27 samples RDF #6 Turnips (roots) 2% CT Totalz= 1323 Totalnz= 27 0.01 0.01 0.02 0.07 0.11 0.13 0.01 0.02 0.03 0.72 0.93 1.01 0.01 0.01 0.02 0.02 0.02 0.04 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Sweet Potato ­ PDP 1559 samples/ 3 detects 1996­ 1998 1/ 2 LOD = 0.011 ppm RDF #7 Sweet potatoes ­ PDP ­ 96­ 98 41 % CT Totalz = 1512 Totalnz = 3 44, 0.0059 0.67 0.01 0.29 Chronic AR = 0.0119 ppm Chronic AR = 0.024 ppm Chronic AR =0.121 ppm Chronic AR = 0.0065 ppm Garden Beet Tops Field Trial Data 24 Samples RDF #8 Garden beet tops 27% CT Totalz= 63 Totalnz= 24 3.96 4.27 4.49 14.48 18.28 21.18 8.45 8.46 9.84 25.47 28.36 42.23 3.19 3.9 3. 91 2.41 2.71 4.65 1.63 1.77 1.9 8.64 9.2 10 Radish Tops (Garden beet tops) Field trial data. 24 samples RDF #9 Radish tops (Garden beet tops ­ FT) 2% CT Totalz= 1176 Totalnz= 24 3.96 4.27 4.49 14.48 18.28 21.18 8.45 8.46 9.84 25.47 28.36 42.23 3.19 3.9 3. 91 2. 41 2.71 4.65 1.63 1.77 1.9 8. 64 9. 2 10 Turnip tops Field Trial data 33 samples RDF #10 Turnip Tops 2% CT Totalz= 1617 Totalnz= 33 6.84 8.19 10.33 51.19 67.8 70.24 5.4 5. 41 5.88 6.91 9.04 9.73 49.12 49.24 50.27 1.07 1.09 1.49 10.97 11.35 14.5 7.69 9.25 11.71 1.56 1.83 1.84 5.28 5.76 6.83 2.07 2.13 3.68 Celery­ PDP 1994 176 samples/ 0 detects 1/ 2 LOD = 0.0152 ppm RDF #11 Celery ­ PDP 1994 6% CT Totalz= 94 Totalnz= 6 0.0152 0.0152 0.0152 0.0152 0.0152 0.0152 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 37 Chronic AR = 10.14 ppm Chronic AR = 10.14 ppm Chronic AR = 15.3 ppm Chronic AR = 0.0152 ppm Spinach ­ PDP data Translated to Dandelions and Parsley 1995­ 1997 1639 samples/ 10 detects 1/ 2 LOD = 0.006 ppm RDF # 12 Spinach PDP 2% CT Totalz= 1767 Totalnz= 10 25, 0.008 0.01 0.01 0.01 0.01 0.068 0.11 0.02 0.02 0.077 0.039 Canned Spinach ­ PDP 1997­ 1998 863 samples/ no detects 1/ 2 LOD = 0.006 ppm RDF #13 Canned Spinach 2% CT Totalz= 98 Totalnz= 2 0.006 0.006 Head Lettuce ­ PDP 1994 691 samples/ no detects 1/ 2 LOD = 0.0169 ppm RDF #14 Lettuce ­ Head 8% CT = Totalz= 92 Totalnz= 8 0.0169 0.0169 0.0169 0.0169 0.0169 0.0169 0.0169 0.0169 Leaf Lettuce ­ FDA translate to Endive 1992­ 1998 241 samples/ no detects 1/ 2 LOD = 0.001 ppm RDF #15 Leaf Lettuce 2% CT Totalz= 98 Totalnz= 2 0.001 0.001 Chronic AR = 0.0082 ppm Chronic AR = 0.006 ppm Chronic AR = 0.0169 ppm Chronic AR = 0.001 ppm Rhubarb/ Swiss Chard (Celery­ PDP 1994) 176 samples/ 0 detects 1/ 2 LOD = 0.0152 ppm RDF #16 Rhubarb (Celery ­ PDP 1994) 2% CT Totalz= 98 Totalnz= 2 0.0152 0.0152 Broccoli ­ PDP 1994 679 samples/ 1 detect 1/ 2 LOD = 0.0125 ppm RDF # 17 Broccoli ­ PDP 1994 9% CT Totalz= 618 Totalnz= 1 60, 0.013 0.007 Brussels sprouts (Cabbage ­ FDA 1992 ­ 1998) 246 samples/ 0 detects 1/ 2 LOD = 0.001 ppm RDF # 18 Brussels sprouts (Cabbage ­ FDA 92­ 98) 67% CT Totalz = 33 TotalFreq = 1 67, 0.001 Cabbage ­ FDA 1992 ­ 1998 246 samples/ 0 detects 1/ 2 LOD = 0.001 ppm RDF # 19 Cabbage ­ FDA 92­ 98 4% CT Totalz= 96 TotalFreq = 1 4, 0.001 Chronic AR = 0.015 ppm Chronic AR = 0.013 ppm Chronic AR = 0.001 ppm Chronic AR = 0.001 ppm Cauliflower (Broccoli ­ PDP 1994) 679 samples/ 1 detect 1/ 2 LOD = 0.0125 ppm RDF # 20 Cauliflower (Broccoli ­ PDP 1994) 4% CT Totalz= 652 Totalnz= 1 26, 0.013 0.007 Collards Mustards FT data 24 samples RDF # 21 Collards (Mustards FT) 10% CT Totalz= 216 Totalnz= 24 0.65 0.72 0.99 1.8 2.31 2.68 3.47 3.63 3.8 2.57 2.79 2.99 0.3 0. 42 0. 95 1.83 3.38 4.71 4.93 7.76 8.29 0.99 1.61 3.23 Mustards, Rape, Kale Mustards FT data 24 samples RDF # 22 Mustards ­ FT 2% CT Totalz= 1176 Totalnz= 24 0.65 0.72 0.99 1.8 2.31 2.68 3.47 3.63 3.8 2.57 2.79 2.99 0.3 0. 42 0. 95 1.83 3.38 4.71 4.93 7.76 8.29 0.99 1.61 3.23 Kohlrabi (Cabbage ­ FDA 1992 ­ 1998) 246 samples/ 0 detects 1/ 2 LOD = 0.001 ppm RDF # 23 Kohrabi (Cabbage ­ FDA 92­ 98) 2% CT Totalz= 98 TotalFreq = 1 2, 0.001 Chronic AR = 0.013 ppm Chronic AR = 2.78 ppm Chronic AR = 2.78 ppm Chronic AR = 0.001 ppm Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 38 Dried Beans ­ Blended FT data 3% CT 1/ 2 LOD = 0.01 ppm Residues = 0.13 0.14 0.15 0.01 0.13 0.13 0.15 0.01 0.05 0.1 0. 16 0.01 0.01 0.01 0.01 0.07 0.01 0.01 0.01 0.06 0.05 Average = 0.067 ppm Acute AR = 0.002 Fresh Succulent Beans PDP 1994­ 1995 1177 samples/ 44 detects 21% CT ­ 4% detects 1/ 2 LOD = 0.01 ppm RDF # 24 Fresh Beans 21% CT Totalz= 930 Totalnz= 44 203, 0.0138 1.6 0. 067 0.45 0.9 0.096 0.064 0.11 0.23 0.37 0.011 0.26 0.086 0.046 0.15 0.06 0.06 0.011 0.04 0.007 0.15 0.007 0.1 0. 18 0. 93 0.15 0.12 0.26 0.082 0.2 0.57 0.25 0.025 0.037 0.31 0.29 0.29 0.13 0.15 1.4 0. 85 0.21 0.02 0.02 0.15 Processed Succulent Beans ­ PDP 1996­ 1998 1588 samples/ 161 detects 16% CT ­ 10 % detects 1/ 2 LOD = 0.006 ppm RDF # 25 Processed Beans 16% CT Totalz= 1334 Totalnz= 161 242, 0.006 See Appendix L for residues Lima Beans (Processed Succulent Beans PDP 1996­ 1998) 1588 samples/ 161 detects 16% CT ­ 10 % detects 1/ 2 LOD = 0.006 ppm RDF # 26 Lima Beans 30% CT Totalz= 1112 Totalnz= 161 315, 0.006 See Appendix L for residues Chronic AR = 0.067 ppm Chronic AR = 0.023 ppm Chronic AR = 0.012 ppm Chronic AR = 0.012 ppm Peas ­ FDA 1992­ 1998 289 samples/ 8 detects 1/ 2 LOD = 0.001 ppm RDF #27 Peas ­ Fresh ­ FDA 7% CT Totalz= 269 Totalnz= 8 12, 0.001 0.041 0.360 1.160 0.005 0.010 0.005 0.005 0.060 Processed Peas ­ PDP 1994­ 1996 1458 samples/ 19 detects 1/ 2 LOD = 0.011 ppm RDF #28 Processed Peas 5% CT Totalz= 1385 Totalnz= 19 54, 0.011 0.13 0.43 0.086 0.12 0.06 0.01 0.028 0.042 0.06 0.14 0.067 0.0802 0.043 0.37 0.12 0.13 0.05 0.11 0.12 Dried Peas (Blended) FT data 9% CT 1/ 2 LOD = 0.01 ppm Residues = 0.046 0.048 0.049 0.205 0.212 0.241 0.53 0.555 0.593 0.059 0.061 0.062 0.064 0.07 0.116 0.16 0.179 0.186 0.01 0.01 0.023 0.01 0.01 0.01 Average = 0.146 Acute AR = 0.013 Soybean (Blended) PDP data 749 samples/ 0 detects 1% CT 1/ 2 LOD = 0.0015 ppm Acute AR = 0.000015 Chronic AR = 0.13 ppm Chronic AR =0.013 ppm Chronic AR =0.146 ppm Chronic AR = 0.0015 ppm Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 39 Eggplant ­ FDA 1993­ 98 112 samples/ 6 detects 1/ 2 LOD = 0.001 ppm 21% CT RDF # 29 Eggplant ­ FDA 21% CT Totalz= 89 Totalnz= 6 17, 0.001 0.01 0.046 0.12 0.061 0.16 0.07 Hot Pepper ­ FDA 1992­ 1998 347 samples/ 66 detects 19% detects ­ 2% CT 1/ 2 LOD = 0.001 ppm RDF # 30 Non­ bell peppers 19% detects Totalz= 281 Totalnz= 66 0.048 0.005 0.844 0.28 0.076 0.005 1 0. 9 0.46 0.03 0.016 0.35 1.6 0. 728 0.12 0.16 0.005 0.4 0. 04 0. 03 2.1 0. 31 1. 58 0. 17 0.22 0.9 2. 4 3.3 0.09 0.3 1. 7 0.1 0.5 1.7 1. 9 0.015 0.26 0.24 1.54 0.21 0.38 0.05 0.16 0.23 0.02 4 0. 43 0. 02 0.12 0.86 0.7 0. 8 0.05 0.25 0.15 0.3 0.2 0.1 0. 05 0. 9 0.2 0. 1 0.1 0. 2 0.02 0.06 Sweet Pepper ­ FDA 1992­ 1998 430 samples/ 28 detects 1/ 2 LOD = 0.001 ppm RDF # 31 Sweet pepper FDA all 30% CT Totalz= 301 Totalnz= 28 101, 0.001 0.300 0.030 0.005 0.170 0.370 0.020 0.600 0.490 0.030 0.175 0.5 0.500 0.800 0.380 0.205 0.100 0.340 0.400 0.090 1.000 0.050 0.120 0.300 0.070 0.050 0.400 0.010 0.100 ProcessedTomatoes ­ PDP 1996­ 1998 1613 samples/ 4 detects (0.2% detects) 1/ 2 LOD = 0.0043 ppm RDF #32 Tomatoes ­ PDP 27 %CT ­ 0.2% detects Totalz= 1177 Totalnz= 4 432, 0.0043 0.008 0.004 0.017 0.007 Chronic AR = 0.005 ppm Chronic AR = 0.108 ppm Chronic AR =0.02 ppm Chronic AR = 0.0044 ppm Fresh Tomatoes ­ PDP 1996­ 1998 1613 samples/ 4 detects (0.2% detects) 1/ 2 LOD = 0.0043 ppm RDF #33 Tomatoes ­ PDP 11% CT ­ 0.2% detects Totalz= 1436 Totalnz= 4 173, 0.0043 0.008 0.004 0.017 0.007 Cucumber ­ FDA 1992­ 1998 420 samples/ 13 detects 1/ 2 LOD = 0.001 ppm RDF # 34 Cucumber ­FDA 32% CT ­ 3% detects Totalz= 286 Totalnz= 13 121, 0.001 0.005 0.005 0.005 0.230 0.182 0.121 0.005 0.100 0.070 0.190 0.018 0.034 0.010 Melons (Cantaloupe ­ PDP 1998) 408 samples/ 2 detects (0.5% detects) 1/ 2 LOD = 0.005 ppm RDF # 35 Cantaloupe ­ PDP 2% CT ­ 0.5% detects Totalz= 400 Totalnz= 2 6, 0.005 0.01 0.01 Cantaloupe ­ PDP 1998 408 samples/ 2 detects (0.5% detects) 1/ 2 LOD = 0.005 ppm RDF # 36 Cantaloupe ­ PDP 9% CT ­ 0.5% detects Totalz= 364 Totalnz= 2 34, 0.005 0.01 0.01 Chronic AR = 0.0044 ppm Chronic AR = 0.0033 ppm Chronic AR = 0.0056 ppm Chronic AR = 0.0056 ppm Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 40 Honey dew (Cantaloupe ­ PDP) 1998 408 samples/ 2 detects (0.5% detects) 1/ 2 LOD = 0.005 ppm RDF # 37 Cantaloupe ­ PDP 44% CT ­ 0.5% detects Totalz= 228 Totalnz= 2 178, 0.005 0.01 0.01 Watermelon ­ FDA 1992­ 1998 330 samples/ 4 detects 1/ 2 LOD = 0.001 ppm RDF # 38 Watermelon ­ FDA 15% CT ­ 1% detects Totalz= 281 Totalnz= 4 56, 0.001 0.06 0.1 0.04 0.094 Pumpkin (Winter Squash ­ PDP 1997 ­98) 970 samples/ 1 detect 1/ 2 LOD = 0.005 ppm RDF # 39 Pumpkin (Winter Squash ­ PDP) 56 % CT ­ 0.1% detects Totalz= 426 Totalnz= 1 543, 0.006 0.013 Winter Squash ­ PDP 1997­ 1998 970 samples/ 1 detect 1/ 2 LOD = 0.005 ppm RDF #40 Winter Squash ­ PDP 27 % CT ­ 0.1% detects Totalz= 708 Totalnz= 1 261, 0.006 0.013 Chronic AR = 0.0056 ppm Chronic AR = 0.0019 ppm Chronic AR = 0.006 ppm Chronic AR = 0.006 ppm Summer Squash ­ FDA 1992­ 1998 406 samples/ 10 detect 1/ 2 LOD ­ 0.001 ppm 27% CT RDF# 41 Summer Squash ­ FDA 27% CT ­ 2% detect Totalz= 296 Totalnz= 10 100, 0.001 0.2 0.37 0.005 0.020 0.15 0.16 0.080 0.059 0.460 4.6 Citrus citron, Lime, Tangelos, Tangerine, Grapefruit, and orange ( partially blended food forms) (Orange ­ PDP 1994­ 1996) 1892 samples/ 184 detects 1/ 2 LOD = 0.009 ppm RDF #42 Citrus ­ PDP 10% detects Totalz= 1656 Totalnz= 184 52, 0.009 see Appendix A for residue values Grapefruit juice (Orange juice PDP data 1997­ 1998) 1392 samples/ 30 detects 2% detects ­ 6% CT 1/ 2 LOD = 0.006 ppm RDF #43 Grapefruit juice (Orange juice PDP) 2% detects ­ 6% CT Totalz= 1308 Totalnz= 30 54, 0.006 21, 0.01 7, 0.013 0.031 0.017 Lemon juice (Orange juice PDP data 1997­ 1998) 1392 samples/ 30 detects 2% detects ­ 7% CT 1/ 2 LOD = 0.006 ppm RDF #44 Lemon juice (Orange juice PDP) 2% detects ­ 7% CT Totalz= 1295 Totalnz= 30 67, 0.006 21, 0.01 7, 0.013 0.031 0.017 Chronic AR = 0.016 ppm Chronic AR = 0.013 ppm Chronic AR = 0.006 ppm Chronic AR = 0.006 ppm Lime, Tangelos, Tangerine, Grapefruit, lemon, and orange (not blended food forms ) (Orange ­ PDP 1994­ 1996) 1892 samples/ 184 detects Residues decomp. (n= 12) Decomposited residues were 0.000043 to 1.68 ppm 1/ 2 LOD = 0.009 ppm RDF #45 Orange ­PDP­ decomposited 10% detects Totalz= 9000 Totalnz= 1000 see Appendix B for residue values Lime juice, tangerine juice (Orange juice PDP data 1997­ 1998) 1392 samples/ 30 detects 2% detects ­ 2% CT 1/ 2 LOD = 0.006 ppm RDF #46 Lime juice (Orange juice PDP) 2% detects ­ 2% CT Totalz= 1362 Totalnz= 30 21, 0.01 7, 0.013 0.031 0.017 Orange juice PDP data 1997­ 1998) 1392 samples/ 30 detects 2% detects ­ 5% CT 1/ 2 LOD = 0.006 ppm RDF #47 Orange juice PDP 2% detects ­ 5% CT Totalz= 1322 Totalnz= 30 40, 0.006 21, 0.01 7, 0.013 0.031 0.017 Apple ­Non­ blended ­ PDP 1994­ 1996 1909 samples/ 285 detects residues decomposited (n = 15) Decomposited residues range from 0.00008 ­ 7.35 ppm 15% detects ­ 31% CT 1/ 2 LOD = 0.013 ppm RDF #48 Apples ­ PDP decomp 31% CT ­ 15% detects Totalz= 4600 Totalnz= 1000 1067, 0.013 (1/ 2 LOD) see Appendix C for residue values Chronic AR = 0.013 ppm Chronic AR = 0.006 ppm Chronic AR =0.006 ppm Chronic AR = 0.03 ppm Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 41 Apples, Dried (Blended) PDP 1994­ 96 1909 samples/ 285 detects 31% CT 1/ 2 LOD = 0.01 ppm see Appendix D for residue values Average = 0.03 Acute AR = 0.009 Apple ­ Partially blended ­ PDP data 1994­ 1996 1909 samples/ 285 detects 15% detects ­ 31% CT 1/ 2 LOD = 0.013 ppm RDF #49 Apples ­ PDP 31% CT ­ 15% detects Totalz= 1317 Totalnz= 285 see Appendix D for residue values Apple Juice PDP 1996­ 1998 1554 samples/ 454 detects 29% detects ­ 31% CT 1/ 2 LOD = 0.006 ppm RDF # 50 Apple juice ­ PDP 31% CT ­ 15% detects Totalz= 1072 Totalnz= 454 28, 0.006 see Appendix E for residue values Pear PDP decomposition 1997­ 1998 1420 samples/ 60 detects 4% detects ­ 6% CT 1/ 2 LOD = 0.0065 ppm n= 13 Decomp. values were 0.000026 to 14.33 RDF # 51 Pear ­ PDP Totalz= 23500 Totalnz= 1000 500, 0.0065 see App. F for residue values Chronic AR = 0.03 ppm Chronic AR = 0.03 ppm Chronic AR = 0.01 ppm Chronic AR = 0.0098 ppm Partially blended Pear ­PDP 1997­ 1998 1420 samples/ 60 detects 4% detects ­ 6% CT 1/ 2 LOD = 0.0065 ppm RDF # 52 Pear ­ PDP Totalz= 1335 Totalnz= 60 25, 0.0065 0.24 0.007 0.058 0.12 0.007 0.007 0.017 0.007 0.007 0.007 0.3 0.007 0.007 0.14 0.013 0.042 0.01 0.017 0.05 0.036 0.007 0.01 0.1 0.013 0.007 0.01 0.053 0.007 0.007 0.007 0.007 0.061 0.81 0.01 0.11 0.035 0.07 0.076 0.042 0.013 0.007 0.007 0.052 0.45 0.013 0.013 0.042 0.41 0.49 0.12 0.013 0.01 0.19 0.14 0.14 0.013 0.033 0.01 0.01 0.089 Quince (Pear PDP) decomposition 1997­ 1998 1420 samples/ 60 detects 4% detects ­ 2% CT 1/ 2 LOD = 0.0065 ppm n= 13 Decomp. values were 0.000026 to 14.33 RDF # 53 Quince ­ PDP Totalz= 73500 Totalnz= 1000 500, 0.0065 see App. F for residue values Crabapple ­ Apple PDP data 1994­ 1996 1909 samples/ 285 detects 15% detects ­ 2% CT 1/ 2 LOD = 0.013 ppm RDF #54 Crabapple (Apple PDP) 2% CT ­ 15% detects Totalz= 28910 Totalnz= 285 305, 0.013 see Appendix D for residue values Apricot (Peach PDP 1994­ 1996) 1088 samples/ 168 detects 2% CT 1/ 2 LOD =0.01 ppm RDF #55 Apricot ­ (Peach PDP) 2 %CT Totalz= 9604 Totalnz= 168 28, 0.01 See Appendix G for residue values Chronic AR = 0.0098 ppm Chronic AR = 0.0098 ppm Chronic AR = 0.033 ppm Chronic AR = 0.07 ppm Apricot (Peach PDP 1994­ 1996) 1088 samples/ 168 detects 2% CT 1/ 2 LOD =0.01 ppm Residues decomp. ranged from 0.000119 ­ 46.3 RDF #56 Apricot ­ (Peach PDP) 2 %CT Totalz= 58800 Totalnz= 1000 200, 0.01 See Appendix H for residue values Sweet Cherries­ FDA 1992­ 98 281 samples/ 89 detects 36% CT 1/ 2 LOD = 0.001 ppm RDF # 57 Sweet Cherries 36% CT Totalz= 180 Totalnz= 89 12, 0.001 see Appendix M for residue values Tart Cherries ­ FDA 1992­ 98 281 samples/ 89 detects 24% CT ­ 32% detects 1/ 2 LOD = 0.001 ppm RDF # 58 Tart Cherries 32% detects Totalz= 192 Totalnz= 89 see Appendix M for residue values Nectarines (Peaches PDP 1994 ­1996) 1088 samples/ 168 detects 24% CT ­ 15% detected Residues decomp. ranged from 0.000119 ­ 46.3 ppm RDF # 59 Peaches ­ PDP ­ decomp 24% CT ­ 15% detected Totalz= 5067 Totalnz= 1000 600, 0.001 see Appendix H for residue values Chronic AR = 0.07 ppm Chronic AR = 0.127 ppm Chronic AR = 0.127 ppm Chronic AR = 0.07 ppm Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 42 Peaches (not blended) PDP Single Serving 2000 1088 samples/ 168 detects 18% CT ­ 15% detected Residues decomp. ranged from 0.000119 ­ 46.3 RDF # 60 Peaches ­ PDP single serving 18% CT ­ 15% detected Totalz= 438 Totalnz= 79 17, 0.003 see Appendix H for residue values Peaches (partially blended) PDP 1994 ­1996 1088 samples/ 168 detects 18% CT ­ 15% detected RDF # 61 Peaches ­ PDP 18% CT ­ 15% detected Totalz= 892 Totalnz= 168 28, 0.001 see Appendix G for residue values Plums FDA FDA 1992­ 98 51 samples/ 2 detects 4% detects ­ 9 % CT 1/ 2 LOD = 0.001 ppm RDF # 62 Plums ­ FDA 9% CT Totalz= 46 Totalnz= 2 3, 0.001 0.002 0.002 Blackberries (Raspberry FDA 1992­ 98) 247 samples/ 51 detects 21 % Detects ­ 44 % CT 1/ 2 LOD =­ 0.001 ppm RDF # 63 Blackberry (Raspberry FDA) 21% CT Totalz= 138 Totalnz= 51 58, 0.001 3.79 1.52 1.18 0.019 0.04 0.436 2.78 0.298 3.43 0.032 0.028 0.005 0.016 1.13 0.021 0.19 0.02 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.03 0.13 0.005 0.045 0.16 0.13 0.08 0.005 0.034 1.07 0.007 0.063 0.16 0.88 0.005 0.026 0.005 0.35 0.06 0.83 0.005 0.06 3.2 0.23 0.005 0.12 Chronic AR = 0.07 ppm Chronic AR = 0.07 ppm Chronic AR = 0.07 ppm Chronic AR = 0.09 ppm Blueberry ­ FDA 1992­ 1998 212 samples/ 23 detects 11 % detects ­ 45% CT 1/ 2 LOD =­ 0.001 ppm RDF #64 Blueberry FDA 45% CT ­ 11% detects Totalz= 117 Totalnz= 23 72, 0.001 0.342 0.245 1.06 0.146 0.112 0.206 0.234 0.005 0.19 4.38 0.119 0.005 0.005 0.52 0.23 2.05 0.08 9.7 0.005 0.02 0.054 0.15 0.012 Boysenberry, Dewberry, Loganberry, Youngberry (Raspberry FDA 1992­ 98) 247 samples/ 51 detects 21 % Detects ­ 2 % CT 1/ 2 LOD =­ 0.001 ppm RDF # 65 Boysenberry (Raspberry FDA) 2% CT Totalz= 2499 Totalnz= 51 3.79 1.52 1.18 0.019 0.04 0.436 2.78 0.298 3.43 0.032 0.028 0.005 0.016 1.13 0.021 0.19 0.02 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.03 0.13 0.005 0.045 0.16 0.13 0.08 0.005 0.034 1.07 0.007 0.063 0.16 0.88 0.005 0.026 0.005 0.35 0.06 0.83 0.005 0.06 3.2 0.23 0.005 0.12 Currant, Elderberries, Gooseberries, Huckleberries, Olliaberry (Blueberry ­ FDA) 1992­ 1998 153 samples/ 15 detects 11 % detects ­ 2% CT 1/ 2 LOD =­ 0.001 ppm RDF #66 Currant (Blueberry FDA) 2% CT Totalz= 4655 Totalnz= 23 72, 0.001 0.342 0.245 1.06 0.146 0.112 0.206 0.234 0.005 0.19 4.38 0.119 0.005 0.005 0.52 0.23 2.05 0.08 9.7 0.005 0.02 0.054 0.15 0.012 Raspberries ­ FDA Raspberry FDA 1992­ 98) 247 samples/ 51 detects 21 % Detects ­ 10 % CT 1/ 2 LOD =­ 0.001 ppm RDF # 67 Raspberry FDA 10% CT ­ 21% detected Totalz= 196 Totalnz= 51 3.79 1.52 1.18 0.019 0.04 0.436 2.78 0.298 3.43 0.032 0.028 0.005 0.016 1.13 0.021 0.19 0.02 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.03 0.13 0.005 0.045 0.16 0.13 0.08 0.005 0.034 1.07 0.007 0.063 0.16 0.88 0.005 0.026 0.005 0.35 0.06 0.83 0.005 0.06 3.2 0.23 0.005 0.12 Chronic AR = 0.09 ppm Chronic AR = 0.09 ppm Chronic AR = 0.09 ppm Chronic AR = 0.09 ppm Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 43 Almonds ­ FT 15 samples RDF # 68 Almonds ­ FT 4% CT Totalz= 360 Totalnz= 15 0.0614 0.0704 0.0786 0.0822 0.0826 0.0932 0.0304 0.0358 0.0380 0.0704 0.0800 0.0840 0.01 0.0300 0.0384 Chestnuts (Almonds ­ FT) 15 samples RDF # 69 Chestnuts (Almonds ­ FT) 2% CT Totalz= 735 Totalnz= 15 0.0614 0.0704 0.0786 0.0822 0.0826 0.0932 0.0304 0.0358 0.0380 0.0704 0.0800 0.0840 0.01 0.0300 0.0384 Filberts (Pecan ­ FT) 18 samples RDF # 70 Filberts (Pecan ­ FT) 12% CT Totalz= 132 Totalnz= 18 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.044 0.053 0.053 0.025 0.026 0.045 0.01 0.023 0.027 Pecan ­ FT 18 samples RDF # 71 Pecan ­ FT 24% CT Totalz= 57 Totalnz= 18 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.044 0.053 0.053 0.025 0.026 0.045 0.01 0.023 0.027 Chronic AR = 0.059 ppm Chronic AR = 0.059 ppm Chronic AR = 0.022 ppm Chronic AR = 0.022 ppm Walnut ­ FT 15 samples 2% CT RDF #72 Walnut ­ FT 2% CT Totalz= 735 Totalnz= 15 0.044 0.064 0.153 0.037 0.043 0.052 0.507 0.811 0.999 0.266 0.389 0.65 0.01 0.01 0.01 Walnut oil ­ FT Blended 15 samples 2% CT Residues = 0.044 0.064 0.153 0.037 0.043 0.052 0.507 0.811 0.999 0.266 0.389 0.65 0.01 0.01 0.01 Average residue = 0.27 Acute AR = 0.0054 Corn, Fresh ­ PDP 1994­ 1996 1306 samples/ 0 detects 1% CT 1/ 2 LOD = 0.0085 RDF # 73 Fresh Corn 1% CT Totalz= 99 Totalnz= 1 0.0085 Chronic AR = 0.27 ppm Chronic AR = 0.27 ppm Chronic AR = 0.0085 ppm Corn grain ­ FT Blended 0 detects 1/ 2 LOD = 0.01 1% CT Acute AR = 0.0001 Millet, Sorghum, Wheat ­ Blended (Wheat grain PDP) 1563 samples/ 6 detects 1% CT 1557 @ 1/ 2 LOD = 0.0015 0.011 0.004 0.01 0.013 0.005 0.005 Average residue = 0.0015 ppm Acute AR = 0.000015 Rice FT Blended 24 samples 1% CT 7.84 8.48 8.89 6.72 7.08 7.46 9.59 11.6 11.8 2.44 2.75 3.1 9.65 10 10.4 5.55 6.19 6.31 9.68 11.3 11.6 2.57 2.98 3.65 Average Residue = 7.4 ppm Acute AR = 0.074 Asparagus ­ FDA 1992­ 98 381 samples/ 6 detects 87% CT 1/ 2 LOD = 0.001 ppm RDF # 74 Asparagus ­ FDA 87% CT Totalz= 50 Totalnz= 6 325, 0.001 0.087 0.504 0.005 0.180 0.069 0.005 Chronic AR = 0.01 ppm Chronic AR = 0.0015 ppm Chronic AR = 7.4 ppm Chronic AR = 0.0032 ppm Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 44 Bananas ­ PDP translate to plantains 1994­ 95 1126 samples/ 0 detects 100 % CT 1/ 2 LOD = 0.01 ppm RDF # 75 Bananas ­ PDP 100% CT Totalz= 0 Totalnz= 1 0.01 Cranberries ­ FDA 1992 ­ 98 111 samples/ 3 detects 1/ 2 LOD = 0.001 ppm RDF # 76 Cranberries ­ FDA 84% CT Totalz= 18 Totalnz= 3 90, 0.001 0.002 0.002 0.002 Flax seed Blended Field Trial 10 samples No detects <0.02 ppm 1% CT Average Residues = 1/ 2 LOD = 0.01 ppm Acute AR = 0.0001 Grapes ­PDP 1994­ 96 1884 samples/ 65 detects 12% CT 1/ 2 LOD = 0.01 ppm RDF # 77 Grapes­ PDP 12% CT Totalz= 1658 Totalnz= 65 161, 0.01 0.94 0.01 0.011 0.011 0.011 0.011 0.013 0.017 0.017 0.017 0.017 0.02 0.02 0.02 0.02 0.025 0.025 0.025 0.025 0.036 0.042 0.042 0.042 0.042 0.047 0.053 0.057 0.061 0.063 0.063 0.067 0.068 0.068 0.071 0.079 0.086 0.088 0.11 0.11 0.12 0.12 0.12 0.13 0.13 0.14 0.15 0.18 0.19 0.19 0.22 0.23 0.23 0.24 0.25 0.29 0.29 0.34 0.38 0.42 0.43 0.48 0.5 0.52 0.54 0.62 Chronic AR = 0.01 ppm Chronic AR = 0.001 ppm Chronic AR =0.01 ppm Chronic AR = 0.016 ppm Grape juice PDP 1998 665 samples/ 245 detects 37% Detects ­ 12 % CT RDF # 78 Grape juice PDP 37% detects (12% CT) Totalz= 420 Totalnz= 245 See Appendix I for residues Okra Field Trials 10 samples RDF # 79 Okra ­ FT 94% CT Totalz= 1 Totalnz= 10 2.5 2.99 0.152 0.155 0.399 0.546 0.105 0.32 1.17 1 .65 Olives Field Trials 12 samples RDF # 80 Olives ­ FT 2% CT Totalz= 588 Totalnz= 12 4.44 5.56 7.49 2.08 2.22 3.95 2.77 3.79 9.83 0.83 1.18 2.11 Olive oil (Olives) Blended Field Trials 12 samples 2% CT 4.44 5.56 7.49 2.08 2.22 3.95 2.77 3.79 9.83 0.83 1.18 2.11 Average residue = 3.85 Acute AR = 0.077 Chronic AR =0.01 ppm Chronic AR = 1.0 ppm Chronic AR = 3.85 ppm Chronic AR = 3.85 ppm Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 45 Peanuts Blended Field Trial 24 samples/ no detects LOD = <0.02 6% CT Average Residue = 1/ 2 LOD = 0.01 Acute AR = 0.0006 ppm Pineapples ­ Mexico (Not blended commodites) Decomposited Used 2.5% i n Analysis FDA 1992­ 98 Imports only 116 Mexican samples/ 94 detects 81% detects 1/ 2 LOD = 0.001 n = 10 Residues were 0.0001 ­ 42.7 RDF #81 Pineapples ­ not blended 81% (detected) Totalz= 235 Totalnz= 1000 see appendix K for residues Pineapples ­Mexico (Partially blended commodities) Used 2.5% i n Analysis FDA 1992­ 98 Imports only 116 Mexican samples/ 94 detects 81% detects 1/ 2 LOD = 0.001 RDF # 82 Pineapples ­ Mexico 81% CT (detected) Totalz= 22 Totalnz= 94 see appendix J for residues Pistachios Field Trials 12 samples RDF #83 Pistachios 38% CT Totalz= 20 Totalnz= 12 0.026 0.026 0.03 0.01 0.01 0.01 0.073 0.089 0.099 0.01 0.01 0.01 Chronic AR = 0.01 ppm Chronic AR =0.053 ppm Chronic AR = 0.053 ppm Chronic AR =0.03 ppm Strawberry ­ FDA 1992 ­ 98 436 samples/ 48 detects 1/ 2 LOD = 0.001 RDF #84 Strawberry ­ FDA 24 % CT Totalz= 331 Totalnz= 48 57, 0.001 0.15 0.2 0. 02 0. 005 0.3 0. 5 0.4 0. 1 0.05 0.3 0. 2 0.005 0.002 0.6 0. 14 0. 005 0.6 3.12 5.3 0. 24 1.35 0.2 0. 24 0. 41 0.005 0.06 0.07 0.03 0.15 0.01 0.35 0.82 1.3 0.01 0.55 0.61 0.13 0.2 1. 1 0.1 3.6 1.7 0. 26 0. 11 0. 44 4 1 Sunflower oil Blended Field Trial data 15 samples 1% CT Residues 0.01 0.029 0.036 0.01 0.01 0.01 0.01 0.01 0.01 0.065 0.079 0.090 0.047 0.077 0.129 Average residue = 0.04 Acute AR = 0.0004 Sunflower seeds Field Trial data 15 samples 1% CT RDF # 85 Sunflower ­ FT 1% CT Totalz= 1485 Totalnz= 15 0.01 0.029 0.036 0.01 0.01 0.01 0.01 0.01 0.01 0.065 0.079 0.090 0.047 0.077 0.129 Milk translate to ruminant meat and fat Feeding study % CT based on alfalfa, feed grains, and forages % CT of 1% RDF #86 Milk 1% CT Totalz= 99 Totalnz= 1 0.0299 Chronic AR = 0.0638 ppm Chronic AR = 0.04 ppm Chronic AR = 0.04 ppm Chronic AR = 0.0003 ppm Ruminant Liver Feeding study % CT based on alfalfa, feed grains, and forages % CT of 1% RDF # 87 Ruminant Liver 1% CT Totalz= 99 Totalnz= 1 0.79 Ruminant Kidney Feeding study % CT based on alfalfa, feed grains, and forages % CT of 1% RDF # 88 Ruminant Kidney 1% CT Totalz= 99 Totalnz= 1 2.1 Swine Meat Feeding study % CT based on feed grains, and forages % CT of 1% RDF # 89 Swine Meat 1% CT Totalz= 99 Totalnz= 1 0.036 Swine Fat Feeding study % CT based on feed grains, and forages % CT of 1% RDF # 90 Swine Fat 1% CT Totalz= 99 Totalnz= 1 0.0192 Chronic AR = 0.0063 Chronic AR = 0.0179 Chronic AR = 0.000348 Chronic AR = 0.000096 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 46 Swine Liver Feeding study % CT based on feed grains, and forages % CT of 1% RDF # 91 Swine Liver 1% CT Totalz= 99 Totalnz= 0.102 Swine Kidney Feeding study % CT based on feed grains, and forages % CT of 1% RDF # 92 Swine Kidney 1% CT Totalz= 99 Totalnz= 0.168 Chronic AR = 0.000792 Chronic AR = 0.001428 Pineapple ­ other countries FDA 1992­ 98 Used 47.5% of analysis No detects 1/ 2 LOD = 0.001 ppm RDF # 95 Pineapples ­ other countries 50% CT (detected) Totalz= 26 Totalfreq= 1 25, 0.001 Plums not blended (Peaches PDP 1994 ­1996 ) 1088 samples/ 168 detects 18% CT ­ 15% detected Residues decomp. ranged from 0.000119 ­ 46.3 RDF # 96 Plums (Peaches ­ PDP ­ decomp) 9% CT ­ 15% detected Totalz= 12133 Totalnz= 1000 200, 0.001 see Appendix H for residue values Pineapple ­ Domestic No exposure Used 50% of analysis RDF # 97 Pineapples ­ domestic 0% detected Totalz= 26 Totalnz = 0 Chronic AR = 0.053 ppm Chronic AR = 0.07 ppm Chronic AR = 0.053 ppm Carbamate Market Basket Study RDFs RDF # 98 Number of samples = 285 Apricots (Peach MBS) 2% CT ­ 20% detected Totalz= 2842 Totalnz= 58 0.0029 0.0013 0.0017 0.0018 0.0011 0.0029 0.0053 0.0019 0.0019 0.0026 1.1 0. 0018 0.56 0.0037 0.52 0.0014 1.2 0. 0025 0.0055 0.0067 1.1 0.13 0.23 0.010 0.0026 0.002 0.0013 0.021 0.0044 0.27 0.033 0.030 0.0096 0.18 0.022 0.0021 0.0061 0.0019 0.20 0.092 0.0019 0.0017 0.021 0.14 0.14 0.031 0.14 0.075 0.077 0.0012 0.061 0.040 0.0013 0.0099 0.26 0.0011 0.0020 0.047 RDF # 99 Number of samples = 395 Cauliflower ­ (Broccoli MBS) 4% CT Totalz= 384 Totalfreq= 1 16, 0.0005 RDF # 100 Number of samples = 399 Other Citrus 2% CT Totalz= 388 Totalnz= 11 0.0032 0.0017 0.015 0.0032 0.0017 0.0047 0.022 0.032 0.043 0.0052 0.013 RDF # 101 Number of samples = 399 Grapefruit (OrangeMBS) 6% CT Totalz= 375 Totalnz= 11 13, 0.0005 0.0032 0.0017 0.015 0.0032 0.0017 0.0047 0.022 0.032 0.043 0.0052 0.013 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 47 RDF # 102 Number of samples = 399 Leaf Lettuce ­ Market Basket Survey 2% CT Totalz= 392 Totalnz= 1 7, 0.0005 0.0014 RDF # 103 Number of samples = 399 Lemon (Orange MBS) 7% CT Totalz= 371 Totalnz= 11 17, 0.0005 0.0032 0.0017 0.015 0.0032 0.0017 0.0047 0.022 0.032 0.043 0.0052 0.013 RDF # 104 Number of samples = 285 Nectarines (Peach MBS) 24% CT ­ 20% detected Totalz= 217 Totalnz= 58 10, 0.0005 0.0029 0.0013 0.0017 0.0018 0.0011 0.0029 0.0053 0.0019 0.0019 0.0026 1.1 0. 0018 0.56 0.0037 0.52 0.0014 1.2 0. 0025 0.0055 0.0067 1.1 0.13 0.23 0.010 0.0026 0.002 0.0013 0.021 0.0044 0.27 0.033 0.030 0.0096 0.18 0.022 0.0021 0.0061 0.0019 0.20 0.092 0.0019 0.0017 0.021 0.14 0.14 0.031 0.14 0.075 0.077 0.0012 0.061 0.040 0.0013 0.0099 0.26 0.0011 0.0020 0.047 RDF # 105 Number of samples = 400 Pears ­ (Apple MBS) 6% CT ­ 8% detected Totalz= 1943 Totalnz= 32 92, 0.0005 0.11 0.0011 0.11 0.21 0.017 0.0064 0.069 0.040 0.050 0.099 0.17 0.003 0.073 0.0011 0.021 0.005 0.0056 0.0059 0.054 0.016 0.0039 0.0012 0.14 0.0035 0.045 0.17 0.0085 0.0017 0.0024 0.035 0.068 0.093 RDF # 106 Number of samples = 285 Plum (Peach MBS) 4% CT ­ 20% detected Totalz= 1392 Totalnz= 58 0.0029 0.0013 0.0017 0.0018 0.0011 0.0029 0.0053 0.0019 0.0019 0.0026 1.1 0. 0018 0.56 0.0037 0.52 0.0014 1.2 0. 0025 0.0055 0.0067 1.1 0.13 0.23 0.010 0.0026 0.002 0.0013 0.021 0.0044 0.27 0.033 0.030 0.0096 0.18 0.022 0.0021 0.0061 0.0019 0.20 0.092 0.0019 0.0017 0.021 0.14 0.14 0.031 0.14 0.075 0.077 0.0012 0.061 0.040 0.0013 0.0099 0.26 0.0011 0.0020 0.047 RDF # 107 Number of samples = 400 Quince/ Crabapples (Apple MBS) 2% CT ­ 8% detected Totalz= 6076 Totalnz= 32 92, 0.0005 0.11 0.0011 0.11 0.21 0.017 0.0064 0.069 0.040 0.050 0.099 0.17 0.003 0.073 0.0011 0.021 0.005 0.0056 0.0059 0.054 0.016 0.0039 0.0012 0.14 0.0035 0.045 0.17 0.0085 0.0017 0.0024 0.035 0.068 0.093 RDF # 108 Number of samples = 400 Apples ­ dried ­ MBS Totalnz= 32 Totalfreq= 1 368, 0.0005 0.11 0.0011 0.11 0.21 0.017 0.0064 0.069 0.040 0.050 0.099 0.17 0.003 0.073 0.0011 0.021 0.005 0.0056 0.0059 0.054 0.016 0.0039 0.0012 0.14 0.0035 0.045 0.17 0.0085 0.0017 0.0024 0.035 0.068 0.093 Replaces RDF # 14 Number of samples = 399 Lettuce ­ Market Basket Survey 8% CT Totalz= 367 Totalnz= 1 31, 0.0005 0.0014 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 48 Replaces RDF # 17 Number of samples = 395 Broccoli ­ Market Basket Survey 9% CT Totalz= 359 Totalfreq= 1 36, 0.0005 Replaces RDF # 33 Number of samples = 399 Tomato ­ Market Basket Survey 27% CT Totalz= 291 Totalfreq= 1 108, 0.0005 Replaces RDF # 45 Number of samples = 399 Orange ­ Market Basket Survey 5% CT ­ Totalz= 379 Totalnz= 11 9, 0.0005 0.0032 0.0017 0.015 0.0032 0.0017 0.0047 0.022 0.032 0.043 0.0052 0.013 Replaces RDF # 48 Number of samples = 400 Apples ­ Market Basket Survey 31% CT ­ 8% detected Totalz= 276 Totalnz= 32 92, 0.0005 0.11 0.0011 0.11 0.21 0.017 0.0064 0.069 0.040 0.050 0.099 0.17 0.003 0.073 0.0011 0.021 0.005 0.0056 0.0059 0.054 0.016 0.0039 0.0012 0.14 0.0035 0.045 0.17 0.0085 0.0017 0.0024 0.035 0.068 0.093 Replaces RDF # 60 Number of samples = 285 Peach ­ Market Basket Survey 18% CT ­ 20% detected Totalz= 227 Totalnz= 58 0.0029 0.0013 0.0017 0.0018 0.0011 0.0029 0.0053 0.0019 0.0019 0.0026 1.1 0. 0018 0.56 0.0037 0.52 0.0014 1.2 0. 0025 0.0055 0.0067 1.1 0.13 0.23 0.010 0.0026 0.002 0.0013 0.021 0.0044 0.27 0.033 0.030 0.0096 0.18 0.022 0.0021 0.0061 0.0019 0.20 0.092 0.0019 0.0017 0.021 0.14 0.14 0.031 0.14 0.075 0.077 0.0012 0.061 0.040 0.0013 0.0099 0.26 0.0011 0.0020 0.047 Replaces RDF # 75 Number of samples = 400 Bananas/ Plantains 100% CT Totalz= 0 Totalnz= 5 395, 0.0005 0.0019 0.0013 0.0011 0.0020 0.0016 Replaces RDF # 77 Number of samples = 393 Grapes ­ Market Basket Survey 12% CT Totalz= 346 Totalnz= 31 16, 0.0005 0.0012 0.0026 0.020 0.21 0.030 0.0031 0.13 0.0027 0.032 0.015 0.28 0.073 0.0085 0.0011 0.012 0.062 0.010 0.19 0.0039 0.0012 0.0012 0.0013 0.0062 0.0032 0.014 0.18 0.78 0.36 0.022 0.0013 0.0011 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 49 Appendix A Orange Residues 0.02 0.043 0.05 0.025 0.055 0.02 0.05 0.025 0.02 0.025 0.089 0.007 0.02 0.007 0.055 0.061 0.025 0.02 0.05 0.033 0.042 0.068 0.02 0.056 0.02 0.054 0.16 0.025 0.11 0.025 0.02 0.15 0.02 0.02 0.02 0.02 0.02 0.098 0.025 0.025 0.079 0.025 0.025 0.033 0.007 0.04 0.12 0.02 0.077 0.007 0.11 0.049 0.083 0.14 0.033 0.04 0.075 0.01 0.03 0.16 0.033 0.053 0.075 0.19 0.081 0.087 0.054 0.087 0.023 0.024 0.11 0.025 0.01 0.01 0.033 0.058 0.038 0.01 0.013 0.01 0.01 0.01 0.033 0.033 0.025 0.04 0.02 0.026 0.028 0.033 0.1 0.11 0.03 0.04 0.059 0.01 0.03 0.12 0.033 0.092 0.04 0.01 0.01 0.01 0.19 0.013 0.01 0.04 0.04 0.026 0.032 0.01 0.013 0.098 0.013 0.089 0.013 0.049 0.036 0.027 0.013 0.013 0.082 0.013 0.033 0.035 0.01 0.01 0.01 0.01 0.033 0.033 0.035 0.033 0.071 0.013 0.013 0.11 0.01 0.013 0.013 0.028 0.013 0.013 0.01 0.06 0.033 0.013 0.042 0.11 0.013 0.013 0.013 0.066 0.024 0.064 0.013 0.1 0.13 0.068 0.033 0.11 0.12 0.035 0.035 0.035 0.11 0.033 0.01 0.01 0.046 0.01 0.035 0.11 0.097 0.01 0.024 0.03 0.034 0.12 0.07 0.07 0.01 0.024 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 50 Appendix B ­ Orange residues decomposited 0.000043 0.000153 0.000227 0.000249 0.000265 0.000276 0.000352 0.000366 0.000376 0.000408 0.000426 0.000450 0.000471 0.000485 0.000516 0.000545 0.000550 0.000571 0.000596 0.000615 0.000642 0.000663 0.000684 0.000699 0.000709 0.000726 0.000746 0.000779 0.000804 0.000807 0.000831 0.000838 0.000876 0.000886 0.000896 0.000897 0.000941 0.000954 0.000982 0.000992 0.001022 0.001027 0.001031 0.001038 0.001080 0.001099 0.001104 0.001107 0.001144 0.001161 0.001171 0.001175 0.001211 0.001231 0.001247 0.001268 0.001286 0.001303 0.001311 0.001314 0.001362 0.001368 0.001396 0.001396 0.001414 0.001418 0.001469 0.001470 0.001478 0.001498 0.001512 0.001531 0.001560 0.001561 0.001601 0.001607 0.001612 0.001629 0.001657 0.001666 0.001681 0.001714 0.001740 0.001746 0.001754 0.001762 0.001798 0.001811 0.001848 0.001851 0.001871 0.001884 0.001900 0.001913 0.001945 0.001951 0.001956 0.001988 0.002000 0.002002 0.002035 0.002060 0.002070 0.002079 0.002106 0.002113 0.002139 0.002152 0.002186 0.002190 0.002217 0.002229 0.002238 0.002245 0.002278 0.002305 0.002321 0.002344 0.002367 0.002379 0.002382 0.002395 0.002425 0.002448 0.002458 0.002477 0.002505 0.002512 0.002544 0.002546 0.002571 0.002575 0.002607 0.002612 0.002645 0.002661 0.002673 0.002675 0.002722 0.002724 0.002762 0.002763 0.002800 0.002807 0.002829 0.002846 0.002875 0.002893 0.002899 0.002901 0.002947 0.002958 0.002986 0.003012 0.003030 0.003045 0.003083 0.003086 0.003107 0.003123 0.003129 0.003167 0.003176 0.003179 0.003213 0.003215 0.003259 0.003265 0.003318 0.003322 0.003357 0.003359 0.003378 0.003385 0.003408 0.003439 0.003456 0.003457 0.003491 0.003498 0.003530 0.003547 0.003570 0.003588 0.003630 0.003638 0.003654 0.003680 0.003702 0.003727 0.003734 0.003744 0.003781 0.003802 0.003824 0.003834 0.003861 0.003864 0.003905 0.003934 0.003972 0.003979 0.004025 0.004030 0.004047 0.004058 0.004089 0.004115 0.004122 0.004126 0.004174 0.004179 0.004231 0.004231 0.004258 0.004279 0.004293 0.004305 0.004351 0.004357 0.004400 0.004414 0.004457 0.004465 0.004485 0.004496 0.004543 0.004551 0.004564 0.004569 0.004645 0.004647 0.004678 0.004699 0.004712 0.004744 0.004748 0.004767 0.004836 0.004838 0.004846 0.004870 0.004920 0.004927 0.004955 0.004973 0.004986 0.004992 0.005069 0.005073 0.005089 0.005090 0.005143 0.005147 0.005182 0.005226 0.005243 0.005264 0.005292 0.005316 0.005342 0.005350 0.005403 0.005405 0.005437 0.005470 0.005491 0.005518 0.005552 0.005556 0.005593 0.005619 0.005657 0.005671 0.005688 0.005694 0.005746 0.005757 0.005798 0.005804 0.005848 0.005877 0.005922 0.005938 0.005982 0.005989 0.006002 0.006005 0.006079 0.006092 0.006118 0.006140 0.006173 0.006183 0.006239 0.006267 0.006275 0.006304 0.006330 0.006363 0.006420 0.006425 0.006443 0.006445 0.006529 0.006529 0.006599 0.006601 0.006641 0.006653 0.006682 0.006710 0.006766 0.006774 0.006790 0.006811 0.006836 0.006840 0.006916 0.006951 0.006973 0.006989 0.007011 0.007042 0.007106 0.007128 0.007137 0.007153 0.007192 0.007224 0.007277 0.007293 0.007336 0.007356 0.007413 0.007417 0.007455 0.007462 0.007513 0.007554 0.007560 0.007616 0.007656 0.007667 0.007690 0.007698 0.007755 0.007794 0.007837 0.007865 0.007876 0.007900 0.007965 0.007992 0.008012 0.008064 0.008124 0.008131 0.008141 0.008155 0.008229 0.008240 0.008275 0.008300 0.008350 0.008377 0.008431 0.008455 0.008480 0.008510 0.008585 0.008607 0.008634 0.008674 0.008683 0.008718 0.008765 0.008816 0.008839 0.008857 0.008894 0.008902 0.008969 0.009025 0.009048 0.009088 0.009133 0.009161 0.009209 0.009237 0.009274 0.009281 0.009322 0.009380 0.009395 0.009441 0.009502 0.009536 0.009563 0.009591 0.009677 0.009684 0.009702 0.009725 0.009773 0.009796 0.009868 0.009914 0.009931 0.009959 0.010049 0.010059 0.010098 0.010157 0.010167 0.010201 0.010265 0.010316 0.010359 0.010363 0.010422 0.010436 0.010485 0.010544 0.010616 0.010618 0.010645 0.010698 0.010758 0.010787 0.010842 0.010871 0.010925 0.010929 0.011029 0.011040 0.011089 0.011112 0.011176 0.011222 0.011270 0.011279 0.011330 0.011370 0.011444 0.011493 0.011550 0.011555 0.011587 0.011634 0.011682 0.011758 0.011797 0.011842 0.011865 0.011872 0.011951 0.012023 0.012065 0.012074 0.012167 0.012185 0.012261 0.012272 0.012345 0.012379 0.012446 0.012480 0.012516 0.012595 0.012616 0.012666 0.012719 0.012760 0.012820 0.012860 0.012919 0.012947 0.013021 0.013075 0.013123 0.013183 0.013209 0.013268 0.013342 0.013382 0.013393 0.013430 0.013508 0.013509 0.013623 0.013656 0.013701 0.013728 0.013878 0.013899 0.013978 0.013992 0.014041 0.014051 0.014130 0.014180 0.014239 0.014319 0.014417 0.014441 0.014493 0.014507 0.014592 0.014638 0.014687 0.014732 0.014797 0.014852 0.014929 0.014953 0.015062 0.015073 0.015139 0.015157 0.015257 0.015330 0.015396 0.015400 0.015491 0.015563 0.015589 0.015650 0.015721 0.015737 0.015842 0.015918 0.015967 0.016059 0.016143 0.016147 0.016203 0.016228 0.016361 0.016396 0.016443 0.016488 0.016616 0.016642 0.016725 0.016749 0.016889 0.016948 0.017015 0.017041 0.017086 0.017104 0.017310 0.017332 0.017428 0.017460 0.017496 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 51 0.017556 0.017705 0.017726 0.017863 0.017866 0.017987 0.017991 0.018091 0.018114 0.018218 0.018228 0.018309 0.018341 0.018449 0.018525 0.018636 0.018725 0.018777 0.018830 0.018938 0.018973 0.019052 0.019056 0.019198 0.019289 0.019450 0.019461 0.019546 0.019561 0.019641 0.019763 0.019829 0.019897 0.019937 0.020018 0.020110 0.020148 0.020262 0.020399 0.020504 0.020542 0.020638 0.020702 0.020730 0.020762 0.020910 0.020939 0.021111 0.021215 0.021223 0.021307 0.021419 0.021437 0.021691 0.021723 0.021730 0.021852 0.021953 0.022014 0.022213 0.022237 0.022262 0.022424 0.022497 0.022522 0.022626 0.022781 0.022904 0.022943 0.023101 0.023156 0.023159 0.023254 0.023365 0.023439 0.023628 0.023699 0.023796 0.023869 0.023922 0.024071 0.024113 0.024237 0.024335 0.024493 0.024655 0.024676 0.024753 0.024842 0.024964 0.024994 0.025151 0.025181 0.025319 0.025415 0.025632 0.025691 0.025765 0.025819 0.026077 0.026119 0.026371 0.026378 0.026394 0.026527 0.026718 0.026797 0.026828 0.026896 0.027182 0.027267 0.027364 0.027411 0.027504 0.027606 0.027899 0.027959 0.028035 0.028140 0.028227 0.028239 0.028450 0.028522 0.028740 0.028897 0.028962 0.029099 0.029266 0.029400 0.029483 0.029540 0.029741 0.029765 0.030160 0.030178 0.030263 0.030411 0.030625 0.030658 0.030729 0.030745 0.031152 0.031167 0.031281 0.031294 0.031560 0.031776 0.031922 0.032052 0.032115 0.032171 0.032400 0.032572 0.032717 0.032869 0.032996 0.033018 0.033276 0.033495 0.033752 0.033773 0.034034 0.034059 0.034156 0.034398 0.034478 0.034665 0.034863 0.034959 0.035274 0.035398 0.035569 0.035634 0.035877 0.035920 0.036088 0.036309 0.036516 0.036561 0.036855 0.037068 0.037153 0.037332 0.037615 0.037747 0.038035 0.038106 0.038159 0.038211 0.038522 0.038838 0.039018 0.039178 0.039458 0.039542 0.039775 0.039835 0.040132 0.040263 0.040681 0.040764 0.041048 0.041168 0.041432 0.041563 0.041702 0.041848 0.042192 0.042325 0.042462 0.042745 0.043063 0.043233 0.043448 0.043487 0.043714 0.043864 0.044270 0.044379 0.044832 0.044992 0.045123 0.045417 0.045529 0.045823 0.046139 0.046379 0.046750 0.046913 0.046957 0.047112 0.047554 0.047704 0.047936 0.048327 0.048548 0.048849 0.049031 0.049258 0.049510 0.049905 0.050240 0.050453 0.050574 0.050717 0.051248 0.051560 0.051677 0.051787 0.052478 0.052505 0.053002 0.053177 0.053544 0.053622 0.054047 0.054063 0.055069 0.055120 0.055384 0.055537 0.055929 0.056273 0.056608 0.056655 0.057376 0.057795 0.058315 0.058434 0.058834 0.059221 0.059751 0.059761 0.060177 0.060325 0.061045 0.061263 0.061885 0.062120 0.062447 0.062557 0.063219 0.063640 0.064056 0.064444 0.064838 0.065158 0.065792 0.065795 0.066202 0.067022 0.067196 0.067372 0.067912 0.068643 0.069225 0.069460 0.069741 0.070091 0.070668 0.071460 0.071918 0.071974 0.072854 0.073362 0.073655 0.074463 0.074614 0.074726 0.075645 0.076691 0.077114 0.077116 0.077932 0.078178 0.079174 0.079748 0.080194 0.080829 0.082242 0.082453 0.082927 0.082978 0.084614 0.084980 0.085079 0.086206 0.086542 0.087447 0.088369 0.088954 0.089815 0.089901 0.091122 0.091908 0.092670 0.093022 0.094136 0.094317 0.095155 0.095646 0.096894 0.097932 0.099240 0.099423 0.100161 0.101358 0.102634 0.103083 0.104062 0.104517 0.106154 0.107556 0.108714 0.109591 0.111546 0.111799 0.112381 0.112941 0.114951 0.115848 0.116366 0.117197 0.120985 0.120991 0.121752 0.122446 0.125247 0.126372 0.127772 0.128838 0.130456 0.131897 0.133229 0.134886 0.135468 0.136782 0.140523 0.140592 0.142335 0.142801 0.146687 0.147895 0.148973 0.150342 0.153141 0.153776 0.159801 0.159913 0.162551 0.163659 0.168510 0.169539 0.171822 0.175426 0.179157 0.180162 0.184585 0.186891 0.188410 0.189242 0.195158 0.196066 0.200657 0.202731 0.211527 0.215130 0.219958 0.223187 0.225791 0.231400 0.235616 0.235634 0.246444 0.248895 0.257043 0.262337 0.268853 0.268969 0.284019 0.288194 0.303912 0.307660 0.322014 0.328990 0.339508 0.343924 0.375344 0.375349 0.420784 0.422542 0.445609 0.455397 0.479871 0.515625 0.553178 0.577879 0.727594 0.777848 0.938138 1.078748 1.183047 1.682955 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 52 Appendix C. Apples Residues Decomposited 1067, 0.013 0.000080 0.000151 0.000192 0.000236 0.000276 0.000280 0.000336 0.000380 0.000393 0.000438 0.000467 0.000496 0.000515 0.000523 0.000575 0.000597 0.000638 0.000650 0.000715 0.000727 0.000736 0.000765 0.000784 0.000821 0.000860 0.000871 0.000902 0.000924 0.000977 0.000992 0.000998 0.001014 0.001056 0.001086 0.001105 0.001140 0.001157 0.001160 0.001255 0.001255 0.001260 0.001276 0.001328 0.001360 0.001397 0.001409 0.001427 0.001460 0.001470 0.001502 0.001547 0.001563 0.001579 0.001582 0.001647 0.001679 0.001709 0.001730 0.001745 0.001762 0.001810 0.001813 0.001855 0.001856 0.001912 0.001913 0.001963 0.001981 0.002024 0.002048 0.002089 0.002106 0.002163 0.002169 0.002191 0.002210 0.002260 0.002267 0.002303 0.002304 0.002377 0.002380 0.002412 0.002455 0.002464 0.002490 0.002526 0.002565 0.002572 0.002575 0.002656 0.002659 0.002695 0.002704 0.002782 0.002796 0.002845 0.002864 0.002889 0.002921 0.002954 0.002957 0.003029 0.003041 0.003071 0.003092 0.003121 0.003162 0.003204 0.003212 0.003243 0.003277 0.003295 0.003295 0.003361 0.003379 0.003426 0.003438 0.003486 0.003512 0.003567 0.003593 0.003615 0.003648 0.003670 0.003727 0.003738 0.003769 0.003818 0.003849 0.003911 0.003914 0.003952 0.003974 0.004042 0.004062 0.004119 0.004129 0.004149 0.004154 0.004213 0.004235 0.004320 0.004328 0.004367 0.004370 0.004407 0.004423 0.004485 0.004534 0.004554 0.004582 0.004624 0.004662 0.004687 0.004698 0.004760 0.004786 0.004876 0.004892 0.004912 0.004925 0.005001 0.005034 0.005058 0.005072 0.005161 0.005188 0.005198 0.005235 0.005268 0.005270 0.005375 0.005404 0.005440 0.005479 0.005493 0.005508 0.005629 0.005636 0.005654 0.005714 0.005766 0.005780 0.005870 0.005877 0.005916 0.005919 0.005992 0.006033 0.006053 0.006090 0.006149 0.006166 0.006221 0.006245 0.006325 0.006329 0.006424 0.006426 0.006481 0.006523 0.006553 0.006569 0.006635 0.006640 0.006699 0.006720 0.006846 0.006864 0.006871 0.006941 0.006959 0.006963 0.007067 0.007093 0.007142 0.007181 0.007257 0.007290 0.007316 0.007326 0.007399 0.007449 0.007491 0.007508 0.007642 0.007643 0.007730 0.007750 0.007769 0.007844 0.007889 0.007927 0.007950 0.007962 0.008051 0.008093 0.008159 0.008202 0.008227 0.008291 0.008363 0.008388 0.008480 0.008482 0.008539 0.008575 0.008626 0.008640 0.008776 0.008790 0.008854 0.008858 0.008956 0.008963 0.009018 0.009087 0.009162 0.009181 0.009229 0.009241 0.009408 0.009409 0.009469 0.009476 0.009582 0.009591 0.009622 0.009698 0.009777 0.009787 0.009840 0.009914 0.009985 0.010044 0.010082 0.010143 0.010234 0.010245 0.010316 0.010333 0.010425 0.010444 0.010577 0.010583 0.010644 0.010694 0.010747 0.010813 0.010822 0.010881 0.010957 0.010969 0.011102 0.011107 0.011217 0.011272 0.011291 0.011346 0.011451 0.011493 0.011528 0.011541 0.011701 0.011716 0.011798 0.011809 0.011919 0.011980 0.012020 0.012071 0.012131 0.012140 0.012266 0.012279 0.012377 0.012484 0.012550 0.012566 0.012638 0.012703 0.012760 0.012842 0.012982 0.013000 0.013036 0.013115 0.013138 0.013209 0.013286 0.013292 0.013441 0.013519 0.013628 0.013663 0.013678 0.013685 0.013857 0.013891 0.013990 0.014056 0.014146 0.014176 0.014277 0.014329 0.014433 0.014453 0.014577 0.014606 0.014664 0.014763 0.014778 0.014785 0.014945 0.015030 0.015108 0.015165 0.015315 0.015324 0.015403 0.015506 0.015539 0.015549 0.015758 0.015771 0.015828 0.015887 0.016066 0.016070 0.016217 0.016261 0.016303 0.016394 0.016426 0.016522 0.016682 0.016731 0.016757 0.016806 0.016896 0.017001 0.017080 0.017213 0.017278 0.017304 0.017391 0.017532 0.017577 0.017694 0.017792 0.017825 0.017975 0.017991 0.018180 0.018184 0.018316 0.018367 0.018384 0.018544 0.018590 0.018593 0.018872 0.018891 0.018992 0.019021 0.019115 0.019182 0.019265 0.019292 0.019465 0.019596 0.019651 0.019766 0.019860 0.019910 0.020114 0.020120 0.020279 0.020333 0.020356 0.020366 0.020554 0.020618 0.020826 0.020886 0.020931 0.021019 0.021238 0.021286 0.021407 0.021472 0.021554 0.021676 0.021704 0.021878 0.021988 0.022011 0.022183 0.022270 0.022353 0.022444 0.022553 0.022609 0.022824 0.022857 0.022951 0.022972 0.023190 0.023253 0.023541 0.023544 0.023563 0.023622 0.023816 0.023869 0.024095 0.024110 0.024298 0.024420 0.024495 0.024509 0.024662 0.024776 0.024940 0.024942 0.025120 0.025197 0.025353 0.025427 0.025594 0.025772 0.025843 0.025929 0.026025 0.026044 0.026401 0.026458 0.026574 0.026577 0.026873 0.026910 0.026986 0.027139 0.027295 0.027373 0.027468 0.027673 0.027863 0.027879 0.028055 0.028169 0.028261 0.028314 0.028556 0.028668 0.028730 0.028780 0.029055 0.029102 0.029255 0.029402 0.029605 0.029726 0.029837 0.029852 0.030058 0.030160 0.030388 0.030473 0.030628 0.030646 0.030899 0.030929 0.031203 0.031325 0.031621 0.031634 0.031736 0.031766 0.032160 0.032263 0.032304 0.032520 0.032708 0.032875 0.032937 0.032979 0.033186 0.033395 0.033554 0.033767 0.033945 0.033960 0.034202 0.034379 0.034627 0.034704 0.034878 0.034964 0.035172 0.035290 0.035528 0.035638 0.035780 0.035924 0.036071 0.036217 0.036330 0.036545 0.036857 0.036910 0.037177 0.037244 0.037480 0.037532 0.037717 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 53 0.037859 0.038028 0.038272 0.038431 0.038548 0.038971 0.039007 0.039121 0.039396 0.039455 0.039706 0.039871 0.040098 0.040259 0.040325 0.040595 0.040841 0.040942 0.041100 0.041279 0.041587 0.041842 0.042018 0.042281 0.042393 0.042496 0.042663 0.042976 0.043090 0.043226 0.043555 0.043738 0.043956 0.044092 0.044332 0.044677 0.044766 0.044973 0.045228 0.045456 0.045645 0.045892 0.045938 0.046195 0.046449 0.046596 0.046892 0.047264 0.047278 0.047624 0.047710 0.047953 0.047971 0.048475 0.048770 0.048781 0.048935 0.049611 0.049621 0.049842 0.049918 0.050423 0.050460 0.050724 0.050746 0.051218 0.051561 0.051672 0.051723 0.052290 0.052524 0.052690 0.053027 0.053219 0.053564 0.053617 0.053904 0.054526 0.054608 0.054796 0.055088 0.055315 0.055496 0.055867 0.056228 0.056357 0.056683 0.056945 0.057114 0.057657 0.057715 0.057962 0.058371 0.058530 0.058750 0.059163 0.059206 0.059656 0.060042 0.060229 0.060502 0.060842 0.061080 0.061816 0.061826 0.062083 0.062441 0.062845 0.062896 0.063395 0.063527 0.063958 0.064449 0.064579 0.064846 0.065289 0.065368 0.065817 0.066433 0.066996 0.067076 0.067367 0.067617 0.068205 0.068281 0.068552 0.069109 0.069664 0.069673 0.069931 0.070318 0.070659 0.070662 0.071379 0.071723 0.072193 0.072506 0.073209 0.073475 0.073754 0.074171 0.074493 0.074965 0.075243 0.075611 0.076318 0.076398 0.076990 0.077283 0.077440 0.077956 0.078585 0.078600 0.079101 0.079137 0.080073 0.080438 0.081390 0.081593 0.081751 0.081949 0.082553 0.083038 0.083765 0.084053 0.084396 0.084908 0.085336 0.085991 0.086724 0.086844 0.087588 0.087763 0.088696 0.088940 0.089193 0.089650 0.089982 0.090043 0.091647 0.091815 0.092078 0.092081 0.093592 0.093701 0.094141 0.094418 0.095274 0.096044 0.096138 0.096371 0.097249 0.097545 0.098417 0.099116 0.100097 0.100504 0.100678 0.101381 0.101922 0.102079 0.103368 0.104018 0.105047 0.105054 0.105903 0.106203 0.107071 0.107197 0.108389 0.108850 0.109444 0.110000 0.111482 0.111619 0.111713 0.112147 0.113321 0.113949 0.114740 0.114852 0.115811 0.116177 0.117889 0.117995 0.119123 0.119400 0.120739 0.121052 0.121765 0.122446 0.123723 0.123769 0.124962 0.125993 0.126286 0.127281 0.128166 0.128629 0.129905 0.130174 0.132278 0.132447 0.132808 0.133472 0.134709 0.135269 0.136405 0.137580 0.138084 0.138213 0.140060 0.141332 0.142595 0.143067 0.144214 0.145013 0.145793 0.146898 0.148021 0.148351 0.150526 0.151264 0.153270 0.153490 0.153804 0.154291 0.156380 0.156854 0.159128 0.159181 0.160454 0.161429 0.164039 0.164651 0.165998 0.166565 0.169353 0.169561 0.170206 0.170309 0.172858 0.173500 0.176301 0.176621 0.177645 0.179900 0.181321 0.182500 0.183663 0.183980 0.186212 0.188244 0.189911 0.190148 0.193151 0.194044 0.194648 0.196374 0.199441 0.200198 0.202472 0.202936 0.205087 0.206291 0.208404 0.210228 0.211100 0.213058 0.214248 0.216181 0.220687 0.220694 0.221407 0.224712 0.225786 0.226590 0.231474 0.232714 0.233423 0.233684 0.237448 0.241132 0.242967 0.243710 0.250005 0.250094 0.253433 0.253838 0.257369 0.258494 0.261149 0.261723 0.268669 0.269991 0.274214 0.275200 0.277474 0.280961 0.281664 0.282342 0.286881 0.292489 0.292971 0.294198 0.301924 0.302931 0.307876 0.308901 0.313259 0.315630 0.321723 0.322531 0.326377 0.331076 0.333324 0.334984 0.342926 0.347277 0.348784 0.350472 0.357178 0.361739 0.369157 0.374225 0.376534 0.377653 0.384214 0.391837 0.394854 0.401850 0.404952 0.407618 0.416874 0.418449 0.428259 0.433796 0.445198 0.449359 0.455684 0.455692 0.465135 0.474726 0.480508 0.492559 0.495851 0.505381 0.510990 0.521837 0.537060 0.541775 0.553794 0.560509 0.566153 0.579012 0.583143 0.596497 0.604191 0.618276 0.649208 0.650433 0.655777 0.668333 0.682272 0.683577 0.711373 0.715882 0.747953 0.748935 0.809611 0.811960 0.842521 0.854182 0.876402 0.906656 0.913831 0.955418 0.970001 1.018766 1.024320 1.072022 1.092786 1.093841 1.176887 1.209392 1.297576 1.306557 1.401623 1.493034 1.619153 1.659000 1.700678 1.805411 2.079092 2.146204 2.435816 2.503414 2.940322 2.978321 3.882973 4.282962 7.289950 7.349416 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 54 Appendix D Apple Residues 305, 0.013 0.007 0.007 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.013 0.013 0.013 0.013 0.013 0.013 0.018 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.024 0.024 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.026 0.027 0.03 0.03 0.03 0.03 0.03 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.035 0.035 0.035 0.036 0.037 0.038 0.04 0.04 0.04 0.04 0.041 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.043 0.043 0.043 0.044 0.046 0.05 0.054 0.055 0.056 0.056 0.056 0.057 0.057 0.058 0.058 0.058 0.059 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.061 0.061 0.061 0.061 0.064 0.067 0.069 0.07 0.07 0.07 0.07 0.075 0.076 0.079 0.08 0.082 0.083 0.083 0.087 0.087 0.088 0.089 0.09 0.09 0.092 0.097 0.098 0.098 0.099 0.099 0.099 0.1 0.1 0.1 0.1 0.1 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.13 0.14 0.14 0.14 0.14 0.14 0.14 0.14 0.14 0.15 0.15 0.17 0.17 0.18 0.18 0.18 0.19 0.19 0.2 0.2 0.2 0.2 0.2 0.21 0.21 0.21 0.22 0.22 0.23 0.23 0.24 0.24 0.25 0.25 0.25 0.25 0.25 0.26 0.27 0.28 0.28 0.28 0.28 0.29 0.29 0.3 0.3 0.3 0.31 0.31 0.33 0.35 0.36 0.36 0.37 0.38 0.38 0.38 0.39 0.42 0.42 0.44 0.44 0.46 0.46 0.47 0.53 0.53 0.55 0.56 0.59 0.64 0.67 0.68 0.73 0.74 0.74 0.86 0.87 0.87 0.91 1 1.2 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 55 Appendix E Apple juice residues 0.011 0.027 0.013 0.013 0.099 0.056 0.05 0.073 0.01 0.027 0.035 0.011 0.042 0.06 0.013 0.028 0.011 0.036 0.025 0.011 0.011 0.011 0.011 0.062 0.011 0.033 0.042 0.064 0.011 0.01 0.01 0.01 0.01 0.01 0.013 0.013 0.046 0.039 0.013 0.036 0.013 0.032 0.011 0.031 0.011 0.03 0.011 0.011 0.062 0.011 0.033 0.09 0.013 0.013 0.013 0.01 0.011 0.007 0.01 0.013 0.013 0.031 0.013 0.076 0.013 0.007 0.017 0.074 0.01 0.018 0.007 0.007 0.017 0.026 0.01 0.021 0.007 0.007 0.007 0.013 0.042 0.007 0.007 0.007 0.013 0.013 0.042 0.017 0.013 0.033 0.007 0.015 0.007 0.027 0.007 0.035 0.013 0.01 0.013 0.007 0.01 0.007 0.007 0.007 0.037 0.017 0.11 0.007 0.022 0.013 0.007 0.015 0.007 0.007 0.014 0.033 0.013 0.013 0.013 0.007 0.042 0.007 0.007 0.007 0.021 0.007 0.007 0.013 0.013 0.007 0.013 0.007 0.094 0.017 0.017 0.01 0.01 0.01 0.042 0.023 0.013 0.007 0.007 0.007 0.023 0.01 0.01 0.01 0.01 0.013 0.007 0.01 0.11 0.036 0.007 0.007 0.007 0.007 0.007 0.007 0.022 0.01 0.031 0.167 0.04 0.017 0.017 0.017 0.022 0.01 0.013 0.014 0.081 0.007 0.042 0.042 0.058 0.007 0.033 0.007 0.007 0.007 0.013 0.007 0.05 0.013 0.013 0.013 0.01 0.028 0.035 0.016 0.007 0.007 0.007 0.055 0.007 0.042 0.01 0.01 0.007 0.007 0.019 0.007 0.01 0.007 0.007 0.06 0.023 0.007 0.04 0.007 0.007 0.079 0.017 0.017 0.01 0.01 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.017 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.013 0.007 0.007 0.007 0.007 0.007 0.007 0.03 0.007 0.007 0.027 0.013 0.057 0.038 0.007 0.007 0.01 0.013 0.013 0.12 0.007 0.007 0.007 0.017 0.017 0.027 0.013 0.013 0.013 0.007 0.01 0.007 0.01 0.007 0.007 0.007 0.007 0.007 0.042 0.01 0.01 0.01 0.01 0.013 0.038 0.042 0.01 0.01 0.01 0.01 0.01 0.01 0.028 0.01 0.047 0.042 0.042 0.013 0.042 0.042 0.01 0.01 0.01 0.01 0.031 0.007 0.007 0.007 0.015 0.007 0.007 0.039 0.042 0.049 0.013 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.019 0.007 0.017 0.01 0.017 0.042 0.013 0.013 0.013 0.01 0.01 0.01 0.01 0.039 0.045 0.036 0.042 0.017 0.017 0.042 0.007 0.007 0.01 0.01 0.01 0.013 0.013 0.013 0.042 0.042 0.042 0.013 0.092 0.007 0.01 0.01 0.01 0.01 0.01 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.042 0.042 0.017 0.017 0.017 0.01 0.044 0.01 0.045 0.01 0.01 0.01 0.01 0.075 0.025 0.042 0.007 0.017 0.042 0.042 0.042 0.034 0.017 0.051 0.017 0.007 0.014 0.007 0.015 0.042 0.01 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.014 0.007 0.007 0.007 0.013 0.01 0.013 0.027 0.01 0.057 0.013 0.042 0.072 0.013 0.013 0.042 0.042 0.017 0.034 0.007 0.043 0.013 0.007 0.007 0.007 0.007 0.007 0.007 0.032 0.013 0.077 0.034 0.025 0.014 0.01 0.007 0.01 0.01 0.01 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.013 0.01 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 56 Appendix F Pear Decomposition Residues 0.000026 0.000036 0.000057 0.000060 0.000072 0.000081 0.000106 0.000110 0.000118 0.000133 0.000146 0.000146 0.000154 0.000156 0.000180 0.000180 0.000206 0.000206 0.000217 0.000221 0.000238 0.000244 0.000252 0.000260 0.000264 0.000273 0.000296 0.000298 0.000312 0.000317 0.000326 0.000328 0.000347 0.000351 0.000356 0.000370 0.000381 0.000384 0.000401 0.000407 0.000410 0.000412 0.000428 0.000439 0.000459 0.000460 0.000470 0.000476 0.000487 0.000498 0.000504 0.000508 0.000527 0.000531 0.000545 0.000550 0.000567 0.000574 0.000587 0.000595 0.000603 0.000607 0.000625 0.000636 0.000640 0.000648 0.000665 0.000667 0.000682 0.000694 0.000704 0.000709 0.000721 0.000726 0.000742 0.000754 0.000758 0.000777 0.000786 0.000790 0.000800 0.000810 0.000822 0.000828 0.000843 0.000861 0.000883 0.000883 0.000901 0.000903 0.000906 0.000911 0.000931 0.000941 0.000957 0.000964 0.000974 0.000977 0.000996 0.001001 0.001019 0.001026 0.001052 0.001053 0.001072 0.001078 0.001088 0.001105 0.001118 0.001126 0.001147 0.001150 0.001154 0.001166 0.001177 0.001185 0.001211 0.001217 0.001231 0.001247 0.001263 0.001268 0.001277 0.001288 0.001303 0.001308 0.001325 0.001335 0.001356 0.001356 0.001373 0.001384 0.001405 0.001419 0.001436 0.001443 0.001450 0.001466 0.001491 0.001493 0.001515 0.001521 0.001533 0.001542 0.001555 0.001562 0.001594 0.001605 0.001609 0.001630 0.001639 0.001651 0.001678 0.001687 0.001709 0.001709 0.001730 0.001735 0.001755 0.001766 0.001782 0.001798 0.001804 0.001812 0.001836 0.001838 0.001863 0.001883 0.001904 0.001909 0.001935 0.001944 0.001947 0.001967 0.001988 0.002000 0.002017 0.002033 0.002042 0.002065 0.002070 0.002088 0.002097 0.002101 0.002147 0.002156 0.002171 0.002179 0.002195 0.002214 0.002246 0.002249 0.002265 0.002283 0.002306 0.002307 0.002331 0.002342 0.002361 0.002365 0.002391 0.002401 0.002423 0.002442 0.002458 0.002461 0.002503 0.002516 0.002531 0.002548 0.002562 0.002565 0.002593 0.002610 0.002626 0.002643 0.002664 0.002687 0.002696 0.002712 0.002731 0.002740 0.002765 0.002790 0.002819 0.002835 0.002845 0.002862 0.002875 0.002904 0.002923 0.002940 0.002979 0.002983 0.003009 0.003015 0.003036 0.003042 0.003083 0.003089 0.003112 0.003114 0.003144 0.003176 0.003197 0.003204 0.003218 0.003255 0.003268 0.003284 0.003307 0.003318 0.003348 0.003359 0.003382 0.003407 0.003434 0.003445 0.003483 0.003501 0.003511 0.003539 0.003549 0.003583 0.003593 0.003619 0.003642 0.003654 0.003677 0.003709 0.003750 0.003754 0.003779 0.003782 0.003811 0.003835 0.003876 0.003876 0.003896 0.003921 0.003942 0.003966 0.004000 0.004015 0.004035 0.004057 0.004078 0.004085 0.004133 0.004168 0.004188 0.004198 0.004227 0.004250 0.004265 0.004293 0.004349 0.004350 0.004366 0.004367 0.004428 0.004451 0.004464 0.004487 0.004532 0.004534 0.004576 0.004601 0.004612 0.004627 0.004662 0.004701 0.004714 0.004763 0.004811 0.004816 0.004839 0.004868 0.004869 0.004872 0.004926 0.004951 0.005019 0.005025 0.005046 0.005068 0.005096 0.005097 0.005151 0.005163 0.005203 0.005204 0.005252 0.005300 0.005350 0.005362 0.005402 0.005414 0.005422 0.005463 0.005502 0.005524 0.005538 0.005563 0.005631 0.005635 0.005684 0.005693 0.005719 0.005735 0.005778 0.005798 0.005854 0.005888 0.005921 0.005950 0.005967 0.006015 0.006058 0.006063 0.006085 0.006119 0.006181 0.006201 0.006270 0.006275 0.006301 0.006313 0.006353 0.006403 0.006460 0.006465 0.006498 0.006522 0.006558 0.006606 0.006652 0.006656 0.006679 0.006695 0.006766 0.006795 0.006813 0.006865 0.006920 0.006946 0.006952 0.007006 0.007038 0.007081 0.007128 0.007141 0.007167 0.007230 0.007263 0.007297 0.007359 0.007366 0.007390 0.007400 0.007490 0.007491 0.007555 0.007595 0.007613 0.007651 0.007749 0.007751 0.007803 0.007838 0.007857 0.007871 0.007930 0.007993 0.008043 0.008045 0.008151 0.008158 0.008171 0.008198 0.008282 0.008320 0.008349 0.008362 0.008425 0.008478 0.008506 0.008557 0.008578 0.008604 0.008668 0.008684 0.008755 0.008810 0.008863 0.008885 0.008968 0.009003 0.009031 0.009037 0.009107 0.009138 0.009204 0.009241 0.009291 0.009310 0.009372 0.009401 0.009496 0.009551 0.009616 0.009618 0.009731 0.009742 0.009771 0.009821 0.009870 0.009907 0.009966 0.009992 0.010037 0.010110 0.010177 0.010226 0.010264 0.010328 0.010424 0.010428 0.010444 0.010480 0.010596 0.010618 0.010712 0.010740 0.010789 0.010843 0.010851 0.010936 0.011001 0.011039 0.011075 0.011103 0.011192 0.011248 0.011297 0.011304 0.011436 0.011437 0.011562 0.011583 0.011675 0.011717 0.011788 0.011794 0.011851 0.011940 0.011972 0.011999 0.012123 0.012159 0.012244 0.012264 0.012359 0.012424 0.012503 0.012530 0.012561 0.012657 0.012681 0.012751 0.012848 0.012881 0.012949 0.012993 0.013123 0.013178 0.013269 0.013304 0.013320 0.013410 0.013519 0.013571 0.013576 0.013598 0.013755 0.013806 0.013910 0.013939 0.014046 0.014058 0.014198 0.014207 0.014285 0.014375 0.014391 0.014392 0.014550 0.014613 0.014795 0.014802 0.014843 0.014904 0.015041 0.015052 0.015216 0.015243 0.015290 0.015357 0.015502 0.015530 0.015649 0.015678 0.015790 0.015815 0.015871 0.015872 0.016079 0.016177 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 57 0.016234 0.016312 0.016372 0.016424 0.016527 0.016612 0.016695 0.016748 0.016834 0.016947 0.017076 0.017154 0.017194 0.017272 0.017358 0.017374 0.017606 0.017652 0.017728 0.017806 0.017892 0.017992 0.018105 0.018219 0.018247 0.018347 0.018501 0.018577 0.018598 0.018760 0.018840 0.018950 0.019024 0.019096 0.019225 0.019336 0.019392 0.019535 0.019713 0.019728 0.019808 0.019878 0.020018 0.020123 0.020210 0.020299 0.020355 0.020501 0.020640 0.020750 0.020754 0.020910 0.021098 0.021103 0.021190 0.021376 0.021411 0.021485 0.021635 0.021784 0.021992 0.022031 0.022171 0.022202 0.022364 0.022479 0.022562 0.022705 0.022927 0.022934 0.023135 0.023178 0.023247 0.023302 0.023574 0.023647 0.023801 0.023827 0.023955 0.024029 0.024230 0.024232 0.024628 0.024669 0.024786 0.024819 0.025018 0.025073 0.025259 0.025262 0.025681 0.025688 0.025915 0.025996 0.026251 0.026280 0.026395 0.026457 0.026675 0.026823 0.026920 0.027001 0.027198 0.027243 0.027598 0.027656 0.027723 0.027782 0.028236 0.028308 0.028427 0.028577 0.028841 0.028915 0.029056 0.029087 0.029326 0.029330 0.029752 0.029859 0.029936 0.030172 0.030479 0.030505 0.030776 0.030854 0.031096 0.031135 0.031386 0.031509 0.031574 0.031787 0.032000 0.032106 0.032265 0.032474 0.032743 0.032892 0.032998 0.033174 0.033456 0.033597 0.033799 0.033859 0.034191 0.034302 0.034685 0.034863 0.034975 0.035135 0.035318 0.035475 0.035906 0.035933 0.036101 0.036263 0.036828 0.036834 0.036954 0.037160 0.037439 0.037667 0.037999 0.038145 0.038393 0.038642 0.038743 0.038758 0.039180 0.039533 0.039930 0.040011 0.040208 0.040488 0.040840 0.040889 0.041328 0.041337 0.041567 0.041647 0.042310 0.042329 0.042616 0.042771 0.042986 0.043216 0.043742 0.043922 0.044349 0.044499 0.044817 0.044817 0.045385 0.045515 0.045684 0.045959 0.046295 0.046762 0.046976 0.047301 0.047917 0.047986 0.048260 0.048476 0.048815 0.048877 0.049215 0.049288 0.050285 0.050412 0.050903 0.051086 0.051526 0.051527 0.051945 0.052163 0.052689 0.052739 0.053267 0.053297 0.053904 0.054248 0.054949 0.055198 0.055466 0.055532 0.056229 0.056386 0.056864 0.057407 0.057816 0.058174 0.058656 0.058734 0.059435 0.059668 0.060055 0.060301 0.061019 0.061449 0.061710 0.062050 0.062542 0.062601 0.063506 0.063842 0.064419 0.064859 0.065114 0.065965 0.066309 0.066439 0.067092 0.067498 0.068612 0.068758 0.069217 0.069542 0.070525 0.070863 0.071203 0.071252 0.072173 0.072851 0.073423 0.073688 0.074314 0.074392 0.075568 0.075581 0.077342 0.077426 0.077740 0.077942 0.079275 0.079825 0.080241 0.081229 0.081595 0.081681 0.083244 0.083277 0.084056 0.084540 0.085699 0.085976 0.087475 0.087514 0.089147 0.089190 0.090024 0.091013 0.091099 0.091170 0.092987 0.093669 0.094206 0.095006 0.096872 0.097395 0.098223 0.098443 0.099170 0.099314 0.101410 0.101706 0.104053 0.104335 0.104988 0.105014 0.106447 0.106487 0.109228 0.110185 0.110769 0.111133 0.113222 0.114098 0.115243 0.116052 0.117677 0.117870 0.119215 0.120431 0.123068 0.123150 0.124365 0.124715 0.127861 0.128509 0.130256 0.130702 0.132692 0.133080 0.134727 0.136408 0.138728 0.139430 0.141720 0.141771 0.144600 0.146428 0.146697 0.147514 0.149910 0.150355 0.153914 0.154046 0.156819 0.158216 0.161423 0.162358 0.164462 0.167179 0.169015 0.169932 0.175049 0.175410 0.180147 0.180488 0.183248 0.183729 0.187348 0.189837 0.193960 0.194021 0.196644 0.201256 0.201855 0.206402 0.212607 0.212995 0.214853 0.215491 0.219796 0.220556 0.226726 0.233148 0.233802 0.233850 0.244874 0.248012 0.249571 0.253431 0.257551 0.260404 0.274717 0.274915 0.281823 0.282263 0.290413 0.295063 0.296701 0.297425 0.310392 0.317638 0.320699 0.329875 0.334089 0.335041 0.354246 0.360994 0.364105 0.367917 0.385087 0.396786 0.407670 0.412517 0.441123 0.442496 0.447060 0.465157 0.477866 0.485059 0.500223 0.522995 0.534092 0.547232 0.585947 0.604628 0.620898 0.654328 0.690641 0.694547 0.767175 0.771163 0.780800 0.824072 0.865476 0.938382 0.977047 0.993300 1.131298 1.141054 1.322287 1.396496 1.594982 1.708157 2.633765 2.742968 4.328884 14.332602 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 58 Appendix G peach residue data 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.013 0.013 0.013 0.013 0.017 0.02 0.02 0.023 0.024 0.025 0.025 0.029 0.029 0.03 0.031 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.034 0.04 0.04 0.041 0.042 0.053 0.055 0.056 0.058 0.059 0.06 0.06 0.06 0.06 0.061 0.066 0.069 0.069 0.072 0.072 0.075 0.082 0.084 0.11 0.11 0.11 0.12 0.12 0.13 0.13 0.13 0.13 0.13 0.14 0.14 0.14 0.14 0.15 0.15 0.16 0.17 0.17 0.17 0.18 0.18 0.18 0.19 0.19 0.2 0.2 0.2 0.21 0.21 0.22 0.24 0.24 0.25 0.28 0.29 0.29 0.29 0.3 0.3 0.3 0.31 0.31 0.33 0.35 0.37 0.37 0.38 0.42 0.42 0.43 0.45 0.45 0.45 0.45 0.46 0.47 0.47 0.47 0.48 0.49 0.5 0.57 0.6 0.6 0.61 0.62 0.63 0.65 0.68 0.7 0.71 0.71 0.71 0.72 0.74 0.79 0.81 0.83 0.86 0.87 0.88 0.91 0.91 0.92 0.93 0.94 0.96 0.97 0.99 1 1.1 1.1 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.3 1.3 1.3 1.4 1.7 1.8 2.3 4.8 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 59 Appendix H Peach Single serving residues 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.011 0.022 0.025 0.026 0.03 0.031 0.031 0.041 0.042 0.046 0.049 0.051 0.052 0.054 0.057 0.06 0.065 0.071 0.073 0.083 0.087 0.094 0.1 0.11 0.11 0.12 0.13 0.14 0.14 0.15 0.15 0.15 0.15 0.15 0.16 0.16 0.18 0.2 0.21 0.24 0.25 0.29 0.34 0.37 0.41 0.49 0.5 0.51 0.54 0.56 0.58 0.59 0.76 0.94 0.94 1.2 1.5 2.7 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 60 Appendix I Grape juice residues 0.007 0.01 0.01 0.01 0.023 0.01 0.01 0.023 0.01 0.01 0.01 0.02 0.022 0.028 0.018 0.007 0.007 0.016 0.016 0.016 0.018 0.007 0.007 0.007 0.025 0.033 0.029 0.017 0.01 0.017 0.01 0.017 0.017 0.017 0.029 0.013 0.013 0.007 0.007 0.017 0.017 0.017 0.01 0.01 0.01 0.042 0.027 0.007 0.007 0.007 0.007 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.007 0.016 0.007 0.01 0.01 0.01 0.01 0.01 0.01 0.042 0.042 0.029 0.007 0.007 0.007 0.014 0.007 0.01 0.01 0.01 0.01 0.021 0.01 0.01 0.01 0.02 0.01 0.01 0.01 0.01 0.01 0.007 0.042 0.007 0.029 0.013 0.017 0.007 0.007 0.007 0.017 0.017 0.007 0.03 0.007 0.035 0.01 0.042 0.013 0.01 0.01 0.01 0.01 0.007 0.042 0.042 0.042 0.042 0.013 0.042 0.042 0.01 0.042 0.007 0.01 0.01 0.039 0.01 0.01 0.01 0.01 0.017 0.017 0.007 0.014 0.007 0.013 0.014 0.037 0.007 0.025 0.007 0.007 0.027 0.007 0.007 0.042 0.042 0.01 0.01 0.01 0.01 0.007 0.01 0.017 0.013 0.042 0.042 0.042 0.042 0.042 0.042 0.017 0.017 0.017 0.017 0.036 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.021 0.01 0.022 0.036 0.01 0.044 0.01 0.01 0.02 0.01 0.007 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.039 0.007 0.007 0.017 0.02 0.007 0.01 0.02 0.017 0.013 0.017 0.017 0.017 0.007 0.007 0.007 0.021 0.007 0.02 0.007 0.007 0.01 0.017 0.017 0.013 0.01 0.044 0.01 0.01 0.017 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.01 0.014 0.036 0.01 0.01 0.01 0.013 0.017 0.007 0.017 0.017 0.017 0.013 0.017 0.017 0.01 0.013 Appendix J Pineapple Residues 0.005 0.005 0.005 0.005 0.005 0.01 0.02 0.02 0.08 0.08 0.09 0.1 0.12 0.14 0.14 0.15 0.16 0.16 0.2 0.21 0.22 0.22 0.26 0.277 0.29 0.3 0.3 0.3 0.37 0.42 0.43 0.45 0.45 0.48 0.5 0.5 0.5 0.5 0.52 0.6 0.6 0.6 0.62 0.627 0.64 0.66 0.66 0.69 0.7 0.7 0.73 0.75 0.76 0.79 0.8 0.91 1.01 1.04 1.06 1.07 1.08 1.08 1.12 1.15 1.2 1.24 1.3 1.3 1.39 1.43 1.5 1.5 1.51 1.6 1.6 1.66 1.72 1.73 1.8 1.94 2.2 2.47 2.6 2.75 3 3.02 3.3 3.42 4.37 4.4 4.47 4.95 5.2 5.22 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 61 Appendix K Pineapple Decomposited Numbers 0.000718 0.000904 0.002900 0.003992 0.004241 0.004793 0.005825 0.005828 0.006173 0.006653 0.006964 0.007583 0.008003 0.008311 0.008964 0.009030 0.009433 0.009514 0.010100 0.010172 0.010969 0.011046 0.011828 0.011889 0.012410 0.012558 0.013003 0.013396 0.013530 0.014095 0.014705 0.014761 0.014918 0.014927 0.015451 0.015780 0.016473 0.016539 0.016900 0.017143 0.017465 0.017658 0.018176 0.018630 0.019267 0.019327 0.019450 0.019993 0.020090 0.020623 0.020755 0.020774 0.021741 0.021851 0.022365 0.022412 0.022888 0.023104 0.023816 0.023843 0.023948 0.024210 0.024577 0.025145 0.025790 0.025838 0.026191 0.026445 0.026600 0.027045 0.027205 0.027240 0.027943 0.028399 0.028509 0.028733 0.029374 0.029390 0.030391 0.030424 0.030858 0.031133 0.031355 0.031493 0.032047 0.032324 0.032734 0.032987 0.033502 0.033509 0.033901 0.034399 0.034851 0.034869 0.035289 0.035816 0.036063 0.036208 0.036645 0.037055 0.037309 0.037800 0.037945 0.038123 0.038602 0.039114 0.039476 0.039545 0.040055 0.040192 0.040767 0.040968 0.041614 0.042092 0.042194 0.042389 0.043001 0.043443 0.043804 0.043942 0.044298 0.044432 0.045195 0.045331 0.045680 0.046375 0.046417 0.046625 0.047648 0.047695 0.048421 0.048435 0.048853 0.048915 0.049453 0.049722 0.050648 0.050665 0.050863 0.050973 0.052070 0.052273 0.052585 0.052898 0.053701 0.053757 0.053955 0.054522 0.054589 0.054612 0.055489 0.055514 0.056313 0.056894 0.057266 0.057600 0.057749 0.058427 0.058678 0.059231 0.059425 0.059724 0.060199 0.060267 0.061360 0.061403 0.061894 0.061963 0.062475 0.062805 0.063381 0.063713 0.064484 0.064642 0.064998 0.065577 0.065818 0.066407 0.066522 0.067164 0.067528 0.067870 0.068758 0.068999 0.069347 0.069468 0.070477 0.070510 0.071189 0.071303 0.072131 0.072236 0.072711 0.072877 0.073625 0.074124 0.074510 0.074933 0.075378 0.075384 0.076065 0.076084 0.077096 0.077311 0.078320 0.078357 0.078744 0.079412 0.079502 0.080086 0.080471 0.081096 0.081897 0.082009 0.082227 0.082704 0.083590 0.083733 0.084132 0.084839 0.084986 0.085672 0.086051 0.086591 0.087703 0.087708 0.088316 0.088326 0.088790 0.088882 0.089862 0.089901 0.090648 0.090981 0.092363 0.092403 0.093216 0.093231 0.093768 0.093982 0.094856 0.095162 0.095518 0.096029 0.096773 0.096894 0.098006 0.098043 0.098705 0.099076 0.099846 0.099935 0.100975 0.101239 0.101832 0.102403 0.103061 0.103273 0.104309 0.104558 0.105248 0.105563 0.105872 0.106098 0.106763 0.107227 0.108458 0.108712 0.109151 0.109648 0.110029 0.110274 0.111900 0.111982 0.112762 0.112802 0.113848 0.114135 0.114528 0.114661 0.115542 0.115558 0.116952 0.117258 0.118700 0.118707 0.119112 0.119704 0.120174 0.120318 0.121229 0.121458 0.123015 0.123127 0.123383 0.123690 0.125564 0.125635 0.125669 0.126641 0.127215 0.127940 0.128311 0.128568 0.129673 0.130140 0.130570 0.131225 0.132105 0.132517 0.133152 0.133178 0.134363 0.134513 0.136077 0.136324 0.137251 0.137584 0.138167 0.138768 0.139087 0.139292 0.140588 0.140803 0.142203 0.142389 0.143440 0.143774 0.144218 0.145359 0.146389 0.146732 0.147195 0.147897 0.148458 0.148497 0.150198 0.150507 0.151832 0.151903 0.152196 0.153353 0.153520 0.154555 0.155283 0.155284 0.156661 0.157478 0.157511 0.158026 0.159515 0.159696 0.160297 0.161139 0.161754 0.162879 0.163226 0.164083 0.164906 0.165119 0.166614 0.166821 0.167447 0.168801 0.169801 0.169969 0.170529 0.171029 0.172334 0.172511 0.173842 0.174723 0.175051 0.176209 0.176495 0.177062 0.178607 0.179051 0.179837 0.180043 0.181105 0.181209 0.182417 0.183640 0.184962 0.185211 0.185843 0.186666 0.188181 0.188511 0.188757 0.190080 0.191511 0.191772 0.192558 0.192866 0.193993 0.194229 0.196442 0.196645 0.196920 0.198333 0.198700 0.199895 0.200224 0.200707 0.202350 0.203122 0.204141 0.204973 0.205489 0.205687 0.207347 0.207994 0.209542 0.209644 0.210533 0.210843 0.212477 0.213307 0.214026 0.215580 0.216184 0.216557 0.217800 0.218188 0.219633 0.220747 0.221154 0.221640 0.223903 0.224067 0.225424 0.226303 0.226732 0.228370 0.228534 0.229366 0.230369 0.230902 0.232654 0.234079 0.234730 0.235669 0.236099 0.236696 0.238257 0.239572 0.240440 0.241780 0.242473 0.243773 0.244849 0.244971 0.246452 0.247856 0.248543 0.249227 0.250296 0.250656 0.252140 0.253627 0.254950 0.254954 0.256461 0.256958 0.258290 0.258452 0.260758 0.261629 0.263017 0.263964 0.265867 0.266310 0.268245 0.268691 0.269026 0.270276 0.271623 0.272078 0.273369 0.273583 0.276637 0.277210 0.279194 0.279570 0.280170 0.281674 0.282474 0.284687 0.286531 0.286776 0.287374 0.288482 0.290124 0.291037 0.292565 0.293980 0.294975 0.295348 0.297263 0.297652 0.300817 0.301101 0.301567 0.303072 0.304310 0.305915 0.307202 0.308212 0.308995 0.309151 0.311996 0.313631 0.314373 0.315218 0.317073 0.317835 0.319003 0.319769 0.321688 0.323136 0.324331 0.325383 0.327617 0.327682 0.331635 0.332065 0.333542 0.334433 0.335579 0.335867 0.340140 0.340172 0.341520 0.342533 0.344072 0.345844 0.347539 0.347986 0.350294 0.350998 0.352585 0.353805 0.355453 0.357014 0.358724 0.358773 0.360903 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 62 0.361124 0.363787 0.364095 0.367969 0.368403 0.370158 0.371736 0.372530 0.374470 0.376488 0.378123 0.378768 0.380798 0.381983 0.383751 0.387275 0.387760 0.388249 0.388661 0.393416 0.393441 0.395311 0.396822 0.398445 0.399399 0.402223 0.402490 0.404933 0.405168 0.408471 0.411116 0.413747 0.414382 0.416421 0.417580 0.418531 0.419885 0.422516 0.422965 0.428129 0.428393 0.428683 0.430054 0.432418 0.433292 0.437375 0.437431 0.441615 0.442027 0.446280 0.446632 0.447884 0.448811 0.451327 0.451548 0.457231 0.457289 0.461332 0.461587 0.462831 0.464419 0.469012 0.469898 0.473803 0.473990 0.475937 0.476037 0.478848 0.481870 0.482272 0.486004 0.486828 0.487444 0.491531 0.492815 0.495931 0.498329 0.499129 0.501354 0.506098 0.506479 0.508190 0.510662 0.512668 0.513480 0.517681 0.519945 0.520945 0.521369 0.527984 0.528875 0.530006 0.530619 0.536849 0.538792 0.541101 0.541169 0.544316 0.546983 0.549240 0.550408 0.554769 0.555107 0.559827 0.560950 0.566796 0.567752 0.570936 0.571899 0.573328 0.574322 0.580862 0.582798 0.584566 0.588228 0.591821 0.593420 0.596863 0.597307 0.600453 0.601810 0.605851 0.606974 0.611799 0.613059 0.619969 0.620466 0.622735 0.623720 0.628878 0.631853 0.634406 0.635409 0.638075 0.642536 0.644705 0.646167 0.650440 0.653341 0.656763 0.657408 0.663254 0.666460 0.672296 0.672532 0.675261 0.677031 0.681322 0.683138 0.691583 0.691919 0.695152 0.695635 0.700351 0.702430 0.707562 0.710357 0.718160 0.719154 0.719715 0.723893 0.730890 0.730949 0.734032 0.738350 0.741023 0.741978 0.748290 0.750664 0.755970 0.756041 0.763608 0.768255 0.772535 0.776043 0.778055 0.782722 0.785676 0.788774 0.797664 0.797964 0.805356 0.806419 0.809958 0.810721 0.816879 0.819778 0.828085 0.830453 0.833670 0.834696 0.842047 0.846172 0.849968 0.852162 0.861878 0.863872 0.866703 0.874579 0.879443 0.879632 0.887051 0.891863 0.893710 0.899926 0.903513 0.908272 0.912342 0.915856 0.923117 0.926621 0.931957 0.932678 0.943922 0.945974 0.953793 0.955540 0.960579 0.970193 0.976637 0.979642 0.988480 0.990757 0.992980 0.998644 1.003321 1.009625 1.022624 1.022892 1.025879 1.029033 1.041915 1.046500 1.055282 1.058114 1.062761 1.064961 1.070699 1.072690 1.083888 1.093247 1.094587 1.105345 1.106683 1.115988 1.126098 1.127716 1.138713 1.141804 1.157459 1.157686 1.168917 1.170819 1.174904 1.179671 1.185744 1.188981 1.202694 1.211911 1.220818 1.227641 1.229894 1.232548 1.248643 1.251963 1.269976 1.270789 1.275805 1.286639 1.300162 1.303747 1.310995 1.317617 1.327844 1.329768 1.343275 1.344433 1.361054 1.372347 1.374447 1.385940 1.394743 1.402588 1.412313 1.420201 1.426382 1.428336 1.453538 1.463878 1.473549 1.473944 1.492403 1.502094 1.503803 1.512574 1.526334 1.532615 1.545653 1.564678 1.568884 1.585634 1.598885 1.602101 1.621827 1.622396 1.654688 1.655237 1.659049 1.677840 1.685873 1.687317 1.706891 1.724662 1.737939 1.738242 1.777588 1.777706 1.793182 1.808240 1.826915 1.834065 1.845563 1.859548 1.882921 1.888277 1.919239 1.923095 1.933142 1.933651 1.966528 1.969017 1.995951 1.999864 2.026351 2.037692 2.057432 2.066328 2.102841 2.107841 2.127051 2.154293 2.187142 2.197683 2.214135 2.214959 2.240506 2.272262 2.277981 2.310907 2.337914 2.354385 2.387846 2.405822 2.430035 2.431878 2.466880 2.487723 2.535230 2.547728 2.559498 2.588159 2.601811 2.640644 2.689642 2.698797 2.749880 2.754528 2.764741 2.794478 2.827427 2.871768 2.899381 2.903460 2.969468 3.002839 3.047839 3.059200 3.101256 3.111153 3.171463 3.173458 3.249091 3.268075 3.322117 3.326842 3.401713 3.404024 3.525221 3.562339 3.584484 3.650788 3.719527 3.764859 3.792282 3.882376 3.888121 3.908085 4.029110 4.045111 4.194307 4.197572 4.299340 4.347200 4.423226 4.455255 4.539802 4.667371 4.832164 4.834577 4.985608 5.019010 5.056245 5.234471 5.311164 5.419913 5.495525 5.659193 5.789586 5.849319 6.214068 6.216228 6.290479 6.341444 6.673090 6.812833 6.910124 6.989939 7.471261 7.543548 7.875357 8.204931 8.491655 8.591465 9.000151 9.209957 9.985838 10.354399 11.132104 11.447346 11.482575 11.749342 13.297935 14.257677 16.355846 17.270558 19.204660 20.976783 24.050741 27.526498 35.483131 35.782844 Attachment 1: Anticipated Residues Summary Table and Residue Distribution Files 63 Appendix L ­ Processed Succulent Green Bean Residues 0.01 0.03 0.025 0.011 0.079 0.013 0.058 0.033 0.007 0.007 0.13 0.007 0.19 0.098 0.034 0.011 0.036 0.032 0.1 0.013 0.016 0.017 0.033 0.054 0.01 0.01 0.01 0.023 0.28 0.037 0.055 0.032 0.01 0.4 0.013 0.036 0.013 0.013 0.013 0.05 0.022 0.024 0.011 0.073 0.13 0.02 0.19 0.061 0.01 0.02 0.7 0.042 0.01 0.017 0.011 0.01 0.011 0.062 0.037 0.011 0.15 0.011 0.022 0.007 0.042 0.38 0.042 0.042 0.013 0.057 0.007 0.013 0.017 0.007 0.14 0.071 0.032 0.013 0.007 0.034 0.095 0.18 0.027 0.007 0.023 0.01 0.007 0.007 0.017 0.043 0.007 0.03 0.007 0.007 0.01 0.01 0.01 0.13 0.007 0.013 0.17 0.007 0.13 0.025 0.13 0.23 0.034 0.013 0.013 0.28 0.048 0.007 0.09 0.33 0.29 0.007 0.014 0.09 0.007 0.6 0.017 0.24 0.24 0.007 0.007 0.36 0.007 0.013 0.007 0.24 0.091 0.01 0.069 0.058 0.032 0.048 0.013 0.007 0.051 0.01 0.01 0.01 0.023 0.007 0.007 0.007 0.007 0.038 0.01 0.1 0.035 0.017 0.062 0.007 0.041 0.042 0.042 0.03 0.013 0.013 0.007 Appendix M ­ Cherry Residues 0.18 0.936 1.44 0.013 0.296 0.172 0.014 0.185 0.12 0.015 1.01 0.046 0.089 0.02 0.515 0.07 0.023 1.516 0.896 2.606 0.374 2.86 3.19 1.42 0.381 0.175 0.47 0.201 0.041 0.12 0.047 0.467 0.031 0.239 0.005 0.005 0.005 0.023 0.145 0.037 0.278 0.147 0.257 0.01 0.131 0.172 0.04 0.005 1.5 0.6 0.1 0.14 0.36 0.053 0.26 0.114 0.15 0.27 0.025 0.023 0.005 0.049 0.005 0.73 0.005 0.04 0.022 0.005 0.005 0.1 0.1 0.06 0.04 0.05 0.005 1.37 0.23 0.18 0.54 1.41 0.376 0.005 2.9 1.48 0.263 0.04 0.005 0.1 0.28 Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities 64 Residue File U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for CARBARYL 1989­ 92 data Residue file: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10chroniccarbarylfinal9. RS7 Adjust. #2 NOT used Analysis Date 04­ 08­ 2002 Residue file dated: 04­ 08­ 2002/ 14: 12: 04/ 8 Reference dose (RfD) = 0.01 mg/ kg bw/ day ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Food Crop RESIDUE Adj. Factors Code Grp Food Name (ppm) #1 #2 ­­­­ ­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­ 1 13A Blackberries 0.092600 1.000 0.280 2 13A Boysenberries 0.092600 1.000 0.010 3 13A Dewberries 0.092600 1.000 0.010 4 13A Loganberries 0.092600 1.000 0.010 5 13A Raspberries 0.092600 1.000 0.040 6 13A Youngberries 0.092600 1.000 0.010 7 13B Blueberries 0.090000 1.000 0.220 8 O Cranberries 0.001000 1.000 0.390 9 O Cranberries­ juice 0.001000 1.100 0.390 10 13B Currants 0.090000 1.000 0.010 11 13B Elderberries 0.090000 1.000 0.010 12 13B Gooseberries 0.090000 1.000 0.010 13 O Grapes 0.016000 1.000 0.080 14 O Grapes­ raisins 11­ Uncooked 0.016000 2.170 0.080 12­ Cooked: NFS 0.016000 1.370 0.080 13­ Baked 0.016000 1.370 0.080 14­ Boiled 0.016000 1.370 0.080 18­ Dried 0.016000 2.170 0.080 42­ Frozen: Cooked 0.016000 1.370 0.080 15 O Grapes­ juice 0.010000 1.200 0.080 16 13B Huckleberries 0.090000 1.000 0.010 17 O Strawberries 0.063800 1.000 0.160 20 10 Citrus citron 0.013000 1.000 0.010 22 10 Grapefruit­ peeled fruit 11­ Uncooked 0.013000 1.000 0.040 12­ Cooked: NFS 0.013000 1.000 0.040 14­ Boiled 0.000000 1.000 1.000 31­ Canned: NFS 0.013000 1.000 0.040 23 10 Grapefruit­ juice 0.006000 1.170 0.040 24 10 Kumquats 0.013000 1.000 0.010 26 10 Lemons­ peeled fruit 0.013000 1.000 0.030 27 10 Lemons­ peel 0.013000 1.160 0.030 28 10 Lemons­ juice 0.006000 1.110 0.030 30 10 Limes­ peeled fruit 0.013000 1.000 0.010 31 10 Limes­ peel 0.013000 1.270 0.010 32 10 Limes­ juice 0.006000 1.110 0.010 33 10 Oranges­ juice­ concentrate 0.006000 3.720 0.030 34 10 Oranges­ peeled fruit 11­ Uncooked 0.013000 1.000 0.030 12­ Cooked: NFS 0.013000 1.000 0.030 31­ Canned: NFS 0.013000 1.000 0.030 35 10 Oranges­ peel 0.013000 1.270 0.030 36 10 Oranges­ juice 0.006000 1.000 0.030 37 10 Tangelos 0.013000 1.000 0.010 38 10 Tangerines 11­ Uncooked 0.013000 1.000 0.010 31­ Canned: NFS 0.013000 1.000 0.010 41­ Frozen: NFS 0.013000 1.000 0.010 39 10 Tangerines­ juice 0.006000 1.280 0.010 40 14 Almonds 0.059000 1.000 0.020 43 14 Chestnuts 0.059000 1.000 0.010 44 14 Filberts (hazelnuts) 0.022000 1.000 0.040 47 14 Pecans 0.022000 1.000 0.200 48 14 Walnuts 0.270000 1.000 0.010 50 O Pistachio nuts 0.030000 1.000 0.170 52 11 Apples 11­ Uncooked 0.030000 1.000 0.230 12­ Cooked: NFS 0.030000 1.000 0.230 13­ Baked 0.030000 1.000 0.230 14­ Boiled 0.030000 1.000 0.230 15­ Fried 0.030000 1.000 0.230 18­ Dried 0.030000 1.000 0.230 Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities 65 31­ Canned: NFS 0.030000 1.000 0.230 32­ Canned: Cooked 0.030000 1.000 0.230 33­ Canned: Baked 0.030000 1.000 0.230 34­ Canned: Boiled 0.030000 1.000 0.230 42­ Frozen: Cooked 0.030000 1.000 0.230 53 11 Apples­ dried 0.030000 2.580 0.230 54 11 Apples­ juice/ cider 0.010000 1.000 0.230 55 11 Crabapples 0.030000 1.000 0.010 56 11 Pears 11­ Uncooked 0.009800 1.000 0.030 12­ Cooked: NFS 0.009800 1.000 0.030 13­ Baked 0.009800 1.000 0.030 14­ Boiled 0.009800 1.000 0.030 31­ Canned: NFS 0.009800 1.000 0.030 57 11 Pears­ dried 0.009800 2.580 0.030 58 11 Quinces 0.009800 1.000 0.010 59 12 Apricots 11­ Uncooked 0.070000 1.000 0.010 12­ Cooked: NFS 0.070000 1.000 0.010 14­ Boiled 0.070000 1.000 0.010 31­ Canned: NFS 0.070000 1.000 0.010 34­ Canned: Boiled 0.070000 1.000 0.010 60 12 Apricots­ dried 0.070000 6.000 0.010 61 12 Cherries 11­ Uncooked 0.127000 1.000 0.250 12­ Cooked: NFS 0.127000 1.000 0.120 13­ Baked 0.127000 1.000 0.120 14­ Boiled 0.127000 1.000 0.120 31­ Canned: NFS 0.127000 1.000 0.120 33­ Canned: Baked 0.127000 1.000 0.120 41­ Frozen: NFS 0.127000 1.000 0.120 62 12 Cherries­ dried 0.127000 4.000 0.250 63 12 Cherries­ juice 0.127000 1.500 0.120 64 12 Nectarines 0.070000 1.000 0.120 65 12 Peaches 11­ Uncooked 0.070000 1.000 0.150 12­ Cooked: NFS 0.070000 1.000 0.150 13­ Baked 0.070000 1.000 0.150 14­ Boiled 0.070000 1.000 0.150 31­ Canned: NFS 0.070000 1.000 0.150 41­ Frozen: NFS 0.070000 1.000 0.150 66 12 Peaches­ dried 0.070000 7.000 0.150 67 12 Plums (damsons) 0.070000 0.260 0.050 68 12 Plums­ prunes (dried) 0.070000 0.150 0.050 69 12 Plums/ prune­ juice 0.070000 1.400 0.050 72 O Bananas 0.010000 1.000 1.000 73 O Bananas­ dried 0.010000 3.900 1.000 81 11 Loquats 0.009800 1.000 0.010 82 O Olives 3.850000 1.000 0.010 89 O Pineapples­ peeled fruit 11­ Uncooked 0.053000 0.540 0.500 12­ Cooked: NFS 0.053000 0.540 0.500 13­ Baked 0.053000 0.540 0.500 14­ Boiled 0.053000 0.540 0.500 31­ Canned: NFS 0.053000 0.540 0.500 33­ Canned: Baked 0.053000 0.540 0.500 41­ Frozen: NFS 0.053000 0.540 0.500 90 O Pineapples­ dried 0.053000 5.000 0.500 91 O Pineapples­ juice 0.053000 0.540 0.500 94 O Plantains­ ripe 0.010000 1.000 1.000 123 19A Dill 0.200000 1.000 0.010 126 1AB Horseradish 0.011600 1.000 0.010 139 8 Paprika 0.108000 1.000 0.010 141 9A Melons­ cantaloupes­ juice 0.005600 1.000 0.070 142 9A Melons­ cantaloupes­ pulp 0.005600 1.000 0.070 143 9A Casabas 0.005600 1.000 0.010 144 9A Crenshaws 0.005600 1.000 0.010 145 9A Melons­ honeydew 0.005600 1.000 0.190 146 9A Melons­ persian 0.005600 1.000 0.010 147 9A Watermelon 0.001900 1.000 0.130 148 9B Cucumbers 0.003300 1.000 0.140 149 9B Pumpkin 0.006270 1.000 0.310 150 9B Squash­ summer 0.016000 1.000 0.110 151 9B Squash­ winter 0.006000 1.000 0.110 152 9B Bitter melon 0.005600 1.000 0.010 154 8 Eggplant 0.005000 1.000 0.090 155 8 Peppers­ sweet( garden) 0.020000 1.000 0.130 156 8 Peppers­ chilli incl jalapeno 0.108000 1.000 0.010 Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities 66 157 8 Peppers­ other 0.108000 1.000 0.010 158 8 Pimientos 0.108000 1.000 0.010 159 8 Tomatoes­ whole 11­ Uncooked 0.004000 1.000 0.050 12­ Cooked: NFS 0.004000 1.000 0.050 13­ Baked 0.004000 1.000 0.050 14­ Boiled 0.004000 1.000 0.050 15­ Fried 0.004000 1.000 0.050 31­ Canned: NFS 0.004000 1.000 0.150 32­ Canned: Cooked 0.004000 1.000 0.150 33­ Canned: Baked 0.004000 1.000 0.150 34­ Canned: Boiled 0.004000 1.000 0.150 42­ Frozen: Cooked 0.004000 1.000 0.150 160 8 Tomatoes­ juice 0.004000 0.520 0.150 161 8 Tomatoes­ puree 0.004000 0.650 0.150 162 8 Tomatoes­ paste 0.004000 0.650 0.150 163 8 Tomatoes­ catsup 0.004000 0.650 0.150 165 2 Beets­ garden­ tops( greens) 10.140000 1.000 0.170 166 4B Celery 0.015200 1.000 0.030 168 5A Broccoli 0.013000 1.000 0.040 169 5A Brussels sprouts 0.001000 1.000 0.330 170 5A Cabbage­ green and red 11­ Uncooked 0.001000 0.250 0.020 12­ Cooked: NFS 0.001000 0.025 0.020 13­ Baked 0.001000 0.025 0.020 14­ Boiled 0.001000 0.025 0.020 15­ Fried 0.001000 0.025 0.020 31­ Canned: NFS 0.001000 0.250 0.020 32­ Canned: Cooked 0.001000 0.025 0.020 51­ Cured: NFS (smoked/ pickled/ saltd) 0.001000 0.025 0.020 171 5A Cauliflower 0.013000 1.000 0.020 172 5B Collards 2.780000 1.000 0.040 174 5B Kale 2.780000 1.000 0.010 175 5A Kohlrabi 0.001000 1.000 0.010 176 4A Lettuce­ leafy varieties 0.001000 1.000 0.010 177 4A Dandelion­ greens 0.008200 1.000 0.010 178 4A Endive­ curley and escarole 0.001000 1.000 0.010 182 4A Lettuce­ unspecified 0.016900 1.000 0.030 183 5B Mustard greens 2.780000 1.000 0.010 184 4A Parsley 0.008200 1.000 0.010 185 4B Rhubarb 0.015200 1.000 0.010 186 4A Spinach 11­ Uncooked 0.008200 1.000 0.010 12­ Cooked: NFS 0.008200 1.000 0.010 13­ Baked 0.008200 1.000 0.010 14­ Boiled 0.008200 1.000 0.010 31­ Canned: NFS 0.006000 1.000 0.010 32­ Canned: Cooked 0.006000 1.000 0.010 34­ Canned: Boiled 0.006000 1.000 0.010 42­ Frozen: Cooked 0.008200 1.000 0.010 44­ Frozen: Boiled 0.008200 1.000 0.010 187 4B Swiss chard 0.015200 1.000 0.010 188 2 Turnips­ tops 15.300000 1.000 0.010 192 4A Lettuce­ head varieties 0.016900 1.000 0.030 195 O Grapes­ leaves 0.016000 1.000 0.080 197 1AB Beets­ garden­ roots 0.024000 1.000 0.170 198 1AB Carrots 0.011600 1.000 0.040 207 1C Potatoes/ white­ whole 11­ Uncooked 0.011900 1.000 0.020 12­ Cooked: NFS 0.011900 1.000 0.020 13­ Baked 0.011900 1.200 0.020 14­ Boiled 0.011900 2.500 0.020 15­ Fried 0.011900 0.040 0.020 31­ Canned: NFS 0.011900 1.000 0.020 208 1C Potatoes/ white­ unspecified 0.011900 1.000 0.020 209 1C Potatoes/ white­ peeled 11­ Uncooked 0.011900 1.000 0.020 12­ Cooked: NFS 0.011900 1.000 0.020 13­ Baked 0.011900 1.200 0.020 14­ Boiled 0.011900 2.500 0.020 15­ Fried 0.011900 0.040 0.020 31­ Canned: NFS 0.011900 1.000 0.020 32­ Canned: Cooked 0.011900 1.000 0.020 34­ Canned: Boiled 0.011900 2.500 0.020 42­ Frozen: Cooked 0.011900 1.000 0.020 43­ Frozen: Baked 0.011900 1.200 0.020 45­ Frozen: Fried 0.011900 0.040 0.020 Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities 67 210 1C Potatoes/ white­ dry 0.011900 0.400 0.020 211 1C Potatoes/ white­ peel only 13­ Baked 0.011900 1.200 0.020 15­ Fried 0.011900 0.040 0.020 212 1AB Radishes­ roots 0.024000 1.000 0.010 213 2 Radishes­ tops 10.140000 1.000 0.010 214 1AB Rutabagas­ roots 0.121000 1.000 0.010 215 2 Rutabagas­ tops 15.300000 1.000 0.010 216 1AB Salsify( oyster plant) 0.011600 1.000 0.010 218 1CD Sweet potatoes (incl yams) 0.006500 1.000 0.180 219 1AB Turnips­ roots 0.121000 1.000 0.010 220 1AB Parsnips 0.011600 1.000 0.010 227 6C Beans­ dry­ great northern 0.067000 1.000 0.010 228 6C Beans­ dry­ kidney 0.067000 1.000 0.010 229 6C Beans­ dry­ lima 0.067000 1.000 0.010 230 6C Beans­ dry­ navy (pea) 0.067000 1.000 0.010 231 6C Beans­ dry­ other 0.067000 1.000 0.010 232 6C Beans­ dry­ pinto 0.067000 1.000 0.010 233 6B Beans­ succulent­ lima 0.011780 1.000 0.130 234 6A Beans­ succulent­ green 11­ Uncooked 0.023200 1.000 0.140 12­ Cooked: NFS 0.023200 1.000 0.140 14­ Boiled 0.023200 1.000 0.140 31­ Canned: NFS 0.011780 1.000 0.100 32­ Canned: Cooked 0.011780 1.000 0.100 34­ Canned: Boiled 0.011780 1.000 0.100 42­ Frozen: Cooked 0.011780 1.000 0.100 44­ Frozen: Boiled 0.011780 1.000 0.100 51­ Cured: NFS (smoked/ pickled/ saltd) 0.011780 1.000 0.100 235 6A Beans­ succulent­ other 0.011780 1.000 0.100 236 6A Beans­ succulent­ yellow/ wax 14­ Boiled 0.023200 1.000 0.140 32­ Canned: Cooked 0.011780 1.000 0.100 42­ Frozen: Cooked 0.011780 1.000 0.100 237 15 Corn/ pop 0.010000 1.000 0.010 238 15 Corn/ sweet 0.008500 1.000 0.010 240 6C Peas (garden)­ dry 12­ Cooked: NFS 0.146000 0.045 0.030 14­ Boiled 0.146000 0.045 0.030 31­ Canned: NFS 0.146000 0.300 0.030 32­ Canned: Cooked 0.146000 0.045 0.030 34­ Canned: Boiled 0.146000 0.045 0.030 241 6AB Peas (garden)­ green 11­ Uncooked 0.130000 0.300 0.020 12­ Cooked: NFS 0.130000 0.300 0.020 13­ Baked 0.130000 0.300 0.020 14­ Boiled 0.130000 0.300 0.020 15­ Fried 0.130000 0.300 0.020 31­ Canned: NFS 0.012700 1.000 0.010 32­ Canned: Cooked 0.012700 1.000 0.010 34­ Canned: Boiled 0.012700 1.000 0.010 42­ Frozen: Cooked 0.012700 1.000 0.010 44­ Frozen: Boiled 0.012700 1.000 0.010 45­ Frozen: Fried 0.012700 1.000 0.010 243 6C Lentils 0.067000 1.000 0.010 244 6C Mung beans (sprouts) 0.067000 1.000 0.010 245 O Okra 12­ Cooked: NFS 1.000000 0.180 0.320 14­ Boiled 1.000000 0.050 0.320 15­ Fried 1.000000 0.180 0.320 32­ Canned: Cooked 1.000000 0.180 0.320 42­ Frozen: Cooked 1.000000 0.180 0.320 44­ Frozen: Boiled 1.000000 0.050 0.320 249 6C Beans­ dry­ broadbeans 0.067000 1.000 0.010 250 6B Beans­ succulent­ broadbeans 0.023200 1.000 0.140 251 6C Beans­ dry­ pigeon beans 0.067000 1.000 0.010 253 6 Beans­ unspecified 0.023200 1.000 0.140 255 6A Soybeans­ sprouted seeds 0.001500 0.330 0.010 256 Beans­ dry­ hyacinth 0.067000 1.000 0.010 257 Beans­ succulent­ hyacinth 0.023200 1.000 0.140 258 6C Beans­ dry­ blackeye peas/ cowpea 0.067000 1.000 0.010 259 6C Beans­ dry­ garbanzo/ chick pea 0.067000 1.000 0.010 260 O Asparagus 0.003200 1.000 0.430 266 15 Corn grain­ endosperm 0.008500 1.000 0.010 267 15 Corn grain­ bran 0.008500 1.000 0.010 268 15 Corn grain/ sugar/ hfcs 0.008500 1.500 0.010 270 15 Rice­ rough (brown) 7.400000 1.000 0.010 Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities 68 271 15 Rice­ milled (white) 7.400000 0.030 0.010 275 15 Sorghum (including milo) 0.001500 1.000 0.010 276 15 Wheat­ rough 0.001500 1.000 0.010 277 15 Wheat­ germ 0.001500 0.650 0.010 278 15 Wheat­ bran 0.001500 1.000 0.010 279 15 Wheat­ flour 0.001500 0.100 0.010 280 15 Millet 0.001500 1.000 0.010 282 1A Sugar­ beet 0.010000 0.040 0.020 287 6C Guar beans 0.023200 1.000 0.140 289 15 Corn grain­ oil 0.008500 0.250 0.010 292 O Flax seed 0.010000 1.000 0.010 293 O Peanuts­ oil 0.010000 0.290 0.030 297 6A Soybeans­ oil 0.001500 0.005 0.010 298 O Sunflower­ oil 0.042000 0.030 0.010 300 O Olive oil 3.850000 0.810 0.010 303 6A Soybean­ other 0.001500 1.000 0.010 304 6A Soybeans­ mature seeds dry 0.001500 1.000 0.010 305 6A Soybeans­ flour (full fat) 0.001500 1.000 0.010 306 6A Soybeans­ flour (low fat) 0.001500 1.000 0.010 307 6A Soybeans­ flour (defatted) 0.001500 1.000 0.010 315 O Grapes­ wine and sherry 0.016000 1.000 0.080 318 D Milk­ nonfat solids 0.000300 1.000 0.230 319 D Milk­ fat solids 0.000300 1.000 0.230 320 D Milk sugar (lactose) 0.000300 1.000 0.230 321 M Beef­ meat byproducts 0.017900 1.000 0.230 322 M Beef­ other organ meats 0.017900 1.000 0.230 323 M Beef­ dried 0.000300 1.920 0.230 324 M Beef­ fat w/ o bones 0.000300 1.000 0.230 325 M Beef­ kidney 0.017900 1.000 0.230 326 M Beef­ liver 0.006300 1.000 0.230 327 M Beef­ lean (fat/ free) w/ o bones 0.000300 1.000 0.230 328 M Goat­ meat byproducts 0.017900 1.000 0.230 329 M Goat­ other organ meats 0.017900 1.000 0.230 330 M Goat­ fat w/ o bone 0.000300 1.000 0.230 331 M Goat­ kidney 0.017900 1.000 0.230 332 M Goat­ liver 0.006300 1.000 0.230 333 M Goat­ lean (fat/ free) w/ o bone 0.000300 1.000 0.230 336 M Sheep­ meat byproducts 0.017900 1.000 0.230 337 M Sheep­ other organ meats 0.017900 1.000 0.230 338 M Sheep­ fat w/ o bone 0.000300 1.000 0.230 339 M Sheep­ kidney 0.017900 1.000 0.230 340 M Sheep­ liver 0.006300 1.000 0.230 341 M Sheep­ lean (fat free) w/ o bone 0.000300 1.000 0.230 342 M Pork­ meat byproducts 0.001428 1.000 0.230 343 M Pork­ other organ meats 0.001428 1.000 0.230 344 M Pork­ fat w/ o bone 0.000094 1.000 0.230 345 M Pork­ kidney 0.001428 1.000 0.230 346 M Pork­ liver 0.000792 1.000 0.230 347 M Pork­ lean (fat free) w/ o bone 0.000348 1.000 0.230 349 F Fish­ shellfish 0.250000 1.000 1.000 377 11 Apples­ juice­ concentrate 0.010000 3.000 0.230 378 O Bananas­ juice 0.010000 1.000 1.000 379 1A Sugar­ beet­ molasses 0.010000 0.040 0.020 380 13A Blackberries­ juice 0.092600 1.000 0.280 383 5B Cabbage­ savoy 0.001000 0.025 0.020 384 4B Celery juice 0.015200 1.000 0.030 388 15 Corn grain/ sugar­ molasses 0.008500 1.500 0.010 389 O Cranberries­ juice­ concentrate 0.001000 3.300 0.390 392 O Grapes­ juice­ concentrate 0.010000 3.600 0.080 398 D Milk­ based water 0.000300 1.000 0.230 402 12 Peaches­ juice 0.070000 1.000 0.150 403 O Peanuts­ butter 0.010000 1.890 0.030 404 11 Pears­ juice 0.009800 0.370 0.030 405 6B Peas­ succulent/ blackeye/ cowpea 12­ Cooked: NFS 0.130000 0.045 0.020 14­ Boiled 0.130000 0.045 0.020 32­ Canned: Cooked 0.012700 0.045 0.010 42­ Frozen: Cooked 0.012700 0.045 0.010 406 O Pineapples­ juice­ concentrate 0.053000 0.540 0.500 407 1AB Radishes­ japanese (daiken) 0.024000 1.000 0.010 408 15 Rice­ bran 7.400000 0.400 0.010 410 12 Apricot juice 0.070000 1.000 0.010 413 6A Snowpeas 11­ Uncooked 0.130000 1.000 0.020 12­ Cooked: NFS 0.130000 1.000 0.020 14­ Boiled 0.130000 1.000 0.020 15­ Fried 0.130000 1.000 0.020 42­ Frozen: Cooked 0.012700 1.000 0.010 Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities 69 415 9B Squash­ spaghetti 0.006000 1.000 0.110 416 O Strawberries­ juice 0.063800 1.000 0.160 417 O Sunflower­ seeds 0.042000 1.000 0.010 420 10 Tangerines­ juice­ concentrate 0.006000 4.080 0.010 423 8 Tomatoes­ dried 0.004000 0.520 0.150 424 M Veal­ fat w/ o bones 0.000300 1.000 0.230 425 M Veal­ lean (fat free) w/ o bones 0.006300 1.000 0.230 426 M Veal­ kidney 0.017900 1.000 0.230 427 M Veal­ liver 0.006300 1.000 0.230 428 M Veal­ other organ meats 0.017900 1.000 0.230 429 M Veal­ dried 0.006300 1.920 0.230 430 M Veal­ meat byproducts 0.017900 1.000 0.230 431 14 Walnut oil 0.270000 1.000 0.010 436 9A Watermelon­ juice 0.001900 1.000 0.130 437 15 Wheat­ germ oil 0.001500 0.650 0.010 439 9B Wintermelon 0.005600 1.000 0.010 441 10 Grapefruit­ juice­ concentrate 0.006000 4.580 0.040 442 10 Lemons­ juice­ concentrate 0.006000 6.330 0.030 443 10 Limes­ juice­ concentrate 0.006000 3.330 0.010 448 10 Grapefruit peel 0.013000 1.000 0.040 480 O Plantains­ green 0.010000 1.000 1.000 481 O Plantains­ dried 0.010000 3.900 1.000 940 O Peanuts­ hulled 0.010000 1.000 0.030 Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities 70 Chronic Results ­ 1989­ 92 Consumption Data U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for CARBARYL (1989­ 92 data) Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10chroniccarbarylfinal9. RS7 Adjustment factor #2 used. Analysis Date 04­ 08­ 2002/ 14: 13: 35 Residue file dated: 04­ 08­ 2002/ 14: 12: 04/ 8 Reference dose (RfD, Chronic) = .01 mg/ kg bw/ day =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Percent of Subgroup body wt/ day Rfd ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­­­ U. S. Population (total) 0.000032 0.3% U. S. Population (spring season) 0.000031 0.3% U. S. Population (summer season) 0.000030 0.3% U. S. Population (autumn season) 0.000034 0.3% U. S. Population (winter season) 0.000033 0.3% Northeast region 0.000039 0.4% Midwest region 0.000023 0.2% Southern region 0.000035 0.3% Western region 0.000031 0.3% Hispanics 0.000025 0.3% Non­ hispanic whites 0.000031 0.3% Non­ hispanic blacks 0.000038 0.4% Non­ hisp/ non­ white/ non­ black 0.000054 0.5% All infants (< 1 year) 0.000054 0.5% Nursing infants 0.000031 0.3% Non­ nursing infants 0.000063 0.6% Children 1­ 6 yrs 0.000057 0.6% Children 7­ 12 yrs 0.000036 0.4% Females 13­ 19 (not preg or nursing) 0.000019 0.2% Females 20+ (not preg or nursing) 0.000028 0.3% Females 13­ 50 yrs 0.000026 0.3% Females 13+ (preg/ not nursing) 0.000031 0.3% Females 13+ (nursing) 0.000032 0.3% Males 13­ 19 yrs 0.000022 0.2% Males 20+ yrs 0.000031 0.3% Seniors 55+ 0.000031 0.3% Pacific Region 0.000033 0.3% ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Cancer Results ­ 1989­ 92 Consumption Data U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for CARBARYL (1989­ 92 data) Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10chroniccarbarylfinal9. RS7 Adjustment factor #2 used. Analysis Date 04­ 08­ 2002/ 14: 13: 17 Residue file dated: 04­ 08­ 2002/ 14: 12: 04/ 8 Q* = 0.000875 =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Lifetime risk Subgroup body wt/ day (Q*= .000875) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­ U. S. Population (total) 0.000032 2.80E­ 08 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Attachment 2: Chronic and Cancer Dietary Exposure Analysis: All Commodities 71 Chronic Results ­ 1994­ 98 Consumption Data U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for CARBARYL (1994­ 98 data) Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10chroniccarbarylfinal9. RS7 Adjustment factor #2 used. Analysis Date 04­ 08­ 2002/ 14: 15: 03 Residue file dated: 04­ 08­ 2002/ 14: 12: 04/ 8 Reference dose (RfD, Chronic) = .01 mg/ kg bw/ day =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Percent of Subgroup body wt/ day Rfd ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­­­ U. S. Population (total) 0.000035 0.3% U. S. Population (spring season) 0.000035 0.3% U. S. Population (summer season) 0.000033 0.3% U. S. Population (autumn season) 0.000036 0.4% U. S. Population (winter season) 0.000035 0.4% Northeast region 0.000042 0.4% Midwest region 0.000028 0.3% Southern region 0.000033 0.3% Western region 0.000038 0.4% Hispanics 0.000033 0.3% Non­ hispanic whites 0.000032 0.3% Non­ hispanic blacks 0.000043 0.4% Non­ hisp/ non­ white/ non­ black 0.000060 0.6% All infants (< 1 year) 0.000059 0.6% Nursing infants 0.000038 0.4% Non­ nursing infants 0.000067 0.7% Children 1­ 6 yrs 0.000074 0.7% Children 7­ 12 yrs 0.000034 0.3% Females 13­ 19 (not preg or nursing) 0.000021 0.2% Females 20+ (not preg or nursing) 0.000029 0.3% Females 13­ 50 yrs 0.000028 0.3% Females 13+ (preg/ not nursing) 0.000028 0.3% Females 13+ (nursing) 0.000031 0.3% Males 13­ 19 yrs 0.000026 0.3% Males 20+ yrs 0.000032 0.3% Seniors 55+ 0.000030 0.3% ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Cancer Results ­ 1994­ 98 Consumption Data U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for CARBARYL (1994­ 98 data) Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10chroniccarbarylfinal9. RS7 Adjustment factor #2 used. Analysis Date 04­ 08­ 2002/ 14: 15: 14 Residue file dated: 04­ 08­ 2002/ 14: 12: 04/ 8 Q* = 0.000875 =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Lifetime risk Subgroup body wt/ day (Q*= .000875) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­ U. S. Population (total) 0.000035 3.04E­ 08 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Attachment 3: Acute Dietary Exposure Analysis: All Commodities 72 Residue File U. S. Environmental Protection Agency Ver. 7.76 DEEM Acute analysis for CARBARYL Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10carbarylfinal9. RS7 Analysis Date 04­ 15­ 2002 Residue file dated: 04­ 02­ 2002/ 14: 55: 15/ 8 Reference dose (aRfD) = 0.01 mg/ kg bw/ day ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RDL indices and parameters for Monte Carlo Analysis: Index Dist Parameter #1 Param #2 Param #3 Comment # Code ­­­­­ ­­­­ ­­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­ 1 6 Gardenbeet. rdf 2 6 Carrot. rdf 3 6 chic hors parsnip salsify. rdf 4 6 Potato. rdf 5 6 radishes. rdf 6 6 Turnip. rdf 7 6 sweetpotato. rdf 8 6 topsgardenbeet. rdf 9 6 topsradish. rdf 10 6 Topsturnip. rdf 11 6 celery. rdf 12 6 spinach. rdf 13 6 cannedspinach. rdf 14 6 lettucehd. rdf 15 6 lettuceleaf. rdf 16 6 rhubarb. rdf 17 6 broccoli. rdf 18 6 brusselssprouts. rdf 19 6 cabbage. rdf 20 6 cauliflower. rdf 21 6 collards. rdf 22 6 mustards. rdf 23 6 kohrabi. rdf 24 6 beanssucculentfresh. rdf 25 6 beanssucculentprocessed. rdf 26 6 beanslima. rdf 27 6 Peasfresh. rdf 28 6 Peasprocessed. rdf 29 6 alleggplant. rdf 30 6 peppersnonbell. rdf 31 6 allsweetpepper. rdf 32 6 tomatoesPB. rdf 33 6 tomatoesNB. rdf 34 6 allcucumber. rdf 35 6 melon. rdf 36 6 cantaloupe. rdf 37 6 honeydew. rdf 38 6 allwatermelon. rdf 39 6 pumpkin. rdf 40 6 wintersquash. rdf 41 6 allsummersquash. rdf 42 6 citrus. rdf 43 6 grapefruitjuice. rdf 44 6 lemonjuice. rdf 45 6 orangesdecomp. rdf 46 6 limejuice. rdf 47 6 orangejuice. rdf 48 6 appledecomp. rdf 49 6 apple. rdf 50 6 applejuice. rdf 51 6 peardecomp. rdf 52 6 pear. rdf 53 6 quince. rdf 54 6 crabapple. rdf 55 6 apricot. rdf 56 6 Apricotss. rdf 57 6 allsweetcherries. rdf 58 6 alltartcherries. rdf 59 6 nectarine. rdf 60 6 peachSS. rdf 61 6 Peach. rdf 62 6 plum2. rdf 63 6 blackberries. rdf 64 6 allblueberry. rdf 65 6 boysenberry. rdf 66 6 currant. rdf Attachment 3: Acute Dietary Exposure Analysis: All Commodities 73 67 6 allraspberries. rdf 68 6 almonds. rdf 69 6 chestnut. rdf 70 6 filbert. rdf 71 6 pecan. rdf 72 6 walnut. rdf 73 6 corn. rdf 74 6 allasparagus. rdf 75 6 banana. rdf 76 6 allcranberry. rdf 77 6 grapes. rdf 78 6 grapejuice. rdf 79 6 okra. rdf 80 6 olives. rdf 81 6 pineappledecomp. rdf 82 6 pineapplemexico. rdf 83 6 pistachio. rdf 84 6 strawberrypdp. rdf 85 6 sunflower. rdf 86 6 milk2. rdf 87 6 ruminantliver2. rdf 88 6 ruminantkidney2. rdf 89 6 swinemeat2. rdf 90 6 swinefat2. rdf 91 6 swineliver2. rdf 92 6 swinekidney2. rdf 93 6 poultry. rdf 94 6 eggs. rdf 95 6 pineappleother. rdf 96 6 Plumdecomp. rdf 97 6 pineappledomestic. rdf 98 6 appledried. rdf 99 6 soybean. rdf 100 6 wheat. rdf Food Crop Food Def Res Adj. Factors ­­­­­­­ RDL Indices and Ratios­­­­­­­ Code Grp Name (ppm) #1 #2 I# 1 Ratio# 1 I# 2 Ratio# 2 I# 3 Ratio# 3 ­­­­ ­­­­ ­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­ 1 13A Blackberries 1.000000 1.000 1.000 63 1.0000 2 13A Boysenberries 1.000000 1.000 1.000 65 1.0000 3 13A Dewberries 1.000000 1.000 1.000 65 1.0000 4 13A Loganberries 1.000000 1.000 1.000 65 1.0000 5 13A Raspberries 1.000000 1.000 1.000 67 1.0000 6 13A Youngberries 1.000000 1.000 1.000 65 1.0000 7 13B Blueberries 1.000000 1.000 1.000 64 1.0000 8 O Cranberries 1.000000 1.000 1.000 76 1.0000 9 O Cranberries­ juice 1.000000 1.100 1.000 76 1.0000 10 13B Currants 1.000000 1.000 1.000 66 1.0000 11 13B Elderberries 1.000000 1.000 1.000 66 1.0000 12 13B Gooseberries 1.000000 1.000 1.000 66 1.0000 13 O Grapes 1.000000 1.000 1.000 77 1.0000 14 O Grapes­ raisins 11­ Uncooked 1.000000 2.170 1.000 77 1.0000 12­ Cooked: NFS 1.000000 1.370 1.000 77 1.0000 13­ Baked 1.000000 1.370 1.000 77 1.0000 14­ Boiled 1.000000 1.370 1.000 77 1.0000 18­ Dried 1.000000 1.370 1.000 77 1.0000 42­ Frozen: Cooked Attachment 3: Acute Dietary Exposure Analysis: All Commodities 74 1.000000 1.370 1.000 77 1.0000 15 O Grapes­ juice 1.000000 1.000 1.000 78 1.0000 16 13B Huckleberries 1.000000 1.000 1.000 66 1.0000 17 O Strawberries 1.000000 1.000 1.000 84 1.0000 20 10 Citrus citron 1.000000 1.000 1.000 42 1.0000 22 10 Grapefruit­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 14­ Boiled 0.000000 1.000 1.000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 23 10 Grapefruit­ juice 1.000000 1.170 1.000 43 1.0000 24 10 Kumquats 1.000000 1.000 1.000 42 1.0000 26 10 Lemons­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 27 10 Lemons­ peel 1.000000 1.190 1.000 42 1.0000 28 10 Lemons­ juice 1.000000 1.110 1.000 44 1.0000 30 10 Limes­ peeled fruit 1.000000 1.000 1.000 45 1.0000 31 10 Limes­ peel 1.000000 1.270 1.000 42 1.0000 32 10 Limes­ juice 1.000000 1.110 1.000 46 1.0000 33 10 Oranges­ juice­ concentrate 1.000000 3.700 1.000 47 1.0000 34 10 Oranges­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 35 10 Oranges­ peel 1.000000 1.270 1.000 42 1.0000 36 10 Oranges­ juice 1.000000 1.000 1.000 47 1.0000 37 10 Tangelos 1.000000 1.000 1.000 45 1.0000 38 10 Tangerines 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 42 1.0000 39 10 Tangerines­ juice 1.000000 1.280 1.000 46 1.0000 40 14 Almonds 1.000000 1.000 1.000 68 1.0000 43 14 Chestnuts 1.000000 1.000 1.000 69 1.0000 44 14 Filberts (hazelnuts) 1.000000 1.000 1.000 70 1.0000 48 14 Walnuts 1.000000 1.000 1.000 72 1.0000 50 O Pistachio nuts 1.000000 1.000 1.000 83 1.0000 52 11 Apples 11­ Uncooked 1.000000 1.000 1.000 48 1.0000 Attachment 3: Acute Dietary Exposure Analysis: All Commodities 75 12­ Cooked: NFS 1.000000 1.000 1.000 48 1.0000 13­ Baked 1.000000 1.000 1.000 48 1.0000 14­ Boiled 1.000000 1.000 1.000 48 1.0000 15­ Fried 1.000000 1.000 1.000 48 1.0000 18­ Dried 0.009000 1.000 1.000 98 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 49 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 49 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 49 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 49 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 49 1.0000 53 11 Apples­ dried 1.000000 2.600 1.000 49 1.0000 54 11 Apples­ juice/ cider 1.000000 1.000 1.000 50 1.0000 55 11 Crabapples 1.000000 1.000 1.000 54 1.0000 56 11 Pears 11­ Uncooked 1.000000 1.000 1.000 51 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 51 1.0000 13­ Baked 1.000000 1.000 1.000 51 1.0000 14­ Boiled 1.000000 1.000 1.000 51 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 52 1.0000 57 11 Pears­ dried 1.000000 2.600 1.000 52 1.0000 58 11 Quinces 1.000000 1.000 1.000 53 1.0000 59 12 Apricots 11­ Uncooked 1.000000 1.000 1.000 56 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 56 1.0000 14­ Boiled 1.000000 1.000 1.000 56 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 55 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 55 1.0000 60 12 Apricots­ dried 1.000000 6.000 1.000 55 1.0000 61 12 Cherries 11­ Uncooked 1.000000 1.000 1.000 57 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 58 1.0000 13­ Baked 1.000000 1.000 1.000 58 1.0000 14­ Boiled 1.000000 1.000 1.000 58 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 58 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 58 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 58 1.0000 62 12 Cherries­ dried 1.000000 4.000 1.000 57 1.0000 63 12 Cherries­ juice 1.000000 1.500 1.000 58 1.0000 64 12 Nectarines 1.000000 1.000 1.000 59 1.0000 65 12 Peaches Attachment 3: Acute Dietary Exposure Analysis: All Commodities 76 11­ Uncooked 1.000000 1.000 1.000 60 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 60 1.0000 13­ Baked 1.000000 1.000 1.000 60 1.0000 14­ Boiled 1.000000 1.000 1.000 60 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 61 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 61 1.0000 66 12 Peaches­ dried 1.000000 7.000 1.000 61 1.0000 67 12 Plums (damsons) 11­ Uncooked 1.000000 1.000 1.000 96 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 96 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 62 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 62 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 62 1.0000 68 12 Plums­ prunes (dried) 1.000000 0.150 1.000 62 1.0000 69 12 Plums/ prune­ juice 1.000000 1.400 1.000 62 1.0000 72 O Bananas 1.000000 1.000 1.000 75 1.0000 73 O Bananas­ dried 1.000000 3.900 1.000 75 1.0000 81 11 Loquats 1.000000 1.000 1.000 53 1.0000 82 O Olives 1.000000 1.000 1.000 80 1.0000 89 O Pineapples­ peeled fruit 11­ Uncooked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 12­ Cooked: NFS 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 13­ Baked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 14­ Boiled 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 31­ Canned: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 33­ Canned: Baked 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 41­ Frozen: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 90 O Pineapples­ dried 1.000000 5.000 1.000 82 0.0250 95 0.4750 97 0.5000 91 O Pineapples­ juice 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 94 O Plantains­ ripe 1.000000 1.000 1.000 75 1.0000 123 19A Dill 0.004000 1.000 1.000 126 1AB Horseradish 1.000000 1.000 1.000 3 1.0000 139 8 Paprika 1.000000 1.000 1.000 30 1.0000 141 9A Melons­ cantaloupes­ juice 1.000000 1.000 1.000 36 1.0000 142 9A Melons­ cantaloupes­ pulp 1.000000 1.000 1.000 36 1.0000 143 9A Casabas 1.000000 1.000 1.000 35 1.0000 144 9A Crenshaws 1.000000 1.000 1.000 35 1.0000 145 9A Melons­ honeydew 1.000000 1.000 1.000 37 1.0000 146 9A Melons­ persian 1.000000 1.000 1.000 35 1.0000 Attachment 3: Acute Dietary Exposure Analysis: All Commodities 77 147 9A Watermelon 1.000000 1.000 1.000 38 1.0000 148 9B Cucumbers 1.000000 1.000 1.000 34 1.0000 149 9B Pumpkin 1.000000 1.000 1.000 39 1.0000 150 9B Squash­ summer 1.000000 1.000 1.000 41 1.0000 151 9B Squash­ winter 1.000000 1.000 1.000 40 1.0000 152 9B Bitter melon 1.000000 1.000 1.000 35 1.0000 154 8 Eggplant 1.000000 1.000 1.000 29 1.0000 155 8 Peppers­ sweet( garden) 1.000000 1.000 1.000 31 1.0000 156 8 Peppers­ chilli incl jalapeno 1.000000 1.000 1.000 30 1.0000 157 8 Peppers­ other 1.000000 1.000 1.000 30 1.0000 158 8 Pimientos 1.000000 1.000 1.000 30 1.0000 159 8 Tomatoes­ whole 11­ Uncooked 1.000000 1.000 1.000 33 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 33 1.0000 13­ Baked 1.000000 1.000 1.000 33 1.0000 14­ Boiled 1.000000 1.000 1.000 33 1.0000 15­ Fried 1.000000 1.000 1.000 33 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 32 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 32 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 32 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 32 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 32 1.0000 160 8 Tomatoes­ juice 1.000000 0.540 1.000 32 1.0000 161 8 Tomatoes­ puree 1.000000 0.650 1.000 32 1.0000 162 8 Tomatoes­ paste 1.000000 0.650 1.000 32 1.0000 163 8 Tomatoes­ catsup 1.000000 0.650 1.000 32 1.0000 165 2 Beets­ garden­ tops( greens) 1.000000 1.000 1.000 8 1.0000 166 4B Celery 1.000000 1.000 1.000 11 1.0000 168 5A Broccoli 1.000000 1.000 1.000 17 1.0000 169 5A Brussels sprouts 1.000000 1.000 1.000 18 1.0000 170 5A Cabbage­ green and red 11­ Uncooked 1.000000 0.250 1.000 19 1.0000 12­ Cooked: NFS 1.000000 0.025 1.000 19 1.0000 13­ Baked 1.000000 0.025 1.000 19 1.0000 14­ Boiled 1.000000 0.025 1.000 19 1.0000 15­ Fried 1.000000 0.025 1.000 19 1.0000 31­ Canned: NFS 1.000000 0.250 1.000 19 1.0000 32­ Canned: Cooked 1.000000 0.025 1.000 19 1.0000 51­ Cured: NFS (smoked/ p 1.000000 0.025 1.000 19 1.0000 Attachment 3: Acute Dietary Exposure Analysis: All Commodities 78 171 5A Cauliflower 1.000000 1.000 1.000 20 1.0000 172 5B Collards 1.000000 1.000 1.000 21 1.0000 174 5B Kale 1.000000 1.000 1.000 22 1.0000 175 5A Kohlrabi 1.000000 1.000 1.000 23 1.0000 176 4A Lettuce­ leafy varieties 1.000000 1.000 1.000 15 1.0000 177 4A Dandelion­ greens 1.000000 1.000 1.000 12 1.0000 178 4A Endive­ curley and escarole 1.000000 1.000 1.000 15 1.0000 182 4A Lettuce­ unspecified 1.000000 1.000 1.000 14 1.0000 183 5B Mustard greens 1.000000 1.000 1.000 22 1.0000 184 4A Parsley 1.000000 1.000 1.000 12 1.0000 185 4B Rhubarb 1.000000 1.000 1.000 16 1.0000 186 4A Spinach 11­ Uncooked 1.000000 1.000 1.000 12 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 12 1.0000 13­ Baked 0.000000 1.000 1.000 14­ Boiled 1.000000 1.000 1.000 12 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 13 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 13 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 13 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 12 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 12 1.0000 187 4B Swiss chard 1.000000 1.000 1.000 16 1.0000 188 2 Turnips­ tops 1.000000 1.000 1.000 10 1.0000 192 4A Lettuce­ head varieties 1.000000 1.000 1.000 14 1.0000 195 O Grapes­ leaves 1.000000 1.000 1.000 77 1.0000 197 1AB Beets­ garden­ roots 1.000000 1.000 1.000 1 1.0000 198 1AB Carrots 1.000000 1.000 1.000 2 1.0000 207 1C Potatoes/ white­ whole 11­ Uncooked 1.000000 1.000 1.000 4 1.0000 12­ Cooked: NFS 1.000000 0.040 1.000 4 1.0000 13­ Baked 1.000000 1.200 1.000 4 1.0000 14­ Boiled 1.000000 2.500 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 4 1.0000 208 1C Potatoes/ white­ unspecified 1.000000 1.000 1.000 4 1.0000 209 1C Potatoes/ white­ peeled 11­ Uncooked 0.000000 1.000 1.000 12­ Cooked: NFS 1.000000 1.000 1.000 4 1.0000 13­ Baked 1.000000 1.200 1.000 4 1.0000 14­ Boiled Attachment 3: Acute Dietary Exposure Analysis: All Commodities 79 1.000000 2.500 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 31­ Canned: NFS 0.000000 1.000 1.000 32­ Canned: Cooked 1.000000 1.000 1.000 4 1.0000 34­ Canned: Boiled 1.000000 2.500 1.000 4 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 4 1.0000 43­ Frozen: Baked 1.000000 1.200 1.000 4 1.0000 45­ Frozen: Fried 1.000000 0.040 1.000 4 1.0000 210 1C Potatoes/ white­ dry 0.000357 0.020 1.000 211 1C Potatoes/ white­ peel only 13­ Baked 1.000000 1.200 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 212 1AB Radishes­ roots 1.000000 1.000 1.000 5 1.0000 213 2 Radishes­ tops 1.000000 1.000 1.000 9 1.0000 214 1AB Rutabagas­ roots 1.000000 1.000 1.000 6 1.0000 215 2 Rutabagas­ tops 1.000000 1.000 1.000 10 1.0000 216 1AB Salsify( oyster plant) 1.000000 1.000 1.000 3 1.0000 218 1CD Sweet potatoes (incl yams) 1.000000 1.000 1.000 7 1.0000 219 1AB Turnips­ roots 1.000000 1.000 1.000 6 1.0000 220 1AB Parsnips 1.000000 1.000 1.000 3 1.0000 227 6C Beans­ dry­ great northern 0.002000 1.000 1.000 228 6C Beans­ dry­ kidney 0.002000 1.000 1.000 229 6C Beans­ dry­ lima 0.002000 1.000 1.000 230 6C Beans­ dry­ navy (pea) 0.002000 1.000 1.000 231 6C Beans­ dry­ other 0.002000 1.000 1.000 232 6C Beans­ dry­ pinto 0.002000 1.000 1.000 233 6B Beans­ succulent­ lima 1.000000 1.000 1.000 26 1.0000 234 6A Beans­ succulent­ green 11­ Uncooked 1.000000 1.000 1.000 24 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 24 1.0000 14­ Boiled 1.000000 1.000 1.000 24 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 25 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 25 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 25 1.0000 235 6A Beans­ succulent­ other 1.000000 1.000 1.000 25 1.0000 236 6A Beans­ succulent­ yellow/ wax 14­ Boiled 1.000000 1.000 1.000 24 1.0000 Attachment 3: Acute Dietary Exposure Analysis: All Commodities 80 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 237 15 Corn/ pop 0.000100 1.000 1.000 238 15 Corn/ sweet 1.000000 1.000 1.000 73 1.0000 240 6C Peas (garden)­ dry 0.013000 0.045 1.000 241 6AB Peas (garden)­ green 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 0.150 1.000 27 1.0000 13­ Baked 1.000000 0.150 1.000 27 1.0000 14­ Boiled 1.000000 0.150 1.000 27 1.0000 15­ Fried 1.000000 0.150 1.000 27 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 28 1.0000 32­ Canned: Cooked 1.000000 0.150 1.000 28 1.0000 34­ Canned: Boiled 1.000000 0.150 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 0.150 1.000 28 1.0000 44­ Frozen: Boiled 1.000000 0.150 1.000 28 1.0000 45­ Frozen: Fried 1.000000 0.150 1.000 28 1.0000 243 6C Lentils 0.002000 1.000 1.000 244 6C Mung beans (sprouts) 0.002000 1.000 1.000 245 O Okra 12­ Cooked: NFS 1.000000 0.180 1.000 79 1.0000 14­ Boiled 1.000000 0.050 1.000 79 1.0000 15­ Fried 1.000000 0.180 1.000 79 1.0000 32­ Canned: Cooked 1.000000 0.180 1.000 79 1.0000 42­ Frozen: Cooked 1.000000 0.180 1.000 79 1.0000 44­ Frozen: Boiled 1.000000 0.050 1.000 79 1.0000 249 6C Beans­ dry­ broadbeans 0.002000 1.000 1.000 250 6B Beans­ succulent­ broadbeans 1.000000 1.000 1.000 24 1.0000 251 6C Beans­ dry­ pigeon beans 0.002000 1.000 1.000 253 6 Beans­ unspecified 1.000000 1.000 1.000 24 1.0000 255 6A Soybeans­ sprouted seeds 0.000015 0.330 1.000 99 1.0000 256 O Beans­ dry­ hyacinth 0.002000 1.000 1.000 257 O Beans­ succulent­ hyacinth 1.000000 1.000 1.000 24 1.0000 258 6C Beans­ dry­ blackeye peas/ cowpea 0.002000 1.000 1.000 259 6C Beans­ dry­ garbanzo/ chick pea 0.002000 1.000 1.000 260 O Asparagus 1.000000 1.000 1.000 74 1.0000 266 15 Corn grain­ endosperm 0.000100 1.000 1.000 267 15 Corn grain­ bran 0.000100 1.000 1.000 268 15 Corn grain/ sugar/ hfcs 0.000100 1.500 1.000 Attachment 3: Acute Dietary Exposure Analysis: All Commodities 81 270 15 Rice­ rough (brown) 0.074000 1.000 1.000 271 15 Rice­ milled (white) 0.074000 0.030 1.000 275 15 Sorghum (including milo) 0.000015 1.000 1.000 100 1.0000 276 15 Wheat­ rough 0.000015 1.000 1.000 100 1.0000 277 15 Wheat­ germ 0.000015 1.000 1.000 278 15 Wheat­ bran 0.000015 1.000 1.000 279 15 Wheat­ flour 0.000015 1.000 1.000 280 15 Millet 0.000015 1.000 1.000 100 1.0000 282 1A Sugar­ beet 0.000400 0.040 1.000 287 6C Guar beans 1.000000 1.000 1.000 24 1.0000 289 15 Corn grain­ oil 0.000100 0.250 1.000 292 O Flax seed 0.000100 1.000 1.000 293 O Peanuts­ oil 0.000600 0.290 1.000 297 6A Soybeans­ oil 0.000015 0.010 1.000 298 O Sunflower­ oil 0.000400 0.670 1.000 300 O Olive oil 0.077000 0.810 1.000 303 6A Soybean­ other 0.000015 1.000 1.000 99 1.0000 304 6A Soybeans­ mature seeds dry 0.000015 1.000 1.000 99 1.0000 305 6A Soybeans­ flour (full fat) 0.000015 1.000 1.000 306 6A Soybeans­ flour (low fat) 0.000015 1.000 1.000 307 6A Soybeans­ flour (defatted) 0.000015 1.000 1.000 315 O Grapes­ wine and sherry 1.000000 1.000 1.000 77 1.0000 318 D Milk­ nonfat solids 0.030000 1.000 1.000 86 1.0000 319 D Milk­ fat solids 0.030000 1.000 1.000 86 1.0000 320 D Milk sugar (lactose) 0.030000 1.000 1.000 86 1.0000 321 M Beef­ meat byproducts 3.675000 1.000 1.000 88 1.0000 322 M Beef­ other organ meats 3.675000 1.000 1.000 88 1.0000 323 M Beef­ dried 0.907000 1.920 1.000 86 1.0000 324 M Beef­ fat w/ o bones 0.368000 1.000 1.000 86 1.0000 325 M Beef­ kidney 3.675000 1.000 1.000 88 1.0000 326 M Beef­ liver 1.390000 1.000 1.000 87 1.0000 327 M Beef­ lean (fat/ free) w/ o bones 0.907000 1.000 1.000 86 1.0000 328 M Goat­ meat byproducts 3.675000 1.000 1.000 88 1.0000 329 M Goat­ other organ meats 3.675000 1.000 1.000 88 1.0000 330 M Goat­ fat w/ o bone 0.368000 1.000 1.000 86 1.0000 331 M Goat­ kidney 3.675000 1.000 1.000 88 1.0000 332 M Goat­ liver 1.390000 1.000 1.000 87 1.0000 333 M Goat­ lean (fat/ free) w/ o bone 0.907000 1.000 1.000 86 1.0000 Attachment 3: Acute Dietary Exposure Analysis: All Commodities 82 336 M Sheep­ meat byproducts 3.675000 1.000 1.000 88 1.0000 337 M Sheep­ other organ meats 3.675000 1.000 1.000 88 1.0000 338 M Sheep­ fat w/ o bone 0.368000 1.000 1.000 86 1.0000 339 M Sheep­ kidney 3.675000 1.000 1.000 88 1.0000 340 M Sheep­ liver 1.390000 1.000 1.000 87 1.0000 341 M Sheep­ lean (fat free) w/ o bone 0.907000 1.000 1.000 86 1.0000 342 M Pork­ meat byproducts 0.260000 1.000 1.000 92 1.0000 343 M Pork­ other organ meats 0.260000 1.000 1.000 92 1.0000 344 M Pork­ fat w/ o bone 0.026000 1.000 1.000 90 1.0000 345 M Pork­ kidney 0.260000 1.000 1.000 92 1.0000 346 M Pork­ liver 0.100000 1.000 1.000 91 1.0000 347 M Pork­ lean (fat free) w/ o bone 0.065000 1.000 1.000 89 1.0000 349 F Fish­ shellfish 0.250000 1.000 1.000 377 11 Apples­ juice­ concentrate 1.000000 3.000 1.000 50 1.0000 378 O Bananas­ juice 1.000000 1.000 1.000 75 1.0000 379 1A Sugar­ beet­ molasses 0.000400 0.040 1.000 380 13A Blackberries­ juice 1.000000 1.000 1.000 63 1.0000 383 5B Cabbage­ savoy 12­ Cooked: NFS 1.000000 0.025 1.000 19 1.0000 384 4B Celery juice 1.000000 1.000 1.000 11 1.0000 388 15 Corn grain/ sugar­ molasses 0.000100 1.500 1.000 389 O Cranberries­ juice­ concentrate 1.000000 3.300 1.000 76 1.0000 392 O Grapes­ juice­ concentrate 1.000000 3.000 1.000 78 1.0000 398 D Milk­ based water 0.030000 1.000 1.000 86 1.0000 402 12 Peaches­ juice 1.000000 1.000 1.000 61 1.0000 403 O Peanuts­ butter 0.000600 1.890 1.000 404 11 Pears­ juice 1.000000 0.370 1.000 52 1.0000 405 6B Peas­ succulent/ blackeye/ cowpea 12­ Cooked: NFS 1.000000 0.150 1.000 27 1.0000 14­ Boiled 1.000000 0.150 1.000 27 1.0000 32­ Canned: Cooked 1.000000 0.150 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 0.150 1.000 28 1.0000 406 O Pineapples­ juice­ concentrate 1.000000 2.000 1.000 82 0.0250 95 0.4750 97 0.5000 407 1AB Radishes­ japanese (daiken) 1.000000 1.000 1.000 5 1.0000 408 15 Rice­ bran 0.074000 0.400 1.000 410 12 Apricot juice 1.000000 1.000 1.000 55 1.0000 413 6A Snowpeas 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 27 1.0000 14­ Boiled Attachment 3: Acute Dietary Exposure Analysis: All Commodities 83 1.000000 1.000 1.000 27 1.0000 15­ Fried 1.000000 1.000 1.000 27 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 28 1.0000 415 9B Squash­ spaghetti 1.000000 1.000 1.000 40 1.0000 416 O Strawberries­ juice 1.000000 1.000 1.000 84 1.0000 417 O Sunflower­ seeds 1.000000 1.000 1.000 85 1.0000 420 10 Tangerines­ juice­ concentrate 1.000000 4.080 1.000 46 1.0000 423 8 Tomatoes­ dried 1.000000 0.520 1.000 32 1.0000 424 M Veal­ fat w/ o bones 0.368000 1.000 1.000 86 1.0000 425 M Veal­ lean (fat free) w/ o bones 0.907000 1.000 1.000 86 1.0000 426 M Veal­ kidney 3.675000 1.000 1.000 88 1.0000 427 M Veal­ liver 1.390000 1.000 1.000 87 1.0000 428 M Veal­ other organ meats 3.675000 1.000 1.000 88 1.0000 429 M Veal­ dried 0.907000 1.920 1.000 86 1.0000 430 M Veal­ meat byproducts 3.675000 1.000 1.000 88 1.0000 431 14 Walnut oil 0.005400 1.000 1.000 436 9A Watermelon­ juice 1.000000 1.000 1.000 38 1.0000 437 15 Wheat­ germ oil 0.000015 1.000 1.000 439 9B Wintermelon 1.000000 1.000 1.000 35 1.0000 441 10 Grapefruit­ juice­ concentrate 1.000000 4.580 1.000 43 1.0000 442 10 Lemons­ juice­ concentrate 1.000000 6.330 1.000 44 1.0000 443 10 Limes­ juice­ concentrate 1.000000 3.330 1.000 46 1.0000 448 10 Grapefruit peel 1.000000 1.000 1.000 42 1.0000 480 O Plantains­ green 1.000000 1.000 1.000 75 1.0000 481 O Plantains­ dried 1.000000 3.900 1.000 75 1.0000 940 O Peanuts­ hulled 0.000600 1.000 1.000 Attachment 3: Acute Dietary Exposure Analysis: All Commodities 84 Results ­ 1989­ 1992 Consumption data U. S. Environmental Protection Agency Ver. 7.76 DEEM ACUTE Analysis for CARBARYL (1989­ 92 data) Residue file: $$$ 10carbarylfinal9. RS7 Adjustment factor #2 NOT used. Analysis Date: 04­ 02­ 2002/ 15: 44: 07 Residue file dated: 04­ 02­ 2002/ 14: 55: 15/ 8 Daily totals for food and foodform consumption used. MC iterations = 1000 MC list in residue file MC seed = 10 Run Comment: "" =============================================================================== Summary calculations (per capita): 95th Percentile 99th Percentile 99.9th Percentile Exposure % aRfD Exposure % aRfD Exposure % aRfD ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ U. S. Population: 0.000505 5.05 0.001381 13.81 0.005989 59.89 All infants: 0.000864 8.64 0.003683 36.83 0.013251 132.51 Nursing infants (< 1 yr old): 0.000283 2.83 0.001208 12.08 0.007703 77.03 Non­ nursing infants (< 1 yr old): 0.001198 11.98 0.004263 42.63 0.014013 140.13 Children 1­ 6 yrs: 0.001309 13.09 0.002552 25.52 0.010974 109.74 Children 7­ 12 yrs: 0.000722 7.22 0.001644 16.44 0.008721 87.21 Females 13+ (preg/ not nursing): 0.000442 4.42 0.000989 9.89 0.006103 61.03 Females 13+ (nursing): 0.000486 4.86 0.001408 14.08 0.008584 85.84 Females 13­ 19 (not preg or nursing): 0.000335 3.35 0.000864 8.64 0.004530 45.30 Females 20+ (not preg or nursing): 0.000299 2.99 0.000967 9.67 0.004767 47.67 Females 13­ 50 yrs: 0.000318 3.18 0.000918 9.18 0.004444 44.44 Males 13­ 19 yrs: 0.000428 4.28 0.000899 8.99 0.003596 35.96 Males 20+ yrs: 0.000318 3.18 0.000929 9.29 0.004223 42.23 Seniors 55+: 0.000307 3.07 0.001068 10.68 0.005789 57.89 Attachment 3: Acute Dietary Exposure Analysis: All Commodities 85 Results ­ 1994­ 1996 Consumption data U. S. Environmental Protection Agency Ver. 7.76 DEEM ACUTE Analysis for CARBARYL (1994­ 98 data) Residue file: $$$ 10carbarylfinal9. RS7 Adjustment factor #2 NOT used. Analysis Date: 04­ 02­ 2002/ 16: 52: 44 Residue file dated: 04­ 02­ 2002/ 14: 55: 15/ 8 Daily totals for food and foodform consumption used. MC iterations = 1000 MC list in residue file MC seed = 10 Run Comment: "" =============================================================================== Summary calculations (per capita): 95th Percentile 99th Percentile 99.9th Percentile Exposure % aRfD Exposure % aRfD Exposure % aRfD ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ U. S. Population: 0.000508 5.08 0.001467 14.67 0.006150 61.50 All infants: 0.000922 9.22 0.004027 40.27 0.013420 134.20 Nursing infants (< 1 yr old): 0.000412 4.12 0.002251 22.51 0.010542 105.42 Non­ nursing infants (< 1 yr old): 0.001165 11.65 0.004406 44.06 0.014247 142.47 Children 1­ 6 yrs: 0.001460 14.60 0.003282 32.82 0.013812 138.12 Children 7­ 12 yrs: 0.000685 6.85 0.001473 14.73 0.007073 70.73 Females 13+ (preg/ not nursing): 0.000404 4.04 0.001077 10.77 0.006308 63.08 Females 13+ (nursing): 0.000378 3.78 0.001166 11.66 0.006904 69.04 Females 13­ 19 (not preg or nursing): 0.000319 3.19 0.000907 9.07 0.004463 44.63 Females 20+ (not preg or nursing): 0.000308 3.08 0.000999 9.99 0.005068 50.68 Females 13­ 50 yrs: 0.000322 3.22 0.000997 9.97 0.004794 47.94 Males 13­ 19 yrs: 0.000420 4.20 0.000929 9.29 0.005181 51.81 Males 20+ yrs: 0.000336 3.36 0.000922 9.22 0.003940 39.40 Seniors 55+: 0.000313 3.13 0.001003 10.03 0.005442 54.42 Attachment 4 ­ Acute ­ Critical Exposure Contribution Analysis 86 U. S. Environmental Protection Agency DEEM Acute Critical Exposure Contribution Analysis (Ver 7.76) CSFII 1989­ 92 Residue file = C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10carbarylfinal9. RS7 Acute report = C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10carbarylfinal9. AC7 Date and time of analysis: 04­ 02­ 2002 14: 58: 48 Daily totals for food and foodform consumption used. Adjustment factor #2 not used. Minimum exposure contribution = 1% Monte Carlo Iterations = 1000 Seed = 10 CEC records generated for first 111 iterations. Exposures divided by body weight ================================================================================ U. S. Population Low percentile for CEC records: 99.5 Exposure (mg/ day) = 0.002066 High percentile for CEC records: 100 Exposure (mg/ day) = 0.697664 Number of actual records in this interval: 21792 Critical foods/ foodforms for this population (as derived from these records): N= number of appearances in all records (including duplicates) %= percent of total exposure for all records (including duplicates) Food, FF, N , Percent, Food Name ­­­­, ­­, ­­­­­, ­­­­­­­, ­­­­­­­­­­­­ 172, 14, 1827, 13.34%, Collards­ Boiled 188, 14, 429, 13.08%, Turnips­ tops­ Boiled 52, 11, 2690, 10.12%, Apples­ Uncooked 398, 16, 7643, 9.86%, Milk­ based water­ Pasteurized 52, 14, 1119, 5.13%, Apples­ Boiled 17, 11, 1071, 4.54%, Strawberries­ Uncooked 165, 14, 261, 4.05%, Beets­ garden­ tops( greens)­ Boiled 65, 12, 1100, 3.10%, Peaches­ Cooked: NFS 65, 31, 480, 2.37%, Peaches­ Canned: NFS 65, 11, 594, 1.70%, Peaches­ Uncooked 349, 12, 598, 1.64%, Fish­ shellfish­ Cooked: NFS 234, 14, 753, 1.55%, Beans­ succulent­ green­ Boiled 215, 12, 52, 1.51%, Rutabagas­ tops­ Cooked: NFS 54, 11, 1306, 1.46%, Apples­ juice/ cider­ Uncooked 64, 11, 251, 1.33%, Nectarines­ Uncooked 326, 15, 446, 1.16%, Beef­ liver­ Fried 156, 11, 470, 1.14%, Peppers­ chilli incl jalapeno­ Uncooked 183, 14, 162, 1.09%, Mustard greens­ Boiled 69, 11, 263, 1.03%, Plums/ prune­ juice­ Uncooked ================================================================================ All infants Low percentile for CEC records: 99.5 Exposure (mg/ day) = 0.005300 High percentile for CEC records: 100 Exposure (mg/ day) = 0.101947 Number of actual records in this interval: 367 Critical foods/ foodforms for this population (as derived from these records): N= number of appearances in all records (including duplicates) %= percent of total exposure for all records (including duplicates) Food, FF, N , Percent, Food Name ­­­­, ­­, ­­­­­, ­­­­­­­, ­­­­­­­­­­­­ 65, 31, 179, 49.83%, Peaches­ Canned: NFS 52, 31, 73, 12.60%, Apples­ Canned: NFS 398, 16, 95, 10.82%, Milk­ based water­ Pasteurized 52, 14, 14, 4.09%, Apples­ Boiled 183, 14, 4, 3.39%, Mustard greens­ Boiled 377, 31, 50, 3.12%, Apples­ juice­ concentrate­ Canned: NFS 65, 12, 7, 2.97%, Peaches­ Cooked: NFS 406, 41, 3, 1.90%, Pineapples­ juice­ concentrate­ Frozen: NFS 61, 31, 11, 1.49%, Cherries­ Canned: NFS 89, 31, 7, 1.35%, Pineapples­ peeled fruit­ Canned: NFS 406, 31, 5, 1.07%, Pineapples­ juice­ concentrate­ Canned: NFS ================================================================================ Attachment 4 ­ Acute ­ Critical Exposure Contribution Analysis 87 Children 1­ 6 yrs Low percentile for CEC records: 99.5 Exposure (mg/ day) = 0.003822 High percentile for CEC records: 100 Exposure (mg/ day) = 0.697664 Number of actual records in this interval: 2205 Critical foods/ foodforms for this population (as derived from these records): N= number of appearances in all records (including duplicates) %= percent of total exposure for all records (including duplicates) Food, FF, N , Percent, Food Name ­­­­, ­­, ­­­­­, ­­­­­­­, ­­­­­­­­­­­­ 52, 11, 409, 16.79%, Apples­ Uncooked 52, 14, 264, 13.68%, Apples­ Boiled 188, 14, 25, 9.42%, Turnips­ tops­ Boiled 172, 14, 103, 6.90%, Collards­ Boiled 17, 11, 95, 5.76%, Strawberries­ Uncooked 398, 16, 698, 4.60%, Milk­ based water­ Pasteurized 65, 12, 162, 4.41%, Peaches­ Cooked: NFS 326, 15, 131, 3.31%, Beef­ liver­ Fried 54, 11, 209, 2.99%, Apples­ juice/ cider­ Uncooked 65, 31, 66, 2.90%, Peaches­ Canned: NFS 349, 12, 111, 2.69%, Fish­ shellfish­ Cooked: NFS 234, 14, 105, 2.41%, Beans­ succulent­ green­ Boiled 65, 11, 69, 2.07%, Peaches­ Uncooked 91, 11, 40, 1.98%, Pineapples­ juice­ Uncooked 416, 11, 27, 1.57%, Strawberries­ juice­ Uncooked 67, 11, 20, 1.42%, Plums (damsons)­ Uncooked 17, 41, 23, 1.02%, Strawberries­ Frozen: NFS Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 88 Residue File U. S. Environmental Protection Agency Ver. 7.76 DEEM Acute analysis for CARBARYL Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\ sensitivity no detects. RS7 Analysis Date 04­ 09­ 2002 Residue file dated: 04­ 08­ 2002/ 16: 54: 03/ 8 Reference dose (aRfD) = 0.01 mg/ kg bw/ day ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RDL indices and parameters for Monte Carlo Analysis: Index Dist Parameter #1 Param #2 Param #3 Comment # Code ­­­­­ ­­­­ ­­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­ 1 6 Gardenbeet. rdf 2 6 Carrot. rdf 3 6 chic hors parsnip salsify. rdf 4 6 Potato. rdf 5 6 radishes. rdf 6 6 Turnip. rdf 7 6 sweetpotato. rdf 8 6 topsgardenbeet. rdf 9 6 topsradish. rdf 10 6 Topsturnip. rdf 11 6 celery. rdf 12 6 spinach. rdf 13 6 cannedspinach. rdf 14 6 lettucehd. rdf 15 6 lettuceleaf. rdf 16 6 rhubarb. rdf 17 6 broccoli. rdf 18 6 brusselssprouts. rdf 19 6 cabbage. rdf 20 6 cauliflower. rdf 21 6 collards. rdf 22 6 mustards. rdf 23 6 kohrabi. rdf 24 6 beanssucculentfresh. rdf 25 6 beanssucculentprocessed. rdf 26 6 beanslima. rdf 27 6 Peasfresh. rdf 28 6 Peasprocessed. rdf 29 6 alleggplant. rdf 30 6 peppersnonbell. rdf 31 6 allsweetpepper. rdf 32 6 tomatoesPB. rdf 33 6 tomatoesNB. rdf 34 6 allcucumber. rdf 35 6 melon. rdf 36 6 cantaloupe. rdf 37 6 honeydew. rdf 38 6 allwatermelon. rdf 39 6 pumpkin. rdf 40 6 wintersquash. rdf 41 6 allsummersquash. rdf 42 6 citrus. rdf 43 6 grapefruitjuice. rdf 44 6 lemonjuice. rdf 45 6 orangesdecomp. rdf 46 6 limejuice. rdf 47 6 orangejuice. rdf 48 6 appledecomp. rdf 49 6 apple. rdf 50 6 applejuice. rdf 51 6 peardecomp. rdf 52 6 pear. rdf 53 6 quince. rdf 54 6 crabapple. rdf 55 6 apricot. rdf 56 6 Apricotss. rdf 57 6 allsweetcherries. rdf 58 6 alltartcherries. rdf 59 6 nectarine. rdf 60 6 peachSS. rdf 61 6 Peach. rdf 62 6 plum2. rdf 63 6 blackberries. rdf 64 6 allblueberry. rdf Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 89 65 6 boysenberry. rdf 66 6 currant. rdf 67 6 allraspberries. rdf 68 6 almonds. rdf 69 6 chestnut. rdf 70 6 filbert. rdf 71 6 pecan. rdf 72 6 walnut. rdf 73 6 corn. rdf 74 6 allasparagus. rdf 75 6 banana. rdf 76 6 allcranberry. rdf 77 6 grapes. rdf 78 6 grapejuice. rdf 79 6 okra. rdf 80 6 olives. rdf 81 6 pineappledecomp. rdf 82 6 pineapplemexico. rdf 83 6 pistachio. rdf 84 6 strawberrypdp. rdf 85 6 sunflower. rdf 86 6 milk2. rdf 87 6 ruminantliver2. rdf 88 6 ruminantkidney2. rdf 89 6 swinemeat2. rdf 90 6 swinefat2. rdf 91 6 swineliver2. rdf 92 6 swinekidney2. rdf 93 6 poultry. rdf 94 6 eggs. rdf 95 6 pineappleother. rdf 96 6 Plumdecomp. rdf 97 6 pineappledomestic. rdf 98 6 appledried. rdf 99 6 soybean. rdf 100 6 wheat. rdf Food Crop Food Def Res Adj. Factors ­­­­­­­ RDL Indices and Ratios­­­­­­­ Code Grp Name (ppm) #1 #2 I# 1 Ratio# 1 I# 2 Ratio# 2 I# 3 Ratio# 3 ­­­­ ­­­­ ­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­ 1 13A Blackberries 1.000000 1.000 1.000 63 1.0000 2 13A Boysenberries 1.000000 1.000 1.000 65 1.0000 3 13A Dewberries 1.000000 1.000 1.000 65 1.0000 4 13A Loganberries 1.000000 1.000 1.000 65 1.0000 5 13A Raspberries 1.000000 1.000 1.000 67 1.0000 6 13A Youngberries 1.000000 1.000 1.000 65 1.0000 7 13B Blueberries 1.000000 1.000 1.000 64 1.0000 8 O Cranberries 1.000000 1.000 1.000 76 1.0000 9 O Cranberries­ juice 1.000000 1.100 1.000 76 1.0000 10 13B Currants 1.000000 1.000 1.000 66 1.0000 11 13B Elderberries 1.000000 1.000 1.000 66 1.0000 12 13B Gooseberries 1.000000 1.000 1.000 66 1.0000 13 O Grapes 1.000000 1.000 1.000 77 1.0000 14 O Grapes­ raisins 11­ Uncooked 1.000000 2.170 1.000 77 1.0000 12­ Cooked: NFS 1.000000 1.370 1.000 77 1.0000 13­ Baked 1.000000 1.370 1.000 77 1.0000 14­ Boiled 1.000000 1.370 1.000 77 1.0000 18­ Dried 1.000000 1.370 1.000 77 1.0000 42­ Frozen: Cooked Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 90 1.000000 1.370 1.000 77 1.0000 15 O Grapes­ juice 1.000000 1.000 1.000 78 1.0000 16 13B Huckleberries 1.000000 1.000 1.000 66 1.0000 17 O Strawberries 1.000000 1.000 1.000 84 1.0000 20 10 Citrus citron 1.000000 1.000 1.000 42 1.0000 22 10 Grapefruit­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 14­ Boiled 0.000000 1.000 1.000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 23 10 Grapefruit­ juice 1.000000 1.170 1.000 43 1.0000 24 10 Kumquats 1.000000 1.000 1.000 42 1.0000 26 10 Lemons­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 27 10 Lemons­ peel 1.000000 1.190 1.000 42 1.0000 28 10 Lemons­ juice 1.000000 1.110 1.000 44 1.0000 30 10 Limes­ peeled fruit 1.000000 1.000 1.000 45 1.0000 31 10 Limes­ peel 1.000000 1.270 1.000 42 1.0000 32 10 Limes­ juice 1.000000 1.110 1.000 46 1.0000 33 10 Oranges­ juice­ concentrate 1.000000 3.700 1.000 47 1.0000 34 10 Oranges­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 35 10 Oranges­ peel 1.000000 1.270 1.000 42 1.0000 36 10 Oranges­ juice 1.000000 1.000 1.000 47 1.0000 37 10 Tangelos 1.000000 1.000 1.000 45 1.0000 38 10 Tangerines 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 42 1.0000 39 10 Tangerines­ juice 1.000000 1.280 1.000 46 1.0000 40 14 Almonds 1.000000 1.000 1.000 68 1.0000 43 14 Chestnuts 1.000000 1.000 1.000 69 1.0000 44 14 Filberts (hazelnuts) 1.000000 1.000 1.000 70 1.0000 48 14 Walnuts 1.000000 1.000 1.000 72 1.0000 50 O Pistachio nuts 1.000000 1.000 1.000 83 1.0000 52 11 Apples 11­ Uncooked 1.000000 1.000 1.000 48 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 48 1.0000 Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 91 13­ Baked 1.000000 1.000 1.000 48 1.0000 14­ Boiled 1.000000 1.000 1.000 48 1.0000 15­ Fried 1.000000 1.000 1.000 48 1.0000 18­ Dried 0.009000 1.000 1.000 98 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 49 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 49 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 49 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 49 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 49 1.0000 53 11 Apples­ dried 1.000000 2.600 1.000 49 1.0000 54 11 Apples­ juice/ cider 1.000000 1.000 1.000 50 1.0000 55 11 Crabapples 1.000000 1.000 1.000 54 1.0000 56 11 Pears 11­ Uncooked 1.000000 1.000 1.000 51 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 51 1.0000 13­ Baked 1.000000 1.000 1.000 51 1.0000 14­ Boiled 1.000000 1.000 1.000 51 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 52 1.0000 57 11 Pears­ dried 1.000000 2.600 1.000 52 1.0000 58 11 Quinces 1.000000 1.000 1.000 53 1.0000 59 12 Apricots 11­ Uncooked 1.000000 1.000 1.000 56 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 56 1.0000 14­ Boiled 1.000000 1.000 1.000 56 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 55 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 55 1.0000 60 12 Apricots­ dried 1.000000 6.000 1.000 55 1.0000 61 12 Cherries 11­ Uncooked 1.000000 1.000 1.000 57 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 58 1.0000 13­ Baked 1.000000 1.000 1.000 58 1.0000 14­ Boiled 1.000000 1.000 1.000 58 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 58 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 58 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 58 1.0000 62 12 Cherries­ dried 1.000000 4.000 1.000 57 1.0000 63 12 Cherries­ juice 1.000000 1.500 1.000 58 1.0000 64 12 Nectarines 1.000000 1.000 1.000 59 1.0000 65 12 Peaches 11­ Uncooked 1.000000 1.000 1.000 60 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 60 1.0000 Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 92 13­ Baked 1.000000 1.000 1.000 60 1.0000 14­ Boiled 1.000000 1.000 1.000 60 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 61 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 61 1.0000 66 12 Peaches­ dried 1.000000 7.000 1.000 61 1.0000 67 12 Plums (damsons) 11­ Uncooked 1.000000 1.000 1.000 96 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 96 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 62 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 62 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 62 1.0000 68 12 Plums­ prunes (dried) 1.000000 0.150 1.000 62 1.0000 69 12 Plums/ prune­ juice 1.000000 1.400 1.000 62 1.0000 81 11 Loquats 1.000000 1.000 1.000 53 1.0000 82 O Olives 1.000000 1.000 1.000 80 1.0000 89 O Pineapples­ peeled fruit 11­ Uncooked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 12­ Cooked: NFS 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 13­ Baked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 14­ Boiled 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 31­ Canned: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 33­ Canned: Baked 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 41­ Frozen: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 90 O Pineapples­ dried 1.000000 5.000 1.000 82 0.0250 95 0.4750 97 0.5000 91 O Pineapples­ juice 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 123 19A Dill 0.004000 1.000 1.000 139 8 Paprika 1.000000 1.000 1.000 30 1.0000 141 9A Melons­ cantaloupes­ juice 1.000000 1.000 1.000 36 1.0000 142 9A Melons­ cantaloupes­ pulp 1.000000 1.000 1.000 36 1.0000 143 9A Casabas 1.000000 1.000 1.000 35 1.0000 144 9A Crenshaws 1.000000 1.000 1.000 35 1.0000 145 9A Melons­ honeydew 1.000000 1.000 1.000 37 1.0000 146 9A Melons­ persian 1.000000 1.000 1.000 35 1.0000 147 9A Watermelon 1.000000 1.000 1.000 38 1.0000 148 9B Cucumbers 1.000000 1.000 1.000 34 1.0000 149 9B Pumpkin 1.000000 1.000 1.000 39 1.0000 150 9B Squash­ summer 1.000000 1.000 1.000 41 1.0000 151 9B Squash­ winter 1.000000 1.000 1.000 40 1.0000 152 9B Bitter melon 1.000000 1.000 1.000 35 1.0000 154 8 Eggplant 1.000000 1.000 1.000 29 1.0000 Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 93 155 8 Peppers­ sweet( garden) 1.000000 1.000 1.000 31 1.0000 156 8 Peppers­ chilli incl jalapeno 1.000000 1.000 1.000 30 1.0000 157 8 Peppers­ other 1.000000 1.000 1.000 30 1.0000 158 8 Pimientos 1.000000 1.000 1.000 30 1.0000 159 8 Tomatoes­ whole 11­ Uncooked 1.000000 1.000 1.000 33 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 33 1.0000 13­ Baked 1.000000 1.000 1.000 33 1.0000 14­ Boiled 1.000000 1.000 1.000 33 1.0000 15­ Fried 1.000000 1.000 1.000 33 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 32 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 32 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 32 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 32 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 32 1.0000 160 8 Tomatoes­ juice 1.000000 0.540 1.000 32 1.0000 161 8 Tomatoes­ puree 1.000000 0.650 1.000 32 1.0000 162 8 Tomatoes­ paste 1.000000 0.650 1.000 32 1.0000 163 8 Tomatoes­ catsup 1.000000 0.650 1.000 32 1.0000 165 2 Beets­ garden­ tops( greens) 1.000000 1.000 1.000 8 1.0000 168 5A Broccoli 1.000000 1.000 1.000 17 1.0000 171 5A Cauliflower 1.000000 1.000 1.000 20 1.0000 172 5B Collards 1.000000 1.000 1.000 21 1.0000 174 5B Kale 1.000000 1.000 1.000 22 1.0000 177 4A Dandelion­ greens 1.000000 1.000 1.000 12 1.0000 178 4A Endive­ curley and escarole 1.000000 1.000 1.000 15 1.0000 183 5B Mustard greens 1.000000 1.000 1.000 22 1.0000 184 4A Parsley 1.000000 1.000 1.000 12 1.0000 186 4A Spinach 11­ Uncooked 1.000000 1.000 1.000 12 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 12 1.0000 13­ Baked 0.000000 1.000 1.000 14­ Boiled 1.000000 1.000 1.000 12 1.0000 31­ Canned: NFS 0.000000 1.000 1.000 32­ Canned: Cooked 0.000000 1.000 1.000 34­ Canned: Boiled 0.000000 1.000 1.000 42­ Frozen: Cooked 1.000000 1.000 1.000 12 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 12 1.0000 188 2 Turnips­ tops 1.000000 1.000 1.000 10 1.0000 195 O Grapes­ leaves 1.000000 1.000 1.000 77 1.0000 Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 94 197 1AB Beets­ garden­ roots 1.000000 1.000 1.000 1 1.0000 212 1AB Radishes­ roots 1.000000 1.000 1.000 5 1.0000 213 2 Radishes­ tops 1.000000 1.000 1.000 9 1.0000 214 1AB Rutabagas­ roots 1.000000 1.000 1.000 6 1.0000 215 2 Rutabagas­ tops 1.000000 1.000 1.000 10 1.0000 218 1CD Sweet potatoes (incl yams) 1.000000 1.000 1.000 7 1.0000 219 1AB Turnips­ roots 1.000000 1.000 1.000 6 1.0000 227 6C Beans­ dry­ great northern 0.002000 1.000 1.000 228 6C Beans­ dry­ kidney 0.002000 1.000 1.000 229 6C Beans­ dry­ lima 0.002000 1.000 1.000 230 6C Beans­ dry­ navy (pea) 0.002000 1.000 1.000 231 6C Beans­ dry­ other 0.002000 1.000 1.000 232 6C Beans­ dry­ pinto 0.002000 1.000 1.000 233 6B Beans­ succulent­ lima 1.000000 1.000 1.000 26 1.0000 234 6A Beans­ succulent­ green 11­ Uncooked 1.000000 1.000 1.000 24 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 24 1.0000 14­ Boiled 1.000000 1.000 1.000 24 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 25 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 25 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 25 1.0000 235 6A Beans­ succulent­ other 1.000000 1.000 1.000 25 1.0000 236 6A Beans­ succulent­ yellow/ wax 14­ Boiled 1.000000 1.000 1.000 24 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 240 6C Peas (garden)­ dry 0.013000 0.045 1.000 241 6AB Peas (garden)­ green 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 0.150 1.000 27 1.0000 13­ Baked 1.000000 0.150 1.000 27 1.0000 14­ Boiled 1.000000 0.150 1.000 27 1.0000 15­ Fried 1.000000 0.150 1.000 27 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 28 1.0000 32­ Canned: Cooked 1.000000 0.150 1.000 28 1.0000 34­ Canned: Boiled 1.000000 0.150 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 0.150 1.000 28 1.0000 44­ Frozen: Boiled Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 95 1.000000 0.150 1.000 28 1.0000 45­ Frozen: Fried 1.000000 0.150 1.000 28 1.0000 243 6C Lentils 0.002000 1.000 1.000 244 6C Mung beans (sprouts) 0.002000 1.000 1.000 245 O Okra 12­ Cooked: NFS 1.000000 0.180 1.000 79 1.0000 14­ Boiled 1.000000 0.050 1.000 79 1.0000 15­ Fried 1.000000 0.180 1.000 79 1.0000 32­ Canned: Cooked 1.000000 0.180 1.000 79 1.0000 42­ Frozen: Cooked 1.000000 0.180 1.000 79 1.0000 44­ Frozen: Boiled 1.000000 0.050 1.000 79 1.0000 249 6C Beans­ dry­ broadbeans 0.002000 1.000 1.000 250 6B Beans­ succulent­ broadbeans 1.000000 1.000 1.000 24 1.0000 251 6C Beans­ dry­ pigeon beans 0.002000 1.000 1.000 253 6 Beans­ unspecified 1.000000 1.000 1.000 24 1.0000 256 O Beans­ dry­ hyacinth 0.002000 1.000 1.000 257 O Beans­ succulent­ hyacinth 1.000000 1.000 1.000 24 1.0000 258 6C Beans­ dry­ blackeye peas/ cowpea 0.002000 1.000 1.000 259 6C Beans­ dry­ garbanzo/ chick pea 0.002000 1.000 1.000 260 O Asparagus 1.000000 1.000 1.000 74 1.0000 270 15 Rice­ rough (brown) 0.074000 1.000 1.000 271 15 Rice­ milled (white) 0.074000 0.030 1.000 275 15 Sorghum (including milo) 0.000015 1.000 1.000 100 1.0000 276 15 Wheat­ rough 0.000015 1.000 1.000 100 1.0000 277 15 Wheat­ germ 0.000015 1.000 1.000 278 15 Wheat­ bran 0.000015 1.000 1.000 279 15 Wheat­ flour 0.000015 1.000 1.000 280 15 Millet 0.000015 1.000 1.000 100 1.0000 287 6C Guar beans 1.000000 1.000 1.000 24 1.0000 298 O Sunflower­ oil 0.000400 0.670 1.000 300 O Olive oil 0.077000 0.810 1.000 315 O Grapes­ wine and sherry 1.000000 1.000 1.000 77 1.0000 321 M Beef­ meat byproducts 3.675000 1.000 1.000 88 1.0000 322 M Beef­ other organ meats 3.675000 1.000 1.000 88 1.0000 325 M Beef­ kidney 3.675000 1.000 1.000 88 1.0000 326 M Beef­ liver 1.390000 1.000 1.000 87 1.0000 328 M Goat­ meat byproducts 3.675000 1.000 1.000 88 1.0000 329 M Goat­ other organ meats 3.675000 1.000 1.000 88 1.0000 331 M Goat­ kidney 3.675000 1.000 1.000 88 1.0000 332 M Goat­ liver 1.390000 1.000 1.000 87 1.0000 Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 96 336 M Sheep­ meat byproducts 3.675000 1.000 1.000 88 1.0000 337 M Sheep­ other organ meats 3.675000 1.000 1.000 88 1.0000 339 M Sheep­ kidney 3.675000 1.000 1.000 88 1.0000 340 M Sheep­ liver 1.390000 1.000 1.000 87 1.0000 342 M Pork­ meat byproducts 0.260000 1.000 1.000 92 1.0000 343 M Pork­ other organ meats 0.260000 1.000 1.000 92 1.0000 345 M Pork­ kidney 0.260000 1.000 1.000 92 1.0000 346 M Pork­ liver 0.100000 1.000 1.000 91 1.0000 349 F Fish­ shellfish 0.250000 1.000 1.000 377 11 Apples­ juice­ concentrate 1.000000 3.000 1.000 50 1.0000 380 13A Blackberries­ juice 1.000000 1.000 1.000 63 1.0000 389 O Cranberries­ juice­ concentrate 1.000000 3.300 1.000 76 1.0000 392 O Grapes­ juice­ concentrate 1.000000 3.000 1.000 78 1.0000 402 12 Peaches­ juice 1.000000 1.000 1.000 61 1.0000 404 11 Pears­ juice 1.000000 0.370 1.000 52 1.0000 405 6B Peas­ succulent/ blackeye/ cowpea 12­ Cooked: NFS 1.000000 0.150 1.000 27 1.0000 14­ Boiled 1.000000 0.150 1.000 27 1.0000 32­ Canned: Cooked 1.000000 0.150 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 0.150 1.000 28 1.0000 406 O Pineapples­ juice­ concentrate 1.000000 2.000 1.000 82 0.0250 95 0.4750 97 0.5000 407 1AB Radishes­ japanese (daiken) 1.000000 1.000 1.000 5 1.0000 408 15 Rice­ bran 0.074000 0.400 1.000 410 12 Apricot juice 1.000000 1.000 1.000 55 1.0000 413 6A Snowpeas 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 27 1.0000 14­ Boiled 1.000000 1.000 1.000 27 1.0000 15­ Fried 1.000000 1.000 1.000 27 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 28 1.0000 415 9B Squash­ spaghetti 1.000000 1.000 1.000 40 1.0000 416 O Strawberries­ juice 1.000000 1.000 1.000 84 1.0000 417 O Sunflower­ seeds 1.000000 1.000 1.000 85 1.0000 420 10 Tangerines­ juice­ concentrate 1.000000 4.080 1.000 46 1.0000 423 8 Tomatoes­ dried 1.000000 0.520 1.000 32 1.0000 426 M Veal­ kidney 3.675000 1.000 1.000 88 1.0000 427 M Veal­ liver 1.390000 1.000 1.000 87 1.0000 428 M Veal­ other organ meats 3.675000 1.000 1.000 88 1.0000 430 M Veal­ meat byproducts 3.675000 1.000 1.000 88 1.0000 431 14 Walnut oil 0.005400 1.000 1.000 Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 97 436 9A Watermelon­ juice 1.000000 1.000 1.000 38 1.0000 437 15 Wheat­ germ oil 0.000015 1.000 1.000 439 9B Wintermelon 1.000000 1.000 1.000 35 1.0000 441 10 Grapefruit­ juice­ concentrate 1.000000 4.580 1.000 43 1.0000 442 10 Lemons­ juice­ concentrate 1.000000 6.330 1.000 44 1.0000 443 10 Limes­ juice­ concentrate 1.000000 3.330 1.000 46 1.0000 448 10 Grapefruit peel 1.000000 1.000 1.000 42 1.0000 Attachment 5 Acute Dietary Exposure Analysis: Excluding All Commodities with No Detects 98 Results U. S. Environmental Protection Agency Ver. 7.76 DEEM ACUTE Analysis for CARBARYL (1989­ 92 data) Residue file: sensitivity no detects. RS7 Adjustment factor #2 NOT used. Analysis Date: 04­ 08­ 2002/ 17: 16: 12 Residue file dated: 04­ 08­ 2002/ 16: 54: 03/ 8 Daily totals for food and foodform consumption used. MC iterations = 1000 MC list in residue file MC seed = 10 Run Comment: "" =============================================================================== Summary calculations (per capita): 95th Percentile 99th Percentile 99.9th Percentile Exposure % aRfD Exposure % aRfD Exposure % aRfD ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ U. S. Population: 0.000230 2.30 0.001012 10.12 0.005870 58.70 All infants: 0.000440 4.40 0.002610 26.10 0.012965 129.65 Nursing infants (< 1 yr old): 0.000097 0.97 0.001223 12.23 0.008363 83.63 Non­ nursing infants (< 1 yr old): 0.000574 5.74 0.003120 31.20 0.013802 138.02 Children 1­ 6 yrs: 0.000473 4.73 0.001967 19.67 0.010765 107.65 Children 7­ 12 yrs: 0.000279 2.79 0.001400 14.00 0.008555 85.55 Females 13+ (preg/ not nursing): 0.000191 1.91 0.000882 8.82 0.005836 58.36 Females 13+ (nursing): 0.000247 2.47 0.001371 13.71 0.007050 70.50 Females 13­ 19 (not preg or nursing): 0.000107 1.07 0.000660 6.60 0.004499 44.99 Females 20+ (not preg or nursing): 0.000197 1.97 0.000943 9.43 0.004810 48.10 Females 13­ 50 yrs: 0.000184 1.84 0.000877 8.77 0.004434 44.34 Males 13­ 19 yrs: 0.000138 1.38 0.000721 7.21 0.003802 38.02 Males 20+ yrs: 0.000214 2.14 0.000863 8.63 0.004178 41.78 Seniors 55+: 0.000207 2.07 0.001008 10.08 0.005703 57.03 Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 99 Residue File U. S. Environmental Protection Agency Ver. 7.76 DEEM Acute analysis for CARBARYL Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10carbarylfinal9 no peaches. RS7 Analysis Date 04­ 15­ 2002 Residue file dated: 04­ 03­ 2002/ 14: 28: 13/ 8 Reference dose (aRfD) = 0.01 mg/ kg bw/ day ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RDL indices and parameters for Monte Carlo Analysis: Index Dist Parameter #1 Param #2 Param #3 Comment # Code ­­­­­ ­­­­ ­­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­ 1 6 Gardenbeet. rdf 2 6 Carrot. rdf 3 6 chic hors parsnip salsify. rdf 4 6 Potato. rdf 5 6 radishes. rdf 6 6 Turnip. rdf 7 6 sweetpotato. rdf 8 6 topsgardenbeet. rdf 9 6 topsradish. rdf 10 6 Topsturnip. rdf 11 6 celery. rdf 12 6 spinach. rdf 13 6 cannedspinach. rdf 14 6 lettucehd. rdf 15 6 lettuceleaf. rdf 16 6 rhubarb. rdf 17 6 broccoli. rdf 18 6 brusselssprouts. rdf 19 6 cabbage. rdf 20 6 cauliflower. rdf 21 6 collards. rdf 22 6 mustards. rdf 23 6 kohrabi. rdf 24 6 beanssucculentfresh. rdf 25 6 beanssucculentprocessed. rdf 26 6 beanslima. rdf 27 6 Peasfresh. rdf 28 6 Peasprocessed. rdf 29 6 alleggplant. rdf 30 6 peppersnonbell. rdf 31 6 allsweetpepper. rdf 32 6 tomatoesPB. rdf 33 6 tomatoesNB. rdf 34 6 allcucumber. rdf 35 6 melon. rdf 36 6 cantaloupe. rdf 37 6 honeydew. rdf 38 6 allwatermelon. rdf 39 6 pumpkin. rdf 40 6 wintersquash. rdf 41 6 allsummersquash. rdf 42 6 citrus. rdf 43 6 grapefruitjuice. rdf 44 6 lemonjuice. rdf 45 6 orangesdecomp. rdf 46 6 limejuice. rdf 47 6 orangejuice. rdf 48 6 appledecomp. rdf 49 6 apple. rdf 50 6 applejuice. rdf 51 6 peardecomp. rdf 52 6 pear. rdf 53 6 quince. rdf 54 6 crabapple. rdf 55 6 apricot. rdf 56 6 Apricotss. rdf 57 6 allsweetcherries. rdf 58 6 alltartcherries. rdf 59 6 nectarine. rdf 60 6 peachSS. rdf 61 6 Peach. rdf 62 6 plum2. rdf 63 6 blackberries. rdf 64 6 allblueberry. rdf 65 6 boysenberry. rdf Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 100 66 6 currant. rdf 67 6 allraspberries. rdf 68 6 almonds. rdf 69 6 chestnut. rdf 70 6 filbert. rdf 71 6 pecan. rdf 72 6 walnut. rdf 73 6 corn. rdf 74 6 allasparagus. rdf 75 6 banana. rdf 76 6 allcranberry. rdf 77 6 grapes. rdf 78 6 grapejuice. rdf 79 6 okra. rdf 80 6 olives. rdf 81 6 pineappledecomp. rdf 82 6 pineapplemexico. rdf 83 6 pistachio. rdf 84 6 strawberrypdp. rdf 85 6 sunflower. rdf 86 6 milk2. rdf 87 6 ruminantliver2. rdf 88 6 ruminantkidney2. rdf 89 6 swinemeat2. rdf 90 6 swinefat2. rdf 91 6 swineliver2. rdf 92 6 swinekidney2. rdf 93 6 poultry. rdf 94 6 eggs. rdf 95 6 pineappleother. rdf 96 6 Plumdecomp. rdf 97 6 pineappledomestic. rdf 98 6 appledried. rdf 99 6 soybean. rdf 100 6 wheat. rdf Food Crop Food Def Res Adj. Factors ­­­­­­­ RDL Indices and Ratios­­­­­­­ Code Grp Name (ppm) #1 #2 I# 1 Ratio# 1 I# 2 Ratio# 2 I# 3 Ratio# 3 ­­­­ ­­­­ ­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­ 1 13A Blackberries 1.000000 1.000 1.000 63 1.0000 2 13A Boysenberries 1.000000 1.000 1.000 65 1.0000 3 13A Dewberries 1.000000 1.000 1.000 65 1.0000 4 13A Loganberries 1.000000 1.000 1.000 65 1.0000 5 13A Raspberries 1.000000 1.000 1.000 67 1.0000 6 13A Youngberries 1.000000 1.000 1.000 65 1.0000 7 13B Blueberries 1.000000 1.000 1.000 64 1.0000 8 O Cranberries 1.000000 1.000 1.000 76 1.0000 9 O Cranberries­ juice 1.000000 1.100 1.000 76 1.0000 10 13B Currants 1.000000 1.000 1.000 66 1.0000 11 13B Elderberries 1.000000 1.000 1.000 66 1.0000 12 13B Gooseberries 1.000000 1.000 1.000 66 1.0000 13 O Grapes 1.000000 1.000 1.000 77 1.0000 14 O Grapes­ raisins 11­ Uncooked 1.000000 2.170 1.000 77 1.0000 12­ Cooked: NFS 1.000000 1.370 1.000 77 1.0000 13­ Baked 1.000000 1.370 1.000 77 1.0000 14­ Boiled 1.000000 1.370 1.000 77 1.0000 18­ Dried 1.000000 1.370 1.000 77 1.0000 42­ Frozen: Cooked 1.000000 1.370 1.000 77 1.0000 Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 101 15 O Grapes­ juice 1.000000 1.000 1.000 78 1.0000 16 13B Huckleberries 1.000000 1.000 1.000 66 1.0000 17 O Strawberries 1.000000 1.000 1.000 84 1.0000 20 10 Citrus citron 1.000000 1.000 1.000 42 1.0000 22 10 Grapefruit­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 14­ Boiled 0.000000 1.000 1.000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 23 10 Grapefruit­ juice 1.000000 1.170 1.000 43 1.0000 24 10 Kumquats 1.000000 1.000 1.000 42 1.0000 26 10 Lemons­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 27 10 Lemons­ peel 1.000000 1.190 1.000 42 1.0000 28 10 Lemons­ juice 1.000000 1.110 1.000 44 1.0000 30 10 Limes­ peeled fruit 1.000000 1.000 1.000 45 1.0000 31 10 Limes­ peel 1.000000 1.270 1.000 42 1.0000 32 10 Limes­ juice 1.000000 1.110 1.000 46 1.0000 33 10 Oranges­ juice­ concentrate 1.000000 3.700 1.000 47 1.0000 34 10 Oranges­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 35 10 Oranges­ peel 1.000000 1.270 1.000 42 1.0000 36 10 Oranges­ juice 1.000000 1.000 1.000 47 1.0000 37 10 Tangelos 1.000000 1.000 1.000 45 1.0000 38 10 Tangerines 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 42 1.0000 39 10 Tangerines­ juice 1.000000 1.280 1.000 46 1.0000 40 14 Almonds 1.000000 1.000 1.000 68 1.0000 43 14 Chestnuts 1.000000 1.000 1.000 69 1.0000 44 14 Filberts (hazelnuts) 1.000000 1.000 1.000 70 1.0000 48 14 Walnuts 1.000000 1.000 1.000 72 1.0000 50 O Pistachio nuts 1.000000 1.000 1.000 83 1.0000 52 11 Apples 11­ Uncooked 1.000000 1.000 1.000 48 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 48 1.0000 13­ Baked Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 102 1.000000 1.000 1.000 48 1.0000 14­ Boiled 1.000000 1.000 1.000 48 1.0000 15­ Fried 1.000000 1.000 1.000 48 1.0000 18­ Dried 0.009000 1.000 1.000 98 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 49 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 49 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 49 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 49 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 49 1.0000 53 11 Apples­ dried 1.000000 2.600 1.000 49 1.0000 54 11 Apples­ juice/ cider 1.000000 1.000 1.000 50 1.0000 55 11 Crabapples 1.000000 1.000 1.000 54 1.0000 56 11 Pears 11­ Uncooked 1.000000 1.000 1.000 51 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 51 1.0000 13­ Baked 1.000000 1.000 1.000 51 1.0000 14­ Boiled 1.000000 1.000 1.000 51 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 52 1.0000 57 11 Pears­ dried 1.000000 2.600 1.000 52 1.0000 58 11 Quinces 1.000000 1.000 1.000 53 1.0000 59 12 Apricots 11­ Uncooked 1.000000 1.000 1.000 56 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 56 1.0000 14­ Boiled 1.000000 1.000 1.000 56 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 55 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 55 1.0000 60 12 Apricots­ dried 1.000000 6.000 1.000 55 1.0000 61 12 Cherries 11­ Uncooked 1.000000 1.000 1.000 57 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 58 1.0000 13­ Baked 1.000000 1.000 1.000 58 1.0000 14­ Boiled 1.000000 1.000 1.000 58 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 58 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 58 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 58 1.0000 62 12 Cherries­ dried 1.000000 4.000 1.000 57 1.0000 63 12 Cherries­ juice 1.000000 1.500 1.000 58 1.0000 64 12 Nectarines 1.000000 1.000 1.000 59 1.0000 67 12 Plums (damsons) 11­ Uncooked 1.000000 1.000 1.000 96 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 96 1.0000 31­ Canned: NFS Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 103 1.000000 1.000 1.000 62 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 62 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 62 1.0000 68 12 Plums­ prunes (dried) 1.000000 0.150 1.000 62 1.0000 69 12 Plums/ prune­ juice 1.000000 1.400 1.000 62 1.0000 72 O Bananas 1.000000 1.000 1.000 75 1.0000 73 O Bananas­ dried 1.000000 3.900 1.000 75 1.0000 81 11 Loquats 1.000000 1.000 1.000 53 1.0000 82 O Olives 1.000000 1.000 1.000 80 1.0000 89 O Pineapples­ peeled fruit 11­ Uncooked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 12­ Cooked: NFS 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 13­ Baked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 14­ Boiled 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 31­ Canned: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 33­ Canned: Baked 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 41­ Frozen: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 90 O Pineapples­ dried 1.000000 5.000 1.000 82 0.0250 95 0.4750 97 0.5000 91 O Pineapples­ juice 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 94 O Plantains­ ripe 1.000000 1.000 1.000 75 1.0000 123 19A Dill 0.004000 1.000 1.000 126 1AB Horseradish 1.000000 1.000 1.000 3 1.0000 139 8 Paprika 1.000000 1.000 1.000 30 1.0000 141 9A Melons­ cantaloupes­ juice 1.000000 1.000 1.000 36 1.0000 142 9A Melons­ cantaloupes­ pulp 1.000000 1.000 1.000 36 1.0000 143 9A Casabas 1.000000 1.000 1.000 35 1.0000 144 9A Crenshaws 1.000000 1.000 1.000 35 1.0000 145 9A Melons­ honeydew 1.000000 1.000 1.000 37 1.0000 146 9A Melons­ persian 1.000000 1.000 1.000 35 1.0000 147 9A Watermelon 1.000000 1.000 1.000 38 1.0000 148 9B Cucumbers 1.000000 1.000 1.000 34 1.0000 149 9B Pumpkin 1.000000 1.000 1.000 39 1.0000 150 9B Squash­ summer 1.000000 1.000 1.000 41 1.0000 151 9B Squash­ winter 1.000000 1.000 1.000 40 1.0000 152 9B Bitter melon 1.000000 1.000 1.000 35 1.0000 154 8 Eggplant 1.000000 1.000 1.000 29 1.0000 155 8 Peppers­ sweet( garden) 1.000000 1.000 1.000 31 1.0000 156 8 Peppers­ chilli incl jalapeno 1.000000 1.000 1.000 30 1.0000 157 8 Peppers­ other 1.000000 1.000 1.000 30 1.0000 158 8 Pimientos 1.000000 1.000 1.000 30 1.0000 Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 104 159 8 Tomatoes­ whole 11­ Uncooked 1.000000 1.000 1.000 33 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 33 1.0000 13­ Baked 1.000000 1.000 1.000 33 1.0000 14­ Boiled 1.000000 1.000 1.000 33 1.0000 15­ Fried 1.000000 1.000 1.000 33 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 32 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 32 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 32 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 32 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 32 1.0000 160 8 Tomatoes­ juice 1.000000 0.540 1.000 32 1.0000 161 8 Tomatoes­ puree 1.000000 0.650 1.000 32 1.0000 162 8 Tomatoes­ paste 1.000000 0.650 1.000 32 1.0000 163 8 Tomatoes­ catsup 1.000000 0.650 1.000 32 1.0000 165 2 Beets­ garden­ tops( greens) 1.000000 1.000 1.000 8 1.0000 166 4B Celery 1.000000 1.000 1.000 11 1.0000 168 5A Broccoli 1.000000 1.000 1.000 17 1.0000 169 5A Brussels sprouts 1.000000 1.000 1.000 18 1.0000 170 5A Cabbage­ green and red 11­ Uncooked 1.000000 0.250 1.000 19 1.0000 12­ Cooked: NFS 1.000000 0.025 1.000 19 1.0000 13­ Baked 1.000000 0.025 1.000 19 1.0000 14­ Boiled 1.000000 0.025 1.000 19 1.0000 15­ Fried 1.000000 0.025 1.000 19 1.0000 31­ Canned: NFS 1.000000 0.250 1.000 19 1.0000 32­ Canned: Cooked 1.000000 0.025 1.000 19 1.0000 51­ Cured: NFS (smoked/ p 1.000000 0.025 1.000 19 1.0000 171 5A Cauliflower 1.000000 1.000 1.000 20 1.0000 172 5B Collards 1.000000 1.000 1.000 21 1.0000 174 5B Kale 1.000000 1.000 1.000 22 1.0000 175 5A Kohlrabi 1.000000 1.000 1.000 23 1.0000 176 4A Lettuce­ leafy varieties 1.000000 1.000 1.000 15 1.0000 177 4A Dandelion­ greens 1.000000 1.000 1.000 12 1.0000 178 4A Endive­ curley and escarole 1.000000 1.000 1.000 15 1.0000 182 4A Lettuce­ unspecified 1.000000 1.000 1.000 14 1.0000 183 5B Mustard greens 1.000000 1.000 1.000 22 1.0000 184 4A Parsley 1.000000 1.000 1.000 12 1.0000 185 4B Rhubarb 1.000000 1.000 1.000 16 1.0000 186 4A Spinach 11­ Uncooked Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 105 1.000000 1.000 1.000 12 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 12 1.0000 13­ Baked 0.000000 1.000 1.000 14­ Boiled 1.000000 1.000 1.000 12 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 13 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 13 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 13 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 12 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 12 1.0000 187 4B Swiss chard 1.000000 1.000 1.000 16 1.0000 188 2 Turnips­ tops 1.000000 1.000 1.000 10 1.0000 192 4A Lettuce­ head varieties 1.000000 1.000 1.000 14 1.0000 195 O Grapes­ leaves 1.000000 1.000 1.000 77 1.0000 197 1AB Beets­ garden­ roots 1.000000 1.000 1.000 1 1.0000 198 1AB Carrots 1.000000 1.000 1.000 2 1.0000 207 1C Potatoes/ white­ whole 11­ Uncooked 1.000000 1.000 1.000 4 1.0000 12­ Cooked: NFS 1.000000 0.040 1.000 4 1.0000 13­ Baked 1.000000 1.200 1.000 4 1.0000 14­ Boiled 1.000000 2.500 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 4 1.0000 208 1C Potatoes/ white­ unspecified 1.000000 1.000 1.000 4 1.0000 209 1C Potatoes/ white­ peeled 11­ Uncooked 0.000000 1.000 1.000 12­ Cooked: NFS 1.000000 1.000 1.000 4 1.0000 13­ Baked 1.000000 1.200 1.000 4 1.0000 14­ Boiled 1.000000 2.500 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 31­ Canned: NFS 0.000000 1.000 1.000 32­ Canned: Cooked 1.000000 1.000 1.000 4 1.0000 34­ Canned: Boiled 1.000000 2.500 1.000 4 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 4 1.0000 43­ Frozen: Baked 1.000000 1.200 1.000 4 1.0000 45­ Frozen: Fried 1.000000 0.040 1.000 4 1.0000 210 1C Potatoes/ white­ dry 0.000357 0.020 1.000 211 1C Potatoes/ white­ peel only 13­ Baked 1.000000 1.200 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 212 1AB Radishes­ roots 1.000000 1.000 1.000 5 1.0000 213 2 Radishes­ tops 1.000000 1.000 1.000 9 1.0000 Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 106 214 1AB Rutabagas­ roots 1.000000 1.000 1.000 6 1.0000 215 2 Rutabagas­ tops 1.000000 1.000 1.000 10 1.0000 216 1AB Salsify( oyster plant) 1.000000 1.000 1.000 3 1.0000 218 1CD Sweet potatoes (incl yams) 1.000000 1.000 1.000 7 1.0000 219 1AB Turnips­ roots 1.000000 1.000 1.000 6 1.0000 220 1AB Parsnips 1.000000 1.000 1.000 3 1.0000 227 6C Beans­ dry­ great northern 0.002000 1.000 1.000 228 6C Beans­ dry­ kidney 0.002000 1.000 1.000 229 6C Beans­ dry­ lima 0.002000 1.000 1.000 230 6C Beans­ dry­ navy (pea) 0.002000 1.000 1.000 231 6C Beans­ dry­ other 0.002000 1.000 1.000 232 6C Beans­ dry­ pinto 0.002000 1.000 1.000 233 6B Beans­ succulent­ lima 1.000000 1.000 1.000 26 1.0000 234 6A Beans­ succulent­ green 11­ Uncooked 1.000000 1.000 1.000 24 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 24 1.0000 14­ Boiled 1.000000 1.000 1.000 24 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 25 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 25 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 25 1.0000 235 6A Beans­ succulent­ other 1.000000 1.000 1.000 25 1.0000 236 6A Beans­ succulent­ yellow/ wax 14­ Boiled 1.000000 1.000 1.000 24 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 237 15 Corn/ pop 0.000100 1.000 1.000 238 15 Corn/ sweet 1.000000 1.000 1.000 73 1.0000 240 6C Peas (garden)­ dry 0.013000 0.045 1.000 241 6AB Peas (garden)­ green 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 0.150 1.000 27 1.0000 13­ Baked 1.000000 0.150 1.000 27 1.0000 14­ Boiled 1.000000 0.150 1.000 27 1.0000 15­ Fried 1.000000 0.150 1.000 27 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 28 1.0000 32­ Canned: Cooked 1.000000 0.150 1.000 28 1.0000 34­ Canned: Boiled 1.000000 0.150 1.000 28 1.0000 42­ Frozen: Cooked Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 107 1.000000 0.150 1.000 28 1.0000 44­ Frozen: Boiled 1.000000 0.150 1.000 28 1.0000 45­ Frozen: Fried 1.000000 0.150 1.000 28 1.0000 243 6C Lentils 0.002000 1.000 1.000 244 6C Mung beans (sprouts) 0.002000 1.000 1.000 245 O Okra 12­ Cooked: NFS 1.000000 0.180 1.000 79 1.0000 14­ Boiled 1.000000 0.050 1.000 79 1.0000 15­ Fried 1.000000 0.180 1.000 79 1.0000 32­ Canned: Cooked 1.000000 0.180 1.000 79 1.0000 42­ Frozen: Cooked 1.000000 0.180 1.000 79 1.0000 44­ Frozen: Boiled 1.000000 0.050 1.000 79 1.0000 249 6C Beans­ dry­ broadbeans 0.002000 1.000 1.000 250 6B Beans­ succulent­ broadbeans 1.000000 1.000 1.000 24 1.0000 251 6C Beans­ dry­ pigeon beans 0.002000 1.000 1.000 253 6 Beans­ unspecified 1.000000 1.000 1.000 24 1.0000 255 6A Soybeans­ sprouted seeds 0.000015 0.330 1.000 99 1.0000 256 O Beans­ dry­ hyacinth 0.002000 1.000 1.000 257 O Beans­ succulent­ hyacinth 1.000000 1.000 1.000 24 1.0000 258 6C Beans­ dry­ blackeye peas/ cowpea 0.002000 1.000 1.000 259 6C Beans­ dry­ garbanzo/ chick pea 0.002000 1.000 1.000 260 O Asparagus 1.000000 1.000 1.000 74 1.0000 266 15 Corn grain­ endosperm 0.000100 1.000 1.000 267 15 Corn grain­ bran 0.000100 1.000 1.000 268 15 Corn grain/ sugar/ hfcs 0.000100 1.500 1.000 270 15 Rice­ rough (brown) 0.074000 1.000 1.000 271 15 Rice­ milled (white) 0.074000 0.030 1.000 275 15 Sorghum (including milo) 0.000015 1.000 1.000 100 1.0000 276 15 Wheat­ rough 0.000015 1.000 1.000 100 1.0000 277 15 Wheat­ germ 0.000015 1.000 1.000 278 15 Wheat­ bran 0.000015 1.000 1.000 279 15 Wheat­ flour 0.000015 1.000 1.000 280 15 Millet 0.000015 1.000 1.000 100 1.0000 282 1A Sugar­ beet 0.000400 0.040 1.000 287 6C Guar beans 1.000000 1.000 1.000 24 1.0000 289 15 Corn grain­ oil 0.000100 0.250 1.000 292 O Flax seed 0.000100 1.000 1.000 293 O Peanuts­ oil 0.000600 0.290 1.000 297 6A Soybeans­ oil 0.000015 0.010 1.000 298 O Sunflower­ oil 0.000400 0.670 1.000 Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 108 300 O Olive oil 0.077000 0.810 1.000 303 6A Soybean­ other 0.000015 1.000 1.000 99 1.0000 304 6A Soybeans­ mature seeds dry 0.000015 1.000 1.000 99 1.0000 305 6A Soybeans­ flour (full fat) 0.000015 1.000 1.000 306 6A Soybeans­ flour (low fat) 0.000015 1.000 1.000 307 6A Soybeans­ flour (defatted) 0.000015 1.000 1.000 315 O Grapes­ wine and sherry 1.000000 1.000 1.000 77 1.0000 318 D Milk­ nonfat solids 0.030000 1.000 1.000 86 1.0000 319 D Milk­ fat solids 0.030000 1.000 1.000 86 1.0000 320 D Milk sugar (lactose) 0.030000 1.000 1.000 86 1.0000 321 M Beef­ meat byproducts 3.675000 1.000 1.000 88 1.0000 322 M Beef­ other organ meats 3.675000 1.000 1.000 88 1.0000 323 M Beef­ dried 0.907000 1.920 1.000 86 1.0000 324 M Beef­ fat w/ o bones 0.368000 1.000 1.000 86 1.0000 325 M Beef­ kidney 3.675000 1.000 1.000 88 1.0000 326 M Beef­ liver 1.390000 1.000 1.000 87 1.0000 327 M Beef­ lean (fat/ free) w/ o bones 0.907000 1.000 1.000 86 1.0000 328 M Goat­ meat byproducts 3.675000 1.000 1.000 88 1.0000 329 M Goat­ other organ meats 3.675000 1.000 1.000 88 1.0000 330 M Goat­ fat w/ o bone 0.368000 1.000 1.000 86 1.0000 331 M Goat­ kidney 3.675000 1.000 1.000 88 1.0000 332 M Goat­ liver 1.390000 1.000 1.000 87 1.0000 333 M Goat­ lean (fat/ free) w/ o bone 0.907000 1.000 1.000 86 1.0000 336 M Sheep­ meat byproducts 3.675000 1.000 1.000 88 1.0000 337 M Sheep­ other organ meats 3.675000 1.000 1.000 88 1.0000 338 M Sheep­ fat w/ o bone 0.368000 1.000 1.000 86 1.0000 339 M Sheep­ kidney 3.675000 1.000 1.000 88 1.0000 340 M Sheep­ liver 1.390000 1.000 1.000 87 1.0000 341 M Sheep­ lean (fat free) w/ o bone 0.907000 1.000 1.000 86 1.0000 342 M Pork­ meat byproducts 0.260000 1.000 1.000 92 1.0000 343 M Pork­ other organ meats 0.260000 1.000 1.000 92 1.0000 344 M Pork­ fat w/ o bone 0.026000 1.000 1.000 90 1.0000 345 M Pork­ kidney 0.260000 1.000 1.000 92 1.0000 346 M Pork­ liver 0.100000 1.000 1.000 91 1.0000 347 M Pork­ lean (fat free) w/ o bone 0.065000 1.000 1.000 89 1.0000 349 F Fish­ shellfish 0.250000 1.000 1.000 377 11 Apples­ juice­ concentrate 1.000000 3.000 1.000 50 1.0000 378 O Bananas­ juice 1.000000 1.000 1.000 75 1.0000 379 1A Sugar­ beet­ molasses 0.000400 0.040 1.000 Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 109 380 13A Blackberries­ juice 1.000000 1.000 1.000 63 1.0000 383 5B Cabbage­ savoy 12­ Cooked: NFS 1.000000 0.025 1.000 19 1.0000 384 4B Celery juice 1.000000 1.000 1.000 11 1.0000 388 15 Corn grain/ sugar­ molasses 0.000100 1.500 1.000 389 O Cranberries­ juice­ concentrate 1.000000 3.300 1.000 76 1.0000 392 O Grapes­ juice­ concentrate 1.000000 3.000 1.000 78 1.0000 398 D Milk­ based water 0.030000 1.000 1.000 86 1.0000 403 O Peanuts­ butter 0.000600 1.890 1.000 404 11 Pears­ juice 1.000000 0.370 1.000 52 1.0000 405 6B Peas­ succulent/ blackeye/ cowpea 12­ Cooked: NFS 1.000000 0.150 1.000 27 1.0000 14­ Boiled 1.000000 0.150 1.000 27 1.0000 32­ Canned: Cooked 1.000000 0.150 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 0.150 1.000 28 1.0000 406 O Pineapples­ juice­ concentrate 1.000000 2.000 1.000 82 0.0250 95 0.4750 97 0.5000 407 1AB Radishes­ japanese (daiken) 1.000000 1.000 1.000 5 1.0000 408 15 Rice­ bran 0.074000 0.400 1.000 410 12 Apricot juice 1.000000 1.000 1.000 55 1.0000 413 6A Snowpeas 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 27 1.0000 14­ Boiled 1.000000 1.000 1.000 27 1.0000 15­ Fried 1.000000 1.000 1.000 27 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 28 1.0000 415 9B Squash­ spaghetti 1.000000 1.000 1.000 40 1.0000 416 O Strawberries­ juice 1.000000 1.000 1.000 84 1.0000 417 O Sunflower­ seeds 1.000000 1.000 1.000 85 1.0000 420 10 Tangerines­ juice­ concentrate 1.000000 4.080 1.000 46 1.0000 423 8 Tomatoes­ dried 1.000000 0.520 1.000 32 1.0000 424 M Veal­ fat w/ o bones 0.368000 1.000 1.000 86 1.0000 425 M Veal­ lean (fat free) w/ o bones 0.907000 1.000 1.000 86 1.0000 426 M Veal­ kidney 3.675000 1.000 1.000 88 1.0000 427 M Veal­ liver 1.390000 1.000 1.000 87 1.0000 428 M Veal­ other organ meats 3.675000 1.000 1.000 88 1.0000 429 M Veal­ dried 0.907000 1.920 1.000 86 1.0000 430 M Veal­ meat byproducts 3.675000 1.000 1.000 88 1.0000 431 14 Walnut oil 0.005400 1.000 1.000 436 9A Watermelon­ juice 1.000000 1.000 1.000 38 1.0000 437 15 Wheat­ germ oil 0.000015 1.000 1.000 439 9B Wintermelon Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 110 1.000000 1.000 1.000 35 1.0000 441 10 Grapefruit­ juice­ concentrate 1.000000 4.580 1.000 43 1.0000 442 10 Lemons­ juice­ concentrate 1.000000 6.330 1.000 44 1.0000 443 10 Limes­ juice­ concentrate 1.000000 3.330 1.000 46 1.0000 448 10 Grapefruit peel 1.000000 1.000 1.000 42 1.0000 480 O Plantains­ green 1.000000 1.000 1.000 75 1.0000 481 O Plantains­ dried 1.000000 3.900 1.000 75 1.0000 940 O Peanuts­ hulled 0.000600 1.000 1.000 Attachment 6 Acute Dietary Exposure Analysis : Excluding Peaches 111 Results U. S. Environmental Protection Agency Ver. 7.76 DEEM ACUTE Analysis for CARBARYL (1989­ 92 data) Residue file: $$$ 10carbarylfinal9 no peaches. RS7 Adjustment factor #2 NOT used. Analysis Date: 04­ 04­ 2002/ 15: 35: 25 Residue file dated: 04­ 03­ 2002/ 14: 28: 13/ 8 Daily totals for food and foodform consumption used. MC iterations = 1000 MC list in residue file MC seed = 10 Run Comment: "" =============================================================================== Summary calculations (per capita): 95th Percentile 99th Percentile 99.9th Percentile Exposure % aRfD Exposure % aRfD Exposure % aRfD ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ U. S. Population: 0.000485 4.85 0.001322 13.22 0.005451 54.51 All infants: 0.000670 6.70 0.002971 29.71 0.007188 71.88 Nursing infants (< 1 yr old): 0.000267 2.67 0.000941 9.41 0.006452 64.52 Non­ nursing infants (< 1 yr old): 0.000890 8.90 0.003260 32.60 0.007493 74.93 Children 1­ 6 yrs: 0.001278 12.78 0.002381 23.81 0.010164 101.64 Children 7­ 12 yrs: 0.000703 7.03 0.001496 14.96 0.008243 82.43 Females 13+ (preg/ not nursing): 0.000431 4.31 0.000913 9.13 0.006439 64.39 Females 13+ (nursing): 0.000470 4.70 0.001469 14.69 0.008557 85.57 Females 13­ 19 (not preg or nursing): 0.000328 3.28 0.000789 7.89 0.004096 40.96 Females 20+ (not preg or nursing): 0.000286 2.86 0.000927 9.27 0.004597 45.97 Females 13­ 50 yrs: 0.000309 3.09 0.000890 8.90 0.004262 42.62 Males 13­ 19 yrs: 0.000420 4.20 0.000865 8.65 0.003535 35.35 Males 20+ yrs: 0.000309 3.09 0.000889 8.89 0.003949 39.49 Seniors 55+: 0.000290 2.90 0.000985 9.85 0.005456 54.56 Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 112 Residue File U. S. Environmental Protection Agency Ver. 7.76 DEEM Acute analysis for CARBARYL Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10carbarylfinal9 no apples. RS7 Analysis Date 04­ 15­ 2002 Residue file dated: 04­ 04­ 2002/ 15: 38: 36/ 8 Reference dose (aRfD) = 0.01 mg/ kg bw/ day ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RDL indices and parameters for Monte Carlo Analysis: Index Dist Parameter #1 Param #2 Param #3 Comment # Code ­­­­­ ­­­­ ­­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­ 1 6 Gardenbeet. rdf 2 6 Carrot. rdf 3 6 chic hors parsnip salsify. rdf 4 6 Potato. rdf 5 6 radishes. rdf 6 6 Turnip. rdf 7 6 sweetpotato. rdf 8 6 topsgardenbeet. rdf 9 6 topsradish. rdf 10 6 Topsturnip. rdf 11 6 celery. rdf 12 6 spinach. rdf 13 6 cannedspinach. rdf 14 6 lettucehd. rdf 15 6 lettuceleaf. rdf 16 6 rhubarb. rdf 17 6 broccoli. rdf 18 6 brusselssprouts. rdf 19 6 cabbage. rdf 20 6 cauliflower. rdf 21 6 collards. rdf 22 6 mustards. rdf 23 6 kohrabi. rdf 24 6 beanssucculentfresh. rdf 25 6 beanssucculentprocessed. rdf 26 6 beanslima. rdf 27 6 Peasfresh. rdf 28 6 Peasprocessed. rdf 29 6 alleggplant. rdf 30 6 peppersnonbell. rdf 31 6 allsweetpepper. rdf 32 6 tomatoesPB. rdf 33 6 tomatoesNB. rdf 34 6 allcucumber. rdf 35 6 melon. rdf 36 6 cantaloupe. rdf 37 6 honeydew. rdf 38 6 allwatermelon. rdf 39 6 pumpkin. rdf 40 6 wintersquash. rdf 41 6 allsummersquash. rdf 42 6 citrus. rdf 43 6 grapefruitjuice. rdf 44 6 lemonjuice. rdf 45 6 orangesdecomp. rdf 46 6 limejuice. rdf 47 6 orangejuice. rdf 48 6 appledecomp. rdf 49 6 apple. rdf 50 6 applejuice. rdf 51 6 peardecomp. rdf 52 6 pear. rdf 53 6 quince. rdf 54 6 crabapple. rdf 55 6 apricot. rdf 56 6 Apricotss. rdf 57 6 allsweetcherries. rdf 58 6 alltartcherries. rdf 59 6 nectarine. rdf 60 6 peachSS. rdf 61 6 Peach. rdf 62 6 plum2. rdf 63 6 blackberries. rdf 64 6 allblueberry. rdf Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 113 65 6 boysenberry. rdf 66 6 currant. rdf 67 6 allraspberries. rdf 68 6 almonds. rdf 69 6 chestnut. rdf 70 6 filbert. rdf 71 6 pecan. rdf 72 6 walnut. rdf 73 6 corn. rdf 74 6 allasparagus. rdf 75 6 banana. rdf 76 6 allcranberry. rdf 77 6 grapes. rdf 78 6 grapejuice. rdf 79 6 okra. rdf 80 6 olives. rdf 81 6 pineappledecomp. rdf 82 6 pineapplemexico. rdf 83 6 pistachio. rdf 84 6 strawberrypdp. rdf 85 6 sunflower. rdf 86 6 milk2. rdf 87 6 ruminantliver2. rdf 88 6 ruminantkidney2. rdf 89 6 swinemeat2. rdf 90 6 swinefat2. rdf 91 6 swineliver2. rdf 92 6 swinekidney2. rdf 93 6 poultry. rdf 94 6 eggs. rdf 95 6 pineappleother. rdf 96 6 Plumdecomp. rdf 97 6 pineappledomestic. rdf 98 6 appledried. rdf 99 6 soybean. rdf 100 6 wheat. rdf Food Crop Food Def Res Adj. Factors ­­­­­­­ RDL Indices and Ratios­­­­­­­ Code Grp Name (ppm) #1 #2 I# 1 Ratio# 1 I# 2 Ratio# 2 I# 3 Ratio# 3 ­­­­ ­­­­ ­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­ 1 13A Blackberries 1.000000 1.000 1.000 63 1.0000 2 13A Boysenberries 1.000000 1.000 1.000 65 1.0000 3 13A Dewberries 1.000000 1.000 1.000 65 1.0000 4 13A Loganberries 1.000000 1.000 1.000 65 1.0000 5 13A Raspberries 1.000000 1.000 1.000 67 1.0000 6 13A Youngberries 1.000000 1.000 1.000 65 1.0000 7 13B Blueberries 1.000000 1.000 1.000 64 1.0000 8 O Cranberries 1.000000 1.000 1.000 76 1.0000 9 O Cranberries­ juice 1.000000 1.100 1.000 76 1.0000 10 13B Currants 1.000000 1.000 1.000 66 1.0000 11 13B Elderberries 1.000000 1.000 1.000 66 1.0000 12 13B Gooseberries 1.000000 1.000 1.000 66 1.0000 13 O Grapes 1.000000 1.000 1.000 77 1.0000 14 O Grapes­ raisins 11­ Uncooked 1.000000 2.170 1.000 77 1.0000 12­ Cooked: NFS 1.000000 1.370 1.000 77 1.0000 13­ Baked 1.000000 1.370 1.000 77 1.0000 14­ Boiled 1.000000 1.370 1.000 77 1.0000 18­ Dried 1.000000 1.370 1.000 77 1.0000 42­ Frozen: Cooked Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 114 1.000000 1.370 1.000 77 1.0000 15 O Grapes­ juice 1.000000 1.000 1.000 78 1.0000 16 13B Huckleberries 1.000000 1.000 1.000 66 1.0000 17 O Strawberries 1.000000 1.000 1.000 84 1.0000 20 10 Citrus citron 1.000000 1.000 1.000 42 1.0000 22 10 Grapefruit­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 14­ Boiled 0.000000 1.000 1.000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 23 10 Grapefruit­ juice 1.000000 1.170 1.000 43 1.0000 24 10 Kumquats 1.000000 1.000 1.000 42 1.0000 26 10 Lemons­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 27 10 Lemons­ peel 1.000000 1.190 1.000 42 1.0000 28 10 Lemons­ juice 1.000000 1.110 1.000 44 1.0000 30 10 Limes­ peeled fruit 1.000000 1.000 1.000 45 1.0000 31 10 Limes­ peel 1.000000 1.270 1.000 42 1.0000 32 10 Limes­ juice 1.000000 1.110 1.000 46 1.0000 33 10 Oranges­ juice­ concentrate 1.000000 3.700 1.000 47 1.0000 34 10 Oranges­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 35 10 Oranges­ peel 1.000000 1.270 1.000 42 1.0000 36 10 Oranges­ juice 1.000000 1.000 1.000 47 1.0000 37 10 Tangelos 1.000000 1.000 1.000 45 1.0000 38 10 Tangerines 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 42 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 42 1.0000 39 10 Tangerines­ juice 1.000000 1.280 1.000 46 1.0000 40 14 Almonds 1.000000 1.000 1.000 68 1.0000 43 14 Chestnuts 1.000000 1.000 1.000 69 1.0000 44 14 Filberts (hazelnuts) 1.000000 1.000 1.000 70 1.0000 48 14 Walnuts 1.000000 1.000 1.000 72 1.0000 50 O Pistachio nuts 1.000000 1.000 1.000 83 1.0000 55 11 Crabapples 1.000000 1.000 1.000 54 1.0000 56 11 Pears 11­ Uncooked 1.000000 1.000 1.000 51 1.0000 Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 115 12­ Cooked: NFS 1.000000 1.000 1.000 51 1.0000 13­ Baked 1.000000 1.000 1.000 51 1.0000 14­ Boiled 1.000000 1.000 1.000 51 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 52 1.0000 57 11 Pears­ dried 1.000000 2.600 1.000 52 1.0000 58 11 Quinces 1.000000 1.000 1.000 53 1.0000 59 12 Apricots 11­ Uncooked 1.000000 1.000 1.000 56 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 56 1.0000 14­ Boiled 1.000000 1.000 1.000 56 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 55 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 55 1.0000 60 12 Apricots­ dried 1.000000 6.000 1.000 55 1.0000 61 12 Cherries 11­ Uncooked 1.000000 1.000 1.000 57 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 58 1.0000 13­ Baked 1.000000 1.000 1.000 58 1.0000 14­ Boiled 1.000000 1.000 1.000 58 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 58 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 58 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 58 1.0000 62 12 Cherries­ dried 1.000000 4.000 1.000 57 1.0000 63 12 Cherries­ juice 1.000000 1.500 1.000 58 1.0000 64 12 Nectarines 1.000000 1.000 1.000 59 1.0000 65 12 Peaches 11­ Uncooked 1.000000 1.000 1.000 60 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 60 1.0000 13­ Baked 1.000000 1.000 1.000 60 1.0000 14­ Boiled 1.000000 1.000 1.000 60 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 61 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 61 1.0000 66 12 Peaches­ dried 1.000000 7.000 1.000 61 1.0000 67 12 Plums (damsons) 11­ Uncooked 1.000000 1.000 1.000 96 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 96 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 62 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 62 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 62 1.0000 68 12 Plums­ prunes (dried) 1.000000 0.150 1.000 62 1.0000 69 12 Plums/ prune­ juice 1.000000 1.400 1.000 62 1.0000 72 O Bananas 1.000000 1.000 1.000 75 1.0000 Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 116 73 O Bananas­ dried 1.000000 3.900 1.000 75 1.0000 81 11 Loquats 1.000000 1.000 1.000 53 1.0000 82 O Olives 1.000000 1.000 1.000 80 1.0000 89 O Pineapples­ peeled fruit 11­ Uncooked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 12­ Cooked: NFS 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 13­ Baked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 14­ Boiled 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 31­ Canned: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 33­ Canned: Baked 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 41­ Frozen: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 90 O Pineapples­ dried 1.000000 5.000 1.000 82 0.0250 95 0.4750 97 0.5000 91 O Pineapples­ juice 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 94 O Plantains­ ripe 1.000000 1.000 1.000 75 1.0000 123 19A Dill 0.004000 1.000 1.000 126 1AB Horseradish 1.000000 1.000 1.000 3 1.0000 139 8 Paprika 1.000000 1.000 1.000 30 1.0000 141 9A Melons­ cantaloupes­ juice 1.000000 1.000 1.000 36 1.0000 142 9A Melons­ cantaloupes­ pulp 1.000000 1.000 1.000 36 1.0000 143 9A Casabas 1.000000 1.000 1.000 35 1.0000 144 9A Crenshaws 1.000000 1.000 1.000 35 1.0000 145 9A Melons­ honeydew 1.000000 1.000 1.000 37 1.0000 146 9A Melons­ persian 1.000000 1.000 1.000 35 1.0000 147 9A Watermelon 1.000000 1.000 1.000 38 1.0000 148 9B Cucumbers 1.000000 1.000 1.000 34 1.0000 149 9B Pumpkin 1.000000 1.000 1.000 39 1.0000 150 9B Squash­ summer 1.000000 1.000 1.000 41 1.0000 151 9B Squash­ winter 1.000000 1.000 1.000 40 1.0000 152 9B Bitter melon 1.000000 1.000 1.000 35 1.0000 154 8 Eggplant 1.000000 1.000 1.000 29 1.0000 155 8 Peppers­ sweet( garden) 1.000000 1.000 1.000 31 1.0000 156 8 Peppers­ chilli incl jalapeno 1.000000 1.000 1.000 30 1.0000 157 8 Peppers­ other 1.000000 1.000 1.000 30 1.0000 158 8 Pimientos 1.000000 1.000 1.000 30 1.0000 159 8 Tomatoes­ whole 11­ Uncooked 1.000000 1.000 1.000 33 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 33 1.0000 13­ Baked 1.000000 1.000 1.000 33 1.0000 14­ Boiled 1.000000 1.000 1.000 33 1.0000 15­ Fried 1.000000 1.000 1.000 33 1.0000 Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 117 31­ Canned: NFS 1.000000 1.000 1.000 32 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 32 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 32 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 32 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 32 1.0000 160 8 Tomatoes­ juice 1.000000 0.540 1.000 32 1.0000 161 8 Tomatoes­ puree 1.000000 0.650 1.000 32 1.0000 162 8 Tomatoes­ paste 1.000000 0.650 1.000 32 1.0000 163 8 Tomatoes­ catsup 1.000000 0.650 1.000 32 1.0000 165 2 Beets­ garden­ tops( greens) 1.000000 1.000 1.000 8 1.0000 166 4B Celery 1.000000 1.000 1.000 11 1.0000 168 5A Broccoli 1.000000 1.000 1.000 17 1.0000 169 5A Brussels sprouts 1.000000 1.000 1.000 18 1.0000 170 5A Cabbage­ green and red 11­ Uncooked 1.000000 0.250 1.000 19 1.0000 12­ Cooked: NFS 1.000000 0.025 1.000 19 1.0000 13­ Baked 1.000000 0.025 1.000 19 1.0000 14­ Boiled 1.000000 0.025 1.000 19 1.0000 15­ Fried 1.000000 0.025 1.000 19 1.0000 31­ Canned: NFS 1.000000 0.250 1.000 19 1.0000 32­ Canned: Cooked 1.000000 0.025 1.000 19 1.0000 51­ Cured: NFS (smoked/ p 1.000000 0.025 1.000 19 1.0000 171 5A Cauliflower 1.000000 1.000 1.000 20 1.0000 172 5B Collards 1.000000 1.000 1.000 21 1.0000 174 5B Kale 1.000000 1.000 1.000 22 1.0000 175 5A Kohlrabi 1.000000 1.000 1.000 23 1.0000 176 4A Lettuce­ leafy varieties 1.000000 1.000 1.000 15 1.0000 177 4A Dandelion­ greens 1.000000 1.000 1.000 12 1.0000 178 4A Endive­ curley and escarole 1.000000 1.000 1.000 15 1.0000 182 4A Lettuce­ unspecified 1.000000 1.000 1.000 14 1.0000 183 5B Mustard greens 1.000000 1.000 1.000 22 1.0000 184 4A Parsley 1.000000 1.000 1.000 12 1.0000 185 4B Rhubarb 1.000000 1.000 1.000 16 1.0000 186 4A Spinach 11­ Uncooked 1.000000 1.000 1.000 12 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 12 1.0000 13­ Baked 0.000000 1.000 1.000 14­ Boiled 1.000000 1.000 1.000 12 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 13 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 13 1.0000 Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 118 34­ Canned: Boiled 1.000000 1.000 1.000 13 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 12 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 12 1.0000 187 4B Swiss chard 1.000000 1.000 1.000 16 1.0000 188 2 Turnips­ tops 1.000000 1.000 1.000 10 1.0000 192 4A Lettuce­ head varieties 1.000000 1.000 1.000 14 1.0000 195 O Grapes­ leaves 1.000000 1.000 1.000 77 1.0000 197 1AB Beets­ garden­ roots 1.000000 1.000 1.000 1 1.0000 198 1AB Carrots 1.000000 1.000 1.000 2 1.0000 207 1C Potatoes/ white­ whole 11­ Uncooked 1.000000 1.000 1.000 4 1.0000 12­ Cooked: NFS 1.000000 0.040 1.000 4 1.0000 13­ Baked 1.000000 1.200 1.000 4 1.0000 14­ Boiled 1.000000 2.500 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 4 1.0000 208 1C Potatoes/ white­ unspecified 1.000000 1.000 1.000 4 1.0000 209 1C Potatoes/ white­ peeled 11­ Uncooked 0.000000 1.000 1.000 12­ Cooked: NFS 1.000000 1.000 1.000 4 1.0000 13­ Baked 1.000000 1.200 1.000 4 1.0000 14­ Boiled 1.000000 2.500 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 31­ Canned: NFS 0.000000 1.000 1.000 32­ Canned: Cooked 1.000000 1.000 1.000 4 1.0000 34­ Canned: Boiled 1.000000 2.500 1.000 4 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 4 1.0000 43­ Frozen: Baked 1.000000 1.200 1.000 4 1.0000 45­ Frozen: Fried 1.000000 0.040 1.000 4 1.0000 210 1C Potatoes/ white­ dry 0.000357 0.020 1.000 211 1C Potatoes/ white­ peel only 13­ Baked 1.000000 1.200 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 212 1AB Radishes­ roots 1.000000 1.000 1.000 5 1.0000 213 2 Radishes­ tops 1.000000 1.000 1.000 9 1.0000 214 1AB Rutabagas­ roots 1.000000 1.000 1.000 6 1.0000 215 2 Rutabagas­ tops 1.000000 1.000 1.000 10 1.0000 216 1AB Salsify( oyster plant) 1.000000 1.000 1.000 3 1.0000 218 1CD Sweet potatoes (incl yams) 1.000000 1.000 1.000 7 1.0000 219 1AB Turnips­ roots 1.000000 1.000 1.000 6 1.0000 220 1AB Parsnips Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 119 1.000000 1.000 1.000 3 1.0000 227 6C Beans­ dry­ great northern 0.002000 1.000 1.000 228 6C Beans­ dry­ kidney 0.002000 1.000 1.000 229 6C Beans­ dry­ lima 0.002000 1.000 1.000 230 6C Beans­ dry­ navy (pea) 0.002000 1.000 1.000 231 6C Beans­ dry­ other 0.002000 1.000 1.000 232 6C Beans­ dry­ pinto 0.002000 1.000 1.000 233 6B Beans­ succulent­ lima 1.000000 1.000 1.000 26 1.0000 234 6A Beans­ succulent­ green 11­ Uncooked 1.000000 1.000 1.000 24 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 24 1.0000 14­ Boiled 1.000000 1.000 1.000 24 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 25 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 25 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 25 1.0000 235 6A Beans­ succulent­ other 1.000000 1.000 1.000 25 1.0000 236 6A Beans­ succulent­ yellow/ wax 14­ Boiled 1.000000 1.000 1.000 24 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 237 15 Corn/ pop 0.000100 1.000 1.000 238 15 Corn/ sweet 1.000000 1.000 1.000 73 1.0000 240 6C Peas (garden)­ dry 0.013000 0.045 1.000 241 6AB Peas (garden)­ green 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 0.150 1.000 27 1.0000 13­ Baked 1.000000 0.150 1.000 27 1.0000 14­ Boiled 1.000000 0.150 1.000 27 1.0000 15­ Fried 1.000000 0.150 1.000 27 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 28 1.0000 32­ Canned: Cooked 1.000000 0.150 1.000 28 1.0000 34­ Canned: Boiled 1.000000 0.150 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 0.150 1.000 28 1.0000 44­ Frozen: Boiled 1.000000 0.150 1.000 28 1.0000 45­ Frozen: Fried 1.000000 0.150 1.000 28 1.0000 243 6C Lentils 0.002000 1.000 1.000 244 6C Mung beans (sprouts) 0.002000 1.000 1.000 245 O Okra 12­ Cooked: NFS Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 120 1.000000 0.180 1.000 79 1.0000 14­ Boiled 1.000000 0.050 1.000 79 1.0000 15­ Fried 1.000000 0.180 1.000 79 1.0000 32­ Canned: Cooked 1.000000 0.180 1.000 79 1.0000 42­ Frozen: Cooked 1.000000 0.180 1.000 79 1.0000 44­ Frozen: Boiled 1.000000 0.050 1.000 79 1.0000 249 6C Beans­ dry­ broadbeans 0.002000 1.000 1.000 250 6B Beans­ succulent­ broadbeans 1.000000 1.000 1.000 24 1.0000 251 6C Beans­ dry­ pigeon beans 0.002000 1.000 1.000 253 6 Beans­ unspecified 1.000000 1.000 1.000 24 1.0000 255 6A Soybeans­ sprouted seeds 0.000015 0.330 1.000 99 1.0000 256 O Beans­ dry­ hyacinth 0.002000 1.000 1.000 257 O Beans­ succulent­ hyacinth 1.000000 1.000 1.000 24 1.0000 258 6C Beans­ dry­ blackeye peas/ cowpea 0.002000 1.000 1.000 259 6C Beans­ dry­ garbanzo/ chick pea 0.002000 1.000 1.000 260 O Asparagus 1.000000 1.000 1.000 74 1.0000 266 15 Corn grain­ endosperm 0.000100 1.000 1.000 267 15 Corn grain­ bran 0.000100 1.000 1.000 268 15 Corn grain/ sugar/ hfcs 0.000100 1.500 1.000 270 15 Rice­ rough (brown) 0.074000 1.000 1.000 271 15 Rice­ milled (white) 0.074000 0.030 1.000 275 15 Sorghum (including milo) 0.000015 1.000 1.000 100 1.0000 276 15 Wheat­ rough 0.000015 1.000 1.000 100 1.0000 277 15 Wheat­ germ 0.000015 1.000 1.000 278 15 Wheat­ bran 0.000015 1.000 1.000 279 15 Wheat­ flour 0.000015 1.000 1.000 280 15 Millet 0.000015 1.000 1.000 100 1.0000 282 1A Sugar­ beet 0.000400 0.040 1.000 287 6C Guar beans 1.000000 1.000 1.000 24 1.0000 289 15 Corn grain­ oil 0.000100 0.250 1.000 292 O Flax seed 0.000100 1.000 1.000 293 O Peanuts­ oil 0.000600 0.290 1.000 297 6A Soybeans­ oil 0.000015 0.010 1.000 298 O Sunflower­ oil 0.000400 0.670 1.000 300 O Olive oil 0.077000 0.810 1.000 303 6A Soybean­ other 0.000015 1.000 1.000 99 1.0000 304 6A Soybeans­ mature seeds dry 0.000015 1.000 1.000 99 1.0000 305 6A Soybeans­ flour (full fat) 0.000015 1.000 1.000 306 6A Soybeans­ flour (low fat) 0.000015 1.000 1.000 307 6A Soybeans­ flour (defatted) Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 121 0.000015 1.000 1.000 315 O Grapes­ wine and sherry 1.000000 1.000 1.000 77 1.0000 318 D Milk­ nonfat solids 0.030000 1.000 1.000 86 1.0000 319 D Milk­ fat solids 0.030000 1.000 1.000 86 1.0000 320 D Milk sugar (lactose) 0.030000 1.000 1.000 86 1.0000 321 M Beef­ meat byproducts 3.675000 1.000 1.000 88 1.0000 322 M Beef­ other organ meats 3.675000 1.000 1.000 88 1.0000 323 M Beef­ dried 0.907000 1.920 1.000 86 1.0000 324 M Beef­ fat w/ o bones 0.368000 1.000 1.000 86 1.0000 325 M Beef­ kidney 3.675000 1.000 1.000 88 1.0000 326 M Beef­ liver 1.390000 1.000 1.000 87 1.0000 327 M Beef­ lean (fat/ free) w/ o bones 0.907000 1.000 1.000 86 1.0000 328 M Goat­ meat byproducts 3.675000 1.000 1.000 88 1.0000 329 M Goat­ other organ meats 3.675000 1.000 1.000 88 1.0000 330 M Goat­ fat w/ o bone 0.368000 1.000 1.000 86 1.0000 331 M Goat­ kidney 3.675000 1.000 1.000 88 1.0000 332 M Goat­ liver 1.390000 1.000 1.000 87 1.0000 333 M Goat­ lean (fat/ free) w/ o bone 0.907000 1.000 1.000 86 1.0000 336 M Sheep­ meat byproducts 3.675000 1.000 1.000 88 1.0000 337 M Sheep­ other organ meats 3.675000 1.000 1.000 88 1.0000 338 M Sheep­ fat w/ o bone 0.368000 1.000 1.000 86 1.0000 339 M Sheep­ kidney 3.675000 1.000 1.000 88 1.0000 340 M Sheep­ liver 1.390000 1.000 1.000 87 1.0000 341 M Sheep­ lean (fat free) w/ o bone 0.907000 1.000 1.000 86 1.0000 342 M Pork­ meat byproducts 0.260000 1.000 1.000 92 1.0000 343 M Pork­ other organ meats 0.260000 1.000 1.000 92 1.0000 344 M Pork­ fat w/ o bone 0.026000 1.000 1.000 90 1.0000 345 M Pork­ kidney 0.260000 1.000 1.000 92 1.0000 346 M Pork­ liver 0.100000 1.000 1.000 91 1.0000 347 M Pork­ lean (fat free) w/ o bone 0.065000 1.000 1.000 89 1.0000 349 F Fish­ shellfish 0.250000 1.000 1.000 378 O Bananas­ juice 1.000000 1.000 1.000 75 1.0000 379 1A Sugar­ beet­ molasses 0.000400 0.040 1.000 380 13A Blackberries­ juice 1.000000 1.000 1.000 63 1.0000 383 5B Cabbage­ savoy 12­ Cooked: NFS 1.000000 0.025 1.000 19 1.0000 384 4B Celery juice 1.000000 1.000 1.000 11 1.0000 388 15 Corn grain/ sugar­ molasses 0.000100 1.500 1.000 389 O Cranberries­ juice­ concentrate 1.000000 3.300 1.000 76 1.0000 392 O Grapes­ juice­ concentrate 1.000000 3.000 1.000 78 1.0000 Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 122 398 D Milk­ based water 0.030000 1.000 1.000 86 1.0000 402 12 Peaches­ juice 1.000000 1.000 1.000 61 1.0000 403 O Peanuts­ butter 0.000600 1.890 1.000 404 11 Pears­ juice 1.000000 0.370 1.000 52 1.0000 405 6B Peas­ succulent/ blackeye/ cowpea 12­ Cooked: NFS 1.000000 0.150 1.000 27 1.0000 14­ Boiled 1.000000 0.150 1.000 27 1.0000 32­ Canned: Cooked 1.000000 0.150 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 0.150 1.000 28 1.0000 406 O Pineapples­ juice­ concentrate 1.000000 2.000 1.000 82 0.0250 95 0.4750 97 0.5000 407 1AB Radishes­ japanese (daiken) 1.000000 1.000 1.000 5 1.0000 408 15 Rice­ bran 0.074000 0.400 1.000 410 12 Apricot juice 1.000000 1.000 1.000 55 1.0000 413 6A Snowpeas 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 27 1.0000 14­ Boiled 1.000000 1.000 1.000 27 1.0000 15­ Fried 1.000000 1.000 1.000 27 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 28 1.0000 415 9B Squash­ spaghetti 1.000000 1.000 1.000 40 1.0000 416 O Strawberries­ juice 1.000000 1.000 1.000 84 1.0000 417 O Sunflower­ seeds 1.000000 1.000 1.000 85 1.0000 420 10 Tangerines­ juice­ concentrate 1.000000 4.080 1.000 46 1.0000 423 8 Tomatoes­ dried 1.000000 0.520 1.000 32 1.0000 424 M Veal­ fat w/ o bones 0.368000 1.000 1.000 86 1.0000 425 M Veal­ lean (fat free) w/ o bones 0.907000 1.000 1.000 86 1.0000 426 M Veal­ kidney 3.675000 1.000 1.000 88 1.0000 427 M Veal­ liver 1.390000 1.000 1.000 87 1.0000 428 M Veal­ other organ meats 3.675000 1.000 1.000 88 1.0000 429 M Veal­ dried 0.907000 1.920 1.000 86 1.0000 430 M Veal­ meat byproducts 3.675000 1.000 1.000 88 1.0000 431 14 Walnut oil 0.005400 1.000 1.000 436 9A Watermelon­ juice 1.000000 1.000 1.000 38 1.0000 437 15 Wheat­ germ oil 0.000015 1.000 1.000 439 9B Wintermelon 1.000000 1.000 1.000 35 1.0000 441 10 Grapefruit­ juice­ concentrate 1.000000 4.580 1.000 43 1.0000 442 10 Lemons­ juice­ concentrate 1.000000 6.330 1.000 44 1.0000 443 10 Limes­ juice­ concentrate 1.000000 3.330 1.000 46 1.0000 448 10 Grapefruit peel 1.000000 1.000 1.000 42 1.0000 480 O Plantains­ green 1.000000 1.000 1.000 75 1.0000 Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 123 481 O Plantains­ dried 1.000000 3.900 1.000 75 1.0000 940 O Peanuts­ hulled 0.000600 1.000 1.000 Attachment 7. Acute Dietary Exposure Analysis: Excluding Apples 124 Results U. S. Environmental Protection Agency Ver. 7.76 DEEM ACUTE Analysis for CARBARYL (1989­ 92 data) Residue file: $$$ 10carbarylfinal9 no apples. RS7 Adjustment factor #2 NOT used. Analysis Date: 04­ 04­ 2002/ 16: 22: 55 Residue file dated: 04­ 04­ 2002/ 15: 38: 36/ 8 Daily totals for food and foodform consumption used. MC iterations = 1000 MC list in residue file MC seed = 10 Run Comment: "" =============================================================================== Summary calculations (per capita): 95th Percentile 99th Percentile 99.9th Percentile Exposure % aRfD Exposure % aRfD Exposure % aRfD ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ U. S. Population: 0.000456 4.56 0.001246 12.46 0.004943 49.43 All infants: 0.000544 5.44 0.003111 31.11 0.011784 117.84 Nursing infants (< 1 yr old): 0.000209 2.09 0.000780 7.80 0.007620 76.20 Non­ nursing infants (< 1 yr old): 0.000774 7.74 0.003644 36.44 0.012798 127.98 Children 1­ 6 yrs: 0.001205 12.05 0.002248 22.48 0.008201 82.01 Children 7­ 12 yrs: 0.000672 6.72 0.001351 13.51 0.006867 68.67 Females 13+ (preg/ not nursing): 0.000410 4.10 0.000788 7.88 0.004787 47.87 Females 13+ (nursing): 0.000385 3.85 0.001176 11.76 0.007275 72.75 Females 13­ 19 (not preg or nursing): 0.000320 3.20 0.000778 7.78 0.003965 39.65 Females 20+ (not preg or nursing): 0.000276 2.76 0.000901 9.01 0.004158 41.58 Females 13­ 50 yrs: 0.000298 2.98 0.000868 8.68 0.003890 38.90 Males 13­ 19 yrs: 0.000410 4.10 0.000819 8.19 0.003014 30.14 Males 20+ yrs: 0.000298 2.98 0.000848 8.48 0.003575 35.75 Seniors 55+: 0.000281 2.81 0.000963 9.63 0.005094 50.94 Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 125 Residue File U. S. Environmental Protection Agency Ver. 7.76 DEEM Acute analysis for CARBARYL Residue file name: C:\$ MyFiles\ Carbaryl\ Rdf files\$$$ 10carbarylfinal9 market basket. RS7 Analysis Date 04­ 15­ 2002 Residue file dated: 04­ 04­ 2002/ 17: 32: 06/ 8 Reference dose (aRfD) = 0.01 mg/ kg bw/ day ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RDL indices and parameters for Monte Carlo Analysis: Index Dist Parameter #1 Param #2 Param #3 Comment # Code ­­­­­ ­­­­ ­­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­­­ ­­­­­­­­­ 1 6 Gardenbeet. rdf 2 6 Carrot. rdf 3 6 chic hors parsnip salsify. rdf 4 6 Potato. rdf 5 6 radishes. rdf 6 6 Turnip. rdf 7 6 sweetpotato. rdf 8 6 topsgardenbeet. rdf 9 6 topsradish. rdf 10 6 Topsturnip. rdf 11 6 celery. rdf 12 6 spinach. rdf 13 6 cannedspinach. rdf 14 6 zmarklettuce. rdf 15 6 lettuceleaf. rdf 16 6 rhubarb. rdf 17 6 zmarkbroccoli. rdf 18 6 brusselssprouts. rdf 19 6 cabbage. rdf 20 6 cauliflower. rdf 21 6 collards. rdf 22 6 mustards. rdf 23 6 kohrabi. rdf 24 6 beanssucculentfresh. rdf 25 6 beanssucculentprocessed. rdf 26 6 beanslima. rdf 27 6 Peasfresh. rdf 28 6 Peasprocessed. rdf 29 6 alleggplant. rdf 30 6 peppersnonbell. rdf 31 6 allsweetpepper. rdf 32 6 tomatoesPB. rdf 33 6 zmarktomato. rdf 34 6 allcucumber. rdf 35 6 melon. rdf 36 6 cantaloupe. rdf 37 6 honeydew. rdf 38 6 allwatermelon. rdf 39 6 pumpkin. rdf 40 6 wintersquash. rdf 41 6 allsummersquash. rdf 42 6 citrus. rdf 43 6 grapefruitjuice. rdf 44 6 lemonjuice. rdf 45 6 zmarkorange. rdf 46 6 limejuice. rdf 47 6 orangejuice. rdf 48 6 zmarkapple. rdf 49 6 apple. rdf 50 6 applejuice. rdf 51 6 peardecomp. rdf 52 6 pear. rdf 53 6 quince. rdf 54 6 crabapple. rdf 55 6 apricot. rdf 56 6 Apricotdecomp. rdf 57 6 allsweetcherries. rdf 58 6 alltartcherries. rdf 59 6 nectarine. rdf 60 6 zmarkpeach. rdf 61 6 Peach. rdf 62 6 plum2. rdf 63 6 blackberries. rdf 64 6 allblueberry. rdf Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 126 65 6 boysenberry. rdf 66 6 currant. rdf 67 6 allraspberries. rdf 68 6 almonds. rdf 69 6 chestnut. rdf 70 6 filbert. rdf 71 6 pecan. rdf 72 6 walnut. rdf 73 6 corn. rdf 74 6 allasparagus. rdf 75 6 zmarkbanana. rdf 76 6 allcranberry. rdf 77 6 zmarkgrape. rdf 78 6 grapejuice. rdf 79 6 okra. rdf 80 6 olives. rdf 81 6 pineappledecomp. rdf 82 6 pineapplemexico. rdf 83 6 pistachio. rdf 84 6 allstrawberry. rdf 85 6 sunflower. rdf 86 6 milk2. rdf 87 6 ruminantliver2. rdf 88 6 ruminantkidney2. rdf 89 6 swinemeat2. rdf 90 6 swinefat2. rdf 91 6 swineliver2. rdf 92 6 swinekidney2. rdf 93 6 poultry. rdf 94 6 eggs. rdf 95 6 pineappleother. rdf 96 6 Plumdecomp. rdf 97 6 pineappledomestic. rdf 98 6 zmarkapricot. rdf 99 6 zmarkcauliflower. rdf 100 6 zmarkcitrus. rdf 101 6 zmarkgrapefruit. rdf 102 6 zmarkleaflettuce. rdf 103 6 zmarklemon. rdf 104 6 zmarknectarine. rdf 105 6 zmarkpear. rdf 106 6 zmarkplum. rdf 107 6 zmarkquincecrabapp. rdf 108 6 appledried. rdf 109 6 soybean. rdf 110 6 wheat. rdf Food Crop Food Def Res Adj. Factors ­­­­­­­ RDL Indices and Ratios­­­­­­­ Code Grp Name (ppm) #1 #2 I# 1 Ratio# 1 I# 2 Ratio# 2 I# 3 Ratio# 3 ­­­­ ­­­­ ­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­­ ­­­ ­­­­­­ 1 13A Blackberries 1.000000 1.000 1.000 63 1.0000 2 13A Boysenberries 1.000000 1.000 1.000 65 1.0000 3 13A Dewberries 1.000000 1.000 1.000 65 1.0000 4 13A Loganberries 1.000000 1.000 1.000 65 1.0000 5 13A Raspberries 1.000000 1.000 1.000 67 1.0000 6 13A Youngberries 1.000000 1.000 1.000 65 1.0000 7 13B Blueberries 1.000000 1.000 1.000 64 1.0000 8 O Cranberries 1.000000 1.000 1.000 76 1.0000 9 O Cranberries­ juice 1.000000 1.100 1.000 76 1.0000 10 13B Currants 1.000000 1.000 1.000 66 1.0000 11 13B Elderberries 1.000000 1.000 1.000 66 1.0000 12 13B Gooseberries 1.000000 1.000 1.000 66 1.0000 13 O Grapes 1.000000 1.000 1.000 77 1.0000 14 O Grapes­ raisins 11­ Uncooked Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 127 1.000000 2.170 1.000 77 1.0000 12­ Cooked: NFS 1.000000 1.370 1.000 77 1.0000 13­ Baked 1.000000 1.370 1.000 77 1.0000 14­ Boiled 1.000000 1.370 1.000 77 1.0000 18­ Dried 1.000000 1.370 1.000 77 1.0000 42­ Frozen: Cooked 1.000000 1.370 1.000 77 1.0000 15 O Grapes­ juice 1.000000 1.000 1.000 78 1.0000 16 13B Huckleberries 1.000000 1.000 1.000 66 1.0000 17 O Strawberries 1.000000 1.000 1.000 84 1.0000 20 10 Citrus citron 1.000000 1.000 1.000 100 1.0000 22 10 Grapefruit­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 101 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 101 1.0000 14­ Boiled 0.000000 1.000 1.000 31­ Canned: NFS 1.000000 1.000 1.000 101 1.0000 23 10 Grapefruit­ juice 1.000000 1.170 1.000 43 1.0000 24 10 Kumquats 1.000000 1.000 1.000 100 1.0000 26 10 Lemons­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 103 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 103 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 103 1.0000 27 10 Lemons­ peel 1.000000 1.190 1.000 103 1.0000 28 10 Lemons­ juice 1.000000 1.110 1.000 44 1.0000 30 10 Limes­ peeled fruit 1.000000 1.000 1.000 100 1.0000 31 10 Limes­ peel 1.000000 1.270 1.000 100 1.0000 32 10 Limes­ juice 1.000000 1.110 1.000 46 1.0000 33 10 Oranges­ juice­ concentrate 1.000000 3.700 1.000 47 1.0000 34 10 Oranges­ peeled fruit 11­ Uncooked 1.000000 1.000 1.000 45 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 45 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 45 1.0000 35 10 Oranges­ peel 1.000000 1.270 1.000 45 1.0000 36 10 Oranges­ juice 1.000000 1.000 1.000 47 1.0000 37 10 Tangelos 1.000000 1.000 1.000 100 1.0000 38 10 Tangerines 11­ Uncooked 1.000000 1.000 1.000 100 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 100 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 100 1.0000 39 10 Tangerines­ juice 1.000000 1.280 1.000 46 1.0000 40 14 Almonds 1.000000 1.000 1.000 68 1.0000 43 14 Chestnuts 1.000000 1.000 1.000 69 1.0000 44 14 Filberts (hazelnuts) Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 128 1.000000 1.000 1.000 70 1.0000 48 14 Walnuts 1.000000 1.000 1.000 72 1.0000 50 O Pistachio nuts 1.000000 1.000 1.000 83 1.0000 52 11 Apples 11­ Uncooked 1.000000 1.000 1.000 48 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 48 1.0000 13­ Baked 1.000000 1.000 1.000 48 1.0000 14­ Boiled 1.000000 1.000 1.000 48 1.0000 15­ Fried 1.000000 1.000 1.000 48 1.0000 18­ Dried 0.001400 1.000 1.000 108 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 48 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 48 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 48 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 48 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 48 1.0000 53 11 Apples­ dried 1.000000 2.600 1.000 48 1.0000 54 11 Apples­ juice/ cider 1.000000 1.000 1.000 50 1.0000 55 11 Crabapples 1.000000 1.000 1.000 107 1.0000 56 11 Pears 11­ Uncooked 1.000000 1.000 1.000 105 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 105 1.0000 13­ Baked 1.000000 1.000 1.000 105 1.0000 14­ Boiled 1.000000 1.000 1.000 105 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 105 1.0000 57 11 Pears­ dried 1.000000 2.600 1.000 105 1.0000 58 11 Quinces 1.000000 1.000 1.000 107 1.0000 59 12 Apricots 11­ Uncooked 1.000000 1.000 1.000 98 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 98 1.0000 14­ Boiled 1.000000 1.000 1.000 98 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 98 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 98 1.0000 60 12 Apricots­ dried 1.000000 6.000 1.000 98 1.0000 61 12 Cherries 11­ Uncooked 1.000000 1.000 1.000 57 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 58 1.0000 13­ Baked 1.000000 1.000 1.000 58 1.0000 14­ Boiled 1.000000 1.000 1.000 58 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 58 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 58 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 58 1.0000 62 12 Cherries­ dried Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 129 1.000000 4.000 1.000 57 1.0000 63 12 Cherries­ juice 1.000000 1.500 1.000 58 1.0000 64 12 Nectarines 1.000000 1.000 1.000 104 1.0000 65 12 Peaches 11­ Uncooked 1.000000 1.000 1.000 60 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 60 1.0000 13­ Baked 1.000000 1.000 1.000 60 1.0000 14­ Boiled 1.000000 1.000 1.000 60 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 60 1.0000 41­ Frozen: NFS 1.000000 1.000 1.000 60 1.0000 66 12 Peaches­ dried 1.000000 7.000 1.000 60 1.0000 67 12 Plums (damsons) 11­ Uncooked 1.000000 1.000 1.000 106 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 106 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 106 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 106 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 106 1.0000 68 12 Plums­ prunes (dried) 1.000000 0.150 1.000 106 1.0000 69 12 Plums/ prune­ juice 1.000000 1.400 1.000 106 1.0000 72 O Bananas 1.000000 1.000 1.000 75 1.0000 73 O Bananas­ dried 1.000000 3.900 1.000 75 1.0000 81 11 Loquats 1.000000 1.000 1.000 107 1.0000 82 O Olives 1.000000 1.000 1.000 80 1.0000 89 O Pineapples­ peeled fruit 11­ Uncooked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 12­ Cooked: NFS 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 13­ Baked 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 14­ Boiled 1.000000 0.540 1.000 81 0.0250 95 0.4750 97 0.5000 31­ Canned: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 33­ Canned: Baked 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 41­ Frozen: NFS 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 90 O Pineapples­ dried 1.000000 5.000 1.000 82 0.0250 95 0.4750 97 0.5000 91 O Pineapples­ juice 1.000000 0.540 1.000 82 0.0250 95 0.4750 97 0.5000 94 O Plantains­ ripe 1.000000 1.000 1.000 75 1.0000 123 19A Dill 0.004000 1.000 1.000 126 1AB Horseradish 1.000000 1.000 1.000 3 1.0000 139 8 Paprika 1.000000 1.000 1.000 30 1.0000 141 9A Melons­ cantaloupes­ juice 1.000000 1.000 1.000 36 1.0000 142 9A Melons­ cantaloupes­ pulp 1.000000 1.000 1.000 36 1.0000 143 9A Casabas 1.000000 1.000 1.000 35 1.0000 144 9A Crenshaws 1.000000 1.000 1.000 35 1.0000 Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 130 145 9A Melons­ honeydew 1.000000 1.000 1.000 37 1.0000 146 9A Melons­ persian 1.000000 1.000 1.000 35 1.0000 147 9A Watermelon 1.000000 1.000 1.000 38 1.0000 148 9B Cucumbers 1.000000 1.000 1.000 34 1.0000 149 9B Pumpkin 1.000000 1.000 1.000 39 1.0000 150 9B Squash­ summer 1.000000 1.000 1.000 41 1.0000 151 9B Squash­ winter 1.000000 1.000 1.000 40 1.0000 152 9B Bitter melon 1.000000 1.000 1.000 35 1.0000 154 8 Eggplant 1.000000 1.000 1.000 29 1.0000 155 8 Peppers­ sweet( garden) 1.000000 1.000 1.000 31 1.0000 156 8 Peppers­ chilli incl jalapeno 1.000000 1.000 1.000 30 1.0000 157 8 Peppers­ other 1.000000 1.000 1.000 30 1.0000 158 8 Pimientos 1.000000 1.000 1.000 30 1.0000 159 8 Tomatoes­ whole 11­ Uncooked 1.000000 1.000 1.000 33 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 33 1.0000 13­ Baked 1.000000 1.000 1.000 33 1.0000 14­ Boiled 1.000000 1.000 1.000 33 1.0000 15­ Fried 1.000000 1.000 1.000 33 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 33 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 33 1.0000 33­ Canned: Baked 1.000000 1.000 1.000 33 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 33 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 33 1.0000 160 8 Tomatoes­ juice 1.000000 0.540 1.000 33 1.0000 161 8 Tomatoes­ puree 1.000000 0.650 1.000 33 1.0000 162 8 Tomatoes­ paste 1.000000 0.650 1.000 33 1.0000 163 8 Tomatoes­ catsup 1.000000 0.650 1.000 33 1.0000 165 2 Beets­ garden­ tops( greens) 1.000000 1.000 1.000 8 1.0000 166 4B Celery 1.000000 1.000 1.000 11 1.0000 168 5A Broccoli 1.000000 1.000 1.000 17 1.0000 169 5A Brussels sprouts 14­ Boiled 1.000000 0.025 1.000 18 1.0000 42­ Frozen: Cooked 1.000000 0.025 1.000 18 1.0000 170 5A Cabbage­ green and red 11­ Uncooked 1.000000 0.250 1.000 19 1.0000 12­ Cooked: NFS 1.000000 0.025 1.000 19 1.0000 13­ Baked 1.000000 0.025 1.000 19 1.0000 14­ Boiled 1.000000 0.025 1.000 19 1.0000 15­ Fried 1.000000 0.025 1.000 19 1.0000 31­ Canned: NFS Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 131 1.000000 0.250 1.000 19 1.0000 32­ Canned: Cooked 1.000000 0.025 1.000 19 1.0000 51­ Cured: NFS (smoked/ p 1.000000 0.250 1.000 19 1.0000 171 5A Cauliflower 1.000000 1.000 1.000 99 1.0000 172 5B Collards 1.000000 1.000 1.000 21 1.0000 174 5B Kale 1.000000 1.000 1.000 22 1.0000 175 5A Kohlrabi 14­ Boiled 1.000000 0.025 1.000 23 1.0000 176 4A Lettuce­ leafy varieties 1.000000 1.000 1.000 102 1.0000 177 4A Dandelion­ greens 1.000000 1.000 1.000 12 1.0000 178 4A Endive­ curley and escarole 1.000000 1.000 1.000 15 1.0000 182 4A Lettuce­ unspecified 1.000000 1.000 1.000 102 1.0000 183 5B Mustard greens 1.000000 1.000 1.000 22 1.0000 184 4A Parsley 1.000000 1.000 1.000 12 1.0000 185 4B Rhubarb 1.000000 1.000 1.000 16 1.0000 186 4A Spinach 11­ Uncooked 1.000000 1.000 1.000 12 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 12 1.0000 13­ Baked 0.000000 1.000 1.000 14­ Boiled 1.000000 1.000 1.000 12 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 13 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 13 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 13 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 12 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 12 1.0000 187 4B Swiss chard 1.000000 1.000 1.000 16 1.0000 188 2 Turnips­ tops 1.000000 1.000 1.000 10 1.0000 192 4A Lettuce­ head varieties 1.000000 1.000 1.000 14 1.0000 195 O Grapes­ leaves 1.000000 1.000 1.000 77 1.0000 197 1AB Beets­ garden­ roots 1.000000 1.000 1.000 1 1.0000 198 1AB Carrots 1.000000 1.000 1.000 2 1.0000 207 1C Potatoes/ white­ whole 11­ Uncooked 1.000000 1.000 1.000 4 1.0000 12­ Cooked: NFS 1.000000 0.040 1.000 4 1.0000 13­ Baked 1.000000 1.200 1.000 4 1.0000 14­ Boiled 1.000000 2.500 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 4 1.0000 208 1C Potatoes/ white­ unspecified 1.000000 1.000 1.000 4 1.0000 209 1C Potatoes/ white­ peeled 11­ Uncooked 0.000000 1.000 1.000 12­ Cooked: NFS Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 132 1.000000 1.000 1.000 4 1.0000 13­ Baked 1.000000 1.200 1.000 4 1.0000 14­ Boiled 1.000000 2.500 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 31­ Canned: NFS 0.000000 1.000 1.000 32­ Canned: Cooked 1.000000 1.000 1.000 4 1.0000 34­ Canned: Boiled 1.000000 2.500 1.000 4 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 4 1.0000 43­ Frozen: Baked 1.000000 1.200 1.000 4 1.0000 45­ Frozen: Fried 1.000000 0.040 1.000 4 1.0000 210 1C Potatoes/ white­ dry 0.000357 0.020 1.000 211 1C Potatoes/ white­ peel only 13­ Baked 1.000000 1.200 1.000 4 1.0000 15­ Fried 1.000000 0.040 1.000 4 1.0000 212 1AB Radishes­ roots 1.000000 1.000 1.000 5 1.0000 213 2 Radishes­ tops 1.000000 1.000 1.000 9 1.0000 214 1AB Rutabagas­ roots 1.000000 1.000 1.000 6 1.0000 215 2 Rutabagas­ tops 1.000000 1.000 1.000 10 1.0000 216 1AB Salsify( oyster plant) 1.000000 1.000 1.000 3 1.0000 218 1CD Sweet potatoes (incl yams) 1.000000 1.000 1.000 7 1.0000 219 1AB Turnips­ roots 1.000000 1.000 1.000 6 1.0000 220 1AB Parsnips 1.000000 1.000 1.000 3 1.0000 227 6C Beans­ dry­ great northern 0.002000 1.000 1.000 228 6C Beans­ dry­ kidney 0.002000 1.000 1.000 229 6C Beans­ dry­ lima 0.002000 1.000 1.000 230 6C Beans­ dry­ navy (pea) 0.002000 1.000 1.000 231 6C Beans­ dry­ other 0.002000 1.000 1.000 232 6C Beans­ dry­ pinto 0.002000 1.000 1.000 233 6B Beans­ succulent­ lima 1.000000 1.000 1.000 26 1.0000 234 6A Beans­ succulent­ green 11­ Uncooked 1.000000 1.000 1.000 24 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 24 1.0000 14­ Boiled 1.000000 1.000 1.000 24 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 25 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 25 1.0000 51­ Cured: NFS (smoked/ p 1.000000 1.000 1.000 25 1.0000 235 6A Beans­ succulent­ other 1.000000 1.000 1.000 25 1.0000 236 6A Beans­ succulent­ yellow/ wax Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 133 14­ Boiled 1.000000 1.000 1.000 24 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 25 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 25 1.0000 237 15 Corn/ pop 0.000100 1.000 1.000 238 15 Corn/ sweet 1.000000 1.000 1.000 73 1.0000 240 6C Peas (garden)­ dry 0.013000 1.000 1.000 241 6AB Peas (garden)­ green 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 27 1.0000 13­ Baked 1.000000 1.000 1.000 27 1.0000 14­ Boiled 1.000000 1.000 1.000 27 1.0000 15­ Fried 1.000000 1.000 1.000 27 1.0000 31­ Canned: NFS 1.000000 1.000 1.000 28 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 28 1.0000 34­ Canned: Boiled 1.000000 1.000 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 28 1.0000 44­ Frozen: Boiled 1.000000 1.000 1.000 28 1.0000 45­ Frozen: Fried 1.000000 1.000 1.000 28 1.0000 243 6C Lentils 0.002000 1.000 1.000 244 6C Mung beans (sprouts) 0.002000 1.000 1.000 245 O Okra 12­ Cooked: NFS 1.000000 0.180 1.000 79 1.0000 14­ Boiled 1.000000 0.050 1.000 79 1.0000 15­ Fried 1.000000 0.180 1.000 79 1.0000 32­ Canned: Cooked 1.000000 0.180 1.000 79 1.0000 42­ Frozen: Cooked 1.000000 0.180 1.000 79 1.0000 44­ Frozen: Boiled 1.000000 0.050 1.000 79 1.0000 249 6C Beans­ dry­ broadbeans 0.002000 1.000 1.000 250 6B Beans­ succulent­ broadbeans 1.000000 1.000 1.000 24 1.0000 251 6C Beans­ dry­ pigeon beans 0.002000 1.000 1.000 253 6 Beans­ unspecified 1.000000 1.000 1.000 24 1.0000 255 6A Soybeans­ sprouted seeds 0.000015 0.330 1.000 109 1.0000 256 O Beans­ dry­ hyacinth 0.002000 1.000 1.000 257 O Beans­ succulent­ hyacinth 1.000000 1.000 1.000 24 1.0000 258 6C Beans­ dry­ blackeye peas/ cowpea 0.002000 1.000 1.000 259 6C Beans­ dry­ garbanzo/ chick pea 0.002000 1.000 1.000 260 O Asparagus 1.000000 1.000 1.000 74 1.0000 266 15 Corn grain­ endosperm 0.000100 1.000 1.000 267 15 Corn grain­ bran 0.000100 1.000 1.000 268 15 Corn grain/ sugar/ hfcs 0.000100 1.500 1.000 Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 134 270 15 Rice­ rough (brown) 0.074000 1.000 1.000 271 15 Rice­ milled (white) 0.074000 0.030 1.000 275 15 Sorghum (including milo) 0.000015 1.000 1.000 110 1.0000 276 15 Wheat­ rough 0.000015 1.000 1.000 110 1.0000 277 15 Wheat­ germ 0.000015 0.650 1.000 278 15 Wheat­ bran 0.000015 1.000 1.000 279 15 Wheat­ flour 0.000015 0.100 1.000 280 15 Millet 0.000015 1.000 1.000 110 1.0000 282 1A Sugar­ beet 0.000400 0.040 1.000 287 6C Guar beans 1.000000 1.000 1.000 24 1.0000 289 15 Corn grain­ oil 0.000100 0.250 1.000 292 O Flax seed 0.000100 1.000 1.000 293 O Peanuts­ oil 0.000600 0.290 1.000 297 6A Soybeans­ oil 0.000015 0.005 1.000 298 O Sunflower­ oil 0.000400 0.030 1.000 300 O Olive oil 0.077000 0.810 1.000 303 6A Soybean­ other 0.000015 1.000 1.000 109 1.0000 304 6A Soybeans­ mature seeds dry 0.000015 1.000 1.000 109 1.0000 305 6A Soybeans­ flour (full fat) 0.000015 1.000 1.000 306 6A Soybeans­ flour (low fat) 0.000015 1.000 1.000 307 6A Soybeans­ flour (defatted) 0.000015 1.000 1.000 315 O Grapes­ wine and sherry 1.000000 1.000 1.000 77 1.0000 318 D Milk­ nonfat solids 0.030000 1.000 1.000 86 1.0000 319 D Milk­ fat solids 0.030000 1.000 1.000 86 1.0000 320 D Milk sugar (lactose) 0.030000 1.000 1.000 86 1.0000 321 M Beef­ meat byproducts 3.675000 1.000 1.000 88 1.0000 322 M Beef­ other organ meats 3.675000 1.000 1.000 88 1.0000 323 M Beef­ dried 0.907000 1.920 1.000 86 1.0000 324 M Beef­ fat w/ o bones 0.368000 1.000 1.000 86 1.0000 325 M Beef­ kidney 3.675000 1.000 1.000 88 1.0000 326 M Beef­ liver 1.390000 1.000 1.000 87 1.0000 327 M Beef­ lean (fat/ free) w/ o bones 0.907000 1.000 1.000 86 1.0000 328 M Goat­ meat byproducts 3.675000 1.000 1.000 88 1.0000 329 M Goat­ other organ meats 3.675000 1.000 1.000 88 1.0000 330 M Goat­ fat w/ o bone 0.368000 1.000 1.000 86 1.0000 331 M Goat­ kidney 3.675000 1.000 1.000 88 1.0000 332 M Goat­ liver 1.390000 1.000 1.000 87 1.0000 333 M Goat­ lean (fat/ free) w/ o bone 0.907000 1.000 1.000 86 1.0000 336 M Sheep­ meat byproducts 3.675000 1.000 1.000 88 1.0000 Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 135 337 M Sheep­ other organ meats 3.675000 1.000 1.000 88 1.0000 338 M Sheep­ fat w/ o bone 0.368000 1.000 1.000 86 1.0000 339 M Sheep­ kidney 3.675000 1.000 1.000 88 1.0000 340 M Sheep­ liver 1.390000 1.000 1.000 87 1.0000 341 M Sheep­ lean (fat free) w/ o bone 0.907000 1.000 1.000 86 1.0000 342 M Pork­ meat byproducts 0.260000 1.000 1.000 92 1.0000 343 M Pork­ other organ meats 0.260000 1.000 1.000 92 1.0000 344 M Pork­ fat w/ o bone 0.026000 1.000 1.000 90 1.0000 345 M Pork­ kidney 0.260000 1.000 1.000 92 1.0000 346 M Pork­ liver 0.100000 1.000 1.000 91 1.0000 347 M Pork­ lean (fat free) w/ o bone 0.065000 1.000 1.000 89 1.0000 349 F Fish­ shellfish 0.250000 1.000 1.000 377 11 Apples­ juice­ concentrate 1.000000 3.000 1.000 50 1.0000 378 O Bananas­ juice 1.000000 1.000 1.000 75 1.0000 379 1A Sugar­ beet­ molasses 0.000400 0.040 1.000 380 13A Blackberries­ juice 1.000000 1.000 1.000 63 1.0000 383 5B Cabbage­ savoy 12­ Cooked: NFS 1.000000 0.025 1.000 19 1.0000 384 4B Celery juice 1.000000 1.000 1.000 11 1.0000 388 15 Corn grain/ sugar­ molasses 0.000100 1.500 1.000 389 O Cranberries­ juice­ concentrate 1.000000 3.300 1.000 76 1.0000 392 O Grapes­ juice­ concentrate 1.000000 3.000 1.000 78 1.0000 398 D Milk­ based water 0.030000 1.000 1.000 86 1.0000 402 12 Peaches­ juice 1.000000 1.000 1.000 60 1.0000 403 O Peanuts­ butter 0.000600 1.890 1.000 404 11 Pears­ juice 1.000000 0.370 1.000 105 1.0000 405 6B Peas­ succulent/ blackeye/ cowpea 12­ Cooked: NFS 1.000000 1.000 1.000 27 1.0000 14­ Boiled 1.000000 1.000 1.000 27 1.0000 32­ Canned: Cooked 1.000000 1.000 1.000 28 1.0000 42­ Frozen: Cooked 1.000000 1.000 1.000 28 1.0000 406 O Pineapples­ juice­ concentrate 1.000000 2.000 1.000 82 0.0250 95 0.4750 97 0.5000 407 1AB Radishes­ japanese (daiken) 1.000000 1.000 1.000 5 1.0000 408 15 Rice­ bran 0.074000 0.400 1.000 410 12 Apricot juice 1.000000 1.000 1.000 98 1.0000 413 6A Snowpeas 11­ Uncooked 1.000000 1.000 1.000 27 1.0000 12­ Cooked: NFS 1.000000 1.000 1.000 27 1.0000 14­ Boiled 1.000000 1.000 1.000 27 1.0000 15­ Fried 1.000000 1.000 1.000 27 1.0000 42­ Frozen: Cooked Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 136 1.000000 1.000 1.000 28 1.0000 415 9B Squash­ spaghetti 1.000000 1.000 1.000 40 1.0000 416 O Strawberries­ juice 1.000000 1.000 1.000 84 1.0000 417 O Sunflower­ seeds 1.000000 1.000 1.000 85 1.0000 420 10 Tangerines­ juice­ concentrate 1.000000 4.080 1.000 46 1.0000 423 8 Tomatoes­ dried 1.000000 0.520 1.000 33 1.0000 424 M Veal­ fat w/ o bones 0.368000 1.000 1.000 86 1.0000 425 M Veal­ lean (fat free) w/ o bones 0.907000 1.000 1.000 86 1.0000 426 M Veal­ kidney 3.675000 1.000 1.000 88 1.0000 427 M Veal­ liver 1.390000 1.000 1.000 87 1.0000 428 M Veal­ other organ meats 3.675000 1.000 1.000 88 1.0000 429 M Veal­ dried 0.907000 1.920 1.000 86 1.0000 430 M Veal­ meat byproducts 3.675000 1.000 1.000 88 1.0000 431 14 Walnut oil 0.005400 1.000 1.000 436 9A Watermelon­ juice 1.000000 1.000 1.000 38 1.0000 437 15 Wheat­ germ oil 0.000015 0.650 1.000 439 9B Wintermelon 1.000000 1.000 1.000 35 1.0000 441 10 Grapefruit­ juice­ concentrate 1.000000 4.580 1.000 43 1.0000 442 10 Lemons­ juice­ concentrate 1.000000 6.330 1.000 44 1.0000 443 10 Limes­ juice­ concentrate 1.000000 3.330 1.000 46 1.0000 448 10 Grapefruit peel 1.000000 1.000 1.000 101 1.0000 480 O Plantains­ green 1.000000 1.000 1.000 75 1.0000 481 O Plantains­ dried 1.000000 3.900 1.000 75 1.0000 940 O Peanuts­ hulled 0.000600 1.000 1.000 Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 137 Results ­ 1989 ­ 1992 Consumption Data Used U. S. Environmental Protection Agency Ver. 7.76 DEEM ACUTE Analysis for CARBARYL (1989­ 92 data) Residue file: $$$ 10carbarylfinal9 market basket. RS7 Adjustment factor #2 NOT used. Analysis Date: 04­ 08­ 2002/ 14: 18: 59 Residue file dated: 04­ 04­ 2002/ 17: 32: 06/ 8 Daily totals for food and foodform consumption used. MC iterations = 1000 MC list in residue file MC seed = 10 Run Comment: "" =============================================================================== Summary calculations (per capita): 95th Percentile 99th Percentile 99.9th Percentile Exposure % aRfD Exposure % aRfD Exposure % aRfD ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ U. S. Population: 0.000462 4.62 0.001241 12.41 0.004623 46.23 All infants: 0.000593 5.93 0.002875 28.75 0.007272 72.72 Nursing infants (< 1 yr old): 0.000265 2.65 0.000950 9.50 0.006218 62.18 Non­ nursing infants (< 1 yr old): 0.000764 7.64 0.003068 30.68 0.007951 79.51 Children 1­ 6 yrs: 0.001241 12.41 0.002280 22.80 0.007344 73.44 Children 7­ 12 yrs: 0.000680 6.80 0.001345 13.45 0.006238 62.38 Females 13+ (preg/ not nursing): 0.000418 4.18 0.000825 8.25 0.004483 44.83 Females 13+ (nursing): 0.000411 4.11 0.001179 11.79 0.007629 76.29 Females 13­ 19 (not preg or nursing): 0.000320 3.20 0.000776 7.76 0.003523 35.23 Females 20+ (not preg or nursing): 0.000274 2.74 0.000867 8.67 0.003792 37.92 Females 13­ 50 yrs: 0.000299 2.99 0.000858 8.58 0.003546 35.46 Males 13­ 19 yrs: 0.000409 4.09 0.000815 8.15 0.002723 27.23 Males 20+ yrs: 0.000297 2.97 0.000836 8.36 0.003423 34.23 Seniors 55+: 0.000275 2.75 0.000905 9.05 0.004810 48.10 Attachment 8 Acute Dietary Exposure Analysis: Market Basket Survey: All Commodities 138 Results ­ 1994­ 1998 Consumption Data U. S. Environmental Protection Agency Ver. 7.76 DEEM ACUTE Analysis for CARBARYL (1994­ 98 data) Residue file: $$$ 10carbarylfinal9 market basket. RS7 Adjustment factor #2 NOT used. Analysis Date: 04­ 08­ 2002/ 15: 15: 48 Residue file dated: 04­ 04­ 2002/ 17: 32: 06/ 8 Daily totals for food and foodform consumption used. MC iterations = 1000 MC list in residue file MC seed = 10 Run Comment: "" =============================================================================== Summary calculations (per capita): 95th Percentile 99th Percentile 99.9th Percentile Exposure % aRfD Exposure % aRfD Exposure % aRfD ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ U. S. Population: 0.000465 4.65 0.001303 13.03 0.004865 48.65 All infants: 0.000650 6.50 0.002630 26.30 0.008091 80.91 Nursing infants (< 1 yr old): 0.000286 2.86 0.001101 11.01 0.006065 60.65 Non­ nursing infants (< 1 yr old): 0.000785 7.85 0.003051 30.51 0.008895 88.95 Children 1­ 6 yrs: 0.001348 13.48 0.002799 27.99 0.009481 94.81 Children 7­ 12 yrs: 0.000643 6.43 0.001214 12.14 0.004921 49.21 Females 13+ (preg/ not nursing): 0.000378 3.78 0.000853 8.53 0.005102 51.02 Females 13+ (nursing): 0.000353 3.53 0.000799 7.99 0.007064 70.64 Females 13­ 19 (not preg or nursing): 0.000301 3.01 0.000799 7.99 0.004039 40.39 Females 20+ (not preg or nursing): 0.000279 2.79 0.000863 8.63 0.004298 42.98 Females 13­ 50 yrs: 0.000298 2.98 0.000878 8.78 0.004224 42.24 Males 13­ 19 yrs: 0.000402 4.02 0.000867 8.67 0.004515 45.15 Males 20+ yrs: 0.000311 3.11 0.000831 8.31 0.003359 33.59 Seniors 55+: 0.000279 2.79 0.000819 8.19 0.004649 46.49 Attachment 9: Quantitative Usage Analysis (QUA) 139 Quantitative Usage Analysis for Carbaryl Case Number: 0080 PC Code: 56801 Date: July 21, 1998 Analyst: Frank Hernandez Based on available pesticide survey usage information for the years of 1987 through 1996, an annual estimate of carbaryl total domestic usage averaged approximately two and one half million pounds active ingredient (a. i.) for over one and one half million acres treated. Carbaryl is an insecticide with its largest markets in terms of total pounds active ingredient allocated to pecans (12%), apples (9%), grapes( 6%), oranges (5%), alfalfa (5%), and corn (4%). Most of the usage is in AR, CA, GA, IL, IN, MI, MS, OH, OK, and TX. Crops with a high percentage of the total U. S. planted acres treated include avocados (67%), Chinese cabbage (57%), asparagus (43%), cranberries (39%), and Brussels sprouts (33%). Crops with less than 1 percent of the crop treated include alfalfa, dry beans, canola, corn, cotton, flax, oats, pasture, green peas, safflower, sod, sorghum, soybeans, sugar cane, sunflowers, sweet corn, walnuts, wheat, and woodland. Attachment 9: Quantitative Usage Analysis (QUA) 140 Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate 1 States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ yr #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) Alfalfa 23,949 120 263 0.50 1.10 130 365 1.1 1. 0 1.1 NE SD OK MT ND IL 77% Almonds 429 7 16 1. 72 3. 61 16 49 2. 1 1.0 2. 1 CA 100% Apples 572 131 175 22.92 30.59 230 282 1.8 1. 4 1.2 WA MI NY CA CT IN 77% Asparagus 88 38 77 43.35 86.69 46 117 1.2 1. 3 0.9 MI WA 97% Avocados 82 55 70 66.93 85.18 1 2 0.0 1. 5 0.0 Beans, Dry 1, 802 12 51 0.65 2.86 6 28 0. 5 1.0 0. 5 CA ND CO 88% Beans, Lima, Fresh 6 1 2 12.49 29.88 1 2 1.1 1. 2 0.9 GA 100% Beans, Snap, Fresh 81 11 17 14.12 21.03 16 23 1.4 1. 6 0.9 NC FL 84% Beans, Snap, Proc. 228 24 36 10.39 15.83 28 43 1.2 1. 6 0.7 IL St OR 83% Beets 12 2 3 16.87 27.45 1 2 0.5 1. 0 0.5 WI TX OR 94% Blackberries 5 1 2 28.39 44.05 2 4 1.7 1. 0 1.7 OR 100% Blueberries 59 13 26 22.43 44.85 26 53 2.0 1. 2 1.7 ME MI 83% Broccoli 114 5 10 4. 43 8. 86 4 8 0. 8 1.0 0. 8 CA OR TX 88% Brussels Sprouts 3 1 2 33.33 66.67 1 2 1.0 1. 1 0.9 Cabbage, Chinese 9 5 7 57.47 80.46 1 2 0.2 1. 1 0.2 CA 90% Cabbage, Fresh 84 1 4 1. 78 4. 40 2 6 1. 6 1.6 1. 0 NC NY 84% Canola 39 0 2 0.31 4.64 0 1 0.5 1. 0 0.5 MT 100% Cantaloupes 113 8 11 7. 27 9. 39 8 13 0.9 1. 1 0.8 CA IL GA TX 83% Carrots 107 4 6 3.67 5.75 9 23 2. 3 2.5 0. 9 WI MI MN 88% Cauliflower 58 1 2 1.55 3.60 1 2 1.1 1. 0 1.1 OR CA WA 83% Celery 37 1 2 2.97 6.13 2 4 1.8 1. 8 1.0 MI WI 89% Cherries, Sweet 47 12 17 25.29 36.45 32 46 2.7 1. 4 1.9 WA MI CA 84% Cherries, Tart 49 6 11 11.79 23.59 13 27 2.3 1. 3 1.9 MI NY 88% Attachment 9: Quantitative Usage Analysis (QUA) Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate 1 States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ yr #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) 141 Citrus, Other 51 2 3 2. 98 5. 65 5 12 3.2 1. 8 1.8 FL 86% Collards 11 0 1 3. 72 10.13 0 1 0.9 1. 0 0.9 NJ 88% Corn 72,284 82 164 0.11 0.23 110 228 1.3 1. 3 1.0 MO NE MS IN GA IL 51% Cotton 12,689 26 77 0.20 0.61 32 94 1.2 1. 1 1.1 TN MS TX CA 83% Cranberries 29 11 24 38.97 83.65 23 48 2.0 1. 0 2.0 WI MA 95% Cucumbers 146 20 46 14.03 31.83 23 51 1.1 1. 0 1.1 NC OH SC NY VA DE 73% Cucumbers, Proc. 117 5 11 4. 69 9. 37 7 15 1.3 2. 2 0.6 NC MI 85% Eggplant 119 11 25 8.87 20.59 22 54 2.0 2. 1 1.0 FL NJ TX IL OR CA 64% Flax 188 1 2 0.46 0.91 1 2 1.1 1. 0 1.1 ND 100% Grapefruit 194 8 11 4. 05 5. 59 18 20 2. 3 1.6 1. 4 FL TX 95% Grapes 825 64 97 7.77 11.81 150 217 2.3 1. 7 1.4 NY CA OR PA MI AR 77% Hay, Other 33,427 91 267 0.27 0.80 87 273 1.0 1. 2 0.8 TX SD FL NC CA LA 81% Hazelnuts (Filberts) 27 1 3 3.90 12.18 3 8 2.5 1. 0 2.5 Lemons 63 2 4 2.77 6.55 6 14 3. 4 1.3 2. 7 CA 91% Lettuce, Head 212 7 17 3. 08 8. 10 8 22 1.3 1. 2 1.1 CA 82% Lots/ Farmsteads/ etc 24,815 58 152 0.23 0.61 60 174 1.0 2. 5 0.4 MA AZ FL PA TX KY 62% Melons, Honeydew 27 5 12 19.09 43.69 4 10 0. 9 1.2 0. 7 CA 100% Nectarines 29 4 7 12.11 24.22 15 30 4.2 1. 1 3.8 Oats/ Rye 6,133 8 18 0. 13 0. 29 6 13 0.7 1. 0 0.7 MN MS ND TX MT MI 77% Okra 3 1 3 32.36 94.03 2 6 1.9 1. 0 1.9 TX 84% Olives 32 3 5 9. 61 15.42 16 26 5.3 1. 0 5.3 CA 100% Onions, Dry 157 6 18 3. 71 11.36 23 72 4.0 7. 0 0.6 MI 100% Oranges 867 28 42 3.27 4.89 130 194 4.6 1. 3 3.4 CA FL 99% Attachment 9: Quantitative Usage Analysis (QUA) Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate 1 States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ yr #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) 142 Other Crops 2,515 35 43 1.39 1.70 63 156 1.8 1. 3 1.4 CA MA TX NJ WA MI 75% Pasture 86,960 27 69 0.03 0.08 25 77 0.9 1. 0 0.9 NC TX SC NE LA 80% Peaches 212 32 38 15.10 18.05 96 203 3.0 2. 9 1.0 GA CA TX OK SC MI 68% Peanuts 1,610 48 96 2.99 5.99 53 107 1.1 1. 4 0.8 GA TX NC AL VA 84% Pears 78 2 5 2. 92 6. 43 3 8 1. 5 1.5 1. 0 WA OR CA PA NY OH 73% Peas, Dry 249 6 22 2. 52 8. 97 6 22 1.0 1. 0 1.0 WA ID TX 93% Peas, Green 386 6 28 1. 59 7. 13 9 40 1.5 1. 0 1.5 MN OR 83% Peas, Green, Proc. 329 2 17 0. 62 5. 23 3 25 1.5 1. 0 1.5 OR 100% Pecans 488 95 115 19.53 23.51 290 610 3.0 2. 2 1.4 GA TX OK MS AR 84% Peppers, Bell 55 6 11 10.15 20.30 9 22 1. 5 1.7 0. 9 FL CA MI 90% Peppers, Sweet 77 10 23 12.95 29.95 14 31 1.3 1. 0 1.3 CA FL KY LA IL 80% Pistachios 52 9 20 16.84 38.06 32 72 3.6 1. 0 3.6 Plums 64 3 6 4. 68 9. 36 12 23 3. 8 1.0 3. 8 CA 81% Potatoes 1, 421 24 38 1.70 2.68 34 50 1.4 1. 7 0.8 ND WA MI ID FL NY 59% Pumpkins 36 11 20 31.21 56.11 37 66 3.2 1. 6 2.0 IL PA IN OH 83% Raspberries 11 0 1 3.57 9.84 1 3 2.8 1. 0 2.8 OR MI 92% Rice 2,921 33 40 1.15 1.37 41 58 1.2 1. 1 1.1 TX CA 80% Safflower 113 1 7 0.98 5.96 0 3 0.4 1. 0 0.4 CA 100% Sod 152 0 7 0.14 4.28 0 15 2. 2 1.0 2. 2 TX NH 100% Sorghum 11,280 23 47 0.21 0.41 31 62 1.3 1. 2 1.1 MO KS TX LA NE MS 75% Soybeans 62,879 101 210 0.16 0.33 86 174 0.9 1. 0 0.9 MN NE SD MS NC IL 60% Squash 53 6 14 11.25 26.77 8 19 1. 4 1.0 1. 4 NJ FL MI CA NY TX 90% Strawberries 51 8 12 16.02 23.62 24 55 2.9 2. 1 1.4 CA FL NC PA 81% Attachment 9: Quantitative Usage Analysis (QUA) Site Acres Grown (000) Acres Treated (000) % of Crop Treated LB AI Applied (000) Average Application Rate 1 States of Most Usage Wtd Avg Est Max Wtd Avg Est Max Wtd Avg Est Max lb ai/ acre/ yr #appl / yr lb ai/ A/ appl (% of total lb ai used on this site) 143 Sugar Beets 1, 415 23 54 1.60 3.80 34 126 1.5 1. 1 1.3 CA TX WA MN OR 84% Sugarcane 852 0 1 0.04 0.07 0 0 0.2 1. 1 0.1 FL 100% Sunflower 2,745 11 40 0.40 1.47 8 31 0. 7 1.1 0. 7 SD ND 92% Sweet Corn, Fresh 233 9 17 3. 84 7. 12 28 52 3. 1 2.5 1. 3 CA MI IL 82% Sweet Corn, Proc. 544 3 21 0. 49 3. 81 8 63 3.0 2. 9 1.1 IL 100% Sweet Potatoes 85 16 35 18.47 40.90 25 55 1.6 1. 0 1.6 LA MS NC 82% Tobacco 695 10 20 1.50 2.85 18 44 1.7 1. 5 1.1 NC KY SC TN IN 84% Tomatoes, Fresh 136 7 15 5. 40 10.80 14 35 1.9 2. 6 0.7 CA FL TX 87% Tomatoes, Proc. 329 48 88 14.47 26.86 72 135 1.5 1. 3 1.2 CA 97% Walnuts 205 1 4 0.54 1.82 2 8 2.1 1. 1 1.9 CA 100% Watermelons 258 33 38 12.71 14.79 16 33 0.5 1. 0 0.5 FL IN MS TX GA 76% Wheat, Spring 20,799 24 48 0.11 0.23 16 32 0.7 1. 0 0.6 ND MN MT 88% Wheat, Winter 45,854 50 106 0.11 0.23 44 78 0.9 1. 0 0.8 KY NC TX WY OR MD 67% Woodland 62,825 31 72 0.05 0.11 26 54 0.8 1. 2 0.7 PA MI FL ND OH IA 79% Total 1659.6 2464 2517.2 3926 COLUMN HEADINGS Wtd Avg = Weighted average­­ the most recent years and more reliable data are weighted more heavily. Est Max = Estimated maximum, which is estimated from available data. Average application rates are calculated from the weighted averages. NOTES ON TABLE DATA Usage data primarily covers 1987 ­ 1996. Calculations of the above numbers may not appear to agree because they are displayed as rounded to the nearest 1000 for acres treated or lb. a. i. (Therefore 0 = < 500) to two decimal percentage points for % of crop treated. Other/ Crop Groups Citrus, Other includes kumquats, limes, tangelos, and tangerines. Other Crops include ornamentals, popcorn, rapeseed/ canola, and safflower. SOURCES: EPA data, USDA, and National Center for Food and Agricultural Policy.

epa

2024-06-07T20:31:42.255468

regulations

EPA-HQ-OPP-2002-0138-0008

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Office of Prevention, Pesticides and Toxic Substances DATE: May 24, 2002 TXR #: 0050726 MEMORANDUM SUBJECT: CARBARYL: UPDATED TOXICOLOGY CHAPTER FOR RED FROM: Virginia A. Dobozy, VMD, MPH, Veterinary Medical Officer Reregistration Branch I Health Effects Division (7509C) THRU: Whang Phang, PhD, Branch Senior Scientist Reregistration Branch I Health Effects Division (7509C) TO: Jeff Dawson, Risk Assessor Reregistration Branch I Health Effects Division (7509C) and Betty Shackleford/ Anthony Britten Special Review and Reregistration Division (7508C) PC Code: 056801 DP Barcode: D282980 Submission: S615586 Case: 818954 Attached is the Updated Toxicology Chapter for Carbaryl for the RED. It replaces the chapter dated December 7, 1999. CARBARYL PC Code: 056801 Updated Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision Document Date completed: May 24, 2002 Health Effects Division Office of Pesticide Programs U. S. Environmental Protection Agency Arlington, VA 22202 Prepared by: Virginia A. Dobozy, VMD, MPH TABLE OF CONTENTS 1. 0 HAZARD CHARACTERIZATION ................................................ 4 2. 0 REQUIREMENTS.............................................................. 6 3. 0 DATA GAP( S)................................................................. 8 4. 0 HAZARD ASSESSMENT ....................................................... 8 4. 1 Acute Toxicity ........................................................... 8 4. 2 Subchronic Toxicity....................................................... 8 4. 3 Prenatal Developmental Toxicity ........................................... 12 4.4 Reproductive Toxicity .................................................... 13 4. 5 Chronic Toxicity ........................................................ 17 4.6 Carcinogenicity ......................................................... 19 4. 7 Mutagenicity ........................................................... 24 4. 8 Neurotoxicity........................................................... 27 4. 9 Metabolism ............................................................ 32 5.0 TOXICITY ENDPOINT SELECTION ............................................. 36 5.1 See Section 9.2 for Endpoint Selection Table. ................................. 36 5. 2 Dermal Absorption ....................................................... 36 5.3 Classification of Carcinogenic Potential ...................................... 36 6. 0 FQPA CONSIDERATIONS ..................................................... 39 6. 1 Degree of Concern Analysis and Residual Uncertainties ......................... 39 6.2 Hazard Based­ Special FQPA Safety Factor Recommendation ..................... 40 7. 0 REFERENCES ............................................................... 41 8. 0 APPENDICES ................................................................ 45 9. 1 Toxicity Profile Summary Tables ........................................... 46 9.1.1 Acute Toxicity Table ............................................... 46 9.1.2 Subchronic, Chronic and Other Toxicity Tables .......................... 46 9.2 Summary of Toxicological Endpoint Selection for Carbaryl ...................... 51 4 1.0 HAZARD CHARACTERIZATION The toxicology data base is of good quality and is essentially complete. A 90­ day inhalation study with cholinesterase measurements is required. The database provides sufficient information for selecting toxicity endpoints for risk assessment and therefore, supports a reregistration eligibility decision for the currently registered uses. Carbaryl is a carbamate insecticide. Its primary mode of toxic action is through cholinesterase inhibition (ChEI) after single or multiple exposures. In most of the toxicology studies in which ChE was measured, it was the endpoint used to set the Lowest Observed Adverse Effect Level (LOAEL). The acute toxicity studies showed that carbaryl was relatively toxic with acute oral dosing (Tox. Category II); but the acute dermal and inhalation toxicities were low (Tox. Categories III and IV, respectively). Carbaryl was not a dermal or eye irritant and was not a dermal sensitizer. The neurotoxicity data showed that carbaryl was not a delayed neurotoxicant in the hen. In the acute neurotoxicity study in the rat after a single dose of 10 mg/ kg carbaryl, ChEI was observed in plasma, whole blood, red blood cells (RBC) and brain. At the next higher dose (50 mg/ kg), clinical signs typical of carbamate toxicity were observed. In the subchronic neurotoxicity study after 90 days of administration, clinical signs of toxicity were seen at the same dose (10 mg/ kg/ day) as plasma, whole blood, RBC and brain ChEI. There was no evidence of structural neuropathology in these studies. No subchronic studies in the rat or dog are available, except for the subchronic neurotoxicity study in rats and 4­ week dermal toxicity studies in rats (one with technical chemical and two with formulations). One of the dermal toxicity studies was useful for risk assessment. In this study, the systemic NOAEL was 20 mg/ kg/ day based on decreased RBC ChE in males and females and brain ChE in males at 50 mg/ kg/ day. The chronic toxicity data showed that, in dogs, decreases in plasma, RBC and brain ChE were observed at 10 mg/ kg/ day; clinical signs of toxicity were also observed in both sexes at 31 mg/ kg/ day. Brain and plasma ChE were decreased in female dogs at 3.1 mg/ kg/ day. In the mouse, clinical signs of toxicity were not typical of ChEI, but there was ChEI (plasma, RBC and brain) at 146 mg/ kg/ day. In the chronic toxicity study in rats, carbaryl at the highest dose (350 mg/ kg/ day in males and 485 mg/ kg/ day in females) caused a variety of toxic effects in the liver, kidneys and urinary bladder. It also induced an increase in the incidence of thyroid follicular cell hypertrophy and degeneration of sciatic nerves and skeletal muscle. RBC ChE was decreased in males at 60 mg/ kg/ day and in females at 79 mg/ kg/ day. The lowest LOAEL in the chronic studies was in the chronic dog study, i. e., 3.1 mg/ kg/ day, which was the lowest dose in females. In a follow­ up 5­ week study in dogs to clarify the NOAEL for ChEI, plasma ChE was decreased in males at 3.83 mg/ kg/ day; no effects were observed at 1.43 mg/ kg/ day. In a prenatal developmental toxicity study in the rat, maternal toxicity was observed at the same dose (10 mg/ kg/ day) as developmental toxicity; the NOAEL was 4 mg/ kg/ day. Developmental effects included decreased fetal body weight and increased incomplete ossification of multiple bones. In a prenatal developmental toxicity study in the rabbit, the maternal and developmental LOAELs were 50 mg/ kg/ day and 150 mg/ kg/ day, respectively. The respective NOAELs were 5 mg/ kg/ day and 50 mg/ kg/ day. The only evidence of developmental toxicity was a decrease in fetal body weight. These studies showed no evidence of a qualitative or quantitative increased susceptibility. In the reproduction study, there was evidence of a quantitative offspring susceptibility. The LOAEL for parental systemic toxicity was 1500 5 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption. The NOAEL was 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females). The LOAEL for offspring toxicity was 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival. The NOAEL was 75 ppm (4.67­ 5.79 mg/ kg/ day for males and 5.56­ 6.41 mg/ kg/ day for females). In the developmental neurotoxicity study, there was evidence of qualitative susceptibility. Clinical signs of toxicity and plasma and brain ChEI were seen in maternal animals at the same dose (10 mg/ kg/ day) as changes in brain morphometric measurements (decreases in cerebellar measurements in females on Day 11 post­ partum) were observed in offspring; however, brain measurements were not conducted at the next lower dose. The Health Effects Division's (HED) Cancer Assessment Review Committee (CARC)( 11/ 7/ 01) classified carbaryl as Likely to be carcinogenic in humans based on an increased incidence of hemangiosarcomas in male mice at all doses tested (100, 1000 and 8000 ppm). The Q1*, based on the CD­ 1 mouse dietary study with ¾ Interspecies Scaling Factor, is 8.75 x 10 ­4 (mg/ kg/ day) ­1 in human equivalents. In addition to the required carcinogenicity studies in mice and rats, the registrant submitted a special study in genetically modified mice. Carbaryl was administered to heterozygous p53­ deficient (knockout) male mice in the diet at concentrations of up to 4000 ppm (716.6 mg/ kg/ day) for six months. There was no evidence of neoplastic or preneoplastic changes in the vascular tissues of any organ. A model validation study demonstrated that vascular tumors occur in heterozygous p53 deficient mice within six months of administration of a known genotoxic carcinogen (urethane). A recent review of the data from the submitted studies and the published literature show that carbaryl is clastogenic in vitro. The wide variety of induced aberrations (both simple and complex) was consistent between the submitted micronucleus study and the open literature. However, there are inconsistencies relative to the requirement for S9 activation. Nevertheless, the two in vivo studies for micronuclei induction or chromosome aberrations were negative. Similarly, the 6­ month p53 knockout transgenic mouse bioassay was negative. Carbaryl was also negative for DNA binding in the livers of mice treated with 8000 ppm for 2 weeks. Metabolism studies identified epoxide intermediates of carbaryl which were found to be conjugated to glucuronide, rapidly metabolized and excreted as any endogenous epoxide would be. Overall, these findings indicate that carbaryl produces epoxides and its DNA reactivity is manifested as chromosomal aberrations in cultured mammalian cells. Other in vitro studies indicate carbaryl's effects on karyokinesis and cytokinesis, as well as stress genes associated with oxidative damage. Based on these considerations, the CARC concluded that there is a concern for mutagenicity, which is somewhat lessened because of the lack of an effect in in vivo mutagenicity studies. The metabolism data in the rat indicated that radiolabeled carbaryl was readily absorbed with oral dosing, distributed to various organs, metabolized and formed conjugated metabolites with compounds such glucuronic acid. A total of 20 components was found, and 2 major metabolites were identified, naphthyl sulfate and naphthyl glucuronide. Much of the radioactivity was eliminated within 24 hours after dosing (86% in urine and 11% in feces). Seven days post dosing, negligible amounts of the administered dose were found in tissues. Several special metabolism studies were conducted to explore a mechanism for the increase in tumor incidence in mice. The results appear to show that high doses of carbaryl treatment (1154 mg/ kg) led to a "phenobarbital" type of induction of liver xenobiotic­ metabolizing enzymes and 6 interaction of carbaryl with chromatin protein in mice. A dermal absorption study indicated that 12.7% of a carbaryl formulation (43.9% a. i.) was absorbed systemically. 2.0 REQUIREMENTS The requirements (CFR 158.340) for food use for CARBARYL are in Table 1. Inclusion of the new guideline numbers does not imply that the new (1998) guideline protocols were used. 7 Table 1. Carbaryl ­ Data Requirements Test Technical Required Satisfied 870.1100 Acute Oral Toxicity ........................... 870.1200 Acute Dermal Toxicity ........................ 870.1300 Acute Inhalation Toxicity ...................... 870.2400 Primary Eye Irritation ......................... 870.2500 Primary Dermal Irritation ...................... 870.2600 Dermal Sensitization .......................... yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ....................... 870.3150 Oral Subchronic (nonrodent) .................... 870.3200 21­ Day Dermal .............................. 870.3250 90­ Day Dermal .............................. 870.3465 90­ Day Inhalation ............................ yes yes yes no yes yes a yes b yes c no no 870.3700a Developmental Toxicity (rodent) ................. 870.3700b Developmental Toxicity (nonrodent) .............. 870.3800 Reproduction ................................ yes yes yes yes yes yes 870.4100a Chronic Toxicity (rodent) ...................... 870.4100b Chronic Toxicity (nonrodent) ................... 870.4200a Oncogenicity (rat) ............................ 870.4200b Oncogenicity (mouse) ......................... 870.4300 Chronic/ Oncogenicity ......................... yes yes yes yes yes yes b yes yes b yes yes 870.5100 Mutagenicity— Gene Mutation ­ bacterial .......... 870.5300 Mutagenicity— Gene Mutation ­ mammalian ....... 870.5385 Mutagenicity— Structural Chromosomal Aberrations 870.5550 Mutagenicity— Other Genotoxic Effects ........... yes yes yes yes yes yes yes d yes 870.6100a Acute Delayed Neurotox. (hen) .................. 870.6100b 90­ Day Neurotoxicity (hen) ..................... 870.6200a Acute Neurotox. Screening Battery (rat) ........... 870.6200b 90 Day Neuro. Screening Battery (rat) ............ 870.6300 Develop. Neuro .............................. yes no yes yes yes yes no yes yes yes 870.7485 General Metabolism .......................... 870.7600 Dermal Penetration ........................... yes yes yes yes Special Studies for Ocular Effects Acute Oral (rat) .............................. Subchronic Oral (rat).......................... Six­ month Oral (dog) .......................... no no no a Satisfied with chronic toxicity study b Satisfied with combined chronic toxicity/ carcinogenicity study c Satisfied with 4­ week non­ guideline study which was satisfactory for risk assessment d Micronucleus study required by the CARC was unacceptable because the doses were not high enough. However, two studies from the open literature tested carbaryl up to the LD50 or 1/ 3 of the LD50, which was higher than the high dose in the submitted study and negative. 8 3.0 DATA GAP( S) 90­ day inhalation study with cholinesterase measurements 4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of data base for acute toxicity: The data base for acute toxicity is considered complete. No additional studies are required at this time. The chemical is moderately acutely toxic by the oral route (Toxicity Category II), relatively nontoxic by the dermal and inhalation routes (Toxicity Category III and IV, respectively), not a primary eye or skin irritant or a dermal sensitizer. The acute toxicity data on CARBARYL Technical is summarized below in Table 2. Table 2. Acute Toxicity Data on CARBARYL Guideline No. Study Type MRIDs # Results Toxicity Category 81­ 1 Acute Oral ­ rat 00148500 LD50 for males = 302.6 mg/ kg; for females = 311.5 mg/ kg; combined = 301.0 mg/ kg II 81­ 2 Acute Dermal rabbit 00148501 LD50 > 2000 mg/ kg III 81­ 3 Acute Inhalation rat 00148502 LC50 > 3.4 mg/ L IV 81­ 4 Primary Eye Irritation 00148503 not a primary eye irritant IV 81­ 5 Primary Skin Irritation 00148504 not a primary skin irritant IV 81­ 6 Dermal Sensitization 00148505 negative 4.2 Subchronic Toxicity Adequacy of data base for Subchronic Toxicity: There are no acceptable subchronic toxicity studies in rodents or nonrodents. However, there are acceptable chronic studies, including a chronic toxicity study in the dog and a combined chronic toxicity/ carcinogenicity study in the rat. Therefore, the requirements for subchronic toxicity studies in dogs and rats can be waived. There is an acceptable subchronic neurotoxicity study in the rat (discussed under G. Neurotoxicity). Three 4­ week non­ guideline 9 dermal toxicity studies in the rat were conducted. One with technical carbaryl was classified as acceptable/ non­ guideline and was used for the risk assessment. The other two with formulations were classified as unacceptable/ non­ guideline. No additional dermal toxicity studies are required at this time. MRID 45630601 In a non­ guideline four­ week dermal toxicity study (MRID 45630601), Carbaryl Technical (99.49% a. i., Lot 211048078) was applied to the shaved skin of 10 Crl: CD (SD) IGS BR rats/ sex/ dose at dose levels of 0, 20, 50 or 100 mg/ kg bw/ day, 6 hours/ day for 5 days/ week during a 4­ week period. The parameters measured included the following: clinical observations, body weight, body weight gain, food consumption, RBC and brain cholinesterase and signs of dermal irritation. There was no treatment­ related effect on mortality, clinical observations, body weight or dermal irritation. The only statistically significant body weight gain changes were a decrease (27%) in the 100 mg/ kg/ day males during Days 5 to 12 and an increase (37%) in 50 mg/ kg/ day males during Days 19 to 26. However, there were non­ significant decreases in the 100 mg/ kg/ day males at Days ­3 to 5 (16%), 12 to 19 (17%) and ­3 to 26 (12%) which are considered toxicologically significant. The only statistically significant decreases in food consumption were in the 50 mg/ kg/ day females on Days 12 to 19 and 50 and in the 100 mg/ kg/ day females on Days 19 to 26. The effects are not considered treatment­ related as there was no dose­ response and the decreases were minimal (9% and 8% in the 50 and 100 mg/ kg/ day groups, respectively). RBC cholinesterase was measured before dosing on Day ­4 and on Days 1, 8, 15 and 22. The only statistically significant effects were in the 100 mg/ kg/ day males at Days 8 (11% decrease) and 22 (13%). Using the repeated measures statistical test, there were also significant decreases in the 50 and 100 mg/ kg/ day females (11% and 10%, respectively) on Day 22. These effects were determined to be not toxicologically significant because they were inconsistent. Measurements were also performed within 1 hour after test material removal on Days 5, 12, 19, and 26. Statistically significant decreases were observed in the 50 mg/ kg/ day (12% decrease) and 100 mg/ kg/ day (15%) males on Day 5 and in the 100 mg/ kg/ day males on Days 12 (21%) and 19 (16%). Using the repeated measures statistical test, there was also a significant decrease (10%) in the 50 mg/ kg/ day males on Day 12. In females, statistically significant decreases were observed in the 50 and 100 mg/ kg/ day groups on Days 5 (13% and 12%, respectively) and Day 12 (20% and 13%, respectively). Brain cholinesterase was statistically significantly decreased in the 50 mg/ kg/ day males (15%) and in the 100 mg/ kg/ day males (15%) and females (24%). There was also a non­ significant decrease in the 50 mg/ kg/ day females (9%). The systemic LOAEL is conservatively established at 50 mg/ kg/ day based on statistically significant decreases in RBC cholinesterase in males and females and brain cholinesterase in males. The systemic NOAEL is 20 mg/ kg/ day. 10 The dermal LOAEL was not established. The dermal NOAEL was 100 mg/ kg/ day. This 4­ week dermal toxicity study in the rat is acceptable (non­ guideline). The study was intended to establish endpoints for short­ term and intermediate­ term occupational and residential postapplication dermal exposure. Although the study does not meet guideline requirements, it is useful for risk assessment for the following reasons: 1) in all oral studies in which cholinesterase was measured, it was the most sensitive endpoint; therefore, other guideline parameters would most likely not establish a lower LOAEL; 2) plasma cholinesterase was not measured; however, in all the oral studies in rats, all three compartments (plasma, RBC and brain) were affected at the same dose level. Therefore, it is likely that plasma cholinesterase would not have been inhibited at a lower level, especially given the minimal effects on RBC and brain cholinesterase. MRID 45630602 In a non­ guideline four­ week dermal toxicity study (MRID 45630602), Sevin® XLR Plus (44.82% a. i., Lot 60618902) was applied to the shaved skin of 8 Crl: CD (SD) IGS BR rats/ sex/ dose at dose levels of 0, 20, 50 or 100 mcL/ kg bw/ day (0, 9.6, 24 or 48 mg/ kg/ day), 6 hours/ day for 5 days/ week during a 4­ week period. The parameters measured included the following: clinical observations, body weight, body weight gain, food consumption, RBC cholinesterase and signs of dermal irritation. There were no treatment­ related effects on clinical observations or body weight or evidence of dermal irritation. Females treated at 100 mcL/ kg/ day gained 167%, 65%, 144% and 40% of control values for Days ­3 to 5, 5 to 12, 12 to 19 and 19 to 26, respectively. Overall (Days ­3 to 26) body weight gain was not affected. It is difficult to determine if there was a treatment­ related effect immediately after dosing as the first body weight measurement was not done until Day 5 of dosing. Although not statistically significant, there does appear to be a treatment­ related decrease on the body weight gain (Days 5 to 12) of females treated at 100 mcL/ kg/ day. RBC cholinesterase was measured before dosing on Week ­1 and on Days 1, 8, 15 and 22. There was no evidence of a treatment­ related effect at these time periods. Measurements were also performed within 1 hour after test material removal on Days 5, 12, 19, and 26. In males, the only statistically significant difference from control values was on Day 26 in the animals dosed at 50 mcL/ kg/ day; the decrease was only 8%. Although not statistically significant, the RBC cholinesterase on Day 12 in males treated at 100 mcL/ kg/ day was decreased by 10%. In females treated at 100 mcL/ kg/ day, values were significantly decreased on Day 5 (12%), Day 12 (12%) and non­ significantly decreased on Days 19 (5%) and Day 26 (7%). There were also significant decreases in the 50 mcL/ kg/ day females on Days 19 (9%) and 26 (14%) and in the 20 mg/ kg/ day group on Day 26 (10%). Although statistically significant, the RBC cholinesterase decreases are not judged to be toxicologically significant due to the small magnitude of the effect and the lack of a dose­ response on Days 19 and 26. The systemic LOAEL in females was 100 mcL/ kg/ day (48 mg/ kg/ day) based on decreased body weight gain. The systemic NOAEL was 50 mcL/ kg/ day (24 mg/ kg/ day). The systemic LOAEL in males was not established. The systemic NOAEL was 100 mcL/ kg/ day (48 mg/ kg/ day). The dermal LOAEL was not established. The dermal NOAEL was 100 mcL/ kg/ day (48 mg/ kg/ day). This 4­ week dermal toxicity study in the rat is unacceptable ( non­ guideline). The study was intended for use in the short­ term and intermediate­ term occupational and residential handler risk assessments for 11 the liquid formulations of carbaryl. It is considered unacceptable and not upgradeable because RBC cholinesterase results were inconsistent and plasma and brain cholinesterase were not measured. In another dermal toxicity study (MRID 45630601), brain cholinesterase inhibition was the most sensitive and reliable endpoint. Determination of cholinesterase inhibition in all three compartments would have helped define the effect level. MRID 45630603 In a non­ guideline four­ week dermal toxicity study (MRID 45630603), Sevin® 80S (80.07% a. i., Lot C8I168025A) was applied to the shaved skin of 8 Crl: CD (SD) IGS BR rats/ sex/ dose at dose levels of 0, 20, 50 or 100 mg/ kg bw/ day, 6 hours/ day for 5 days/ week during a 4­ week period. The parameters measured included the following: clinical observations, body weight, body weight gain, food consumption, RBC cholinesterase and signs of dermal irritation. There was no treatment­ related effect on mortality, clinical observations, body weight or dermal irritation. Body weight gain (relative to control values) in the 100 mg/ kg/ day males was highly variable between time periods. There were non­ significant decreases of 15% and 20% on Days ­3 to 5 and 19 to 26, respectively but increases of 9% and 53% were observed on Days 5 to 12 and 12 to 19, respectively. Since body weight was not measured at treatment initiation, it is difficult to determine if there was an effect during the first time period. However, food consumption was significantly decreased by 12% on Days ­1 to 5 in this group, which correlates with an initial treatment­ related effect. Therefore, the decrease in body weight gain in the 100 mg/ kg/ day males is considered treatment­ related. RBC cholinesterase was measured before dosing on Week ­1 and on Days 1, 8, 15 and 22. Statistically significant decreases were observed in the 50 and 100 mg/ kg/ day females on Day 8 (10% and 12%, respectively). These effects are not considered toxicologically significant given the inconsistency of the findings. Measurements were also performed within 1 hour after test material removal on Days 5, 12, 19, and 26. In males, statistically significant decreases were observed in animals treated at 50 mg/ kg/ day on Days 12 (10%), 19 (13%) and 26 (8%). In males treated at 100 mg/ kg/ day, there were significant decreases on Days 12 (20%), 19 (19%) and 26 (19%). Although not statistically significant, there was also a 12% decrease on Day 5 in this group. In females, statistically significant decreases were observed in animals treated at 50 mg/ kg/ day on Days 12 (16%) and 19 (12%). Using the repeated measures ANOVA test, there was also a significant decrease on Day 5 (12%) in this group. In females at 100 mg/ kg/ day, there were significant decreases on Days 12 (18%) and 19 (15%) and Day 26 (15%). The systemic LOAEL is 50 mg/ kg/ day based on statistically significant decreases in RBC cholinesterase in males and females. The systemic NOAEL is 20 mg/ kg/ day. The dermal LOAEL was not established. The dermal NOAEL was 100 mg/ kg/ day. This 4­ week dermal toxicity study in the rat is unacceptable ( non­ guideline). The study was intended for use in the short­ term and intermediate­ term occupational and residential handler risk assessments for the solid formulations of carbaryl. It is considered unacceptable and not upgradeable because only RBC cholinesterase was measured. In the dermal toxicity study with the technical chemical (MRID 45630601), brain cholinesterase inhibition was the most sensitive and reliable endpoint. While this study does support the RBC cholinesterase effects in MRID 45630601, the lack of plasma and brain cholinesterase 12 measurements makes the study unacceptable for use in risk assessment. 4.3 Prenatal Developmental Toxicity Adequacy of data base for Prenatal Developmental Toxicity: The data base for prenatal developmental toxicity is considered complete. No additional studies are required at this time. There are acceptable prenatal developmental toxicity studies in the rat and rabbit. There was no evidence of increased fetal susceptibility in these studies. 870.3700a Prenatal Developmental Toxicity Study ­ Rat In a developmental toxicity study (MRID 44732901), Carbaryl (99% a. i.) in an aqueous methylcellulose suspension was administered by gavage at 0, 1, 4, and 30 mg/ kg/ day to pregnant Crl: CD (SD) BR rats (25/ dose) during gestation days (GDs) 6 through 20. At GD 21, surviving dams were sacrificed and necropsied. There were no treatment­ related gross pathologic findings noted in any of the dams. There were no differences of toxicological concern in mortality, pregnancy rate, numbers of corpora lutea, implantations, viable fetuses, pre­ and post­ implantation losses, placental weights, and sex ratio. At 30 mg/ kg/ day, at least one occurrence of post­ dosing salivation occurred in 18/ 25 of the dams (vs 0/ 25 controls). This clinical sign appeared within 20 minutes of treatment, disappeared after approximately one hour, and was observed from GD 13 to 20. There were no deaths and no other treatment­ related clinical signs. Body weights of the high­ dose dams were 3­ 8% less than controls throughout the study (not statistically significant); their corrected (for gravid uterine weight) body weights and body weight gains were decreased (p 0.01) by 7 and 38%, respectively. Body weight gains in this group were decreased immediately after initiation of dosing (GDs 6­ 9, 9 108%, p 0.01) and throughout treatment (overall, 9 27%, p 0.01). Food consumption (g/ animal/ day) was decreased throughout the treatment period ( 10­ 17%, p 0.01). There were no differences of toxicological concern observed in the mid­ and low­ dose groups. The maternal LOAEL is 30 mg/ kg/ day based on clinical signs of toxicity, decreased body weight gains and food consumption. The maternal NOAEL is 4 mg/ kg/ day. In the high­ dose fetuses, mean fetal body weights were reduced ( 7­ 8%, p 0.01). Additionally, the following were observed in the high­ dose male and female fetuses: (I) an increase in incomplete ossification of the 5th sternebra, (ii) unossified 7th cervical centrum, (iii) incomplete ossification of 7th cervical centrum, and (iv) unossified 1st metatarsal. No effects on fetal viability were observed. There were no treatment related effects in developmental parameters observed in the mid­ and low­ dose groups. The developmental LOAEL is 30 mg/ kg/ day based on decreased fetal body weights and increased 13 incomplete ossification of multiple bones. The developmental NOAEL is 4 mg/ kg/ day. The developmental toxicity study in the rat is classified as acceptable (§ 83­ 3( a)) and satisfies the guideline requirement for a developmental toxicity study in the rat. 870.3700b Prenatal Developmental Toxicity Study ­ Rabbit In a developmental toxicity study (MRID 44904202), carbaryl (99% a. i.) in an aqueous methylcellulose suspension was administered by gavage at doses of 0, 5, 50 or 150 mg/ kg/ day to pregnant New Zealand White rabbits (22/ dose) during Gestation Days (GD) 6­ 29. On GD 25, blood was collected 1 hour postdosing for plasma and red blood cell (RBC) cholinesterase (ChE) measurements. At GD 30, surviving dams were sacrificed and necropsied; fetuses were examined for evidence of developmental effects. Maternal toxicity at 150 mg/ kg/ day was observed as statistically significant decreased body weight gain as compared to the control value during GD 6­ 9 (208%), GD 6­ 29 (dosing period, 53%), GD 3­ 30 (33%) and gestation (GD 0­ GD 30, 38%). Corrected body weight change was also decreased at this dose 219.73 g vs ­81.86 g in the control). Although not statistically significant, the body weight decreases at 50 mg/ kg/ day can be considered biologically significant for GD 6­ 9 (55%), GD 6­ 29 (25%), GD 3­ 30 (14%) and gestation (14%). There was no treatment­ related effect on food consumption. Statistically significantly decreases in plasma (46­ 68%) and RBC (19­ 27%) ChE were seen at 50 and 150 mg/ kg/ day. Maternal LOAEL = 50 mg/ kg/ day based on decreased body weight gain and decreased plasma and RBC ChE; Maternal NOAEL = 5 mg/ kg/ day The only evidence of developmental toxicity was a statistically significant decrease in fetal body weights of 10% (when calculated for all fetuses or individually for males and females) at 150 mg/ kg/ day. There were no treatment­ related developmental effects observed in the mid­ and low­ dose groups. Developmental Toxicity LOAEL is 150 mg/ kg/ day based on decreased fetal weight. Developmental Toxicity NOAEL is 50 mg/ kg/ day The developmental toxicity study in the rabbit is classified as acceptable/ guideline and does satisfy the guideline requirement for a developmental toxicity study in the rabbit. 4.4 Reproductive Toxicity Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered complete. No additional studies are required at this time. In the reproduction study in rats, there was evidence of quantitative susceptibility of offsprings. The LOAEL for parental systemic toxicity was based on decreased body weight, weight gain, and feed consumption; the NOAEL was 27 mg/ kg/ day in males and 30 mg/ kg/ day in females. In the offspring the LOAEL was based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival; the NOAEL was 5 mg/ kg/ day in males and 6 mg/ kg/ day in females. Several articles have been published in the open literature describing effects on spermatogenesis and developmental/ reproduction parameters at high doses. There is also an epidemiology study conducted in farmers exposed to multiple pesticides, which concluded that the miscarriage rate was 14 increased in parents where the father was exposed to carbaryl. There was no association between the use of carbaryl and preterm delivery, small for gestational age or altered sex ratio measurements. The studies and articles are summarized below. 870.3800 Reproduction and Fertility Effects ­ Rat In a two­ generation reproduction study (MRID 45448101), carbaryl (99.1% a. i, Lot No. E1208008) was given in the diet to groups of 30 male and 30 female F0 and F1 rats (CD ® [SD] IGS BR (Sprague­ Dawley)) at concentrations of 0, 75, 300, or 1500 ppm. The dietary concentrations corresponded to doses of 4.67, 31.34, and 92.43 mg/ kg/ day for F0 males; 0, 5.56, 36.32, and 110.78 mg/ kg/ day for F0 females; 0, 5.79, 23.49, and 124.33 mg/ kg/ day for F1 males; and 0, 6.41, 26.91, and 135.54 mg/ kg/ day for F1 females averaged over the premating period. Each group received treated or control diet continuously for 70 days prior to mating and during mating, gestation, and lactation of one litter per generation. F1 pups selected to parent the F2 generation were weaned onto the same food as their parents. Parental males were sacrificed after delivery of their litters and parental females were sacrificed after weaning of their litters. No treatment­ related deaths, clinical signs, organ weight changes, gross lesions, or microscopic lesions were observed in adult rats of either generation. No treatment­ related effects were observed on body weights, weight gain, feed consumption, or food efficiency in 75­ or 300­ ppm group F0 or F1 male or female rats at any time during the study including the gestation and lactation periods of the females. F0 and F1 male and female rats fed the 1500­ ppm diet weighed significantly (p< 0.01 or <0.05) less and gained less weight during the premating period. The F0 males weighed 5­ 6% less than controls during premating, gained 14­ 23% less weight during three weekly intervals up to day 45, and gained 9% less weight over the entire premating period; they also gained 8% less weight than controls over the mating/ postmating period. The F1 males weighed 10­ 19% less than controls during the entire study, gained 16% and 11% less weight during the first two weekly intervals, and gained 8% less weight than controls averaged over the entire premating period. The F0 females weighed 4­ 5% less than controls during the first 42 days of premating, gained 27% less weight during the first week, and 7% (N. S.) less averaged over the entire premating period. The F1 females weighed 8­ 22% less than controls throughout premating and gained 9% less weight during the first week; weight gain for the remaining weekly intervals and for the entire premating period was similar to that of controls. Food consumption and food efficiency for F0 and F1 rats followed patterns similar to that of body weight and weight gain; the largest difference between the 1500­ ppm groups and controls occurred during the early part of the premating period. When averaged over the entire premating period, F0 and F1 males consumed 6­ 7% less food than control and had food efficiency values similar to those of the controls. Feed consumption and food efficiency for the F0 females were similar to those of the control group, whereas F1 females consumed 9% (p< 0.01) less feed and had a food efficiency value 10% (p< 0.01) greater than that of controls. F0 and F1 females in the 1500 ppm group weighed less and gained less weight than controls during gestation, with the effect being greater in the F1 females. During lactation weight gain was markedly reduced in F1 females during the first 4 days, but was greater than that of controls averaged over the entire lactation period. The lowest­ observed­ effect level (LOAEL) for parental systemic toxicity is 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) based on decreased body weight, 15 weight gain, and feed consumption. The no­ observed­ adverse­ effect (NOAEL) level is 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females). No treatment­ related effects were observed on the estrous cycle of either F0 or F1 females at any dose level or on percent motile sperm, sperm count, percent progressively motile sperm, epididymal sperm count, spermatid head count, daily sperm production, or efficiency of daily sperm production in F0 or F1 males at any dose level. There was a dose­ related increase in the percentage of abnormal sperm in the treated males but no statistical significance at any dose level. No treatment­ related gross or microscopic effects were observed in male or female rats of either generation. No treatment­ related effects were observed on any parameter of reproductive performance including, mating and fertility indexes, gestation index, pregnancy index, precoital duration, gestation length, or number of females producing live litters. The LOAEL for reproductive toxicity could not be established because no effects were observed at any dose level; therefore, the NOAEL is $ 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females). No treatment­ related effects were observed on implantation sites/ litter, number of live pups born/ litter, number of dead pups born/ litter, live birth index, sex ratio, clinical signs, or organ weight or necropsy findings in pups surviving to 21 days. Pup survival was decreased at 300 and 1500 ppm for both generations. Increased number of deaths in the F2 generation males and females resulted in an 18­ 19% decrease in mean litter size on postnatal day 4 (p< 0.01 or <0.05) and decreased viability and lactation indexes at 1500 ppm. A large number of pups that died had no milk in their stomachs. In addition, pup weight/ litter and pup weight gain in the 1500­ ppm group pups were reduced for both generations starting with postnatal day 4 (11­ 15% for F1 and 13­ 23% for F2 pups); body weight gain was reduced throughout lactation with the greatest effect occurring during the first 7 days for F1 pups and the first 14 days for F2 pups. Sexual maturation was delayed in 1500­ ppm group F1 offspring as evidenced by delayed balanopreputial separation in the males (+ 2.1 days) and vaginal patency in the females (+ 1.4 days). The differences remained statistically significant after adjustment for body weight decreases. Anogenital distance was significantly reduced in F2 male pups in the 1500­ ppm group, but not when the distance was adjusted for body weight. The LOAEL for offspring toxicity was 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival. The NOAEL is 75 ppm (4.67­ 5.79 mg/ kg/ day for males and 5.56­ 6.41 mg/ kg/ day for females). This study is Acceptable/ Guideline and satisfies the guideline requirement for a two­ generation reproductive study (OPPTS 870.3800; OECD 416) in the rat. Literature Articles In a 1996 study in the open literature, carbaryl was administered to four groups of 6 young and 6 adult 1 Pant N, Shankar R, Srivastava SP (1996). Spermatotoxic effects of carbaryl in rats. Human Exp Toxicol 15( 9); 736­ 38. 2 Pant N, Srivastava SC, Prasad AK, Shankar R, Srivastava SP (1995). Effects of Carbaryl on the Rat's Male Reproductive System. Vet Human Toxicol 37( 5): 421­ 425. 16 Druckery albino rats per group at doses of 0, 25, 50 or 100 mg/ kg/ day for 60 days. 1 Body weight was recorded at initiation and completion of the study. On the 61st day, the animals were sacrificed and the testes, epididymides, seminal vesicles, ventral prostrate and coagulating glands were weighed. Epididymal sperm were used for sperm counts and examination of motility and morphology. No overt toxicity or mortality was observed. There were dose­ related effects on body weight for the 50 and 100 mg/ kg/ day groups. The absolute weights of the testes, epididymides, seminal vesicle, ventral prostrate and coagulating glands were significantly decreased at 100 mg/ kg/ day for young rats. The relative organ weights were not affected at any doses. The organ weights were not affected in adult animals. Young rats receiving carbaryl 50 mg/ kg/ day had a 24.4% and 25% decrease in sperm motility and sperm count, respectively; the changes at 100 mg/ kg/ day were 42.9% and 37.5%, respectively. Adults receiving the 50 mg/ kg/ day dose had a 15.1% and 12.5% reduction in sperm motility and count, respectively; the changes at 100 mg/ kg/ day were 26.4% and 25%, respectively. The percentage of young rats with abnormal sperm was 19.8% and 33.7% at 50 and 100 mg/ kg/ day, respectively. In adults, the percentages were 16.1% and 23.1% for the respective doses. In another study from this laboratory, three groups of 8 male Wistar rats per group were administered carbaryl by gavage at doses of 0, 50 or 100 mg/ kg/ day for 90 days. 2 Body weight was measured periodically throughout the study. On the 91st day, the animals were sacrificed and the male reproductive glands were weighed. One testis from each animal was preserved for histopathology and the other was homogenized for testicular enzyme assay. Epididymal sperm were used for sperm counts and examination of motility and morphology. No clinical signs of toxicity were observed, except for lethargy. Body weights were decreased in the 100 mg/ kg/ day group after 60 days. There were no changes in the weights of reproductive organs. There were significant changes in the testicular enzymes of the 100 mg/ kg/ day group: decreases in SDH and G6PDH and increases in GGT and LDH. At both doses, there were significant decreases in the total epididymal sperm count, percent sperm motility and increases in the percent with morphological abnormalities in head, neck and tail. At 50 mg/ kg/ day, the testes had slight to moderate congestion and edema. A few tubules showed moderately depressed spermatogenesis and loss of sperm. There was moderate atrophy of seminiferous tubules with prominent interstitial spaces in the center of the testes, but the Leydig cells were intact. At 100 mg/ kg/ day, there were increases in the intensity of congestion and the edematous reaction was seen both peripherally and in the central region. Most of the seminiferous tubules had disturbed spermatogenesis as well as accumulations of cellular masses in their lumens. In a study conducted at EPA's Health Effects Research Laboratory, 16 pregnant Fischer 344 rats were administered carbaryl by gavage on gestation days (GD) 6­ 19 at doses of 78 or 104 mg/ kg/ day; 21 3 Narotsky MG, Kavlock RJ (1995). A Multidisciplinary Approach to Toxicological Screening: II. Developmental Toxicity. Journal of Toxicology and Environmental Health 45: 145­ 171. 4 Savitz DA, Arbuckle T, Kaczor D, Curtis KM (1997). Male Pesticide Exposure and Pregnancy Outcome. Am J Epidemiol 146( 12): 1025­ 36. 17 control animals were used. 3 The high dose, selected to produce overt maternal toxicity, was based on the results of a 14­ day repeated dose study in nonpregnant female rats. The low dose was 75% of the high dose. Maternal body weights were determined on GD 6, 8, 10, 13, 16 and 20. All rats were examined periodically for clinical signs of toxicity. Pups in each litter were examined and counted on postnatal day (PD) 1, 3, and 6 and weighed collectively on PD 1 and 6. After the final litter examination, the dams were killed and uterine implantation sites counted. Females that did not deliver by GD 24 were killed and their uteri examined for pregnancy status. Clinical signs of toxicity observed in the dams included tremors, motor depression, and lacrimation, usually during the first three days of treatment. Jaw clonus was observed throughout the treatment period. (The article does not indicate if clinical signs were observed at both doses.) Marked weight loss was observed early in treatment. Over the entire treatment period, carbaryl produced extrauterine weight loss at the high dose and reduced weight gains at the low dose. There was increased prenatal mortality at the high dose; this effect was attributed to two (15%) fully resorbed litters in this group. In addition, high dose pup weights were significantly reduced on PD 1. The PD­ 1 pup weights in the low dose and the PD 6 pup weights in both carbaryl­ exposed groups were also significantly reduced, but only when analyzed using the number of live pups on PD 1 as the covariate. In a recent epidemiology study, the effects of exposure of male farmers in Ontario, Canada, to agricultural pesticides and pregnancy outcome was investigated. 4 Miscarriage risk was not associated with participation in farm activities for all types of chemical applications, but was increased in combination with reported use of thiocarbamates, carbaryl and unclassified pesticides on the farm (Odds ratio = 1.9, 95% C. I. 1.1­ 3.1). There was no association between use of carbaryl and preterm delivery, small for gestational age or altered sex ratio measurements. 4.5 Chronic Toxicity Adequacy of data base for chronic toxicity: The data base for chronic toxicity is considered complete. No additional studies are required at this time. In the chronic toxicity study in dogs, at the lowest dose tested, plasma ChEI in females and brain ChEI in males were observed. In a 5­ week study to establish the ChEI NOAEL, plasma ChEI was the basis for setting the NOAEL/ LOAEL. 870.4100b Chronic Toxicity ­ Dog In a chronic toxicity study (MRID No. 40166701), Carbaryl (99%) was administered in the diet to 6 beagle dogs/ sex/ group at doses of 0, 125, 400 or 1250 ppm for one year. Nominal doses were 3.1, 10 and 31.3 mg/ kg/ day. There were no deaths during the study. With the 1250 ppm females, there was an increased incidence of clinical signs of toxicity, including emesis, lacrimation, salivation and tremors. Mean body weight gain 18 was decreased (50%) in the 1250 ppm females for weeks 0­ 6. Mean food consumption was decreased (16­ 24%, not statistically significant) in the 1250 ppm females at multiple time periods during the study. No treatment­ related ophthalmoscopic changes were observed. There was a statistically significant increase in white blood cell and segmented neutrophil counts at some of the testing intervals for the 1250 ppm group males. Albumin levels were significantly decreased (9­ 11%) at all of the testing periods in the 1250 ppm females. Plasma cholinesterase (ChE) levels in males were significantly decreased in the 400 ppm (30­ 36% 9 ) and 1250 ppm (58­ 66% 9 ) groups at all testing intervals (weeks 5, 13, 26 and 52). Plasma ChE levels in females were significantly decreased at most intervals in the 125 ppm group (12­ 23% 9 ), 400 ppm group (9­ 31% 9 ) and 1250 ppm group (47­ 60 ). RBC ChE levels in males were significantly decreased in the 400 ppm group (23­ 28% 9 at weeks 5 and 13) and 1250 ppm group (46­ 56% 9 for all intervals). RBC ChE levels in females were significantly decreased in the 400 ppm group (29­ 34% 9 at weeks 5, 13 and 26) and 1250 ppm (29­ 38% 9 for all intervals). Brain ChE in males was not statistically significantly decreased but biologically decreased in the 400 ppm group (32% 9 ) and 1250 ppm group (25% 9 ). Brain ChE in females was significantly decreased (20­ 36% 9 ) in all the groups. No treatment­ related effects were seen in urinalysis parameters. At necropsy, there was a statistically significant increase in the absolute weight of the liver/ gall bladder in the 1250 ppm group males. Relative and liver­ to­ brain weights were also increased but not significantly. There was a dose­ related decrease in the absolute, relative and organ­ to­ brain weights of the pituitary in males, although none of the changes was statistically significant. There was also a significant decrease in the relative weight of the thyroid in this group. However, since there were no accompanying microscopic changes in these organs, the toxicological significance of these organ weight effects is questionable. The LOAEL for systemic toxicity was 1250 ppm (31.3 mg/ kg/ day) based on an increased incidence of clinical signs (females), decreased body weight and food consumption (females) and alterations in clinical pathology parameters (both sexes); NOAEL was 400 ppm (10 mg/ kg/ day). The LOAEL for plasma cholinesterase inhibition was 125 ppm (3.1 mg/ kg/ day) for females; a NOAEL was not established. The LOAEL for plasma cholinesterase inhibition was 400 ppm (10 mg/ kg/ day) for males; the NOAEL was 125 ppm (3.1 mg/ kg/ day). The LOAEL for RBC cholinesterase inhibition was 400 ppm (10 mg/ kg/ day) for males and females; the NOAEL was 125 ppm (3.1 mg/ kg/ day). The LOAEL for brain cholinesterase inhibition was 125 ppm (3.1 mg/ kg/ day) for females; a NOAEL was not established. The LOAEL for brain cholinesterase inhibition was 400 ppm (10 mg/ kg/ day) for males; the NOAEL was 125 ppm (3.1 mg/ kg/ day). In a five­ week study (MRID # 42022801), Carbaryl (99.3% a. i.) was administered in the diet to six beagles/ sex/ group at doses of 0, 20, 45 or 125 ppm. Actual mg/ kg/ day doses for males were 0, 0.59, 1.43 and 3.83 mg/ kg/ day, respectively; doses for females were 0, 0.64, 1.54 and 4.11 mg/ kg/ day, respectively. The following parameters were measured: clinical observations, body weights, food consumption, ophthalmoscopic examinations, plasma and RBC cholinesterase (at days ­11, ­8 and ­5 pretest and then days 14 and 32 of the study), brain cholinesterase (at termination) and gross necropsies. 19 This study was conducted to complete the information needed to satisfy the chronic toxicity study requirement in nonrodent species. There were no deaths or treatment­ related clinical signs of toxicity. There were no treatment­ related effects on body weights, food consumption or ophthalmoscopic examinations. In males, there was a statistically and biologically significant decrease in plasma cholinesterase for the 125 ppm (22% 9 ) group. The LOAEL for systemic toxicity and for RBC and brain cholinesterase inhibition was >125 ppm (males: 3.83 mg/ kg/ day; females: 4.11 mg/ kg/ day); the NOAEL was $ 125 ppm. The LOAEL for plasma cholinesterase inhibition for males was 125 ppm; the NOAEL was 45 ppm (1.43 mg/ kg/ day). The LOAEL for cholinesterase inhibition for females was >125 ppm; the NOAEL was $ 125 ppm. Together, these studies are acceptable and satisfy the guideline requirements for a chronic toxicity study in a nonrodent species (83­ 1). 4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The data base for carcinogenicity is considered complete. No additional studies are required at this time. In both the rat combined chronic toxicity/ carcinogenicity study and the mouse carcinogenicity study, there was an increase incidence of tumors, including kidney, liver and vascular tumors, in the treated groups. However, the highest dose in both studies was considered excessive based on evidence of severe toxicity. In addition to the required carcinogenicity studies in mice and rats, the registrant submitted a special study in genetically modified mice. Carbaryl was administered in the diet to heterozygous p53­ deficient (knockout) male mice at concentrations of up to 4000 ppm (716.6 mg/ kg/ day) for six months. There was no evidence of neoplastic or preneoplastic changes in the vascular tissues of any organ. A model validation study demonstrated that vascular tumors occur in heterozygous p53 deficient mice within six months of administration of a known genotoxic carcinogen (urethane). The CARC (11/ 7/ 01) considered all the available toxicity data and concluded that the malignant vascular tumors (hemangiosarcomas) in male mice occurred at doses which were adequate and not excessive. In females these tumors occurred only at the highest dose which was excessively toxic. Nevertheless, the findings in female mice were supportive of vascular tumors in male mice. The CARC classified carbaryl as "Likely to be carcinogenic in humans" based on an increased incidence of hemangiosarcomas in male mice at all doses tested (100, 1000 and 8000 ppm). The Q1*, based on the CD­ 1 mouse dietary study with ¾ Interspecies Scaling Factor, is 8.75 x 10 ­4 (mg/ kg/ day) ­1 in human equivalents. 870.4200b Carcinogenicity (feeding) ­ Mouse In a carcinogenicity study (MRID No. 42786901), 80 CD­ 1® mice/ sex/ group were administered technical Carbaryl (99.3% a. i.) in the diet at dosages of either 0, 100, 1000 or 8000 ppm for 104 weeks (males: 0, 14.73, 145.99 and 1248.93 mg/ kg/ day; females: 0, 18.11, 180.86 and 1440.62 mg/ kg/ day, 20 respectively.) Four males in the 8000 ppm group died during the first week of treatment; the cause of death was not determined. Survival rates were not affected by treatment. Animals in the 8000 ppm group, especially the females, developed clinical signs of toxicity, including hunched posture, thin and languid appearance, squinted and opaque eyes, urine stains, redness to various body areas, rough hair coat, soft feces and low body temperature. Mean body weights were statistically significantly decreased for the 8000 ppm males and females for the majority of the study (males 9­ 13%; females 5­ 14%). Mean body weight gain for the 8000 ppm males and females was decreased throughout the study (males 23­ 38%; females 10­ 32%). Mean food consumption was statistically significantly decreased in the 8000 ppm females (7­ 10%). Hematology parameters, including RBC, hemoglobin and hematocrit, were statistically significantly decreased in the 8000 ppm females at week 53 and 8000 ppm group males at week 105. Total leukocyte count and counts of lymphocytes and eosinophils were significantly increased in the 8000 ppm group females at week 53. Platelet counts were significantly increased in this group at week 105. RBC cholinesterase (ChE) was statistically significantly decreased in the 1000 ppm (23% 9 ) and 8000 ppm (30% 9 ) group males at week 53. RBC ChE was decreased in the 8000 ppm group females (24% 9 ) at week 105, although the change was not statistically significant. Brain ChE was statistically significantly decreased in the 1000 and 8000 ppm group males at both weeks 53 and 105 (13­ 18% 9 for the 1000 ppm group; 40­ 57% 9 for the 8000 ppm group) and in the 8000 ppm females (34­ 47% 9 ). Brain ChE was also significantly decreased (13% 9 ) in the 1000 ppm group females at week 53. However, the percentage decreases from the control level were less than 20% for the 1000 ppm group males and females at both weeks 53 and 105. Therefore, the biological significance of these findings is questionable. Plasma ChE values were not affected by treatment. There were no treatment­ related macroscopic effects at the week 53 sacrifice, however at the week 105 sacrifice the incidence of opaque eyes was increased in the 8000 ppm group (males: 1/ 37 controls vs. 4/ 30; females: 2/ 34 controls vs. 16/ 32). The most consistent organ weight changes at both necropsies were increased relative liver and kidney weights. On microscopic examination, there was an increased incidence of chronic progressive nephropathy in the 1000 ppm males and 8000 ppm males and females at the interim sacrifice. The severity of extramedullary hematopoiesis and pigment in the spleen in the 8000 ppm males and females was increased at the interim sacrifice. There was a dose­ related increased incidence of intracytoplasmic protein­ like droplets in the urinary bladder in the 1000 and 8000 ppm group males and females at the terminal and unscheduled sacrifices. The incidence of animals with cataracts was increased, but not dose­ related, in the 8000 ppm group males and females. The study demonstrated that Carbaryl is carcinogenic in mice at doses of 100 ppm (14.73 mg/ kg/ day) and higher in males and 8000 ppm (1440.62 mg/ kg/ day) in females. There was an increased incidence of vascular neoplasms (hemangiomas and hemangiosarcomas) in all treated males and in the 8000 ppm group females at the terminal and unscheduled necropsies but not at week 53. Considering all animals, there was an increased incidence of adenomas, multiple adenomas and carcinomas of the kidney in the 8000 ppm group males. The incidence of hepatic neoplasms (adenomas, carcinomas and one hepatoblastoma) was increased in the 8000 ppm group females. The HED CPRC concluded that the 8000 ppm dose was excessive based on the significantly decreased body weight gain in males (33%) and females (19%) during week 13, a significant decrease in RBC and brain cholinesterase activity, 21 clinical signs of toxicity and histopathological changes in the bladder, kidneys and spleen in both sexes. The systemic LOAEL was 1000 ppm (M: 145.99 mg/ kg/ day; F: 180.86 mg/ kg/ day) based on an increased incidence of intracytoplasmic droplets in the superficial epithelial cells of the urinary bladder in males and females and chronic progressive nephropathy in males. The systemic NOAEL was 100 ppm (M: 14.73 mg/ kg/ day; F: 18.11 mg/ kg/ day). The RBC cholinesterase inhibition LOAEL in males was 1000 ppm (23% 9 at week 53); the NOAEL was 100 ppm. The RBC cholinesterase inhibition LOAEL in females was 8000 ppm (24% 9 at week 105); the NOAEL was 1000 ppm. The plasma cholinesterase inhibition LOAEL was >8000 ppm (M: 1248.93 mg/ kg/ day; F: 1440.62 mg/ kg/ day); the NOAEL was $ 8000 ppm. The brain cholinesterase inhibition LOAEL for males and females was 8000 ppm (M: 40­ 57% 9 ; F: 34­ 47% 9 ); the NOAEL was 1000 ppm. This study is classified as Acceptable and satisfies the guidelines for a carcinogenicity study in mice (§ 83­ 2). 870.4300 Combined Chronic Toxicity/ Carcinogenicity Study ­ rat In a combined carcinogenicity/ chronic toxicity study (MRID No. 42918801), 70 Sprague­ Dawley Crl: CD® BR rats/ sex/ group were administered technical Carbaryl (99% a. i.) in the diet at dosages of either 0, 250, 1500 or 7500 ppm for 104 weeks (males: 0, 10.0, 60.2 and 349.5 mg/ kg/ day; females: 0, 12.6, 78.6 and 484.6 mg/ kg/ day). An additional 10 animals/ sex/ dose were administered the same doses and were sacrificed after 53 weeks. Another 10 animals/ sex from the control and high dose group animals were sacrificed at week 57 after switching the diet of the high dose animals to control feed for weeks 53­ 57 of the study. There was no treatment­ related effect on survival. There was an increased incidence of clinical signs of toxicity, including hunched posture, thin appearance, chromodacryorrhea and urine stains in the 7500 ppm group males. There was an increased incidence of alopecia and urine strains in the 7500 ppm group females. Statistically significant decreases in mean body weight were observed in the 7500 ppm males (24­ 35%) and females (24­ 45%) and the 1500 ppm females (4­ 12%). Mean body weight gain over the course of the study was decreased in the 7500 ppm males (53%) and females (69%). There was a 18% decrease in body weight gain in the 1500 ppm females for the week 0­ 104 period only. Food consumption in the 7500 ppm group males and females was decreased (4­ 16% in males; 11­ 21% in females) during the study. In the recovery group, rebound in food consumption and body weight gain was seen, but mean body weight was still decreased 23% for both the 7500 ppm males and females at week 57. There was an increased incidence of unilateral and bilateral cataracts in the 7500 ppm males and females. A consistent decrease in WBC and lymphocyte count in the 7500 ppm males and females was seen. 22 Alterations in clinical chemistry in the 7500 ppm males and females included significant increases in cholesterol and BUN and significant decreases in AST, ALT and CPK. Plasma cholinesterase was decreased in the 7500 ppm males (27­ 42%) and females (46­ 57%) at all of the testing intervals (weeks 27, 53, 79 and 105), however all of the changes were not statistically significant. RBC cholinesterase was decreased in the 7500 males (19­ 37%) and females (25­ 38%) and in the 1500 ppm males (10­ 23%) and females (12­ 26%) at most of the testing intervals. At weeks 53 and 105, brain cholinesterase was statistically significantly decreased in the 7500 ppm males (8­ 28%) and females (22­ 31%). In the recovery group, cholinesterase values had returned to normal levels by week 56. There was a slightly increased incidence of erythrocytes in the urine of the 7500 ppm males and occult blood in the 7500 ppm males and females. An increased incidence of dark urine in the 1500 ppm females and in the 7500 ppm males and females was also found. There were no treatment­ related macroscopic findings at the week 53 and 57 necropsies. At the week 105 necropsy, the macroscopic findings at an increased incidence in the 7500 ppm males and females, which were also associated with microscopic changes, included pale areas in the lungs and liver and urinary bladder masses. A decreased absolute weight and an increased relative weight of the kidneys, lungs, spleen and liver were found in the 7500 ppm males and females. At the week 53 necropsy, there were slight increases in the incidence of microscopic changes in the kidney and liver of the 7500 ppm males and females. At the week 105 necropsy, there was a wide variety of changes in multiple organs of males and females in the 7500 ppm group. In the liver, there was an increased incidence in the following: hepatocytic hypertrophy in males and females; and eosinophilic foci and pigment in females. In the urinary bladder, there was an increased incidence of transitional cell hyperplasia, squamous metaplasia, high mitotic index and atypia in males and females. In the lung, there was an increased incidence of focal pneumonitis and foamy macrophages in males and females. In the kidney, there was an increased incidence of transitional cell hyperplasia in males. In the thyroid, there was an increased incidence of follicular cell hypertrophy in males and females. Degeneration of the sciatic nerve and skeletal muscle was observed at an increased incidence in males and females. The study demonstrated that Carbaryl is carcinogenic in male and female rats at 7500 ppm. There was an increased incidence of liver adenomas in females. In the bladder, there was an increased incidence of benign transitional cell papilloma and transitional cell carcinomas in males and females. One transitional cell carcinoma was also observed in the kidney of a male rat. In the thyroid, the incidence of benign follicular cell adenomas was increased in males; one follicular cell carcinoma was also seen in a male. The HED CPRC evaluated the toxicity data on Carbaryl and considered 7500 ppm to be an excessive dose based on the following findings: 1) changes in body weight gain during week 13 for males and females by 40% and 52%, respectively, as compared to controls; 2) decreased food efficiency; 3) alterations in hematology and clinical chemistry; and 4) decreases in plasma, RBC and brain cholinesterase at weeks 53 and 105. The systemic LOAEL was 1500 ppm (78.6 mg/ kg/ day) in females based on decreased body weight and body weight gain; the NOAEL was 250 ppm (12.6 mg/ kg/ day). The systemic LOAEL was 7500 ppm (349.5 mg/ kg/ day) in males based on an increased incidence of clinical signs of toxicity, decreases in 23 body weight, body weight gain and food consumption, an increased incidence of cataracts, alterations in clinical pathology parameters, organ weight changes, and an increased incidence of nonneoplastic microscopic changes. The systemic NOAEL was 1500 ppm (60.2 mg/ kg/ day) in males. The LOAEL for plasma cholinesterase inhibition was 7500 ppm in males (27­ 47% decrease) and females (46­ 57% decrease); the NOAEL was 1500 ppm. The LOAEL for RBC cholinesterase inhibition was 1500 ppm in males (10­ 23% decrease) and females (12­ 26% decrease); the NOAEL was 250 ppm. The LOAEL for brain cholinesterase inhibition was 7500 ppm in males (8­ 28% decrease) and females (22­ 31% decrease); the NOAEL was 1500 ppm. This study is classified as Acceptable and satisfies the guidelines for a combined carcinogenicity/ chronic toxicity feeding study in rats (83­ 5). Carcinogenicity and Other Studies in p53 Knockout Mice In a special, non­ guideline study (MRID 45281801, 45281802, 45236603), heterozygous p53­ deficient (knockout) male mice (20/ group) were administered carbaryl in the diet at concentrations of 0, 10, 30, 100, 300, 1000 and 4000 ppm (approximately 0, 1.8, 5.2, 17.5, 51.2, 164.5 and 716.6 mg/ kg/ day, respectively) for six months. The doses selected for this study were based on two 28­ day studies (MRID 45236603) in wild­ type mice in which body weight decreases were observed at 4000 and 8000 ppm concentrations of carbaryl in the diet. A validation study (MRID 45281802) demonstrated that vascular tumors occur in heterozygous p53­ deficient mice within 6 months of administration of a known genotoxic carcinogen (urethane). These studies were conducted to demonstrate that carbaryl is a non­ genotoxic carcinogen. In the standard mouse carcinogenicity study (MRID 42786901) at dietary concentrations of 0, 100, 1000 or 8000 ppm, there was an increased incidence of vascular neoplasms (hemangiomas and hemangiosarcomas) in all treated males and in the 8000 ppm group females. There was an increased incidence of adenomas, multiple adenomas and carcinomas of the kidney in the 8000 ppm group males. The incidence of hepatic neoplasms (adenomas, carcinomas and one hepatoblastoma) was increased in the 8000 ppm group females. At meetings on October 27 and December 8, 1993, the HED Cancer Peer Review Committee concluded that the 8000 ppm dose was excessive. Therefore, the relevance of tumors at this dose was questionable. In the p53 knockout mouse study with carbaryl, there was a slight decrease in body weight and food consumption in the 4000 ppm group. No other treatment­ related effects were observed, except globular deposits in the urinary bladder were observed in a high proportion of the mice treated at 100 ppm of carbaryl and above with a dose­ related increase in incidence and severity. There was no evidence of local irritation or hypertrophy of the bladder epithelium. There was no evidence of neoplastic or preneoplastic changes in the vascular tissue of any organs examined. The study is classified Acceptable (non­ guideline). This is a special study not submitted to fulfill a data requirement. 24 4.7 Mutagenicity Adequacy of data base for Mutagenicity: The data base for mutagenicity is considered complete and no additional studies are required at this time. A recent review of the data from the submitted studies and the published literature were in general agreement and showed that carbaryl was clastogenic in vitro. The wide variety of induced aberrations (both simple and complex) was consistent between the submitted study and the open literature. However, there were inconsistencies relative to the requirement for S9 activation. Nevertheless, the two in vivo studies for micronuclei induction or chromosome aberrations were negative. Similarly, the 6­ month p53 knockout transgenic mouse bioassay (see Section 4.6) was negative up to a high level (4000 ppm, . 720 mg/ kg/ day) that approached the limit dose for a mouse carcinogenicity assay. Carbaryl was also negative for DNA binding in the livers of mice treated with 8000 ppm for 2 weeks but the study was considered to be of limited sensitivity by the CARC Metabolism Subgroup. The same Subgroup identified epoxide intermediates of carbaryl which were found to be conjugated to glucuronide, "rapidly metabolized and excreted as any endogenous epoxide would be". Overall, these findings indicate that carbaryl produces epoxides and its DNA reactivity is manifested as chromosomal aberrations in cultured mammalian cells. Other in vitro studies indicate carbaryl's effects on karyokinesis and cytokinesis, as well as stress genes associated with oxidative damage. Based on these considerations, it was concluded that there is a concern for mutagenicity, which is somewhat lessened because of the lack of an effect in in vivo mutagenicity studies. GENE MUTATIONS Mutagenicity ­ Salmonella typhimurium/ Mammalian Microsome Mutagenicity Assay (Ames test) In a Salmonella/ mammalian activation gene mutation assay (MRID 41370303), carbaryl technical (99.3%) was initially evaluated in the Salmonella typhimurium/ microsome mutagenicity assay over a concentration range of 5 to 1000 µg/ plate. The test material was not mutagenic, however the highest assayed dose was cytotoxic in S. typhimurium strains TA98 and TA100, but not in strains TA1535, TA1537, or TA1538. Accordingly, the assay was repeated with six concentrations (10 to 2000 µg/ plate +/­ S9). Results from the repeat assay indicated that 2000 µg/ plate +/­ S9 was cytotoxic in strains TA98 and TA100, and the remaining doses were not mutagenic. It is concluded, therefore, that carbaryl technical was assayed to an appropriately high concentration with no evidence of mutagenicity in a wellconducted study. The study is classified as acceptable/ guideline and satisfies the guideline requirements (§ 84­ 2) of bacterial reverse mutation test. Mutagenicity ­ Mammalian Cells in Culture Gene Mutation Assay in Chinese Hamster Ovary (CHO) Cells In a mammalian cells in culture gene mutation assay in Chinese Hamster Ovary (CHO) Cells (MRIDs 41370302, 41420201), carbaryl technical (99.3%) was evaluated in two nonactivated and three 25 S­ 9 activated Chinese hamster ovary (CHO) cell forward mutation assays. The findings from both nonactivated assays were in good agreement and indicated that over a concentration range of 1 to 300 µg/ mL, the test material did not induce a mutagenic response. Doses $ 200 µg/ mL were severely cytotoxic (< 10% cell survival), and <50% of the cells survived exposure to $ 50 µg/ mL. Carbaryl was less cytotoxic in the presence of S9 activation as indicated by increased survival at comparable levels in the preliminary cytotoxicity test (e. g., 29.5% survival at 62.5 µg/ mL ­S9 as compared with 95.7% survival at 62.5 µg/ mL +S9) and the initial mutation assay (e. g., 18.1% survival at 100 µg/ mL ­S9 as compared with 46.8% at 100 µg/ mL +S9). There was no definitive evidence of increased mutation frequencies (MFs) in this trial. The second S9­ activated trial was aborted because of excessive cytotoxicity at test material levels of $ 10 µg/ mL. Results from the third S9­ activated trial (dose range: 1 to 80 µg/ mL) showed severe cytotoxic effects at levels $ 60 µg/ mL; no evidence of mutagenic effect was seen at the remaining doses. The results of the assays provide no clear indication of a mutagenic response, however, the study does not fully support a negative conclusion. The conflicting cytotoxicity data for the S9­ activated assays provide no assurance that the final S9­ activated mutation assay was conducted over an appropriate dose range. The study is classified as unacceptable/ guideline and does not satisfy the guideline requirements (§ 84­ 2) for an in vitro mammalian cell gene mutation test. CHROMOSOME ABERRATIONS Mutagenicity ­ Mammalian Cells in Culture Cytogenetic Assay Carbaryl (technical) was assayed for clastogenic effects in both the presence and absence of S9 activation using Chinese hamster ovary (CHO) cells (MRID 41370304). Because of severe cell cycle delay, which was more pronounced without S9 activation, a 20­ hour cell harvest was selected to evaluate seven nonactivated doses ranging from 5 to 100 : g/ mL. In the presence of S9 activation, cells exposed to carbaryl at doses of 25, 50, 75, 100, 150, 200, 250, and 300 : g/ mL were harvested 30 hours post treatment. Results indicated that the nonactivated test material was more cytotoxic than the S9­ activated test material (i. e., few metaphases were recovered at 75 and 100 : g/ mL , and moderate to slight cytotoxic effects were seen at doses $ 10.0 : g/ mL). With the exception of a single rare complex aberration (quadriradial) scored at the 50.0­ : g/ mL dose level, there was no evidence of a clastogenic effect. By contrast, in the S9­ activated assays, all scored doses (150, 200, 250, and 300 : g/ mL) at both harvest times induced significant (p 0.01) increases in the percentage of cells with aberrations. The majority of S9­ activated doses (both harvests) also induced significant (p 0.01) increases in the percentage of cells with >1 aberration. At both the 20­ and 30­ hour harvest times, cytotoxicity (i. e., reduced monolayers, dead cells, and/ or reduced mitotic cells) were observed at levels $ 200 : g/ mL. Induced structural damage included simple (i. e., chromatid and chromosome breaks) and complex aberrations (i. e., triadials, quadriradials, complex rearrangements, dicentrics and rings). The data show little or no dose responsiveness and the lowest reactive level of carbaryl was not determined. It was concluded, however, that the study was technically sound and, therefore, acceptable/ guideline. The study satisfies the Guideline requirements (§ 84­ 2) for an in vitro mammalian cell chromosomal aberration test. Mutagenicity ­ Mouse Micronucleus Test 26 In a mouse micronucleus assay (MRID No: 44069301), groups of five male and five female CD­ 1 mice received single oral gavage administrations of 50, 100 or 200 mg/ kg carbaryl (99.9%) once daily for 2 days. Based on analytical determinations, average daily doses were . 34, 79 or 180 mg/ kg. Mice were sacrificed at 24 and 48 hours postadministration of the second dose and harvested bone marrow cells were examined for the incidence of micronucleated polychromatic erythrocytes (MPEs). The test material was delivered as suspensions prepared in 0.5% carboxymethyl cellulose. The minimal toxicity (i. e., lethargy which lasted for 2 hours) in the absence of cytotoxicity to the target cells does not support the testing of the maximum tolerated dose (MTD). The positive control induced the expected high yield of MPEs in males and females. Carbaryl did not induce a clastogenic or aneugenic effect in either sex at any dose or sacrifice time. However, there was no convincing evidence that the MTD was achieved. The study is classified as unacceptable/ guideline and does not satisfy the guideline requirements(§ 84­ 2; OPPTS 870.5385) for in vivo cytogenetic mutagenicity data. OTHER MUTAGENIC EFFECTS Mutagenicity ­ UDS Assay In a UDS Assay in primary rat hepatocytes (MRID 41370301), under the conditions of two independent trials, six doses of carbaryl technical (99.3%) ranging from 0.5 to 25.0 µg/ mL in the first assay and six doses ranging from 5.0 to 25.0 µg/ mL in the repeat assay did not induce an appreciable increase in the net nuclear grain counts of treated rat hepatocytes. Doses >25.0 µg/ mL were severely cytotoxic; reduced cell survival ( 25%) was observed at 25.0 µg/ mL in both assays. Although an increase in the percentage of cells with $ 6 grains per nucleus was seen in the initial test, the increase was confined to a single dose (10 µg/ mL) and was not dose­ related or reproducible. The study demonstrated that carbaryl is not genotoxic in this test system at doses of 5.0 to 25.0 µg/ mL. The study is classified as acceptable/ guideline and satisfies the guideline requirements (§ 84­ 2) for a unscheduled DNA synthesis in mammalian cells in culture. 27 STUDIES FROM THE OPEN LITERATURE Studies in the open literature indicate that Carbaryl is not mutagenic in bacteria but produced conflicting results in Chinese hamster V79 gene mutation assays [negative in the study of Onfelt and Klasterska (1984) but weakly positive minus S9 metabolic activation as reported by Ahmed et al. (1977)]. Nonactivated carbaryl induced aneuploidy and sister chromatid exchanges in V79 cells; the addition of S9 or an excess of glutathione eliminated these responses (Onfelt and Klasterska 1983, 1984). In the former study, multiple chromatid exchanges (quadriradials and complex rearrangements) plus chromosome breaks were also induced by 100 mM carbaryl; this effect was largely abolished by the simultaneous addition of S9 or glutathione. There were positive data for DNA damage in a human lymphoblastoid cell line (induction of CYP1A1 genes); carbaryl also activated other stress genes known to be sensitive to oxidative damage (Delescluse et al., 2001). Also, carbaryl caused depolymerization of spindle microtubules and an apparent uncoupling of karyokinesis and cytokinesis in cultured V79 cells (Renglin et al, 1988, 1989). In contrast to the in vitro data, carbaryl administered by oral gavage at 1/ 3 of the LD50 (146 mk/ kg/ day) for 2 consecutive days was negative for micronuclei induction in Swiss albino male mice (Usha Rani et al., 1980). Carbaryl was also negative for the induction of chromosome aberrations in bone marrow cells of Syrian hamsters treated with 1/ 10, 1/ 5 and ½, of the LD50 and the LD50 (Dzwonkowska and Hubner, 1986). 4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: Available neurotoxicity studies are adequate to satisfy the guideline requirements. There was no evidence of delayed neurotoxicity in hens. In the acute neurotoxicity study in rats, the LOAEL was based on plasma, RBC and brain ChEI; a NOAEL could not be established. In the subchronic neurotoxicity study in rats, clinical signs of toxicity were seen at the same dose as plasma, whole blood, RBC and brain ChEI. There was no evidence of structural neuropathology in these studies. In the developmental neurotoxicity study in rats, clinical signs of toxicity and plasma and brain ChEI were seen in maternal animals at the same dose as changes in brain morphometric measurements in offspring. The HED Hazard Identification Assessment Committee (HIARC) determined that this was evidence of qualitative susceptibility. 5 Carpenter, C. P., Weil, C. S., Palm, P. E. et al. Mammalian Toxicity of 1­ napthyl­ N­ methyl carbamate (Sevin Insecticide). J. Agri. Food Chem. 9( 1): 30­ 39, 1961. 28 870.6100 Delayed Neurotoxicity Study ­ Hen In a study by Carpenter et al 5 , Carbaryl was negative for delayed neuropathy at a dose of 2000 mg/ kg, the approximate LD50 in hens. 870.6200 Acute Neurotoxicity Screening Battery In an acute neurotoxicity study (MRID # 43845201­ 43845204), groups of 12 male and 12 female Sprague­ Dawley rats were administered Carbaryl technical grade in 0.5% carboxymethylcellulose / 0.1% Tween 80 at doses of 10, 50, or 125 mg/ kg/ day. Doses were selected on the basis of results from a benchmark toxicity study (MRID # 43845201) and a "time of peak effects" study (MRID # 43845202). In the benchmark study, clinical signs of toxicity and body weight loss were observed at 50 mg/ kg/ and above, and mortality was observed at 500 mg/ kg and above. In the time of peak effects study, peak effect for cholinesterase inhibition and functional observational battery changes was determined to be 0.5 to 1.0 hr post­ dose. Body weight was mildly but significantly decreased in male rats at the 125 mg/ kg dose level, while weight gain was significantly decreased in male and female rats for days 0­ 7 of the study at 125 mg/ kg. Food consumption during week 1 was decreased at the 125 mg/ kg dose by 18­ 20%, in excess of the decrease in body weight gain, supporting a treatment­ related effect at the high dose for week 1 of the study. Several measurements from Functional Observational Battery assessment were significantly altered at the 50 and 125 mg/ kg dose, including an increased incidence of tremors, ataxic gait, decreased body temperature, and decreased arousal. Salivation incidence was increased at the high dose, as was hindlimb splay. Forelimb and hindlimb grip strength were decreased significantly at the high dose. Significant decreases in total motor activity were observed in male and female rats at all dose levels tested. Significant inhibition of plasma, blood, and brain cholinesterase (30­ 40%) was also observed in both sexes at the 10, 30 and 90 mg/ kg doses. Peak inhibition of cholinesterase occurred during the time of FOB and motor activity measurements. Based on the data in this study, the systemic LEL = 10 mg/ kg for male and female rats, based on significant inhibition of red cell, plasma, whole blood, and brain cholinesterase at the 10 mg/ kg dose level. The systemic NOAEL < 10 mg/ kg for male and female rats. Although significant signs of cholinergic toxicity were observed in this study, there was no definitive evidence of a neurotoxic effect for Carbaryl technical grade in this study. This study is classified as acceptable and satisfies the guideline requirement for an acute neurotoxicity study (§ 81­ 8) in rats. 870.6200 Subchronic Neurotoxicity Screening Battery In a subchronic neurotoxicity study (MRID 44122601), 12 Crl: CD( SD) BR rats/ sex/ group were administered technical Carbaryl (99.1%) by gavage at doses of 0, 1, 10 or 30 mg/ kg/ day for 13 weeks. Cholinesterase (RBC, whole blood, plasma and brain) determinations were done on an additional three groups of five rats/ sex/ group at Weeks 4, 8 and 13. Neurobehavioral screening, consisting of Functional Observational Battery (FOB) and motor activity evaluations, was performed prior to treatment and during 29 Weeks 4, 8 and 13. At terminal sacrifice, six animals/ sex/ dose were anesthetized and perfusion fixed in situ for neuropathological evaluation. There were no deaths during the study. There was an increased incidence of clinical signs of toxicity, including slight and moderate salivation and tremors, in the 30 mg/ kg/ day males and females. Body weight over the course of the study was statistically significantly decreased in the 30 mg/ kg/ day males (14%) and females (15%). Body weight gain for these groups was decreased 27% in males and 37% in females, compared to controls. Food consumption was decreased during most of the study for the 30 mg/ kg/ day males and females. Males and females in the 30 mg/ kg/ day group had a statistically significant decrease in RBC (M: 42­ 46%; F: 52­ 55%), whole blood (M: 49­ 51%; F: 59­ 63%) and plasma cholinesterase values (M: 63­ 69%; F: 63­ 69%) at most of the testing periods. Males and females in the 10 mg/ kg/ day group had a statistically significant decrease in RBC (M: 26­ 38%; F: 17­ 24%); whole blood (M: 30­ 41%; F: 21­ 26%) and plasma cholinesterase values (M: 43­ 48%; F: 23­ 30%). There was a statistically significant decrease in brain cholinesterase in males and females in the 10 mg/ kg/ day (M: 27­ 61%; F: 20­ 58%) and 30 mg/ kg/ day (M: 36­ 80%; F: 50­ 73%) groups. For the 1 mg/ kg/ day males, there were statistically significant decreases in whole blood (13%) at week 13 and for plasma (20%) at week 8. These changes are not considered toxicologically significant since they occurred infrequently and were relatively minor effects. Multiple qualitative and quantitative FOB parameters were affected in the 10 and 30 mg/ kg/ day males and females, including the following: slight tremors, gait alterations, pinpoint pupils, increased salivation, reduced extensor thrust, decreased pinna reflex, reduced number of rearings, decreased vocalizations, decreased body temperature and decreased forelimb grip. Reduced number of defecations was observed only at 30 mg/ kg/ day. There was an occasional alteration at the 1 mg/ kg/ day dose. At week 8, males had a very slight increase in the incidence of pinpoint pupils (incidence in control, 1, 10 and 30 mg/ kg/ day groups was 0/ 12, 1/ 12, 6/ 12 and 10/ 12, respectively). A statistically significant decrease in forelimb grip was observed at week 4 in males (values for control, 1, 10 and 30 mg/ kg/ day groups were 1060.8, 943.8, 943.8 and 950.0, respectively). The number of defecations was statistically reduced in females at week 13 (mean number of defecations in control, 1, 10 and 30 mg/ kg/ day groups were 1.4, 0.2, 0.5 and 0.0, respectively). The toxicological significance of these effects in the 1 mg/ kg/ day group is questionable since the incidence was either low or there was no dose­ response relationship. Motor activity was statistically significantly decreased in the 30 mg/ kg/ day males at Week 4 and the 30 mg/ kg/ day females at Weeks 4 and 8. On necropsy, there was an increased incidence of dark areas in the meninges of the 30 mg/ kg/ day males; these animals had an increased incidence of hemorrhage on microscopic examination. One female in the 30 mg/ kg/ day group also had retinal atrophy. There were no differences in brain length or width measurements. The LOAEL for neurotoxicity was 10.0 mg/ kg/ day based on an increased incidence of FOB changes; the NOAEL was 1.0 mg/ kg/ day. The LOAEL for cholinesterase inhibition was 10.0 mg/ kg/ day based on statistically significant decreases in RBC, whole blood, plasma and brain cholinesterase; the NOAEL was 1.0 mg/ kg/ day. 30 The subchronic neurotoxicity study in the rat is classified acceptable/ guideline and does satisfy the guideline requirement for a subchronic neurotoxicity study (OPPTS 870.6200) in the rat. 870.6300 Developmental Neurotoxicity Study In a developmental neurotoxicity study (MRID # 44393701, 44904204, 45456701, 45456702, 45456703), 26 pregnant female Sprague­ Dawley rats/ group were administered carbaryl (99.1% a. i.) by gavage from Gestation Day (GD) 6 through Lactation Day (LD) 10 at doses of either 0, 0.1, 1.0 or 10 mg/ kg/ day. An additional 6 pregnant females/ group were dosed at the same levels for the cholinesterase (ChE) phase of the study. ChE measurements were done pre­ dosing (GD 6) and post­ dosing at time of peak effect (1 hour post­ dosing) on GD 6, 15 and 20 and LD 4 and 10. Functional Observational Battery (FOB) measurements were performed at approximately 0.5 and 2 hours post­ dosing on the same days as body weight measurements during the dosing period (GD 0, 6, 9, 12, 15, 18 and 20 and LD 4, 7, 11, 13 and 21). Measures of reproductive performance were evaluated. Offspring were examined for body weight, physical development landmarks (tooth eruption and eye opening), FOB assessments (days 4, 7, 11, 13, 17 and 21) and motor activity (days 13, 17 and 21). On LD 11, 1 animal/ sex/ litter was sacrificed for brain weights; of these, six/ sex were randomly selected for neuropathological evaluation. The eyes from all dose groups were examined. After LD 21, 3 animals/ sex/ litter were separated from the dams and constituted the F1 adult generation. These animals were evaluated for body weight, physical development (vaginal opening and preputial separation), motor activity (day 60), startle habituation response (days 22 and 60), passive avoidance (day 23) and water maze behavior (day 60). After completion of the behavior test period (at approximately 10 weeks of age), 12 animals/ sex/ group were anesthetized and perfused for post­ mortem examination. Tissues from 6 animals/ sex of the control and high dose group were processed for neuropathological evaluation and morphometric measurements; the eyes from the low and mid­ dose group of all perfused animals were examined. For the F0 generation animals, there were no carbaryl­ associated deaths. No treatment­ related clinical signs of toxicity were observed. There was a statistically significant decrease (92%) in body weight gain for females in the 10 mg/ kg/ day group for the period GD 6­ 9. Unfortunately, food consumption was not measured during the study. During the FOB measurements, the incidence of females in the 10 mg/ kg/ day group with decreased pupil size (pinpoint pupils) was increased on all occasions during the dosing period. An increased incidence of dams with slight tremors affecting the head, body and/ or limbs was noted on the majority of assessment occasions in the dosing period. There were also occasional occurrences of ataxic gait/ overall gait in­ capacity which was considered to be of toxicological significance due to other effects upon gait. For the 10 mg/ kg/ day group, RBC and whole blood ChE levels were statistically significantly decreased (28% and 32­ 34%, respectively) on GD 20 and LD 10. Although the plasma ChE levels were not statistically significantly altered, the percentage decreases on GD 20, LD 4 and LD 10 were 32­ 39%. Brain ChE levels were statistically significantly decreased (42%). There were no treatment­ related effects on gross necropsy findings for the F0 generation animals. 31 There were no effects observed on maternal performance parameters of pregnancy rate, gestation index, length of gestation, numbers of live pups, dead or malformed pups, implantation scars, sex ratio or postimplantation loss. There was a slight (P> 0.05) increase in the number of dead pups in the 10 mg/ kg/ day group, however the value was within the historical control range for this strain. For the F1 generation pups, there were no treatment­ related effects on pup weight, pup survival indices, developmental landmarks (tooth eruption and eye opening), FOB measurements or motor activity assessments. At sacrifice on LD 11, there were no treatment­ related effects on brain weight and gross or microscopic pathology. Significant differences noted in the morphometric measurements included an increase in Line B of the right forebrain and Line F of the left cerebellum in the 10 mg/ kg/ day males. In the 10 mg/ kg/ day females, Line F through both the right and left cerebellum were significantly decreased (15% and 22%, respectively). For the F1 generation adults, there were no treatment­ related effects on clinical condition, body weight, physical development (vaginal opening and preputial separation), motor activity, auditory startle response, passive avoidance and water maze measurements. At sacrifice, there were no gross or microscopic neuropathological lesions observed for animals examined in this study that were attributable to treatment with the test article. There was an increased incidence of retinal fold/ rosette in the 10 mg/ kg/ day group (1/ 12 for control vs. 4/ 12 for males; 0/ 12 for control vs. 2/ 12 for females). The finding was not considered of toxicological significance since the incidence was within the historical control range for males, occurred at a low rate and was not dose­ dependent. For the morphometric measurements, there was a significant bilateral decrease in Line A through the forebrain (7.7­ 9.8%) and a significant increase in Line F through the right cerebellum of the 10 mg/ kg/ day males. Increases originally noted in 10 mg/ kg adult females in Line G, width of the cerebellum, were found to be based on erroneous measurements, and additional measures were submitted. Now, for the 10 mg/ kg/ day females, there were significant bilateral increases in Line F through the cerebellum (7.4­ 15%). Measurements of the size of the thickness of lobes and of the granule cell layers of the cerebellum in high dose pups and adults did not differ from those of controls. While additional statistical analyses by the registrant indicated no treatment related effects, HED's additional statisical analyses did indicate treatment related effects. The maternal toxicity LOAEL was 10 mg/ kg/ day based on decreased body weight gain, alterations in FOB measurements and RBC, plasma, whole blood and brain cholinesterase inhibition. The maternal NOAEL was 1.0 mg/ kg/ day. The developmental neurotoxicity LOAEL was 10 mg/ kg/ day based on a bilateral decrease in the size of the forebrain (Line A) in adult males (7.7­ 9.8%); a bilateral decrease in the length of the cerebella (Line F) in female pups (15­ 22%); and a bilateral increase in the length of the cerebella (Line F) in female adults (7.4­ 15%). The developmental NOAEL was 1 mg/ kg/ day. Morphometric assessment at the mid and low doses could not be conducted due to inadequate tissue storage; however, based on the minimal findings at the LOAEL, it is HED's judgment that effects would be unlikely to occur at 1 mg/ kg/ day, which is 10% of the LOAEL. 32 4.9 Metabolism Adequacy of data base for metabolism: Available metabolism data are adequate to satisfy the guideline requirements and have delineated the metabolic pathway in the rat. Carbaryl was broken down into over 20 metabolites. The major route of elimination was via the urine. No significant tissue accumulation was reported. Additional special studies have been conducted to determine if there are alterations in metabolism at high doses. 870.7485 Metabolism ­ Rat In a rat metabolism study (MRID # 43332101), 14 C­ Carbaryl was administered orally in carboxymethylcellulose or intravenously in sodium phosphate buffer (pH 6.8) to groups (5 sex/ dose) of male and female Sprague­ Dawley rats at nominal doses of 1 mg/ kg (single and repeated low oral doses; intravenous dose) and 50 mg/ kg (single high oral dose). Absorption was essentially complete for all dose groups of male and female rats. At 168 hours post­ dose, there were negligible percentages of the dose found in any tissue examined. On a µg/ g tissue basis, kidney and blood were found to contain the highest concentrations of residual radioactivity, with female rats showing slightly higher values than males. Excretion of carbaryl derived radioactivity was largely through urine, where 88­ 95% of the dose was recovered for all dose groups. There were no significant dose­ or sex­ related differences in excretion. Conjugated metabolites of carbaryl identified in this study included the glucuronic acid conjugate of dihydro­ dihydroxy carbaryl (2.2% of the dose), the S( N­ acetylcysteine) conjugate of dihydro­ hydroxy carbaryl (3.7% of the dose), naphthyl glucuronide (2.0% of the dose), and naphthyl sulfate (6.4% of the dose). Non­ conjugated metabolites identified were 1­ naphthol, 5­ hydroxycarbaryl, 5,6­ dihydro­ 5,6­ dihydroxycarbaryl, 4­ hydroxycarbaryl, and N­( hydroxymethyl)­ hydroxycarbaryl. These accounted for 14.5%, 12.8%, 8.2%, 6.3%, and 5.7% of the administered dose, respectively. Three new metabolites were identified in this study which were the N­( hydroxymethyl)­ hydroxycarbaryl metabolite, hydroxy­ desmethylcarbaryl (0.5% of the dose), and the S­( N­ acetylcysteinyl)­ dihydro­ dihydroxycarbaryl conjugate. Based on these data, a metabolic scheme for carbaryl was proposed. This study is classified as acceptable/ guideline and satisfies the data requirements for a metabolism study in rats under Subdivision F guideline §85­ 1. Metabolism ­ Special Study In a rat metabolism study (MRID No. 44402501), 1­ naphthyl­ 14 C­ labeled carbaryl (ca 100% a. i.) was administered to 15 month old male Iffa Credo CD (Sprague­ Dawley derived) rats (5 animals/ group) as a single oral gavage dose of 50 mg/ kg (group A) or as a daily oral dose of 2 mg/ kg for 7 days following a 83­ day dietary administration with non­ radioactive carbaryl (25 animals/ group) at 0 (group B), 250 (group C), 1500 (group E), or 7500 ppm (group D). This study was designed to "investigate the mechanisms that caused the appearance of an increased incidence of tumors during the final year of a chronic dietary feeding study in the rat at the high dose level of 7500 ppm." In all dietary dosing regimens, urinary and fecal excretion totaled 96­ 103% of the administered dose. Most of the radioactivity was eliminated in the urine and feces within 24 hours after dosing. In the 33 group A, 86% and 11% of the test compound administered was excreted in the urine and feces, respectively, over a 7­ day period after a single dose via gavage of radiolabeled carbaryl at 50 mg/ kg. In the groups B­ E (0, 250, 1500, and 7500 ppm), 3 days after the 7th consecutive administration of radiolabeled carbaryl, 79­ 89% and 7­ 10% of the total administered dose (sum of the 7 daily doses) were excreted in the urine and feces, respectively. Tissue distribution study showed that the levels of radioactivity in the tissues of the animals from group A were 0.4% of the administered dose at sacrifice (168 hours after dosing). In groups B­ E, the levels of radioactivity in the tissues ranged from 0.4­ 0.8% of the administered dose 3 days after the 7th dose of radiolabeled carbaryl at 2 mg/ kg. This indicates that the potential for bioaccumulation of carbaryl in rats is minimal. HPLC analysis of carbaryl metabolites in 24­ hour urine samples showed a total of 23 components. Four components identified by LC/ MS technique were as follows: UMET/ 8 (trans­ 5,6­ dihydro­ 5,6­ dihydroxy­ 1­ naphthyl N­ methylcarbamate) (accounted for 3.75­ 6.38% of the dose); UMET/ 11 (glucuronide of dihydro­ dihydroxy­ 1­ naphthyl N­ methylcarbamate) (18.55%­ 28.46% of the dose); UMET/ 18 ( ­naphthyl $ ­D­ glucuronide sodium salt or " ­naphthyl sulfate potassium salt (15.69­ 21.75 % of the dose); and UMET/ 23 (naphthyl sulfate) (17.78%­ 30.01% of the dose). A total of 20 components was detected in the 24­ hour feces by HPLC analysis. One component (FMET/ 15) was identified as parent and accounted for 0.2­ 1.4% of the administered dose by LC/ MS technique. The remaining 19 components were not identified because the levels of radioactivity in these components were too low. There were 2 major metabolites in the tissues from groups B­ E at 6 hours after administration of 14 Ccarbaryl These metabolites were confirmed by LC/ MS analysis as naphthyl sulfate (found in plasma, kidney, and urinary bladder) and naphthyl glucuronide (found in the kidney and urinary bladder). Quantitative identification for these metabolites was not available because the levels of radioactivity in these tissues were too low. The sulfate conjugation pathway appears to be saturable following a subchronic (83­ day) feeding of carbaryl at a high dose (group D, 7500 ppm). This saturation of the sulfate conjugation pathway is seen in the urinary levels of UMET/ 23 (naphthyl sulfate) between the dose groups following the 83­ day dietary administration of non­ radioactive carbaryl. The level of radioactivity associated with UMET/ 23 (naphthyl sulfate) was higher (23­ 27% of the dose) in 0, 250, and 1500 ppm dose groups and lower (12% of the dose) in the 7500 ppm group. On the other hand, the level of radioactivity associated with UMET/ 11 (naphthyl glucuronide) was lower (15­ 21% of the administered dose) in 0, 250, and 1500 ppm dose groups and higher (28%) in the group 7500 ppm group. Statistically significant decreases (p< 0.05 or p< 0.01) in body weight (9­ 20%) when compared to the control group were observed only in the 7500 ppm group as early as study day 14 and sustained throughout the remainder of the study. In the 7500 ppm group, the statistically significant decreases (p< 0.05 or p< 0.01) in food consumption were observed at week 1 (74%), week 2 (61%), week 3 (40%), and weeks 4­ 11 (19­ 31%). In the 1500 ppm group, the statistically significant decreases (p< 0.05) in food consumption were observed at week 5 (8%), week 10 (21%), and week 11 (12%). 34 Significant increases (statistical analyses were not performed) in kidney, spleen, and thyroid weights were observed in the 1500 or 7500 ppm groups when compared to the control group. Absolute and relative liver weights increased 18% and 39%, respectively, at 7500 ppm. Absolute spleen weight increased 30% at 7500 ppm and relative spleen weight increased 24% and 30% at 7500 and 1500 ppm, respectively. Absolute thyroid weight increased 63% and 69% at 7500 and 1500 ppm, respectively, and relative thyroid weight increased 103% and 121% at 7500 and 1500 ppm, respectively. Statistically significant increases (p< 0.01) in total glutathione concentrations (higher by 79% per g of liver or 102% per g of protein) were observed at 7500 ppm only, compared to the controls. The incidences of hepatocellular adenoma (benign) were 1/ 5, 0/ 5, 0/ 5, and 2/ 5 at 0, 250, 1500, and 7500 ppm, respectively. Although the authors concluded that "there was no treatment­ related change in the incidence of tumors under carbaryl treatment," definite conclusion cannot be made from this finding based on the limited number of animals used. Significant treatment­ related changes were noted in liver, thyroid glands, and kidneys at 7500 ppm only. The incidences of centrilobular hypertrophy of the hepatocytes, pericholangitis (an inflammatory cell infiltrate around biliary ducts), and bile duct hyperplasia were 5/ 5, 3/ 5, and 3/ 5, respectively. The incidences of follicular cell hypertrophy of the thyroid glands were 0/ 5, 3/ 5, 5/ 5, and 5/ 5 and the incidences of transitional cell hyperplasia of the renal pelvis were 0/ 5, 0/ 5, 1/ 5 and 2/ 5 at 0, 250, 1500, and 7500 ppm, respectively. This metabolism study in the rat is classified acceptable for its intended purpose of investigating "the mechanisms that caused the appearance of an increased incidence of tumors during the final year of a chronic dietary feeding study in the rat at the high dose level of 7500 ppm." Although the study supplies some information to the Agency, this study does not satisfy the guideline requirement for a metabolism study (85­ 1) in rats. Metabolism ­ Special Study The present investigation (MRID # 43832601) was conducted to identify and phenotype the potential for Carbaryl to induce hepatic cytochrome P­ 450 in male CD­ 1 mice following dietary administration of 8000 ppm Carbaryl in the diet. The data in this study represent results from mice used in a previous study (MRID # 432822­ 01) whose livers had been stored for biochemical analyses. These mice had received pre­ treatment with 8000 ppm (1143 mg/ kg/ day) Carbaryl for 14 days. The results of biochemical analyses in the liver can be summarized as follows: Carbaryl pre­ treatment produced significant increases in microsomal protein (132% of control), cytochrome P­ 450 (134% of control), ethoxyresorufin O­ deethylase activity (190% of control), pentoxyresorufin O­ depentylase activity (313% of control), and increases in specific testosterone hydroxylase activities (6­ alpha, 2ß­, 11ß,­ and 16ß­ hydroxylase activities). Taken together, these data appear to indicate a `phenobarbital­ type' of induction of liver xenobiotic­ metabolizing enzymes as a result of Carbaryl pre­ treatment at a high oral dose (1154 mg/ kg/ day). The similarity of the pattern of induction of liver xenobiotic­ metabolizing enzymes by Carbaryl and phenobarbital is supported in part by literature data (Kelley et al., Biochem. Pharmacol. 15;( 39) 12: 1991­ 1998). While this study provides useful information on the general type of induction observed after pretreatment with a high oral dose of Carbaryl, the actual relationship of induction to 35 Carbaryl toxicity was not addressed, as no metabolites of Carbaryl after this type of exposure were investigated. This study is classified as acceptable (non­ guideline) and demonstrates the inductive effect of repeated high dose exposure to Carbaryl by the oral route. Metabolism ­ Special Study In a special study (MRID # 43282201), [1­ 14 C]­ naphthyl­ N­ methylcarbamate (14­ C carbaryl) was tested for the ability to bind to liver DNA in male CD1 mice treated with a single radiolabelled dose of carbaryl (75 mg/ kg) or in mice pretreated with 8000 ppm (approximately 1143 mg/ kg/ day) unlabelled carbaryl in the diet for two weeks followed by a single 75 mg/ kg radiolabelled dose. Binding of radiolabel to chromatin protein isolated from the livers of mice treated with a single dose or in pretreated mice was similar (specific activities ranging from 340.3­ 537.0 dpm/ mg). No radioactivity was detectable in DNA samples isolated from mice treated with radiolabelled carbaryl (Covalent Binding Index < 0.1). According to the report, this maximum binding ability of carbaryl is more than 5 orders of magnitude below the Covalent Binding Index of aflatoxin B1, and more than 4000 times lower than the Covalent Binding Index for 2­ acetylaminofluorene. This study demonstrated the interaction of carbaryl with chromatin protein, but no significant interaction with DNA in the liver of male CD1 mice treated with either a single 75 mg/ kg dose or in mice pretreated with 8000 ppm (1143 mg/ kg/ day) carbaryl in the diet followed by a single 75 mg/ kg radiolabelled dose. This study was not conducted to satisfy a specific guideline requirement, but fulfills the purpose for which it was conducted. 870.7600 Dermal Absorption ­ Rat Two dermal absorption studies in rats were conducted. In the study with a formulation containing 43.9% carbaryl (MRID 43552901), animals were exposed for 0.5, 1, 2, 4, 10 or 24 hours at doses of 35.6, 403 or 3450 µg/ cm 2 . Percent absorbed ranged from 2.14 to 24.9, 1.01 to 24.7 and 0.07 to 3.17 for the 35.6, 403 or 3450 µg/ cm 2 doses, respectively (see Section 5.2 below). The HIARC determined that a 12.7% absorption (relative to an oral dose) should be used for risk assessment. This rate was based on the highest absorption rate at 10 hours, which is considered the duration of possible occupational exposure during a work day. 36 5.0 TOXICITY ENDPOINT SELECTION 5.1 See Section 9.2 for Endpoint Selection Table (page 51). 5.2 Dermal Absorption Dermal Absorption Factor: 12.7 % from MRID 43552901 (findings discussed above) The dermal absorption factor is required for long­ term dermal and inhalation risk assessments since oral doses were selected for these exposure periods. In a dermal absorption study (MRID # 43552901), radiolabeled 14 C­ Carbaryl LXR Plus (43.9% a. i.) was applied to the skin of three groups of four male rats/ group at doses of 35.6, 403 or 3450 µg/ cm 2 for 0.5, 1, 2, 4, 10 or 24 hours. The ranges for percent of carbaryl absorbed for the 35.6, 403 and 3450 µg/ cm 2 groups were 2.14­ 24.9, 1.01­ 24.7 and 0.07­ 3.17, respectively; the percent absorbed at 10 hours was 12.7, 7.44 and 1.93, respectively. This study is classified as Acceptable (guideline) and satisfies the guidelines for a dermal absorption study. In a dermal absorption study (MRID # 43339701), radiolabeled 14 C­ Carbaryl Sevin (80.1% a. i.) was applied to the skin of three groups of four male rats/ group at doses of 63, 626 or 3410 µg/ cm 2 for 0.5, 1, 2, 4, 10 or 24 hours. The ranges for percent of carbaryl absorbed for the 63, 626 and 3410 µg/ cm 2 doses were 0.66­ 16.6, <0.01­ 1.27 and 0.07­ 1.2, respectively; the percent absorbed at 10 hours was 8.90, 0.62 and 0.48, respectively. This study is classified as Acceptable (guideline) and satisfies the guidelines for a dermal absorption study. 5.3 Classification of Carcinogenic Potential 5.3.1 The CARC concluded that carbaryl was carcinogenic to male mice at doses which were adequate and not excessive. Tumors in male and female rats and female mice, as well as other tumors in male mice, occurred at excessively toxic high dose levels. However, preneoplastic lesions in the target organs in male rats occurred at the mid dose level which was below the dose adequate for testing the carcinogenic potential of carbaryl. The findings of the rat combined chronic toxicity/ carcinogenicity study are discussed below. 1. The reanalyses of rat tumor data showed that male rats had significant increasing trends and significant differences in pair­ wise comparisons of the 7500 ppm dose group with the controls for thyroid follicular cell adenomas and combined adenomas/ carcinomas, as well as for urinary bladder transitional cell papillomas, carcinomas, and combined papillomas/ carcinomas, all at p< 0.01. The increase in the incidence of combined thyroid follicular cell adenomas/ carcinomas at 37 7500 ppm was driven by the adenomas. At 7500 ppm, the incidences of thyroid follicular cell adenomas, as well as combined urinary transitional cell papillomas and carcinomas, exceeded their respective range for the historical controls. The female rats had a significant increasing trend (p< 0.01) and a significant increase by pair wise comparison of the 7500 ppm dose group with the controls for hepatocellular adenomas (p< 0.05). The re­ read of tumor data by the Pathology Working Group (PWG) showed that the female rats had a significant increasing trend for urinary bladder transitional cell papillomas, carcinomas and combined papillomas/ carcinomas, all at p< 0.01. There were significant differences in the pair­ wise comparisons of the 7500 ppm dose group with the controls for urinary bladder transitional cell papillomas (p< 0.05), carcinomas (p< 0.05), and combined carcinomas/ papillomas (p< 0.01). The incidences of hepatocellular adenomas, urinary bladder transitional cell papillomas and urinary transitional cell carcinomas exceeded the respective ranges for the historical controls. The CARC noted that at the week 53 necropsy, transitional epithelial hyperplasia, a preneoplastic stage, was observed in the urinary bladder of mid dose tested (MDT) males and highest dose tested (HDT) males and females. After the 4­ week recovery period, this change was still present in HDT males and females. At the terminal necropsy, the transitional cell hyperplasia was observed in HDT males and females, along with an increased incidence of squamous cell metaplasia, high mitotic index and atypia. The HDT was judged to be excessive based on a significant (p< 0.5) decrease in body weight gains during week 13 for males and females by 40% and 52%, respectively, as compared to controls. Decreased food efficiency and alterations in hematology and clinical chemistry values were also reported in both sexes at the high dose level. By weeks 52­ 53, plasma, RBC and brain cholinesterase (ChE) activities were significantly (p< 0.05) decreased in males by 40%, 22% and 28%, respectively, and in females by 56%, 36% and 37%, respectively, as compared to controls. By week 104, plasma, RBC and brain ChE activities were significantly decreased in males by 42%, 30% and 9%, respectively, and in females by 46%, 38% and 22%, respectively. The MDT was judged to be below the adequate dose for testing the carcinogenic potential of carbaryl. At this dose, there was no effect on body weight/ body weight gain and only minor ChE inhibition (less than 20% inhibition of plasma, RBC and brain ChE in males and females at week 53, except for 26% inhibition of RBC in females; at week 105, only female RBC and brain ChE were decreased (22% and 16%, respectively). The CARC noted that the MDT male rats had transitional cell hyperplasia of the bladder, a preneoplastic lesion, at the week 53 necropsy. If the dose had been adequate, bladder tumors seen at the HDT may have occurred at the MDT. 2. The reanalyses of mouse tumor data showed that male mice had significant increasing trends in kidney tubule cell adenomas (p< 0.05), carcinomas (p< 0.05) and combined adenomas/ carcinomas (p< 0.01). In mice, hemangiomas in the liver and spleen can progress to hemangiosarcomas. Therefore, the incidence of hemangiomas and hemangiosarcomas at various sites was combined and analyzed. There were significant differences (p< 0.05) in the pair­ wise comparison of the $ 100 ppm (all doses tested) with the controls for hemangiosarcomas and in combined hemangiomas/ hemangiosarcomas at 1000 and 8000 ppm. In addition, a significant difference in the pair­ wise comparison of the 8000 ppm dose group with controls was noted for combined kidney tubule cell adenomas/ carcinomas (p< 0.05). 38 The female mice had significant increasing trend in hepatocellular adenomas (p< 0.01), combined hepatocellular adenomas/ carcinomas (p< 0.01), hemangiosarcomas (p< 0.01), and combined hemangiomas/ hemangiosarcomas (p< 0.05). There were also significant differences in the pairwise comparison of the 8000 ppm dose group with the controls for hepatocellular adenomas (p< 0.05), combined hepatocellular adenomas/ carcinomas/ hepatoblastomas (p< 0.01), and hemangiosarcomas (p< 0.05). Appropriate historical control data for various types of tumors were not available for comparison. However, based on recently submitted historical control data on vascular tumors in the liver and spleen (sites for most hemangiomas/ hemangiosarcomas), the incidence of hemangiosarcomas exceeded the range for the historical controls in both male and female mice. The CARC considered the dosing at the HDT in male and female mice to be excessive because the decrease in body weight gain, clinical signs and ChE inhibition, and histopathological changes in various organs were indicative of excessive toxicity. The CARC concluded that the malignant vascular tumors (hemangiosarcomas) in male mice occurred at doses which were adequate and not excessive. In females these tumors occurred only at the highest dose which was excessively toxic. Nevertheless, the findings in female mice were supportive of vascular tumors in male mice. Carbaryl produces epoxides and its genotoxicity is manifested as chromosomal aberrations in cultured mammalian cells while older in vivo studies indicate negative results for aberrations. More recent studies with cultured cells have demonstrated effects on microtubule assembly, karyokinesis and cytokinesis as well as stress genes associated with oxidative damage. 5.3.2 Classification of Carcinogenic Potential In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC classified carbaryl into the category "Likely to be carcinogenic to humans" based on the following weight­ of­ the­ evidence considerations: 1. Carbaryl induced a statistically significant increase in urinary bladder tumors in male and female rats, thyroid tumors in male rats and liver tumors in female rats. These tumors were induced at an excessively toxic dose (7500 ppm) and, therefore, were not relevant for human cancer risk assessment. However, there was evidence of preneoplastic lesions in the bladder in males at 1500 ppm, a dose which was below the adequate dose for testing the carcinogenic potential of carbaryl. In mice, a treatment­ related increase in malignant vascular tumors (hemangiosarcomas) was noted in males at all doses, both excessive and adequate, whereas in females, this same tumor type was seen only at excessive doses. 2. Carbaryl is clastogenic in in vitro studies with effects on aberrations; aneuploidy­ associated events are also observed and further, a single report from the published literature suggests that carbaryl may induce oxidative stress. These types of effects may contribute to carbaryl­ induced tumors. Nevertheless, carbaryl is negative for micronucleus induction in one mouse strain, not clastogenic in Syrian hamsters, and negative in a p53 knockout transgenic mouse bioassay. 39 5.3.3 Quantification of Carcinogenic Potential The Committee recommended a low­ dose linear extrapolation approach using all dose levels for the quantification of human cancer risk based on the most potent vascular tumors in mice. This approach was supported by the lack of confirmation of a mode of action. The Q1*, based on the CD­ 1 mouse dietary study with ¾ Interspecies Scaling Factor, is 8.75 x 10 ­4 (mg/ kg/ day) ­1 in human equivalents. 6.0 FQPA CONSIDERATIONS 6.1 Degree of Concern Analysis and Residual Uncertainties The HIARC concluded that there is no residual concern in the two­ generation reproduction study because the dose­ response effects in pups are well­ characterized and the NOAEL for the offspring effects is above that was used for establishing the chronic Reference Dose (RfD) for chronic dietary risk assessment. The HIARC selected the LOAEL of 3.1 mg/ kg/ day established in the chronic toxicity study in dogs for establishing the chronic RfD. Since a LOAEL was used, an additional uncertainty factor of 3X was applied (i. e, lack of a NOAEL) to the LOAEL. Although a NOAEL was not established in this study, the HIARC determined that a 3X was adequate (as opposed to a higher value) because: 1) cholinesterase inhibition in females was not accompanied by clinical signs; 2) no inhibition was seen for any cholinesterase compartment in males at this dose; 3) the magnitude of inhibition of plasma cholinesterase inhibition (12­ 23% decrease) was comparable to the magnitude of inhibition (22%) seen in the 5­ week study in dogs indicating no cumulative effects following long­ term exposure; 4) the study was wellconducted and there are sufficient data from subchronic and chronic duration studies in the other species which support cholinesterase inhibition as the critical effect. In addition, based on the cholinesterase inhibition data, the dog appears to be more sensitive than the rat in long­ term studies. Furthermore, use of the LOAEL of 3 mg/ kg/ day from the 1­ year dog study with an uncertainty factor of 300 results in a NOAEL of 1 mg/ kg/ day. This extrapolated NOAEL is identical to that of the offspring NOAEL of 1.0 mg/ kg/ day established in the the developmental neurotoxicity study. Thus, the NOAEL of 1 mg/ kg/ day used for establishing the chronic RfD is below the NOAEL of 5 mg/ kg/ day for offspring toxicity and the chronic RfD would be protective of the effects of concern for infants and children following chronic dietary exposures. With regard to the developmental neurotoxicity study, the HIARC concluded that there was a low level of concern based on the following residual uncertainties ° The first uncertainty was the lack of a demonstrated effect level since morphometric measurements of brains in the offsprings were not performed at the mid­ dose (1 mg/ kg/ day). However, this concern was negated since even at the high dose of 10 mg/ kg/ day, the morphometric changes were minimal and therefore, it is unlikely that adverse effects would be seen at 1 mg/ kg/ day, which is 10% of the LOAEL. 40 ° The second uncertainty was the lack of comparative data in adults and offspring for cholinesterase inhibition. This concern was negated since no FOB alterations were seen in pups. Other studies in the data base have shown that when FOB alterations were seen in adult animals, they are usually accompanied with cholinesterase inhibition. Also, the results of the National Institute for Environmental Health Sciences study (discussed below) showed no difference in cholinesterase inhibition in pups and adults. There was a doserelated decrease in cholinesterase activity in the brain and blood of dams at gestation day 19 and fetuses taken at this time also showed a very similar level in fetal brain cholinesterase. The HIARC concluded, that the NOAEL of 1 mg/ kg/ day selected for establishing the acute RfD would address the low level of concern for the residual concerns and would be protective of the effects of concern for infants and children following a single oral exposure. 6.2 Hazard Based­ Special FQPA Safety Factor Recommendation The HIARC concluded that the hazard based special FQPA safety factor should be reduced to 1x based on the following reasons: 1. The toxicology database is complete 2. There was no quantitative or qualitative evidence of increased susceptibility in rat or rabbit fetuses following in utero exposures 3. There was evidence of qualitative susceptibility and a low level of concern due to some residual uncertainties in the developmental neurotoxicity study. However, as discussed in Section I. 3, the acute RfD would address these residual uncertainties and would be protective of the pre­ pre/ post natal toxicity following an acute dietary exposure. 4. There was evidence of increased susceptibility in the offsprings in the two generation reproduction study, but there was no residual uncertainties. The chronic RfD would be protective of the pre­ pre/ post natal toxicity following chronic dietary exposures. 5. The dose selected for residential exposures, would be protective of the pre­ pre/ post natal toxicity following non­ dietary exposures. 41 7.0 REFERENCES in MRID order MRID 00148500. Acute Oral Toxicity ­ Rat. Cosmopolitan Safety Evaluation, Inc. Study Number 1290A, July 17, 1985. Unpublished MRID 00148501. Acute Dermal Toxicity ­ Rabbit. Cosmopolitan Safety Evaluation, Inc. Study Number 1290B, June 8, 1985. Unpublished MRID 00148502. Acute Inhalation ­ Rats. Cosmopolitan Safety Evaluation, Inc. Study Number 1290C, August 3, 1985. Unpublished MRID 00148503. Primary Eye Irritation ­ Rabbit. Cosmopolitan Safety Evaluation, Inc., Study Number 1290D, May 3, 1985. Unpublished. MRID 00148504. Primary Dermal Irritation ­ Rabbit. Cosmopolitan Safety Evaluation, Inc., Study Number 1290E, May 11, 1985. Unpublished. MRID 00148505. Sensitization Study ­ Guinea Pig. Cosmopolitan Safety Evaluation, Inc., Study Number 1290F, June 9, 1985. Unpublished. MRID No. 40166701. Hamada, N. (1987) One­ Year Oral Toxicity Study in Beagle Dogs. Hazleton Laboratories. HLA 400­ 715, March 18, 1987. Unpublished. MRID 41370301. Cifone, M. (1989) Mutagenicity Test on Carbaryl Technical in the in vitro Rat Primary Hepatocyte Unscheduled DNA Synthesis Assay. Hazleton Laboratories America, Inc., Kensington, MD. Study Number 10862­ 0­ 447, November 22, 1989. Unpublished. MRIDs 41370302 and 41420201. Young, R. (1989) Mammalian Cells in Culture Gene Mutation Assay in Chinese Hamster Ovary (CHO) Cells. Hazleton Laboratories America, Inc., Kensington, MD. Study Number 10862­ 0­ 435, November 6, 1989. Unpublished. MRID 41370303. Lawlor, T. (1989) Mutagenicity Test on Carbaryl (Technical) in the Ames Salmonella/ Microsome Reverse Mutation Assay. Hazleton Laboratories America, Inc., Kensington, MD. Study Number 10862­ 0­ 401, September 6, 1989. Unpublished. MRID 41370304. Murli, H. (1989) Mutatgenicity Test on Carbaryl Technical in an in vitro Cytogenetic Assay Measuring Chromosomal Aberration Frequencies in Chinese Hamster Ovary (CHO) Cells. Hazleton Laboratories America, Inc., Kensington, MD. Study Number 10862­ 0­ 437, August 31, 1989. Unpublished. MRID No. 42022801. Hamada, N. (1991) Subchronic Toxicity Study in Dogs with Carbaryl Technical. Hazleton Laboratories. HLA 656­ 152, March 28, 1991. Unpublished. MRID No. 42786901. Hamada, N. (1993) Oncogenicity Study with Carbaryl Technical in CD­ 1® 42 Mice. Hazleton Washington, Inc., Vienna, VA. HWA 656­ 138., May 20, 1993. Unpublished. MRID No. 42918801. Hamada, N. (1993) Combined Chronic Toxicity and Oncogenicity Study with Carbaryl Technical in Sprague­ Dawley Rats. Hazleton Washington, Inc., Vienna, VA. HWA 656­ 139, September 7, 1993. Unpublished. MRID 43282201. Sagelsdorff, P. (1994) Investigation of the Potential for Protein­ and DNA­ Binding of Carbaryl. CIBA­ GEIGY Limited, Toxicology Services/ Cell Biology, Basel, Switzerland. Study Number CB93/ 52, April 28, 1994. Unpublished. MRID 43332101. Struble, C. (1994) Metabolism of 14­ C Carbaryl in Rats (Preliminary and Definitive Phases). Hazleton Wisconsin, Inc. Study Number EC­ 92­ 222, August 5, 1994. Unpublished. MRID 43339701. Cheng, T (1994) Dermal Absorption of (carbon 14)­ Carbaryl (80S) in Male Rats (Preliminary and Definitive Phases). Hazleton Wisconsin, Final Report: Lab Project Number: HWI 6224­ 207. Unpublished. MRID 43552901. Cheng, T (1995) Dermal Absorption of (carbon 14)­ Carbaryl (XLR Plus) in Male Rats (Preliminary and Definitive Phases). Hazleton Wisconsin, Final Report: Lab Project Number: HWI 6224­ 206. Unpublished MRID 43832601. Thomas, H. (1994) Carbaryl: Liver Cytochrome P­ 450 Inducer Phenotype in the Male CD­ 1 Mouse. Ciba­ Geigy Limited, Toxicology Services, Basel, Switzerland. Laboratory Project Number: CB 94/ 23, October 21, 1994. Unpublished. MRIDs 43845201 and 43845202. Brooks, W. et al (1995) An Acute Benchmark Dose Toxicity Study of Orally Administered Carbaryl, Technical Grade, in Rats. Bio­ Research Laboratories, Ltd., Quebec, Canada. Study Number 97387, Unpublished. MRID 43845203. Brooks, W. et al (1995) An Acute Study of the Time Course of Cholinesterase Inhibition by Orally Administered Carbaryl, Technical Grade. Bio­ Research Laboratories, Ltd., Quebec, Canada. Unpublished. MRID 43845204. Brooks, W. et al (1995) An Acute Study of the Potential Effects of a Single Orally Administered Dose of Carbaryl, Technical Grade, on Behavior and Neuromorphology in Rats. BioResearch Laboratories, Ltd., Quebec, Canada. Study 97389. Unpublished. MRID 44069301. Marshall, R. (1996). Carbaryl: Induction of Micronuclei in the Bone Marrow of Treated Mice. Corning Hazelton (Europe), Harrogate, North Yorkshire, England. Study No. 198/ 89/ 1052, March 13, 1996. Unpublished. MRID 44122601. Robinson, K and B. Broxup (1996) A 13 Week Study of the Potential Effects of Orally Administered Carbaryl, Technical Grade, on Behavior, Neurochemistry and Neuromorphology in Rats. Bio­ Research Laboratories Ltd., Senneville, Quebec. Laboratory Project I. D. 97390, September 24, 1996. 43 Unpublished MRID 44393701. Robinson, K. and B. Broxup (1997) A Developmental Neurotoxicity Study of Orally Administered Carbaryl, Technical Grade, in the Rat. ClinTrials BioResearch, Ltd. Quebec, Canada. Laboratory Project I. D. 97391, September 23, 1997. Unpublished MRID No. 44402501. Totis, M. (1997) Investigation of the Metabolism of 14 C­ Carbaryl in the 15­ Month­ Old Male Rat Following Chronic Dietary Administration. Final Report. Rhone­ Poulenc Agrochimie, Centre de Recherche, 355 rue Dostoievski, BP. 153, F­ 06903 Sophia Antipolis, France. Study No. 95288. Oct. 3, 1997. Unpublished MRID 44732901. Repetto­ Larsay, M. (1998) Carbaryl Developmental Toxicity Study in the Rat by Gavage. Rhône­ Poulenc Agro Centre de Recherche, Sophia Antipolis, France. Study SA 98070, October 21, 1998. Unpublished MRID 44904202. Tyl, RW; Marr, MC; Myers, CB. (1999) Developmental Toxicity Evaluation (with Cholinesterse Assessment) of Carbaryl Administered by Gavage to New Zealand White Rabbits. Reproductive & Developmental Toxicology Laboratory, Center for Life Sciences and Toxicology, Research Triangle Park, NC. RTI Identification No. 65C­ 7297­ 200/ 100, June 3, 1999. Unpublished. MRID 44904204. Robinson, K. and Broxup, B. (1999) A Developmental Neurotoxicity Study of Orally Administered Carbaryl, Technical Grade, in the Rat. ClinTrials BioResearch Ltd., Senneville, Quebec, Canada. Laboratory Project I. D. 97391, June 1, 1999. Unpublished. MRID 45281801. Chu zel F (1999). Carbaryl 6­ Month Carcinogenicity Study in p53 Knockout Mice by Dietary Administration. Rhône­ Poulenc Agro Centre de Recherche, Sophia Antipolis Cedex, France. Study Number SA98155, July 8, 1999. Unpublished. MRID 45281802. Bigot D (1999). Validation on Transgenic Mice ­ p53 Knockout Mice ­ to Predict Rodent Carcinogenicity. Rhône­ Poulenc Agro Centre de Recherche, Sophia Antipolis Cedex, France. Study Number SA97040, November 10, 1999. Published with the following citation: Carmichael NG, Debruyne EL, Bigot­ Lasserre D (2000). The p53 heterozygous knockout mouse as a model for chemical carcinogenesis in vascular tissue. Environ Health Perspect 108( 1): 61­ 5. MRID 45236603. Dan ge M (1998). Carbaryl, Prelimina ry 28­ Day Toxicity Study in the Male TSG p53 Wild Type Mouse by Dietary Administration. Rhône­ Poulenc Agro Centre de Recherche, Sophia Antipolis Cedex, France. Study Numbers SA 97499 and SA 97538, April 10, 1998. Unpublished. MRID 45448101. Tyl, R., C. Myers, M. Marr. (2001). Two­ generation reproductive toxicity evaluation of carbaryl (RPA007744) administered in the feed to CD ® (Sprague­ Dawley) rats. Reproductive and Developmental Laboratory, Center for Life Sciences and Toxicology, Chemistry and Life Sciences, Research Triangle Institute, Life Sciences and Toxicology, Research Triangle Park, NC 27709. Laboratory report number 65C­ 07407­ 400, May 24, 2001. Unpublished. 44 MRID 45456701. Robinson K, and Broxup B. (2001) Final Report Amendment No. 2 Supplement to MRID 44393701­ A Developmental Neurotoxicity Study of Orally Administered Carbaryl, Technical Grade, in the Rat. ClinTrials BioResearch Ltd., Quebec, Canada. Laboratory Project I. D. 97391. July 10, 2001. Unpublished. MRID 45456702. Hamelin N, Yipchuck G. (2001) Morphometric Evaluation of Rat Brain Areas for Developmental Neuropathology. ClinTrials Bioresearch Ltd., Quebec, Canada. Laboratory Project I. D. 99579. July 9, 2001. Unpublished. MRID 45456703. Robinson K, and Broxup B. (2001) Final Report Amendment No. 1 Supplement to MRID 44393701­ A Developmental Neurotoxicity Study of Orally Administered Carbaryl, Technical Grade, in the Rat. ClinTrials BioResearch Ltd., Quebec, Canada. Laboratory Project I. D. 97391. July 6, 2001. Unpublished. MRID 45630601. Austin, E. W. (2002). 4 Week Repeated­ Dose Dermal Toxicity Study with Carbaryl Technical in Rats. Covance Laboratories, Madison, WI. Laboratory Study Identification Number 6224­ 268, March 8, 2002. Unpublished. MRID 45630602. Austin, E. W. (2002). 4 Week Repeated­ Dose Dermal Toxicity Study with SEVIN® XLR Plus in Rats. Covance Laboratories, Madison, WI. Laboratory Study Identification Number 6224­ 267, March 7, 2002. Unpublished. MRID 45630603. Austin, E. W. (2002). 4 Week Repeated­ Dose Dermal Toxicity Study with SEVIN® 80S in Rats. Covance Laboratories, Madison, WI. Laboratory Study Identification Number 6224­ 266, March 8, 2002. Unpublished. 45 9.0 APPENDICES Tables for Use in Risk Assessment 46 9.1 Toxicity Profile Summary Tables 9.1.1 Acute Toxicity Table ­ See Section 4.1 9.1.2 Subchronic, Chronic and Other Toxicity Tables Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90­ Day oral toxicity rodents N/ A 870.3150 90­ Day oral toxicity in nonrodents N/ A 870.3200 21/ 28­ Day dermal toxicity with technical carbaryl 45630601( 2002) acceptable/ nonguideline 0, 20, 50, 100 mg/ kg/ day systemic NOAEL = 20 mg/ kg/ day systemic LOAEL = 50 mg/ kg/ day based on decreased RBC cholinesterase in males and females and brain cholinesterase in males dermal NOAEL = 100 mg/ kg/ day dermal LOAEL not established 870.3200 21/ 28­ Day dermal toxicity with Sevin® XLR Plus (44.82% a. i.) 45630602 (2002) unacceptable/ nonguideline 0, 20, 50, 100 mcL/ kg/ day (0, 9.6, 24, 48 mg/ kg/ day) systemic NOAEL = 50 mcL/ kg/ day (24 mg/ kg/ day) systemic LOAEL = 100 mcL/ kg/ day (48 mg/ kg/ day) based on decreased body weight gain dermal NOAEL = 100 mcL/ kg/ day (48 mg/ kg/ day) dermal LOAEL not established 870.3200 21/ 28­ Day dermal toxicity with Sevin® 80S (80.07% a. i.) 45630603 (2002) unacceptable/ nonguideline 0, 20, 50, 100 mg/ kg/ day systemic NOAEL = 20 mg/ kg/ day systemic LOAEL = 50 mg/ kg/ day based on decreased RBC cholinesterase in males and females dermal NOAEL = 100 mg/ kg/ day dermal LOAEL not established 870.3250 90­ Day dermal toxicity N/ A 870.3465 90­ Day inhalation toxicity N/ A 870.3700a Prenatal developmental in rats 44732901 (1998) acceptable/ guideline 0, 1, 4, 30 mg/ kg/ day (oral gavage) Maternal NOAEL = 4 mg/ kg/ day LOAEL = 30 mg/ kg/ day based on clinical signs, decreased body weight gain (BWG) and food consumption Developmental NOAEL = 4 mg/ kg/ day LOAEL = 30 mg/ kg/ day based on decreased fetal body weight and incomplete ossification of multiple bones Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 47 870.3700b Prenatal developmental in rabbits 44904202 (1999) Acceptable/ guideline 0, 5, 50, 150 mg/ kg/ day (oral gavage) Maternal NOAEL = 5 mg/ kg/ day LOAEL = 50 mg/ kg/ day based on decreased BWG and plasma cholinesterase inhibition (ChEI) Developmental NOAEL = 50 mg/ kg/ day LOAEL = 150 mg/ kg/ day based on decreased fetal weight 870.3800 Reproduction and fertility effects 45448101 (2001) acceptable/ guideline 0, 75, 300, 1500 ppm (4.67, 31.34, and 92.43 mg/ kg/ day for F0 males; 0, 5.56, 36.32, and 110.78 mg/ kg/ day for F0 females; 0, 5.79, 23.49, and 124.33 mg/ kg/ day for F1 males; and 0, 6.41, 26.91, and 135.54 mg/ kg/ day for F1 females averaged over the premating period) Parental NOAEL = 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) Parental LOAEL = 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption Reproductive toxicity NOAEL is $ 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) Reproductive toxicity LOAEL not be established Offspring NOAEL = 75 ppm (4.67­ 5.79 mg/ kg/ day for males and 5.56­ 6.41 mg/ kg/ day for females). Offspring LOAEL = 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival. 870.4100a Chronic toxicity in rodents N/ A 870.4100b Chronic toxicity in dogs 40166701 (1987) 0, 125, 400, 1250 ppm (0, 3.1, 10, 31.3 mg/ kg/ day) 42022801 (1991) 0, 20, 45, 125 ppm (5 weeks) (M: 0, 0.59, 1.43, 3.83; F: 0, 0,64, 1.54, 4.11 mg/ kg/ day) Together, the studies are Acceptable/ guideline MRID 40166701: NOAEL = not established in females LOAEL = 125 ppm based based on plasma and brain ChEI MRID 42022801: NOAEL = 45 ppm in males LOAEL = 125 ppm in males based on plasma ChEI Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 48 870.4200 Carcinogenicity in mice 42786901 (1993) Acceptable/ guideline 0, 100, 1000 or 8000 ppm (M: 0, 14.73, 145.99, 1248.93 mg/ kg/ day; F: 0, 18.11, 180.86, 1440.62) systemic LOAEL = 1000 ppm based on increased intracytoplasmic droplets in bladder in males and females, chronic progressive nephropathy in males; NOAEL = 100 ppm RBC ChEI LOAEL for males = 1000 ppm , for females = 8000 ppm; NOAEL = 100 ppm for males, 1000 ppm for females plasma ChEI for males and females LOAEL > 8000 ppm; NOAEL $ 8000 ppm brain ChEI for males and females LOAEL = 8000 ppm; NOAEL = 1000 ppm increase in vascular tumors in all treated males and in females at 8000 ppm increase in adenomas, multiple adenomas, carcinomas of kidney in males at 8000 ppm increase in hepatic neoplasms (adenomas, carcinomas, one hepatoblastoma) in females at 8000 ppm 870.4300 Chronic Toxicity/ Carcinogenicity in rats 42918801 (1993) Acceptable/ guideline 0, 250, 1500 & 7500 ppm (M: 0, 10, 60.2, 349.5 mg/ kg/ day; F: 0, 12.6, 78.6, 484.6 mg/ kg/ day) systemic LOAEL = 1500 ppm in females based on decreased BW and BWG; 7500 ppm in males based on increased clinical signs, decreased BW, BWG and food consumption, increase in cataracts, clinical pathology changes, organ weight changes, nonneoplastic changes; NOAEL = 250 ppm in females and 1500 ppm in males plasma ChEI LOAEL = 7500 ppm in males and females; NOAEL = 1500 ppm RBC ChEI LOAEL = 1500 ppm in males and females; NOEL = 250 ppm brain ChEI LOAEL = 7500 ppm in males and females; NOEL = 1500 ppm at 7500 ppm, increase in liver adenomas in females, increase in benign transitional cell papillomas and transitional cell carcinomas in males and females, transitional cell carcinoma in kidney of one male, increase in benign thyroid follicular cell adenomas in males, follicular cell carcinoma in one male Bacterial reverse mutation test 870.5100 41370303 (1989) Acceptable/ guideline 5­ 1000 ug/ plate No evidence of mutagenicity in strains TA1535, TA 1537, TA1538, TA98 and TA100 with and without metabolic activation In vitro mammalian chromosome aberration test (Chinese hamster ovary cells) 870.5385 41370304 (1989) Acceptable/ guideline without S9 activation: 5­ 100 ug/ mL, harvest at 20 hrs.; with S9 activation: 25­ 300 ug/ mL, harvest at 30 hrs Increase in chromosome aberrations with S9 activation In vitro mammalian chromosome aberration test 870.5385 41370302; 41420201 (1989) Unacceptable/ guideline S9 activation: 1­ 300 ug/ mL in 3 trials; without S9 activation: 1­ 300 ug/ mL in 2 trials Results provide no clear indication of a mutagenic response, however study had several deficiencies Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 49 Mammalian erythrocyte micronucleus test 870. 5395 44069301 (1996) Unacceptable/ guideline single oral gavage dose of 50, 100, 200 mg/ kg Carbaryl did not induce a clastogenic or aneugenic effect, however there was no convincing evidence that MTD was achieved Unscheduled DNA synthesis 870.5550 41370301; 41810601 (1989) Acceptable/ guideline 0.5 ­ 25.0 ug/ mL Negative 870.6200a Acute neurotoxicity screening battery in rats MRID: 43845201­ 43845204 (1995) Acceptable/ guideline 0, 10, 50, 125 mg/ kg (oral gavage) Separate study for ChE: 0, 10, 30, 50 mg/ kg; ChE done 1, 8, 24, 48 hrs post­ dosing Systemic LOAEL = 10 mg/ kg based on decreased RBC, plasma, blood, brain ChE; NOAEL < 10 mg/ kg 870.6200b Subchronic neurotoxicity screening battery in rats MRID: 44122601 (1996) Acceptable/ guideline 0, 1, 10, 30 mg/ kg/ day (oral gavage) LOAEL for neurotoxicity = 10 mg/ kg/ day based on increased FOB changes; NOAEL = 1 mg/ kg/ day LOAEL for ChEI = 10 mg/ kg/ day based on decreased plasma, blood, RBC, brain ChE; NOAEL = 1 mg/ kg/ day 870.6300 Developmental neurotoxicity in rats 44393701 (1997) Acceptable/ guideline 0, 0.1, 1.0, 10 mg/ kg (oral gavage) Maternal NOAEL = 1.0 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on decreased BWG; FOB changes; RBC, plasma, whole blood, brain ChEI Offspring tentative NOAEL = 1.0 mg/ kg/ day tentative LOAEL = 10 mg/ kg/ day based on alterations in morphometric measurements (measurements were not done at lower doses) 870.7485 Metabolism and pharmacokinetics in rats 43332101 (1994) Acceptable/ guideline 1 mg/ kg (single and repeated oral doses; intravenous dose) and 50 mg/ kg (single oral dose) Absorption was complete at all doses. At 168 hrs., post­ dose, negligible percentages of dose in any tissues. Kidney and blood contained highest concentrations of radioactivity. Excretion mostly through urine. A metabolic scheme with conjugated and nonconjugated metabolites was proposed. 870.7485 Metabolism and pharmacokinetics in rats 44402501 (1997) Acceptable/ nonguideline 50 mg/ kg (single oral radiolabeled dose); daily oral radiolabeled dose of 2 mg/ kg for 7 days followed by 83 daily unlabeled doses of 0, 250, 1500 or 7500 ppm; males only In all dosing regimens, urinary and fecal excretion was 93­ 103% of administered dose and tissue levels of radioactivity were minimal at 168 hrs. post­ dosing. Two major metabolites in tissues at 6 hrs. post­ dosing were naphthyl sulfate and naphthyl glucuronide, however quantitation was not possible. A total of 23 and 20 components were identified in the urine and feces, respectively. The sulfate conjugation pathway appears to be saturable following a 83­ day feeding at 7500 ppm. BW and food consumption were decreased at 7500 ppm. Increases in kidney, spleen and thyroid weights were observed at 1500 and 7500 ppm. Non­ neoplastic changes in liver, thyroids and kidneys were observed at 7500 ppm. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 50 870.7600 Dermal penetration in rats 43552901 (1995) 43.9% a. i. Acceptable 35.6, 403, 3450 ug/ cm 2 % absorbed at 10 hrs.: 12.7, 7.44 and 1.93 at 35.6, 403 and 3450 ug/ cm 2 , respectively 870.7600 Dermal penetration in rats 43339701 (1994) 80.1% a. i. Acceptable 63, 626, 3410 ug/ cm 2 % absorbed at 10 hrs: 8.90, 0.62 and 0.48 at 63, 626 and 3410 ug/ cm 2 , respectively Special studies in mice 43282201 (1994) Acceptable/ nonguideline male mice: single radiolabeled dose of 75 mg/ kg; pretreatment with 8000 ppm unlabeled carbaryl for 2 wks., then single radiolabeled dose of 75 mg/ kg Negative for DNA binding in liver Special studies in mice 43832601 (1994) Acceptable/ nonguideline continuation of MRID 43282201 in liver from mice treated at 8000 ppm, increase in microsomal protein, cytochrome P450, ethoxyresorufin O­ deethylase, pentoxyresorufin O­ depentylase, and testosterone hydrolases indicates phenobarbital type of induction of metabolizing enzymes Special study in mice 45281801, 45281802, 45236603 (1998­ 1999) Acceptable/ nonguideline 0, 10, 30, 100, 300, 1000 and 4000 ppm (0, 1.8, 5.2, 17.5, 51.2, 164.5 and 716.6 mg/ kg/ day) There was no evidence of neoplastic or preneoplastic changes in vascular tissue in heterozygous p53­ deficient male mice treated with carbaryl for six months. N/ A Not Available 51 9.2 Summary of Toxicological Dose and Endpoints for CARBARYL for Use in Human Risk Assessment 1 Table 2: Summary of Toxicology Endpoint Selection for Carbaryl Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Dietary Risk Assessments Acute Dietary general population including infants and children NOAEL = 1 UF = 100 Acute RfD = 0.01 mg/ kg/ day 1 Developmental Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes on the first day of dosing in maternal animals Chronic Dietary all populations LOAEL= 3.1 UF = 300 Chronic RfD = 0.01 mg/ kg/ day 1 Chronic toxicity ­ dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females. Incidental Oral Short­ Term (1 ­ 30 Days) Residential Only NOAEL= 1 MOE= TBD 1 Developmental Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes and decreases in RBC, whole blood, plasma and brain cholinesterase Incidental Oral Intermediate­ Term (1 ­ 6 Months) Residential Only NOAEL= 1 MOE = TBD 1 Subchronic Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase. Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment 52 Non­ Dietary Risk Assessments Dermal Short­ Term (1 ­ 30 days) Dermal NOAEL= 20 4­ week dermal toxicity ­ rat systemic LOAEL = 50 mg/ kg/ day based on statistically significant decreases in RBC cholinesterase in males and females and brain cholinesterase in males. Residential MOE = TBD 1 Occupational 100 1 Dermal Intermediate­ Term (1 ­ 6 Months) Dermal NOAEL= 20 4­ week dermal toxicity ­ rat systemic LOAEL = 50 mg/ kg/ day based on statistically significant decreases in RBC cholinesterase in males and females and brain cholinesterase in males. Residential MOE = TBD 1 Occupational 100 1 Dermal Long­ Term a (> 6 Months) Oral NOAEL= 3.1 Chronic toxicity ­ dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females. Residential MOE = TBD 1 Occupational 300 1 Inhalation Short­ Term b (1 ­ 30 days) Oral NOAEL= 1 Developmental Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes and statistically significant decreases in RBC, whole blood, plasma and brain cholinesterase Residential MOE = TBD 1 Occupational 100 1 Inhalation Intermediate­ Term b (1 ­ 6 Months) Oral NOAEL= 1 Subchronic Neurotoxicity ­ rat LOAEL = 10 mg/ kg/ day based on increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase. Residential MOE = TBD 1 Occupational 100 1 Inhalation Long­ Term b (> 6 Months) Oral NOAEL= 3.1 Chronic toxicity ­ dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females. Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment 53 Residential MOE = TBD 1 Occupational 300 1 Cancer Classification: Q1* = 8.75 x 10 ­4 a Since an oral NOAEL/ LOAEL was selected, a dermal absorption factor of 12.7% should be used in route­ to­ route extrapolation. b Since an oral NOAEL was selected, an inhalation factor of 100% should be used in route­ to­ route extrapolation. TBD = To Be Determined. Target MOEs for residential exposures will be determined by the FQPA Safety Factor Committee.

epa

2024-06-07T20:31:42.308529

regulations

EPA-HQ-OPP-2002-0138-0009

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Office of Prevention, Pesticides and Toxic Substances TXR NO. 0050533 DATE: March 5, 2002 MEMORANDUM SUBJECT: Carbaryl ­ 5 th Report of the Hazard Identification Assessment Review Committee. FROM: Virginia A. Dobozy, VMD, MPH Reregistration Branch I, Health Effects Division (7509C) THROUGH: Jess Rowland, Co­ Chair and Elizabeth Doyle, Co­ Chair Hazard Identification Assessment Review Committee Health Effects Division (7509C) TO: Jeff Dawson, Risk Assessor Reregistration Branch I, Health Effects Division (7509C) PC Code: 056801 On February 19, 2002, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reevaluated CARBARYL with regard to the potential for increased susceptibility of infants and children from exposure to CARBARYL as required by the Food Quality Protection Act (FQPA) of 1996. The toxicological endpoints used for acute and chronic Reference Doses (RfDs) and occupational/ residential risk assessments were also re­ evaluated. New data, including a multi­ generation reproduction study in rats and revised brain morphometric measurements from the developmental neurotoxicity study in rats, were reviewed. Previous HIARC meetings were on July 7, 1998, April 6, 1999, November 2, 1999 and March 1, 2001. The conclusions drawn at this meeting are presented in this report. 2 Committee Members in Attendance Members present were: Ayaad Assaad, William Burnam, Paula Deschamp, Elizabeth Doyle, Virginia Fornillo, John Liccione, Elizabeth Mendez, David Nixon, Jess Rowland Member( s) in absentia: Pamela Hurley Data evaluation prepared by: Virginia A. Dobozy, VMD, MPH Also in attendance were: Jeff Dawson (HED), Felicia Fort (HED), Michael Metzger (HED), Anthony Britten (SRRD) Data Evaluation / Report Presentation Virginia A. Dobozy, VMD, MPH Toxicologist 1 Significant changes in some of the brain morphometric measurements were observed in offspring at the high dose; only control and high dose groups were examined. EPA requested that measurements be done in the low­ and mid­ dose groups. The registrant responded that the requested examinations were not possible because the tissues of the low­ and mid­ dose animals had been stored in a fixative for two years, which caused shrinkage. Therefore, comparison to the control group, which was not similarly stored, would not be valid. A re­ examination of the control and high­ dose groups was conducted. The re­ assessment uncovered errors in some measures and confirmed some of the original findings. The additional statistical analyses, which attempted to account for multiple comparisons, rendered far fewer statistically significant findings, but some results, including data on pup cerebellar length, remained statistically significant. The decrease in the length of the cerebellum in 10 mg/ kg/ day female pups was still regarded as a treatment­ related effect. The NOAEL/ LOAEL for this study was originally regarded as tentative, awaiting information from the registrant. Since morphometric examinations of the mid­ dose group were impossible, there remained some uncertainty about the NOAEL/ LOAEL. 3 1. INTRODUCTION The toxicology data base on carbaryl has been evaluated by the HIARC on four occasions as described below. °. On July 7, 1998, the HIARC evaluated the data base, reassessed the RfD established in 1994 and selected endpoints for the acute dietary as well as occupational/ residential risk assessments. At the time of that evaluation, the data base was incomplete. There were no acceptable developmental or reproduction studies (July 7, 1998 report). ° At the April 6, 1999 meeting, a recently submitted rat developmental study was considered. The HIARC concluded that there was no basis to amend the 10X FQPA Safety Factor as there were still critical data gaps, i. e., no acceptable rabbit developmental study or reproduction study (April 28, 1999 report). ° At the November 2, 1999 meeting of the HIARC, the FQPA Safety Factor was again reconsidered with the submission of an acceptable rabbit developmental study. The Committee concluded that, based on the satisfaction of the rat and rabbit developmental study data requirements in which there was no fetal susceptibility, the FQPA Safety Factor recommendation could be reduced from 10X to 3X (November 15, 1999 report). At the November 29, 1999 meeting of the FQPA Safety Factor Committee, it was concluded that the 10X safety factor should be retained because: 1) the toxicology data base was incomplete, i. e., lack of reproduction study; 2) an assessment of susceptibility following pre­/ post­ natal exposure to carbaryl could not be made due to the data gaps for the reproduction study; 3) there was concern for the results of the developmental neurotoxicity study. 1 The Committee concluded that the 10X Safety Factor should be applied to acute and chronic dietary exposures and residential (nonoccupational) exposures (December 13, 1999 report). ° On March 1, 2001, the HIARC reevaluated carbaryl with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection for use in occupational/ residential exposure risk assessments (April 5, 2001 report). On April 16, 2001, the FQPA Safety Factor Committee again confirmed that the 10x factor should be retained based on the same criteria as described at the 4 November 29, 1999 meeting (April 30, 2001 report). The February 19, 2002 meeting was convened to discuss the following issues: 1) A multi­ generation reproduction study (MRID 45448101) has been submitted and evaluated. There is evidence of offspring susceptibility. The LOAEL for parental systemic toxicity was 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption. The NOAEL was 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females). The LOAEL for offspring toxicity was 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival. The NOAEL was 75 ppm (4.67­ 5.79 mg/ kg/ day for males and 5.56­ 6.41 mg/ kg/ day for females). The HIARC was requested to consider how the study results affect the determination of fetal/ offspring susceptibility and the Special FQPA Safety Factor recommendation. 2) The registrant has conducted new brain morphometric measurements of the control and high­ dose animals from the developmental neurotoxicity study. In prior reviews, HED concluded that there was a significant increase in the thickness of the right forebrain in male pups and a significant decrease in the left forebrain of adult males. The new submission reanalyzed the combined (left and right) data on the forebrain (Line B) in male pups and the forebrain (Line A) in adult males. Based on a statistical analysis of combined (left and right) forebrain measurements, there was no difference from controls in both pups and adults. However, HED's statistical analysis found a decrease in the size of the forebrain in adult males. In prior reviews, HED concluded that there was a statistically significant bilateral decrease in the length of the cerebellum (Line F) of female pups and a statistically significant bilateral increase in the width of the cerebellum (Line G) of adult females. The new submission contains measurements of different layers of the cerebellum in pups and adults. There were no statistically significant differences between treated and control animals. HED concluded that these measurements of individual cell layers do not negate the original findings in the cerebellum of female pups and adults. The HIARC was requested to consider how these revisions affect the determination of fetal/ offspring susceptibility and the Special FQPA Safety Factor recommendation. 3) At the March 1, 2001 HIARC meeting, the endpoint selection for occupational/ residential (ORE) risk assessments was based on current duration of exposure definitions, which have been changed (June 4, 2001 Memorandum from HED Division Director). The registrant has conducted 4­ week dermal exposure studies (one with technical and two with formulations); however, they have not been submitted. RRB1 is proposing to maintain the endpoints selected for the ORE exposures at the March 1 meeting until the dermal studies have been submitted and reviewed. The HIARC concluded that the occupational/ residential durations used for the risk assessment at the March 1, 2001 meeting should be maintained until the dermal exposure studies have been submitted and evaluated. The following document includes the endpoint selection and FQPA considerations from the February 19, 2001 meeting and cancer reclassification (November 7, 2001 meeting of the Cancer Assessment Review Committee). 2. HAZARD IDENTIFICATION 5 2.1 Acute Reference Dose (RfD) ­ General Population Study Selected: Developmental Neurotoxicity Study in Rats §81­ 8; OPPTS 870.6300 MRID Nos.: 44393701, 45456701, 45456702, 45456703 Executive Summary: In a developmental neurotoxicity study (MRID # 44393701, 45456701, 45456702, 45456703), 26 pregnant female Sprague­ Dawley rats/ group were administered carbaryl (99.1% a. i.) by gavage from Gestation Day (GD) 6 through Lactation Day (LD) 10 at doses of either 0, 0.1, 1.0 or 10 mg/ kg/ day. An additional 6 pregnant females/ group were dosed at the same levels for the cholinesterase (ChE) phase of the study. ChE measurements were done pre­ dosing (GD 6) and post­ dosing at time of peak effect (1 hour post­ dosing) on GD 6, 15 and 20 and LD 4 and 10. Functional Observational Battery (FOB) measurements were performed at approximately 0.5 and 2 hours post­ dosing on the same days as body weight measurements during the dosing period (GD 0, 6, 9, 12, 15, 18 and 20 and LD 4, 7, 11, 13 and 21). Measures of reproductive performance were evaluated. Offspring were examined for body weight, physical development landmarks (tooth eruption and eye opening), FOB assessments (days 4, 7, 11, 13, 17 and 21) and motor activity (days 13, 17 and 21). On LD 11, 1 animal/ sex/ litter was sacrificed for brain weights; of these, six/ sex were randomly selected for neuropathological evaluation. The eyes from all dose groups were examined. After LD 21, 3 animals/ sex/ litter were separated from the dams and constituted the F1 adult generation. These animals were evaluated for body weight, physical development (vaginal opening and preputial separation), motor activity (day 60), startle habituation response (days 22 and 60), passive avoidance (day 23) and water maze behavior (day 60). After completion of the behavior test period (at approximately 10 weeks of age), 12 animals/ sex/ group were anesthetized and perfused for post­ mortem examination. Tissues from 6 animals/ sex of the control and high dose group were processed for neuropathological evaluation and morphometric measurements; the eyes from the low and mid­ dose group of all perfused animals were examined. For the F0 generation animals, there were no carbaryl­ associated deaths. No treatment­ related clinical signs of toxicity were observed. There was a statistically significant decrease (92%) in body weight gain for females in the 10 mg/ kg/ day group for the period GD 6­ 9. Unfortunately, food consumption was not measured during the study. During the FOB measurements, the incidence of females in the 10 mg/ kg/ day group with decreased pupil size (pinpoint pupils) was increased on all occasions during the dosing period. An increased incidence of dams with slight tremors affecting the head, body and/ or limbs was noted on the majority of assessment occasions in the dosing period. There were also occasional occurrences of ataxic gait/ overall gait in­ capacity which was considered to be of toxicological significance due to other effects upon gait. For the 10 mg/ kg/ day group, RBC and whole blood ChE levels were statistically significantly decreased (28% and 32­ 34%, respectively) on GD 20 and LD 10. Although the plasma ChE levels were not statistically significantly altered, the percentage decreases on GD 20, LD 4 and LD 10 were 32­ 39%. Brain ChE levels were statistically significantly decreased (42%). There 6 were no treatment­ related effects on gross necropsy findings for the F0 generation animals. There were no effects observed on maternal performance parameters of pregnancy rate, gestation index, length of gestation, numbers of live pups, dead or malformed pups, implantation scars, sex ratio or post­ implantation loss. There was a slight (P> 0.05) increase in the number of dead pups in the 10 mg/ kg/ day group, however the value was within the historical control range for this strain. For the F1 generation pups, there were no treatment­ related effects on pup weight, pup survival indices, developmental landmarks (tooth eruption and eye opening), FOB measurements or motor activity assessments. At sacrifice on LD 11, there were no treatmentrelated effects on brain weight and gross or microscopic pathology. Significant differences noted in the morphometric measurements included an increase in Line B of the right forebrain and Line F of the left cerebellum in the 10 mg/ kg/ day males. In the 10 mg/ kg/ day females, Line F through both the right and left cerebellum were significantly decreased (15% and 22%, respectively). For the F1 generation adults, there were no treatment­ related effects on clinical condition, body weight, physical development (vaginal opening and preputial separation), motor activity, auditory startle response, passive avoidance and water maze measurements. At sacrifice, there were no gross or microscopic neuropathological lesions observed for animals examined in this study that were attributable to treatment with the test article. There was an increased incidence of retinal fold/ rosette in the 10 mg/ kg/ day group (1/ 12 for control vs. 4/ 12 for males; 0/ 12 for control vs. 2/ 12 for females). The finding was not considered of toxicological significance since the incidence was within the historical control range for males, occurred at a low rate and was not dose­ dependent. For the morphometric measurements, there was a significant bilateral decrease in Line A through the forebrain (7.7­ 9.8%) and a significant increase in Line F through the right cerebellum of the 10 mg/ kg/ day males. Increases originally noted in 10 mg/ kg adult females in Line G, width of the cerebellum, were found to be based on erroneous measurements, and additional measures were submitted. Now, for the 10 mg/ kg/ day females, there were significant bilateral increases in Line F through the cerebellum (7.4­ 15%). Measurements of the size of the thickness of lobes and of the granule cell layers of the cerebellum in high dose pups and adults did not differ from those of controls. While additional statistical analyses by the registrant indicated no treatment related effects, HED's additional statisical analyses did indicate treatment related effects. The maternal toxicity LOAEL was 10 mg/ kg/ day based on decreased body weight gain, alterations in FOB measurements and RBC, plasma, whole blood and brain cholinesterase inhibition. The maternal NOAEL was 1.0 mg/ kg/ day. The developmental neurotoxicity LOAEL was 10 mg/ kg/ day based on a bilateral decrease in the size of the forebrain (Line A) in adult males (7.7­ 9.8%); a bilateral decrease in the length of the cerebella (Line F) in female pups (15­ 22%); and a bilateral increase in the length of the cerebella (Line F) in female adults (7.4­ 15%). The developmental NOAEL was 1 mg/ kg/ day. Morphometric assessment at the mid and 7 low doses could not be conducted due to inadequate tissue storage; however, based on the minimal findings at the LOAEL, it is HED's judgment that effects would be unlikely to occur at 1 mg/ kg/ day, which is 10% of the LOAEL. Co­ critical Study: Study Selected: Acute Neurotoxicity Study in Rats §81­ 8; OPPTS 870.6200a MRID Nos.: 43845201­ 43845204 Executive Summary: In an acute neurotoxicity study (MRID # 43845204), groups of 12 male and 12 female Sprague­ Dawley rats were administered carbaryl technical grade in 0.5% carboxymethylcellulose / 0.1% Tween 80 at doses of 10, 50, or 125 mg/ kg/ day. Doses were selected on the basis of results from a benchmark toxicity study (MRID # 43845201) and a "time of peak effects" study (MRID # 43845202). In the benchmark study, clinical signs of toxicity and body weight loss were observed at 50 mg/ kg and above, and mortality was observed at 500 mg/ kg and above. In the time of peak effects study, peak effect for cholinesterase inhibition and functional observational battery changes was determined to be 0.5 to 1.0 hr post­ dose. Body weight was mildly but significantly decreased in male rats at the 125 mg/ kg dose level, while weight gain was significantly decreased in male and female rats for days 0­ 7 of the study at 125 mg/ kg. Food consumption during week 1 was decreased at the 125 mg/ kg dose by 18­ 20%, in excess of the decrease in body weight gain, supporting a treatment­ related effect at the high dose for week 1 of the study. Several measurements from Functional Observational Battery assessment were significantly altered at the 50 and 125 mg/ kg dose, including an increased incidence of tremors, ataxic gait, decreased body temperature, and decreased arousal. Salivation incidence was increased at the high dose, as was hindlimb splay. Forelimb and hindlimb grip strength were decreased significantly at the high dose. Significant decreases in total motor activity were observed in male and female rats at all dose levels tested. Significant inhibition of plasma, blood, and brain cholinesterase (30­ 40%) was also observed in both sexes at the 10 mg/ kg dose. Peak inhibition of cholinesterase occurred during the time of FOB and motor activity measurements. Based on the data in this study, the systemic LOAEL = 10 mg/ kg for male and female rats, based on significant inhibition of red cell, plasma, whole blood, and brain cholinesterase at the 10 mg/ kg dose level. The systemic NOAEL < 10 mg/ kg for male and female rats. This study is classified as acceptable and satisfies the guideline requirement for an acute neurotoxicity study (§ 81­ 8; OPPTS 870.6200) in rats. Dose and Endpoint for Establishing RfD: Maternal NOAEL of 1 mg/ kg based on alterations in FOB parameters on the first day of dosing at 10 mg/ kg Uncertainty Factor (UF): 100 [10 for intraspecies variation and 10 for interspecies variation]. 8 Comments about Study/ Endpoint/ Uncertainty Factor: Previously (March 1, 2001), the HIARC selected the acute neurotoxicity study this risk assessment. However, upon reevaluation and comparison of the results of the acute neurotoxicity and the developmental neurotoxicity studies, the HIARC determined that the maternal effects in the developmental neurotoxicity study observed after a single oral dose were most appropriate for this risk assessment. This is also the dose at which effects were observed in offspring; therefore, use of the maternal NOAEL is protective for infants and children. Additionally, use of the LOAEL from the acute neurotoxicity study with a 3x uncertainty factor would result in a calculated NOAEL of 3 mg/ kg/ day and an acute RfD of 0.03 mg/ kg. The HIARC determined that it was more conservative and protective of all populations (including females 13­ 50) to use the developmental neurotoxicity study. 2.2 Chronic Reference Dose (RfD) Study Selected: Chronic Toxicity ­ Dog § 83­ 1, OPPTS 870.4100 MRID Nos.: 40166701, 42022801 Executive Summary: In a chronic toxicity study (MRID No. 40166701), carbaryl (99%) was administered in the diet to 6 beagle dogs/ sex/ group at doses of 0, 125, 400 or 1250 ppm for one year. Nominal doses were 3.1, 10 and 31.3 mg/ kg/ day. There were no deaths during the study. With the 1250 ppm females, there was an increased incidence of clinical signs of toxicity, including emesis, lacrimation, salivation and tremors. Mean body weight gain was decreased (50%) in the 1250 ppm females for weeks 0­ 6. Mean food consumption was decreased (16­ 24%, not statistically significant) in the 1250 ppm females at multiple time periods during the study. No treatment­ related ophthalmoscopic changes were observed. There was a statistically significant increase in white blood cell and segmented neutrophil counts at some of the testing intervals for the 1250 ppm group males. Albumin levels were significantly decreased (9­ 11%) at all of the testing periods in the 1250 ppm females. Plasma cholinesterase (ChE) levels in males were significantly decreased in the 400 ppm (30­ 36% 9 ) and 1250 ppm (58­ 66% 9 ) groups at all testing intervals (weeks 5, 13, 26 and 52). Plasma ChE levels in females were significantly decreased at most intervals in the 125 ppm group (12­ 23% 9 ), 400 ppm group (9­ 31% 9 ) and 1250 ppm group (47­ 60 ). RBC ChE levels in males were significantly decreased in the 400 ppm group (23­ 28% 9 at weeks 5 and 13) and 1250 ppm group (46­ 56% 9 for all intervals). RBC ChE levels in females were significantly decreased in the 400 ppm group (29­ 34% 9 at weeks 5, 13 and 26) and 1250 ppm (29­ 38% 9 for all intervals). Brain ChE in males was not statistically significantly decreased but biologically decreased in the 400 ppm group (32% 9 ) and 1250 ppm group (25% 9 ). Brain ChE in females was significantly decreased (20­ 36% 9 ) in all the groups. No treatment Acute RfD = 1 mg/ kg = 0.01 mg/ kg 100 9 related effects were seen in urinalysis parameters. At necropsy, there was a statistically significant increase in the absolute weight of the liver/ gall bladder in the 1250 ppm group males. Relative and liver­ to­ brain weights were also increased but not significantly. There was a dose­ related decrease in the absolute, relative and organ­ to­ brain weights of the pituitary in males, although none of the changes was statistically significant. There was also a significant decrease in the relative weight of the thyroid in this group. However, since there were no accompanying microscopic changes in these organs, the toxicological significance of these organ weight effects is questionable. The LOAEL for systemic toxicity was 1250 ppm (31.3 mg/ kg/ day) based on an increased incidence of clinical signs (females), decreased body weight and food consumption (females) and alterations in clinical pathology parameters (both sexes); NOAEL was 400 ppm (10 mg/ kg/ day). The LOAEL for plasma cholinesterase inhibition was 125 ppm (3.1 mg/ kg/ day) for females; a NOAEL was not established. The LOAEL for plasma cholinesterase inhibition was 400 ppm (10 mg/ kg/ day) for males; the NOAEL was 125 ppm (3.1 mg/ kg/ day). The LOAEL for RBC cholinesterase inhibition was 400 ppm (10 mg/ kg/ day) for males and females; the NOAEL was 125 ppm (3.1 mg/ kg/ day). The LOAEL for brain cholinesterase inhibition was 125 ppm (3.1 mg/ kg/ day) for females; a NOAEL was not established. The LOAEL for brain cholinesterase inhibition was 400 ppm (10 mg/ kg/ day) for males; the NOAEL was 125 ppm (3.1 mg/ kg/ day). In a five­ week study (MRID # 42022801) done to upgrade the chronic study, carbaryl (99.3% a. i.) was administered in the diet to six beagles/ sex/ group at doses of 0, 20, 45 or 125 ppm. Actual mg/ kg/ day doses for males were 0, 0.59, 1.43 and 3.83 mg/ kg/ day, respectively; doses for females were 0, 0.64, 1.54 and 4.11 mg/ kg/ day, respectively. The following parameters were measured: clinical observations, body weights, food consumption, ophthalmoscopic examinations, plasma and RBC cholinesterase (at days ­11, ­8 and ­5 pretest and then days 14 and 32 of the study), brain cholinesterase (at termination) and gross necropsies. This study was conducted to complete the information needed to satisfy the chronic toxicity study requirement in nonrodent species. There were no deaths or treatment­ related clinical signs of toxicity. There were no treatmentrelated effects on body weights, food consumption or ophthalmoscopic examinations. In males, there was a statistically and biologically significant decrease in plasma cholinesterase for the 125 ppm (22% 9 ) group. The LOAEL for systemic toxicity and for RBC and brain cholinesterase inhibition was >125 ppm (males: 3.83 mg/ kg/ day; females: 4.11 mg/ kg/ day); the NOAEL was $ 125 ppm. The LOAEL for plasma cholinesterase inhibition for males was 125 ppm; the NOAEL was 45 ppm (1.43 mg/ kg/ day). The LOAEL for cholinesterase inhibition for females was >125 ppm; 10 the NOAEL was $ 125 ppm. Dose and Endpoint for Establishing RfD: LOAEL =3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females. Uncertainty Factor( s): 300 [10 for intra species variation, 10 for interspecies variation and 3 for use of a LOAEL]. Comments about Study/ Endpoint/ Uncertainty Factor: The HIARC determined that the LOAEL from the 1­ year dog study was appropriate for the following reasons: 1) An additional uncertainty factor of 3X was applied because of the use of a LOAEL (i. e., lack of a NOAEL in a critical study). Although a NOAEL was not established in this study, the Committee determined that an additional factor of 3X (as opposed to a higher value) was adequate because: 1) cholinesterase inhibition was not accompanied by clinical signs; 2) no inhibition was seen for any cholinesterase compartment in males at this dose; 3) the magnitude of inhibition of plasma cholinesterase inhibition (12­ 23% decrease) was comparable to the magnitude of inhibition (22%) seen in the 5­ week study in dogs indicating no cumulative effects following long­ term exposure; and 4) the study was well­ conducted and there are sufficient data from subchronic and chronic duration studies in the other species which support cholinesterase inhibition as the critical effect 2) Based on the cholinesterase inhibition data, the dog appears to be more sensitive than the rat in long­ term studies. Male and female rats treated at 10 and 13 mg/ kg/ day, respectively, of carbaryl in the diet for 53 weeks demonstrated negligible plasma, RBC and brain cholinesterase inhibition, whereas dogs treated at a comparable dose for the same duration had inhibition of all three compartments. 3) The HIARC determined that use of the LOAEL from the 1­ year study (plasma and brain cholinesterase inhibition in females) provided more convincing evidence of a toxicological effect than use of the NOAEL of 1.43 mg/ kg/ day based on plasma cholinesterase inhibition in males from the 5 week study. 4) Use of the LOAEL from the 1­ year dog study with an uncertainty factor of 300 results in a chronic RfD which would be identical to that derived if the offspring NOAEL (1.0 mg/ kg/ day) from the developmental neurotoxicity study was used with an uncertainty factor of 100; therefore, infants and children will also be protected by using the 1­ year dog study. 2.3 Occupational/ Residential Exposure 2.3.1 Short­ Term (1­ 7 days) Incidental Oral Exposure Chronic RfD = 3.1 mg/ kg/ day = .01 mg/ kg/ day 300 11 Study Selected: Developmental Neurotoxicity Study §81­ 8; OPPTS 870.6300 MRID No.: 44393701, 45456701, 45456702, 45456703 Executive Summary: See 2.1 Acute Reference Dose (RfD) ­ General Population Dose and Endpoint for Risk Assessment: Maternal NOAEL of 1 mg/ kg based on alterations in FOB parameters on the first day of dosing at 10 mg/ kg Comments about Study/ Endpoint: The HIARC determined that study is appropriate for the short­ term oral exposure time period because effects (FOB alterations) were observed after a single dose and continued after multiple days of dosing and are appropriate for the population of concern (infants and children). Although a maternal NOAEL was used, this dose would be protective of offspring effects since the NOAEL/ LOAEL were the same for offspring toxicity. 2.3.2 Intermediate­ Term (7 Days to Several Months) Incidental Oral Exposure Study: Subchronic Neurotoxicity Study Study Guideline#: § 81­ 8, OPPTS 870.6200 MRID No.: 44122601 Executive Summary: In a subchronic neurotoxicity study, 12 Crl: CD( SD) BR rats/ sex/ group were administered technical carbaryl (99.1%) by gavage at doses of 0, 1, 10 or 30 mg/ kg/ day for 13 weeks. Cholinesterase (RBC, whole blood, plasma and brain) determinations were done on an additional three groups of five rats/ sex/ group at Weeks 4, 8 and 13. Neurobehavioral screening, consisting of Functional Observational Battery (FOB) and motor activity evaluations, was performed prior to treatment and during Weeks 4, 8 and 13. At terminal sacrifice, six animals/ sex/ dose were anesthetized and perfusion fixed in situ for neuropathological evaluation. There were no deaths during the study. There was an increased incidence of clinical signs of toxicity, including slight and moderate salivation and tremors, in the 30 mg/ kg/ day males and females. Body weight over the course of the study was statistically significantly decreased in the 30 mg/ kg/ day males (14%) and females (15%). Body weight gain for these groups was decreased 27% in males and 37% in females, compared to controls. Food consumption was decreased during most of the study for the 30 mg/ kg/ day males and females. Males and females in the 30 mg/ kg/ day group had a statistically significant decrease in RBC (M: 42­ 46%; F: 52­ 55%), whole blood (M: 49­ 51%; F: 59­ 63%) and plasma (M: 63­ 69%; F: 63­ 69%) at most of the testing periods. Males and females in the 10 mg/ kg/ day group had a statistically significant decrease in RBC (M: 26­ 38%; F: 17­ 24%); whole blood (M: 30­ 41%; F: 21­ 26%) and plasma (M: 43­ 48%; F: 23­ 30%). There was a statistically significant decrease in brain cholinesterase in males and females in the 10 mg/ kg/ day (M: 27­ 61%; F: 20­ 58%) and 30 mg/ kg/ day (M: 36­ 80%; F: 50­ 73%) groups. For the 1 mg/ kg/ day males, there were 12 statistically significant decreases in whole blood (13%) at week 13 and for plasma (20%) at week 8. These changes are not considered toxicologically significant since they occurred infrequently and were relatively minor effects. Multiple qualitative and quantitative FOB parameters were affected in the 10 and 30 mg/ kg/ day males and females, including the following: slight tremors, gait alterations, pinpoint pupils, increased salivation, reduced extensor thrust, decreased pinna reflex, reduced number of rearings, decreased vocalizations, decreased body temperature and decreased forelimb grip. Reduced number of defecations was observed only at 30 mg/ kg/ day. There was an occasional alteration at the 1 mg/ kg/ day dose. At week 8, males had a very slight increase in the incidence of pinpoint pupils (incidence in control, 1, 10 and 30 mg/ kg/ day groups was 0/ 12, 1/ 12, 6/ 12 and 10/ 12, respectively). A statistically significant decrease in forelimb grip was observed at week 4 in males (values for control, 1, 10 and 30 mg/ kg/ day groups were 1060.8, 943.8, 943.8 and 950.0, respectively). The number of defecations was statistically reduced in females at week 13 (mean number of defecations in control, 1, 10 and 30 mg/ kg/ day groups were 1.4, 0.2, 0.5 and 0.0, respectively). The toxicological significance of these effects is questionable since the incidence was either low or there was no dose­ response relationship. Motor activity was statistically significantly decreased in the 30 mg/ kg/ day males at Week 4 and the 30 mg/ kg/ day females at Weeks 4 and 8. On necropsy, there was an increased incidence of dark areas in the meninges of the 30 mg/ kg/ day males; these animals had an increased incidence of hemorrhage on microscopic examination. One female in the 30 mg/ kg/ day group also had retinal atrophy. There were no differences in brain length or width measurements. The LOAEL for neurotoxicity was 10.0 mg/ kg/ day based on an increased incidence of FOB changes; the NOAEL was 1.0 mg/ kg/ day. The LOAEL for cholinesterase inhibition was 10.0 mg/ kg/ day based on statistically significant decreases in RBC, whole blood, plasma and brain cholinesterase; the NOAEL was 1.0 mg/ kg/ day. Dose and Endpoint for Risk Assessment: NOAEL = 1.0 mg/ kg/ day based on plasma, whole blood, RBC and brain cholinesterase inhibition and FOB changes at 10 mg/ kg/ day. Comments about Proposed Study/ Endpoint: The study was selected because the route of administration (oral) and the duration (90 days) are appropriate for this risk assessment. It is supported by the five­ week dietary study in dogs (MRID 4202801) done to upgrade the chronic toxicity study. The NOAEL in males was 1.43 mg/ kg/ day based on plasma cholinesterase inhibition at 3.83 mg/ kg/ day. This dose and endpoint are appropriate for the population of concern (infants and children). 2.3.3 Dermal Absorption Dermal Absorption Factor: A dermal absorption factor of 12.7% was selected at the July 7, 1998 HIARC meeting; no reevaluation was conducted at the present meeting. 13 2.3.4 Short­ Term Dermal (1­ 7 days) Exposure Study Selected: Developmental Neurotoxicity Study §81­ 8; OPPTS 870.6300 MRID No.: 44393701, 45456701, 45456702, 45456703 Executive Summary: See 2.1 Acute Reference Dose (RfD) ­ General Population Dose and Endpoint for Risk Assessment: Maternal NOAEL of 1 mg/ kg based on alterations in FOB parameters on the first day of dosing at 10 mg/ kg Comments about Study/ Endpoint: No dermal toxicity studies are available. The HIARC determined that study is appropriate for the short­ term exposure time period because effects (FOB alterations) were observed after a single dose and continued after multiple days of dosing. Since an oral NOAEL was used for this endpoint, a dermal absorption factor of 12.7% should be used in the risk assessment. 2.3.5 Intermediate­ Term Dermal (7 Days to Several Months) Exposure Study Selected: Subchronic Neurotoxicity Study § 81­ 8, OPPTS 870.6200 MRID Nos.: 44122601 Executive Summary: See 2.3.2 Intermediate­ Term Incidental Oral Exposure Dose/ Endpoint for Risk Assessment: NOAEL = 1.0 mg/ kg/ day based on plasma, whole blood, RBC and brain cholinesterase inhibition and FOB changes at 10 mg/ kg/ day. Comments about Study/ Endpoint: No dermal studies are available. Since an oral NOAEL was used for this endpoint, a dermal absorption factor of 12.7% should be employed in the risk assessment. 2.3.6 Long­ Term Dermal (Longer than 6 months) Exposure Study Selected: Chronic Toxicity ­ Dog § 83­ 1, OPPTS 870.4100 MRID Nos.: 40166701, 42022801 Executive Summary: See Chronic Dietary section Dose and Endpoint for Risk Assessment: 3.1 mg/ kg/ day (LOAEL) based on plasma and brain cholinesterase inhibition in females in the 1 year study Comments about Study/ Endpoint: No dermal studies are available. Since an oral NOAEL was used for this endpoint, a dermal absorption factor of 12.7% should be employed in the risk 14 assessment. The reasons for selecting this oral study to assess long­ term exposure are described under 2.2 Chronic Reference Dose (RfD). 2.3.7 Inhalation Exposure (All Durations) There are no studies available in which carbaryl was administered via the inhalation route, except for the acute oral study [Toxicity Category IV (LC50 > 3.4 mg/ L)]. 2.3.7.1 Short­ Term Inhalation (1­ 7 days) Exposure Study Selected: Developmental Neurotoxicity Study §81­ 8; OPPTS 870.6300 MRID No.: 44393701, 45456701, 45456702, 45456703 Executive Summary: See 2.1 Acute Reference Dose (RfD) ­ General Population Dose and Endpoint for Risk Assessment: Maternal NOAEL of 1 mg/ kg based on alterations in FOB parameters on the first day of dosing at 10 mg/ kg Comments about Study/ Endpoint: No inhalation toxicity studies are available. The HIARC determined that the study is appropriate for the short­ term exposure time period because effects (FOB alterations) were observed after a single dose and continued after multiple days of dosing. Since an oral NOAEL was used for this endpoint, an inhalation factor of 100% should be used in the risk assessment. 2.3.7.2 Intermediate­ Term Inhalation (7 Days to Several Months) Exposure Study Selected: Subchronic Neurotoxicity Study § 81­ 8, OPPTS 870.6200 MRID Nos.: 44122601 Executive Summary: See 2.3.2 Intermediate­ Term Incidental Oral Exposure Dose/ Endpoint for Risk Assessment: NOAEL = 1.0 mg/ kg/ day based on plasma, whole blood, RBC and brain cholinesterase inhibition and FOB changes at 10 mg/ kg/ day. Comments about Study/ Endpoint: No inhalation studies are available. Since an oral NOAEL was used for this endpoint, an inhalation absorption factor of 100% should be employed in the risk assessment. 2.3.7.3 Long­ Term Inhalation (Longer than 6 months) Exposure Study Selected: Chronic Toxicity ­ Dog § 83­ 1, OPPTS 870.4100 MRID Nos.: 40166701, 42022801 15 Executive Summary: See Chronic Dietary section Dose and Endpoint for Risk Assessment: LOAEL of 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females in the 1 year study. Comments about Study/ Endpoint: No inhalation studies are available. Since an oral NOAEL was used for this endpoint, an inhalation absorption factor of 100% should be employed in the risk assessment. The reasons for selecting this oral study to assess long­ term exposure are described under 2.2 Chronic Reference Dose (RfD). 2.3.5 Margins of Exposure for Occupational/ Residential Risk Assessments The HIARC determined that the acceptable MOE for occupational exposures should be 300 for the following risk assessments: long­ term dermal exposure and long­ term inhalation exposure. The additional 3X is required since a LOAEL was used in these assessments. The acceptable MOEs for residential exposure will be determined by the FQPA SF committee. 2.4 Recommendation for Aggregate Exposure Risk Assessments A common toxicological endpoint of concern (alterations in FOB parameters) was identified for short­ term oral, dermal (oral equivalent) and inhalation (oral equivalent) exposure scenarios. Therefore, these routes can be aggregated for the appropriate populations. A common toxicological endpoint of concern (cholinesterase inhibition) was selected for intermediate­ and long­ term oral, dermal (oral equivalent) and inhalation (oral equivalent) exposure scenarios. Therefore, these routes can be aggregated for these scenarios for the appropriate populations. 3 CLASSIFICATION OF CARCINOGENIC POTENTIAL 1. Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No.: 42918801 Discussion of Tumor Data:. Male rats had significant increasing trends, and significant differences in the pair­ wise comparisons of the 7500 ppm dose group with the controls, for thyroid follicular cell adenomas and combined adenomas and/ or carcinomas, and urinary bladder transitional cell papillomas, carcinomas, and combined papillomas and/ or carcinomas, all at p < 0.01. Female rats had significant increasing trends in urinary bladder transitional cell papillomas, carcinomas, and combined papillomas and/ or carcinomas, all at p < 0.01. There were significant differences in the pair­ wise comparisons of the 7500 ppm dose group with the controls for urinary bladder transitional cell papillomas (p < 0.05), carcinomas (p < 0.05), and 16 combined carcinomas and/ or papillomas (p < 0.01). Adequacy of the Dose Levels Tested: At meetings on October 27 and December 8, 1993, the HED Cancer Peer Review Committee determined that the 7500 ppm dose was excessive based on the following findings: 1) changes in body weight gain during week 13 for males and females by 40% and 52%, respectively, as compared to controls; 2) decreased food efficiency; 3) alterations in hematology and clinical chemistry; and 4) decreases in plasma, RBC and brain cholinesterase at weeks 53 and 105. The CPRC also concluded that the mid dose (1500 ppm) was not adequate for carcinogenicity testing. The November 7, 2001 CARC meeting affirmed that the high dose was excessive and the mid dose was not sufficiently high enough to test the carcinogenic potential of carbaryl in rats. 2. Carcinogenicity Study in Mice MRID No.: 42786901 Discussion of Tumor Data: Male mice had significant increasing trends in kidney tubule cell adenomas (p < 0.05), carcinomas (p < 0.05) and combined adenomas and/ or carcinomas (p < 0.01). There was also a significant difference in the pair­ wise comparison of the 8000 ppm dose group with the controls for combined kidney tubule cell adenomas and/ or carcinomas at p < 0.05. There were significant differences in the pair­ wise comparisons of all dose groups (100, 1000 and 8000 ppm) with the controls for hemangiosarcomas, all at p < 0.05. There were significant differences in the pair­ wise comparisons of 1000 and 8000 ppm dose groups with the controls for hemangiomas and/ or hemangiosarcomas combined, both at p < 0.05. Female mice had significant increasing trends in hepatocellular adenomas and adenomas, carcinomas and/ or hepatoblastomas combined, both at p < 0.01. There were significant differences in the pair­ wise comparisons of the 8000 ppm dose group with the controls for hepatocellular adenomas at p < 0.05 and for hepatocellular adenomas, carcinomas and/ or hepatoblastomas combined at p < 0.01. There was a significant increasing trend at p < 0.01, and a significant difference in the pair­ wise comparison of the 8000 ppm dose group with the controls at p < 0.05, for hemangiosarcomas. There was also a significant increasing trend for hemangiomas and/ or hemangiosarcomas combined at p < 0.05. Adequacy of the Dose Levels Tested: At meetings on October 27 and December 8, 1993, the HED Cancer Peer Review Committee concluded that the 8000 ppm dose was excessive based on the significantly decreased body weight gain in males (33%) and females (19%) during week 13, a significant decrease in RBC and brain cholinesterase activity, clinical signs of toxicity and histopathological changes in the bladder, kidneys and spleen in both sexes. The November 7, 2001 CARC meeting affirmed that the high dose was excessive. 3. Carcinogenicity and Other Studies in p53 Knockout Mice In a special, non­ guideline study (MRID 45281801), heterozygous p53­ deficient (knockout) male mice (20/ group) were administered carbaryl in the diet at concentrations of 0, 10, 30, 17 100, 300, 1000 and 4000 ppm (approximately 0, 1.8, 5.2, 17.5, 51.2, 164.5 and 716.6 mg/ kg/ day, respectively) for six months. The doses selected for this study were based on two 28­ day studies (MRID 45236603) in wild­ type mice in which body weight decreases were observed at 4000 and 8000 ppm concentrations of carbaryl in the diet. A validation study (MRID 45281802) demonstrated that vascular tumors occur in heterozygous p53­ deficient mice within 6 months of administration of a known genotoxic carcinogen (urethane). These studies were conducted to demonstrate that carbaryl is a non­ genotoxic carcinogen. In the standard mouse carcinogenicity study (MRID 42786901) at dietary concentrations of 0, 100, 1000 or 8000 ppm, there was an increased incidence of vascular neoplasms (hemangiomas and hemangiosarcomas) in all treated males and in the 8000 ppm group females. There was an increased incidence of adenomas, multiple adenomas and carcinomas of the kidney in the 8000 ppm group males. The incidence of hepatic neoplasms (adenomas, carcinomas and one hepatoblastoma) was increased in the 8000 ppm group females. At meetings on October 27 and December 8, 1993, the HED Cancer Peer Review Committee concluded that the 8000 ppm dose was excessive. Therefore, the relevance of tumors at this dose was questionable. In the p53 knockout mouse study with carbaryl, there was a slight decrease in body weight and food consumption in the 4000 ppm group. No other treatment­ related effects were observed, except globular deposits in the urinary bladder were observed in a high proportion of the mice treated at 100 ppm of carbaryl and above with a dose­ related increase in incidence and severity. There was no evidence of local irritation or hypertrophy of the bladder epithelium. There was no evidence of neoplastic or preneoplastic changes in the vascular tissue of any organs examined. The study is classified Acceptable (non­ guideline). This is a special study not submitted to fulfill a data requirement. 4. Classification of Carcinogenic Potential. The carcinogenic potential of carbaryl was evaluated by the HED Carcinogenicity Peer Review Committee on October 27 and December 8, 1993 (May 12, 1994 report). The Committee concluded that carbaryl induced tumors at multiple sites in the rat and mouse at doses considered to be excessively toxic. Only hemangiosarcomas in the CD­ 1 male mouse occurred at a dose which was considered adequate and not excessive. The Committee concluded that carbaryl should be classified as a Group C ­ possible human carcinogen. Both the low­ dose extrapolation (Q1*) approach and a margin of exposure (MOE) approach were suggested as methods of quantifying the cancer risk in humans. In addition, a RfD approach was suggested to provide the most sensitive non­ cancer health endpoint for comparison to the linear and MOE approaches. The Committee requested additional metabolism studies and genotoxicity studies to: 1) direct the selection of the more appropriate quantitative approach; and 2) provide insight into the significance of tumors seen only at excessively toxic doses. Additional metabolism studies were submitted and evaluated by a subgroup of the HED Cancer Assessment Review Committee (CARC) in a memorandum signed October 5, 1998. The subgroup concluded that the available metabolism studies were not adequate to support a nonlinear mode of action and recommended that the default linear approach be used for risk 18 quantitation. In 1996, the registrant convened a Pathology Working Group (PWG) which reevaluated all histopathology findings of both the two­ year rat and mouse studies. The results of this PWG are discussed below with the study summaries. At a November 7, 2001 meeting, the HED CARC classified carbaryl as "Likely to be carcinogenic to humans" based on a statistically significant increase in hemangiosarcomas in male mice at all doses tested (100, 1000 and 8000 ppm), all at p< 0.05. In addition, there were preneoplastic lesions in the bladders of male rats at the mid dose (1500 ppm) which was not considered adequate for carcinogenicity testing. Bladder tumors were observed in male rats at the high dose which was considered excessive. The unit risk, Q1 * (mg/ kg/ day) ­1 , of Carbaryl is 8.75 x 10 ­4 in human equivalents based on the 1996 PWG re­ read of the male mouse hemangiosarcoma tumor rates. 4 MUTAGENICITY During the meetings on October 27, and December 8, 1993, the CPRC (1994) recommended that an in vivo cytogenetic assay in rodents be conducted to provide insight into the structural and/ or numerical aberrations, which were observed in the gene mutation assay and reported in the open literature. In response to CPRC's request, a mouse micronucleus assay (MRID 44069301) was submitted to fulfill the guideline requirement but it was classified as unacceptable. A recent review of the data from the submitted studies and the published literature were in general agreement and show that carbaryl is clastogenic in vitro. The wide variety of induced aberrations (both simple and complex) was consistent between the submitted study and the open literature. However, there are inconsistencies relative to the requirement for S9 activation. Nevertheless, the two in vivo studies for micronuclei induction or chromosome aberrations were negative. Similarly, the 6­ month p53 knockout transgenic mouse bioassay was negative up to a high level (4000 ppm, . 720 mg/ kg/ day) that approached the limit dose for a mouse carcinogenicity assay. Carbaryl was also negative for DNA binding in the livers of mice treated with 8000 ppm for 2 weeks but the study was considered to be of limited sensitivity by the CARC Metabolism Subgroup (HED Document No. 012892). The same Subgroup identified epoxide intermediates of carbaryl which were found to be conjugated to glucuronide, "rapidly metabolized and excreted as any endogenous epoxide would be". Overall, these findings indicate that carbaryl produces epoxides and its DNA reactivity is manifested as chromosomal aberrations in cultured mammalian cells. Other in vitro studies indicate carbaryl's effects on karyokinesis and cytokinesis, as well as stress genes associated with oxidative damage. Based on these considerations, it was concluded that there is a concern for mutagenicity, which is somewhat lessened because of the lack of an effect in in vivo mutagenicity studies. 19 GENE MUTATIONS Mutagenicity ­ Salmonella typhimurium/ Mammalian Microsome Mutagenicity Assay (Ames test) In a Salmonella/ mammalian activation gene mutation assay (MRID 41370303), carbaryl technical (99.3%) was initially evaluated in the Salmonella typhimurium/ microsome mutagenicity assay over a concentration range of 5 to 1000 µg/ plate. The test material was not mutagenic, however the highest assayed dose was cytotoxic in S. typhimurium strains TA98 and TA100, but not in strains TA1535, TA1537, or TA1538. Accordingly, the assay was repeated with six concentrations (10 to 2000 µg/ plate +/­ S9). Results from the repeat assay indicated that 2000 µg/ plate +/­ S9 was cytotoxic in strains TA98 and TA100, and the remaining doses were not mutagenic. It is concluded, therefore, that carbaryl technical was assayed to an appropriately high concentration with no evidence of mutagenicity in a wellconducted study. The study is classified as acceptable/ guideline and satisfies the guideline requirements (§ 84­ 2) of bacterial reverse mutation test. Mutagenicity ­ Mammalian Cells in Culture Gene Mutation Assay in Chinese Hamster Ovary (CHO) Cells In a mammalian cells in culture gene mutation assay in Chinese Hamster Ovary (CHO) Cells (MRIDs 41370302, 41420201), carbaryl technical (99.3%) was evaluated in two nonactivated and three S­ 9 activated Chinese hamster ovary (CHO) cell forward mutation assays. The findings from both nonactivated assays were in good agreement and indicated that over a concentration range of 1 to 300 µg/ mL, the test material did not induce a mutagenic response. Doses $ 200 µg/ mL were severely cytotoxic (< 10% cell survival), and <50% of the cells survived exposure to $ 50 µg/ mL. Carbaryl was less cytotoxic in the presence of S9 activation as indicated by increased survival at comparable levels in the preliminary cytotoxicity test (e. g., 29.5% survival at 62.5 µg/ mL ­S9 as compared with 95.7% survival at 62.5 µg/ mL +S9) and the initial mutation assay (e. g., 18.1% survival at 100 µg/ mL ­S9 as compared with 46.8% at 100 µg/ mL +S9). There was no definitive evidence of increased mutation frequencies (MFs) in this trial. The second S9­ activated trial was aborted because of excessive cytotoxicity at test material levels of $ 10 µg/ mL. Results from the third S9­ activated trial (dose range: 1 to 80 µg/ mL) showed severe cytotoxic effects at levels $ 60 µg/ mL; no evidence of mutagenic effect was seen at the remaining doses. The results of the assays provide no clear indication of a mutagenic response, however, the study does not fully support a negative conclusion. The conflicting cytotoxicity data for the S9­ activated assays provide no assurance that the final S9­ activated mutation assay was conducted over an appropriate dose range. The study is classified as unacceptable/ guideline and does not satisfy the guideline requirements (§ 84­ 2) for an in vitro mammalian cell gene mutation test. 20 CHROMOSOME ABERRATIONS Mutagenicity ­ Mammalian Cells in Culture Cytogenetic Assay Carbaryl (technical) was assayed for clastogenic effects in both the presence and absence of S9 activation using Chinese hamster ovary (CHO) cells (MRID 41370301). Because of severe cell cycle delay, which was more pronounced without S9 activation, a 20­ hour cell harvest was selected to evaluate seven nonactivated doses ranging from 5 to 100 : g/ mL. In the presence of S9 activation, cells exposed to carbaryl at doses of 25, 50, 75, 100, 150, 200, 250, and 300 : g/ mL were harvested 30 hours post treatment. Results indicated that the nonactivated test material was more cytotoxic than the S9­ activated test material (i. e., few metaphases were recovered at 75 and 100 : g/ mL , and moderate to slight cytotoxic effects were seen at doses $ 10.0 : g/ mL). With the exception of a single rare complex aberration (quadriradial) scored at the 50.0­ : g/ mL dose level, there was no evidence of a clastogenic effect. By contrast, in the S9­ activated assays, all scored doses (150, 200, 250, and 300 : g/ mL) at both harvest times induced significant (p 0.01) increases in the percentage of cells with aberrations. The majority of S9­ activated doses (both harvests) also induced significant (p 0.01) increases in the percentage of cells with >1 aberration. At both the 20­ and 30­ hour harvest times, cytotoxicity (i. e., reduced monolayers, dead cells, and/ or reduced mitotic cells) were observed at levels $ 200 : g/ mL. Induced structural damage included simple (i. e., chromatid and chromosome breaks) and complex aberrations (i. e., triadials, quadriradials, complex rearrangements, dicentrics and rings). The data show little or no dose responsiveness and the lowest reactive level of carbaryl was not determined. It was concluded, however, that the study was technically sound and, therefore, acceptable/ guideline. The study satisfies the Guideline requirements (§ 84­ 2) for an in vitro mammalian cell chromosomal aberration test. Mutagenicity ­ Mouse Micronucleus Test In a mouse micronucleus assay (MRID No: 44069301), groups of five male and five female CD­ 1 mice received single oral gavage administrations of 50, 100 or 200 mg/ kg carbaryl (99.9%) once daily for 2 days. Based on analytical determinations, average daily doses were . 34, 79 or 180 mg/ kg. Mice were sacrificed at 24 and 48 hours postadministration of the second dose and harvested bone marrow cells were examined for the incidence of micronucleated polychromatic erythrocytes (MPEs). The test material was delivered as suspensions prepared in 0.5% carboxymethyl cellulose. The minimal toxicity (i. e., lethargy which lasted for 2 hours) in the absence of cytotoxicity to the target cells does not support the testing of the maximum tolerated dose (MTD). The positive control induced the expected high yield of MPEs in males and females. Carbaryl did not induce a clastogenic or aneugenic effect in either sex at any dose or sacrifice time. However, there was no convincing evidence that the MTD was achieved. The study is classified as unacceptable/ guideline and does not satisfy the guideline requirements(§ 84­ 2; OPPTS 870.5385) for in vivo cytogenetic mutagenicity data. 2 Onfelt, A., Klasterska, I. (1984). Sister ­chromatid exchanges and thioguanine resistance in V79 Chinese hamster cells after treatment with the aneuploidy­ inducing agent carbaryl +/­ S9 mix. Mutat Res 125( 2): 269­ 274 3 Ahmed, F. E., Lewis, N. J., Hart, R. W. (1977). Pesticide induced ouabain resistant mutants in Chinese hamsterV79 cells. Chem Biol Interact, 19: 369­ 374. 4 Onfelt, A., Klasterska, I. (1983). Spindle disturbances in mammalian cells II. Induction of viable aneuploidy/ polyploidy cells and multiple chromatid exchanges after treatment of V79 Chinese hamster cells with carbaryl, modifying effect of glutathione and S9. Mutat Res 119: 319­ 330. 5 Delescluse, C. et al (2001). Induction of cytochrome P450 1A1 gene expression, oxidative stress, and genotoxicity by carbaryl and thiabendazole in transfected human HepG2 and lymphoblastoid cells. Biochem Pharmacol. 61( 4): 399­ 407. 6 Renglin, A., Olsson A., Wachtmeister, C., Onfelt, A. (1998). Mitotic disturbance by carbaryl and the metabolite 1­ naphthol may induce kinase­ mediated phosphorylation of 1­ naphthol to the protein 21 OTHER MUTAGENIC EFFECTS Mutagenicity ­ UDS Assay In a UDS Assay in primary rat hepatocytes (MRID 41370301), under the conditions of two independent trials, six doses of carbaryl technical (99.3%) ranging from 0.5 to 25.0 µg/ mL in the first assay and six doses ranging from 5.0 to 25.0 µg/ mL in the repeat assay did not induce an appreciable increase in the net nuclear grain counts of treated rat hepatocytes. Doses >25.0 µg/ mL were severely cytotoxic; reduced cell survival ( 25%) was observed at 25.0 µg/ mL in both assays. Although an increase in the percentage of cells with $ 6 grains per nucleus was seen in the initial test, the increase was confined to a single dose (10 µg/ mL) and was not dose­ related or reproducible. The study demonstrated that carbaryl is not genotoxic in this test system at doses of 5.0 to 25.0 µg/ mL. The study is classified as acceptable/ guideline and satisfies the guideline requirements (§ 84­ 2) for a unscheduled DNA synthesis in mammalian cells in culture. STUDIES FROM THE OPEN LITERATURE Studies in the open literature indicate that Carbaryl is not mutagenic in bacteria but produced conflicting results in Chinese hamster V79 gene mutation assays [negative in the study of Onfelt and Klasterska 2 but weakly positive minus S9 metabolic activation as reported by Ahmed et al. 3 Nonactivated carbaryl induced aneuploidy and sister chromatid exchanges in V79 cells; the addition of S9 or an excess of glutathione eliminated these responses (Onfelt and Klasterska 4,2 ). In the former study, multiple chromatid exchanges (quadriradials and complex rearrangements) plus chromosome breaks were also induced by 100 mM carbaryl; this effect was largely abolished by the simultaneous addition of S9 or glutathione. There are positive data for DNA damage in a human lymphoblastoid cell line (induction of CYP1A1 genes); carbaryl also activated other stress genes known to be sensitive to oxidative damage (Delescluse et al. 5 ). Also, carbaryl causes depolymerization of spindle microtubules and an apparent uncoupling of karyokinesis and cytokinesis in cultured V79 cells (Renglin et al, 6,7 ). phosphatase inhibitor 1­ naphthyl phosphate. Mutagenesis 13: 345­ 352. 7 Renglin, A., Harmala­ Brasken, A., Eriksson, J., Onfelt, A. (1999). Mitotic aberrations by carbaryl reflect tyrosine kinase inhibition with coincident up­ regulation of serine/ threonine protein phosphatase activity: implications for coordination of karyokinesis and cytokinesis. Mutagenesis 14: 327­ 333. 8 Usha Rani, M. V., Reddi, O. S. and Reddy, P. P. (1980). Mutagenicity Studies Involving Aldrin, Endosulfan, Dimethoate, Phosphamidon, Carbaryl and Ceresan. Bull Environm. Contam. Toxicol 25: 277­ 282. 9 Dzwonkowska, A., Hubner, H. (1986). Induction of chromosomal aberrations in the Syrian hamster by insecticides tested in vivo. Arch Toxicol 58( 3): 152­ 156. 22 In contrast to the in vitro data, carbaryl administered by oral gavage at 1/ 3 of the LD50 (146 mk/ kg/ day) for 2 consecutive days was negative for micronuclei induction in Swiss albino male mice (Usha Rani et al. 8 ). Carbaryl was also negative for the induction of chromosome aberrations in bone marrow cells of Syrian hamsters treated with 1/ 10, 1/ 5 and ½ of the LD50 and the LD50 (Dzwonkowska and Hubner 9 ). 5 FQPA CONSIDERATIONS 5.1 Adequacy of the Data Base The data base is adequate for FQPA considerations. The following acceptable studies are available: ­­ Acute delayed neurotoxicity study in hen ­­ Acute and subchronic neurotoxicity studies in rats ­­ Developmental toxicity studies in rats and rabbits ­­ Multi­ generation reproduction study in rats ­­ Developmental neurotoxicity study in rats 5.2 Neurotoxicity Carbaryl was not a delayed neurotoxicant in the hen. In the acute neurotoxicity study with gavage administration, FOB changes (increased tremors and ataxia, decreased body temperature and arousal) and decreased motor activity were observed in males and females at 50 and 125 mg/ kg. Decreases in plasma (males only), whole blood, RBC and brain cholinesterase were seen at 10, 50 and 125 mg/ kg/ day. In the subchronic neurotoxicity study with gavage administration, there was an increased incidence of tremors and salivation in males and females at 30 mg/ kg/ day. FOB changes (increases in tremors, gait alteration, pinpoint pupils, salivation, etc.) were observed in males and females at 10 and 30 mg/ kg/ day. Motor activity was decreased in males and females at 30 mg/ kg/ day. Plasma, RBC, whole blood and brain ChE were decreased in males and females at 10 and 30 mg/ kg/ day. At necropsy, there was an increase in dark areas of the meninges of the 30 mg/ kg/ day males. 23 In the developmental neurotoxicity study with gavage administration, changes in FOB parameters (increases in pinpoint pupils, tremors, ataxia, overall gait incapacity) were seen in the maternal animals at 10 mg/ kg/ day. RBC and whole blood ChE was decreased on gestation day (GD) 20 and lactation day (LD) 10 at 10 mg/ kg/ day. Plasma ChE was decreased on GD 20, LD4 and LD10 at 10 mg/ kg/ day. Brain ChE was decreased at 10 mg/ kg/ day. In both the F1 pups and adults, there were differences in the morphometric measurements from the control group at 10 mg/ kg/ day. In the chronic dog study with dietary administration, clinical signs of neurotoxicity (emesis, lacrimation, salivation and tremors) were observed in females at 1250 ppm (31.3 mg/ kg/ day). Plasma and brain ChE were decreased in females at doses of 125 ppm (3.1 mg/ kg/ day) and above and in males at 400 ppm (10 mg/ kg/ day) and above. RBC ChE was decreased in males and females at 400 ppm and above. In a five­ week study done to upgrade the chronic study, plasma ChE was decreased in males at 125 ppm (3.83 mg/ kg/ day), the highest dose tested. In the mouse carcinogenicity study with dietary administration, there were clinical signs of toxicity (hunched posture, thin and languid appearance, squinted and opaque eyes, etc.) at 8000 ppm (M: 1248.93 mg/ kg/ day; F: 1440.62 mg/ kg/ day) but they were not the usual signs seen with cholinesterase inhibiting chemicals. RBC cholinesterase (ChE) was statistically significantly decreased in the 1000 ppm (145.99 mg/ kg/ day) (23% 9 ) and 8000 ppm (30% 9 ) group males at week 53. RBC ChE was decreased in the 8000 ppm group females (24% 9 ) at week 105, although the change was not statistically significant. Brain ChE was statistically significantly decreased in the 1000 and 8000 ppm group males at both weeks 53 and 105 (13­ 18% 9 for the 1000 ppm group; 40­ 57% 9 for the 8000 ppm group) and in the 8000 ppm females (34­ 47% 9 ). Brain ChE was also significantly decreased (13% 9 ) in the 1000 ppm (180.86 mg/ kg/ day) group females at week 53. However, the percentage decreases from the control level were less than 20% for the 1000 ppm group males and females at both weeks 53 and 105. Therefore, the biological significance of these findings is questionable. Plasma ChE values were not affected by treatment. In the rat combined chronic toxicity/ carcinogenicity study with dietary administration, there were increased signs of toxicity in the 7500 ppm (M: 349.5 mg/ kg/ day; F: 484.6 mg/ kg/ day) group, but they were not the usual signs seen with cholinesterase inhibiting chemicals. Plasma cholinesterase was decreased in the 7500 ppm males (27­ 42%) and females (46­ 57%) at all of the testing intervals (weeks 27, 53, 79 and 105), however all of the changes were not statistically significant. RBC cholinesterase was decreased in the 7500 males (19­ 37%) and females (25­ 38%) and in the 1500 ppm (60.2 mg/ kg/ day) males (10­ 23%) and females (12­ 26%) at most of the testing intervals. At weeks 53 and 105, brain cholinesterase was statistically significantly decreased in the 7500 ppm males (8­ 28%) and females (22­ 31%). In the recovery group, cholinesterase values had returned to normal levels by week 56. 24 5.3 Developmental Toxicity Prenatal developmental toxicity study in the rat In a developmental toxicity study (MRID 44732901), carbaryl (99% a. i.) in an aqueous methylcellulose suspension was administered by gavage at 0, 1, 4, and 30 mg/ kg/ day to pregnant Crl: CD (SD) BR rats (25/ dose) during gestation days (GDs) 6 through 20. At GD 21, surviving dams were sacrificed and necropsied. There were no treatment­ related gross pathologic findings noted in any of the dams. There were no differences of toxicological concern in mortality, pregnancy rate, numbers of corpora lutea, implantations, viable fetuses, pre­ and post­ implantation losses, placental weights, and sex ratio. At 30 mg/ kg/ day, at least one occurrence of post­ dosing salivation occurred in 18/ 25 of the dams (vs 0/ 25 controls). This clinical sign appeared within 20 minutes of treatment, disappeared after approximately one hour, and was observed from GD 13 to 20. There were no deaths and no other treatment­ related clinical signs. Body weights of the high­ dose dams were 3­ 8% less than controls throughout the study (not statistically significant); their corrected (for gravid uterine weight) body weights and body weight gains were decreased (p 0.01) by 7 and 38%, respectively. Body weight gains in this group were decreased immediately after initiation of dosing (GDs 6­ 9, 9 108%, p 0.01) and throughout treatment (overall, 9 27%, p 0.01). Food consumption (g/ animal/ day) was decreased throughout the treatment period ( 10­ 17%, p 0.01). There were no differences of toxicological concern observed in the mid­ and low­ dose groups. The maternal LOAEL is 30 mg/ kg/ day based on clinical signs of toxicity, decreased body weight gains and food consumption. The maternal NOAEL is 4 mg/ kg/ day. In the high­ dose fetuses, mean fetal body weights were reduced ( 7­ 8%, p 0.01). Additionally, the following were observed in the high­ dose male and female fetuses: (i) an increase in incomplete ossification of the 5th sternebra, (ii) unossified 7th cervical centrum, (iii) incomplete ossification of 7th cervical centrum, and (iv) unossified 1st metatarsal. No effects on fetal viability were observed. There were no treatment related effects in developmental parameters observed in the mid­ and low­ dose groups. The developmental LOAEL is 30 mg/ kg/ day based on decreased fetal body weights and increased incomplete ossification of multiple bones. The developmental NOAEL is 4 mg/ kg/ day. The developmental toxicity study in the rat is classified as acceptable (§ 83­ 3( a)) and does satisfy the guideline requirement for a developmental toxicity study in the rat. 25 Prenatal developmental toxicity study in the rabbit In a developmental toxicity study (MRID 44904202), carbaryl (99% a. i.) in an aqueous methylcellulose suspension was administered by gavage at doses of 0, 5, 50 or 150 mg/ kg/ day to pregnant New Zealand White rabbits (22/ dose) during Gestation Days (GD) 6­ 29. On GD 25, blood was collected 1 hour post­ dosing for plasma and red blood cell (RBC) cholinesterase (ChE) measurements. At GD 30, surviving dams were sacrificed and necropsied; fetuses were examined for evidence of developmental effects. Maternal toxicity at 150 mg/ kg/ day was observed as statistically significant decreased body weight gain as compared to the control value during GD 6­ 9 (208%), GD 6­ 29 (dosing period, 53%), GD 3­ 30 (33%) and gestation (GD 0­ GD 30, 38%). Corrected body weight change was also decreased at this dose (­ 219.73 g vs ­81.86 g in the control). Although not statistically significant, the body weight decreases at 50 mg/ kg/ day can be considered biologically significant for GD 6­ 9 (55%), GD 6­ 29 (25%), GD 3­ 30 (14%) and gestation (14%). There was no treatment­ related effect on food consumption. Statistically significantly decreases in plasma (46­ 68%) and RBC (19­ 27%) ChE were seen at 50 and 150 mg/ kg/ day. Maternal LOAEL = 50 mg/ kg/ day based on decreased body weight gain and decreased plasma and RBC ChE; Maternal NOAEL = 5 mg/ kg/ day The only evidence of developmental toxicity was a statistically significant decrease in fetal body weights of 10% (when calculated for all fetuses or individually for males and females) at 150 mg/ kg/ day. There were no treatment­ related developmental effects observed in the mid­ and low­ dose groups. Developmental Toxicity LOAEL is 150 mg/ kg/ day based on decreased fetal weight. Developmental Toxicity NOAEL is 50 mg/ kg/ day The developmental toxicity study in the rabbit is classified as acceptable/ guideline and does satisfy the guideline requirement for a developmental toxicity study in the rabbit. 5.4 Reproductive Toxicity In a two­ generation reproduction study (MRID 45448101), carbaryl (99.1% a. i, Lot No. E1208008) was given in the diet to groups of 30 male and 30 female F0 and F1 rats (CD ® [SD] IGS BR (Sprague­ Dawley)) at concentrations of 0, 75, 300, or 1500 ppm. The dietary concentrations corresponded to doses of 4.67, 31.34, and 92.43 mg/ kg/ day for F0 males; 0, 5.56, 36.32, and 110.78 mg/ kg/ day for F0 females; 0, 5.79, 23.49, and 124.33 mg/ kg/ day for F1 males; and 0, 6.41, 26.91, and 135.54 mg/ kg/ day for F1 females averaged over the premating period. Each group received treated or control diet continuously for 70 days prior to mating and during mating, gestation, and lactation of one litter per generation. F1 pups selected to parent the F2 generation were weaned onto the same food as their parents. Parental males were sacrificed after delivery of their litters and parental females were sacrificed after weaning of their litters. No treatment­ related deaths, clinical signs, organ weight changes, gross lesions, or 26 microscopic lesions were observed in adult rats of either generation. No treatment­ related effects were observed on body weights, weight gain, feed consumption, or food efficiency in 75­ or 300­ ppm group F0 or F1 male or female rats at any time during the study including the gestation and lactation periods of the females. F0 and F1 male and female rats fed the 1500­ ppm diet weighed significantly (p< 0.01 or <0.05) less and gained less weight during the premating period. The F0 males weighed 5­ 6% less than controls during premating, gained 14­ 23% less weight during three weekly intervals up to day 45, and gained 9% less weight over the entire premating period; they also gained 8% less weight than controls over the mating/ postmating period. The F1 males weighed 10­ 19% less than controls during the entire study, gained 16% and 11% less weight during the first two weekly intervals, and gained 8% less weight than controls averaged over the entire premating period. The F0 females weighed 4­ 5% less than controls during the first 42 days of premating, gained 27% less weight during the first week, and 7% (N. S.) less averaged over the entire premating period. The F1 females weighed 8­ 22% less than controls throughout premating and gained 9% less weight during the first week; weight gain for the remaining weekly intervals and for the entire premating period was similar to that of controls. Food consumption and food efficiency for F0 and F1 rats followed patterns similar to that of body weight and weight gain; the largest difference between the 1500­ ppm groups and controls occurred during the early part of the premating period. When averaged over the entire premating period, F0 and F1 males consumed 6­ 7% less food than control and had food efficiency values similar to those of the controls. Feed consumption and food efficiency for the F0 females were similar to those of the control group, whereas F1 females consumed 9% (p< 0.01) less feed and had a food efficiency value 10% (p< 0.01) greater than that of controls. F0 and F1 females in the 1500 ppm group weighed less and gained less weight than controls during gestation, with the effect being greater in the F1 females. During lactation weight gain was markedly reduced in F1 females during the first 4 days, but was greater than that of controls averaged over the entire lactation period. The lowest­ observed­ effect level (LOAEL) for parental systemic toxicity is 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption. The no­ observed­ adverseeffect (NOAEL) level is 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females). No treatment­ related effects were observed on the estrous cycle of either F0 or F1 females at any dose level or on percent motile sperm, sperm count, percent progressively motile sperm, epididymal sperm count, spermatid head count, daily sperm production, or efficiency of daily sperm production in F0 or F1 males at any dose level. There was a dose­ related increase in the percentage of abnormal sperm in the treated males but no statistical significance at any dose level. No treatment­ related gross or microscopic effects were observed in male or female rats of either generation. No treatment­ related effects were observed on any parameter of reproductive performance including, mating and fertility indexes, gestation index, pregnancy index, precoital duration, gestation length, or number of females producing live litters. 27 The LOAEL for reproductive toxicity could not be established because no effects were observed at any dose level; therefore, the NOAEL is $ 1500 ppm (92.43­ 124.33 mg/ kg/ day for males and 110.78­ 135.54 mg/ kg/ day for females). No treatment­ related effects were observed on implantation sites/ litter, number of live pups born/ litter, number of dead pups born/ litter, live birth index, sex ratio, clinical signs, or organ weight or necropsy findings in pups surviving to 21 days. Pup survival was decreased at 300 and 1500 ppm for both generations. Increased number of deaths in the F2 generation males and females resulted in an 18­ 19% decrease in mean litter size on postnatal day 4 (p< 0.01 or <0.05) and decreased viability and lactation indexes at 1500 ppm. A large number of pups that died had no milk in their stomachs. In addition, pup weight/ litter and pup weight gain in the 1500­ ppm group pups were reduced for both generations starting with postnatal day 4 (11­ 15% for F1 and 13­ 23% for F2 pups); body weight gain was reduced throughout lactation with the greatest effect occurring during the first 7 days for F1 pups and the first 14 days for F2 pups. Sexual maturation was delayed in 1500­ ppm group F1 offspring as evidenced by delayed balanopreputial separation in the males (+ 2.1 days) and vaginal patency in the females (+ 1.4 days). The differences remained statistically significant after adjustment for body weight decreases. Anogenital distance was significantly reduced in F2 male pups in the 1500­ ppm group, but not when the distance was adjusted for body weight. The LOAEL for offspring toxicity was 300 ppm (23.49­ 31.34 mg/ kg/ day for males and 26.91­ 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival. The NOAEL is 75 ppm (4.67­ 5.79 mg/ kg/ day for males and 5.56­ 6.41 mg/ kg/ day for females). This study is Acceptable/ Guideline and satisfies the guideline requirement for a twogeneration reproductive study (OPPTS 870.3800; OECD 416) in the rat. 5.5 Developmental Neurotoxicity (Executive Summary has been revised based on new morphometric measurements from MRID 45456701) In a developmental neurotoxicity study (MRID # 44393701, 45456701, 45456702, 45456703), 26 pregnant female Sprague­ Dawley rats/ group were administered carbaryl (99.1% a. i.) by gavage from Gestation Day (GD) 6 through Lactation Day (LD) 10 at doses of either 0, 0.1, 1.0 or 10 mg/ kg/ day. An additional 6 pregnant females/ group were dosed at the same levels for the cholinesterase (ChE) phase of the study. ChE measurements were done pre­ dosing (GD 6) and post­ dosing at time of peak effect (1 hour post­ dosing) on GD 6, 15 and 20 and LD 4 and 10. Functional Observational Battery (FOB) measurements were performed at approximately 0.5 and 2 hours post­ dosing on the same days as body weight measurements during the dosing period (GD 0, 6, 9, 12, 15, 18 and 20 and LD 4, 7, 11, 13 and 21). Measures of reproductive performance were evaluated. Offspring were examined for body weight, physical development landmarks (tooth eruption and eye opening), FOB assessments (days 4, 7, 11, 13, 17 and 21) and motor activity (days 13, 17 and 21). On LD 11, 1 animal/ sex/ litter was sacrificed for brain weights; of these, six/ sex were randomly selected for neuropathological evaluation. The eyes from all dose groups were examined. After LD 21, 28 3 animals/ sex/ litter were separated from the dams and constituted the F1 adult generation. These animals were evaluated for body weight, physical development (vaginal opening and preputial separation), motor activity (day 60), startle habituation response (days 22 and 60), passive avoidance (day 23) and water maze behavior (day 60). After completion of the behavior test period (at approximately 10 weeks of age), 12 animals/ sex/ group were anesthetized and perfused for post­ mortem examination. Tissues from 6 animals/ sex of the control and high dose group were processed for neuropathological evaluation and morphometric measurements; the eyes from the low and mid­ dose group of all perfused animals were examined. For the F0 generation animals, there were no carbaryl­ associated deaths. No treatment­ related clinical signs of toxicity were observed. There was a statistically significant decrease (92%) in body weight gain for females in the 10 mg/ kg/ day group for the period GD 6­ 9. Unfortunately, food consumption was not measured during the study. During the FOB measurements, the incidence of females in the 10 mg/ kg/ day group with decreased pupil size (pinpoint pupils) was increased on all occasions during the dosing period. An increased incidence of dams with slight tremors affecting the head, body and/ or limbs was noted on the majority of assessment occasions in the dosing period. There were also occasional occurrences of ataxic gait/ overall gait incapacity which was considered to be of toxicological significance due to other effects upon gait. For the 10 mg/ kg/ day group, RBC and whole blood ChE levels were statistically significantly decreased (28% and 32­ 34%, respectively) on GD 20 and LD 10. Although the plasma ChE levels were not statistically significantly altered, the percentage decreases on GD 20, LD 4 and LD 10 were 32­ 39%. Brain ChE levels were statistically significantly decreased (42%). There were no treatment­ related effects on gross necropsy findings for the F0 generation animals. There were no effects observed on maternal performance parameters of pregnancy rate, gestation index, length of gestation, numbers of live pups, dead or malformed pups, implantation scars, sex ratio or post­ implantation loss. There was a slight (P> 0.05) increase in the number of dead pups in the 10 mg/ kg/ day group, however the value was within the historical control range for this strain. For the F1 generation pups, there were no treatment­ related effects on pup weight, pup survival indices, developmental landmarks (tooth eruption and eye opening), FOB measurements or motor activity assessments. At sacrifice on LD 11, there were no treatmentrelated effects on brain weight and gross or microscopic pathology. Significant differences noted in the morphometric measurements included an increase in Line B of the right forebrain and Line F of the left cerebellum in the 10 mg/ kg/ day males. In the 10 mg/ kg/ day females, Line F through both the right and left cerebellum was decreased (15% and 22%, respectively). For the F1 generation adults, there were no treatment­ related effects on clinical condition, body weight, physical development (vaginal opening and preputial separation), motor activity, auditory startle response, passive avoidance and water maze measurements. At sacrifice, there were no gross or microscopic neuropathological lesions observed for animals examined in this study that were attributable to treatment with the test article. There was an increased incidence of retinal fold/ rosette in the 10 mg/ kg/ day group (1/ 12 for control vs. 4/ 12 for males; 0/ 12 for control vs. 2/ 12 for females). The finding was not considered of toxicological significance since the incidence was within the historical control range for 10 Personal communication with Robert Chapin, one of the study authors 29 males, occurred at a low rate and was not dose­ dependent. For the morphometric measurements, there was a significant bilateral decrease in Line A through the forebrain (7.7­ 9.8%) and a significant increase in Line F through the right cerebellum of the 10 mg/ kg/ day males. Increases originally noted in the 10 mg/ kg adult females in Line G, width of the cerebellum, were found to be based on erroneous measurements, and additional measures were submitted. Now, for the 10 mg/ kg/ day females, there were significant bilateral increases in Line F through the cerebellum (7.4­ 15%). Measurements of the size of the thickness of lobes and of the granule cell layers of the cerebellum in high dose pups and adults did not differ from those of controls. While additional statistical analyses by the registrant indicated no treatment related effects, HED's additional statistical analyses did indicate treatment related effects. The maternal toxicity LOAEL was 10 mg/ kg/ day based on decreased body weight gain, alterations in Functional Observational Battery measurements and RBC, plasma, whole blood and brain cholinesterase inhibition. The maternal NOAEL was 1.0 mg/ kg/ day. The developmental neurotoxicity LOAEL was 10 mg/ kg/ day based bilateral decrease in the size of the forebrain (Line A) in adult males (7.7­ 9.8%); a bilateral decrease in the length of the cerebella (Line F) in female pups (15­ 22%); and a bilateral increase in the length of the cerebella (Line F) in female adults (7.4­ 15%). The developmental NOAEL was 1.0 mg/ kg/ day. Morphometric assessment at the mid and low doses could not be conducted due to inadequate tissue storage; however, based on the minimal findings at the LOAEL, it is HED's judgment that effects would be unlikely to occur at 1 mg/ kg/ day, which is 10% of the LOAEL. This developmental neurotoxicity study is classified acceptable and does satisfy the guideline requirement for a developmental neurotoxicity study (OPPTS 870.6300) in rats. 5.6 Additional Information from Literature Sources In an unpublished study from the National Health and Ecological Effects Research Laboratories, EPA, and the National Institute for Environmental Health Sciences/ National Toxicology Program, pregnant Sprague­ Dawley rats (n= 36 or 38) were dosed by gavage with carbaryl at doses of 0, 6, 12 or 25 mg/ kg/ day. 10 The following description of the study design and findings was extracted from tables and posters discussing various aspects of the study. The dams were dosed from gestational day (GD) 14 to postnatal day (PND) 7, after which the pups were directly dosed with the same dose levels until PND 21 (weaning) or PND 42. Analyses for carbaryl and 1­ naphthol in the dam's plasma and milk and pup's plasma were performed. A sample of milk was incubated with a preparation of rat brain to provide a bioassay of ChE activity. The brains were taken from a dam and two fetuses sacrificed at various times after dosing on GD 18 to measure ChE. Some pups (n= 4­ 6/ dose/ sex) were sacrificed on PND 1, 7, 21 and 47 and body and brain weights recorded. FOB and motor 11 Pant N, Shankar R, Srivastava SP (1996). Spermatotoxic effects of carbaryl in rats. Human Exp Toxicol 15( 9); 736­ 38. 30 activity were measured on PND 26/ 27, 47/ 48, 62/ 63 and 81/ 82. In the post­ weaning period, cognitive function was evaluated using a simple test of associative learning, passive avoidance, and in adulthood by assessing between­ session habituation of motor activity. Sperm counts, organ weights and clinical pathology were done on males at necropsy. Carbaryl or 1­ naphthol were not present in the pups' plasma above the limit of detection at any exposure concentration. In the dams' plasma, carbaryl was below the limit of detection for the 6 mg/ kg/ day dose, but was present in some or most of the animals from the other two doses. 1­ naphthol was present in all treated groups in a dose­ related increase. In general, milk concentrations followed the trends seen in plasma, however 1­ napthol was about 3­ 5 times lower in milk compared to plasma. There was a dose­ related suppression of brain ChE produced by the blood samples. There was a dose­ related decrease in ChE activity in the brain and blood of dams at GD 19, and fetuses taken at that time also showed a very similar level of inhibition in fetal brain. There was a decrease in the number of live pups/ litter in the 25 mg/ kg/ day group at PND 0, 7, and 21. The average pup weight was decreased in the 25 mg/ kg/ day group at PND 1, 7, 14 and 21. There were no changes in cognitive function. For brain weights measured on PND 0, 7, 21 and 47, the only change was on PND 21 when the 25 mg/ kg/ day group was decreased in males and the low and high dose groups were decreased in females. Equivocal changes in FOB parameters were observed in males at PND62/ 63 and in females at PND 47/ 48. There were no evidence of an effect on the necropsy parameters. In a 1996 study in the open literature, carbaryl was administered to four groups of 6 young and 6 adult Druckery albino rats per group at doses of 0, 25, 50 or 100 mg/ kg/ day for 60 days. 11 Body weight was recorded at initiation and completion of the study. On the 61st day, the animals were sacrificed and the testes, epididymides, seminal vesicles, ventral prostrate and coagulating glands were weighed. Epididymal sperm were used for sperm counts and examination of motility and morphology. No overt toxicity or mortality was observed. There were dose­ related effects on body weight for the 50 and 100 mg/ kg/ day groups. The absolute weights of the testes, epididymides, seminal vesicle, ventral prostrate and coagulating glands were significantly decreased at 100 mg/ kg/ day for young rats. The relative organ weights were not affected at any doses. The organ weights were not affected in adult animals. Young rats receiving carbaryl 50 mg/ kg/ day had a 24.4% and 25% decrease in sperm motility and sperm count, respectively; the changes at 100 mg/ kg/ day were 42.9% and 37.5%, respectively. Adults receiving the 50 mg/ kg/ day dose had a 15.1% and 12.5% reduction in sperm motility and count, respectively; the changes at 100 mg/ kg/ day were 26.4% and 25%, respectively. The percentage of young rats with abnormal sperm was 19.8% and 33.7% at 50 and 100 mg/ kg/ day, respectively. In adults, the percentages were 16.1% and 23.1% for the respective doses. In another study from this laboratory, three groups of 8 male Wistar rats per group were 12 Pant N, Srivastava SC, Prasad AK, Shankar R, Srivastava SP (1995). Effects of Carbaryl on the Rat's Male Reproductive System. Vet Human Toxicol 37( 5): 421­ 425. 13 Narotsky MG, Kavlock RJ (1995). A Multidisciplinary Approach to Toxicological Screening: II. Developmental Toxicity. Journal of Toxicology and Environmental Health 45: 145­ 171. 31 administered carbaryl by gavage at doses of 0, 50 or 100 mg/ kg/ day for 90 days. 12 Body weight was measured periodically throughout the study. On the 91st day, the animals were sacrificed and the male reproductive glands were weighed. One testis from each animal was preserved for histopathology and the other was homogenized for testicular enzyme assay. Epididymal sperm were used for sperm counts and examination of motility and morphology. No clinical signs of toxicity were observed, except for lethargy. Body weights were decreased in the 100 mg/ kg/ day group after 60 days. There were no changes in the weights of reproductive organs. There were significant changes in the testicular enzymes of the 100 mg/ kg/ day group: decreases in SDH and G6PDH and increases in GGT and LDH. At both doses, there were significant decreases in the total epididymal sperm count, percent sperm motility and increases in the percent with morphological abnormalities in head, neck and tail. At 50 mg/ kg/ day, the testes had slight to moderate congestion and edema. A few tubules showed moderately depressed spermatogenesis and loss of sperm. There was moderate atrophy of seminiferous tubules with prominent interstitial spaces in the center of the testes, but the Leydig cells were intact. At 100 mg/ kg/ day, there were increases in the intensity of congestion and the edematous reaction was seen both peripherally and in the central region. Most of the seminiferous tubules had disturbed spermatogenesis as well as accumulations of cellular masses in their lumens. In a study conducted at EPA's Health Effects Research Laboratory, 16 pregnant Fischer 344 rats were administered carbaryl by gavage on gestation days (GD) 6­ 19 at doses of 78 or 104 mg/ kg/ day; 21 control animals were used. 13 The high dose, selected to produce overt maternal toxicity, was based on the results of a 14­ day repeated dose study in nonpregnant female rats. The low dose was 75% of the high dose. Maternal body weights were determined on GD 6, 8, 10, 13, 16 and 20. All rats were examined periodically for clinical signs of toxicity. Pups in each litter were examined and counted on postnatal day (PD) 1, 3, and 6 and weighed collectively on PD 1 and 6. After the final litter examination, the dams were killed and uterine implantation sites counted. Females that did not deliver by GD 24 were killed and their uteri examined for pregnancy status. Clinical signs of toxicity observed in the dams included tremors, motor depression, and lacrimation, usually during the first three days of treatment. Jaw clonus was observed throughout the treatment period. (The article does not indicate if clinical signs were observed at both doses.) Marked weight loss was observed early in treatment. Over the entire treatment period, carbaryl produced extrauterine weight loss at the high dose and reduced weight gains at the low dose. There was increased prenatal mortality at the high dose; this effect was attributed to two (15%) fully resorbed litters in this group. In addition, high dose pup weights were significantly reduced on PD 1. The PD­ 1 pup weights in the low dose and the PD 6 pup weights in both carbaryl­ exposed groups were also significantly reduced, but only when analyzed using the number of live pups on PD 1 as the 14 Savitz DA, Arbuckle T, Kaczor D, Curtis KM (1997). Male Pesticide Exposure and Pregnancy Outcome. Am J Epidemiol 146( 12): 1025­ 36. 32 covariate. In a recent epidemiology study, the effects of exposure of male farmers in Ontario, Canada, to agricultural pesticides and pregnancy outcome was investigated. 14 Miscarriage risk was not associated with participation in farm activities for all types of chemical applications, but was increased in combination with reported use of thiocarbamates, carbaryl and unclassified pesticides on the farm (Odds ratio = 1.9, 95% C. I. 1.1­ 3.1). There was no association between use of carbaryl and preterm delivery, small for gestational age or altered sex ratio measurements. At the 1996 Joint Meeting on Pesticide Residues (JMPR), it was concluded that carbaryl induces developmental toxicity, manifested as deaths in utero, reduced fetal weight, and malformations, but only at doses that cause overt maternal toxicity. The shortcomings of the developmental studies made them inadequate for identifying NOAELs for developmental toxicity that could be used for assessing risk under conditions of exposure other than in the diet. The Committee recommended studies of teratogenicity in rats and rabbits and study of developmental neurotoxicity and/ or screening for acute or subchronic neurotoxicity. Two dog studies were cited in the report. In these studies, maternal toxicity (dystocia, at parturition only) was observed at a dose of 3.1 mg/ kg/ day. Various birth defects were observed in the pups at doses $ 5 mg/ kg/ day. Thus the LOAEL for maternal toxicity was 3.1 mg/ kg/ day, which was the NOAEL for birth defects in the offspring. The report states that studies on reproductive toxicity were conducted some time ago and had some deficiencies in relation to currently acceptable scientific standards. The Meeting recommended that a new two­ generation reproductive toxicity study should be carried out on rats, with special attention to the male reproductive system since effects on this system were observed in some long­ term studies of toxicity at gavage doses significantly lower than those evaluated in the dietary studies of reproductive toxicity. 5.7 Determination of Susceptibility There was no evidence of quantitative or qualitative susceptibility following in utero exposures in developmental studies in the rat and rabbit. In the reproduction study, there was evidence of quantitative susceptibility of offsprings. The LOAEL for parental systemic toxicity was based on decreased body weight, weight gain, and feed consumption; the NOAEL was 27 mg/ kg/ day in males and 30 mg/ kg/ day in females. In the offspring the LOAEL was based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival; the NOAEL was 5 mg/ kg/ day in males and 6 mg/ kg/ day in females. No adverse effects were observed in the reproductive parameters; the NOAEL was the highest dose tested. 33 In the developmental neurotoxicity study, there was evidence of qualitative susceptibility. For maternal toxicity, the LOAEL was based on decreased body weight gain, alterations in Functional Observational Battery measurements and inhibition of plasma, whole blood and brain cholinesterase activity; the NOAEL was 1 mg/ kg/ day. For developmental neurotoxicity, the LOAEL was based on the morphometric changes seen in the brain of the offsprings; the NOAEL was 1 mg/ kg/ day. 5.8 Degree of Concern Analysis and Residual Uncertainties The HIARC concluded that there is no residual concern in the two­ generation reproduction study because the dose­ response effects in pups are well­ characterized and the NOAEL for the offspring effects is above that was used for establishing the chronic Reference Dose (RfD) for chronic dietary risk assessment. The HIARC selected the LOAEL of 3.1 mg/ kg/ day established in the chronic toxicity study in dogs for establishing the chronic RfD. Since a LOAEL was used, an additional uncertainty factor of 3X was applied (i. e, lack of a NOAEL) to the LOAEL. Although a NOAEL was not established in this study, the HIARC determined that a 3X was adequate (as opposed to a higher value) because: 1) cholinesterase inhibition in females was not accompanied by clinical signs; 2) no inhibition was seen for any cholinesterase compartment in males at this dose; 3) the magnitude of inhibition of plasma cholinesterase inhibition (12­ 23% decrease) was comparable to the magnitude of inhibition (22%) seen in the 5­ week study in dogs indicating no cumulative effects following long­ term exposure; 4) the study was wellconducted and there are sufficient data from subchronic and chronic duration studies in the other species which support cholinesterase inhibition as the critical effect. In addition, based on the cholinesterase inhibition data, the dog appears to be more sensitive than the rat in long­ term studies. Furthermore, use of the LOAEL of 3 mg/ kg/ day from the 1­ year dog study with an uncertainty factor of 300 results in a NOAEL of 1 mg/ kg/ day. This extrapolated NOAEL is identical to that of the offspring NOAEL of 1.0 mg/ kg/ day established in the the developmental neurotoxicity study. Thus, the NOAEL of 1 mg/ kg/ day used for establishing the chronic RfD is below the NOAEL of 5 mg/ kg/ day for offspring toxicity and the chronic RfD would be protective of the effects of concern for infants and children following chronic dietary exposures. With regard to the developmental neurotoxicity study, the HIARC concluded that there was a low level of concern based on the following residual uncertainties ° The first uncertainty was the lack of a demonstrated effect level since morphometric measurements of brains in the offsprings were not performed at the mid­ dose (1 mg/ kg/ day). However, this concern was negated since even at the high dose of 10 mg/ kg/ day, the morphometric changes were minimal and therefore, it is unlikely that adverse effects would be seen at 1 mg/ kg/ day, which is 10% of the LOAEL. ° The second uncertainty was the lack of comparative data in adults and offspring for cholinesterase inhibition. This concern was negated since no FOB alterations were seen in pups. Other studies in the data base have shown that when FOB alterations 34 were seen in adult animals, they are usually accompanied with cholinesterase inhibition. Also, the results of the National Institute for Environmental Health Sciences study (discussed below) showed no difference in cholinesterase inhibition in pups and adults. There was a dose­ related decrease in cholinesterase activity in the brain and blood of dams at gestation day 19 and fetuses taken at this time also showed a very similar level in fetal brain cholinesterase. The HIARC concluded, that the NOAEL of 1 mg/ kg/ day selected for establishing the acute RfD would address the low level of concern for the residual concerns and would be protective of the effects of concern for infants and children following a single oral exposure. 5.9 Hazard Based­ Special FQPA Safety Factor Recommendation The HIARC concluded that the hazard based special FQPA safety factor should be reduced to 1x based on the following reasons: 1. The toxicology database is complete 2. There was no quantitative or qualitative evidence of increased susceptibility in rat or rabbit fetuses following in utero exposures 3. There was evidence of qualitative susceptibility and a low level of concern due to some residual uncertainties in the developmental neurotoxicity study. However, as discussed in Section I. 3, the acute RfD would address these residual uncertainties and would be protective of the pre­ pre/ post natal toxicity following an acute dietary exposure. 4. There was evidence of increased susceptibility in the offsprings in the two generation reproduction study, but there was no residual uncertainties. The chronic RfD would be protective of the pre­ pre/ post natal toxicity following chronic dietary exposures. 5. The dose selected for residential exposures, would be protective of the pre­ pre/ post natal toxicity following non­ dietary exposures. 35 6. HAZARD CHARACTERIZATION Carbaryl is a carbamate insecticide. Its mode of toxic action is through plasma, RBC and brain cholinesterase inhibition (ChEI). In most studies in which ChE was measured, it was the endpoint used for setting the NOAEL. Carbaryl is relatively acutely toxic by the oral route (Toxicity Category II) but non­ toxic acutely by the dermal and inhalation routes. It is not a dermal or eye irritant or a dermal sensitizer. Carbaryl was negative for delayed neurotoxicity in the hen. Clinical signs compatible with ChEI were seen in most of the short­ and long­ term studies in rodents and non­ rodents. There was no evidence of structural neuropathology in the acute and subchronic neurotoxicity studies in rats. In the developmental neurotoxicity study in the rat, changes in brain morphometric measurements were observed in female offspring; however, their toxicological significance is unknown. Carbaryl has been classified as a Likely to be carcinogenic to humans based on an increased incidence of hemangiosarcomas and combined hemangiomas/ hemangiosarcomas in CD­ 1 mice at 100 ppm (15 mg/ kg/ day) and above. Other tumors, including kidney tubular cell tumors in male mice, liver tumors in female mice, thyroid tumors in male rats, bladder tumors in male and female rats and liver tumors in female rats were observed at excessive doses. Mechanistic metabolism studies were considered inadequate to demonstrate a mode of action for the vascular tumors. The default linear extrapolation will be used for risk assessment; the Q1* is 8.75 x 10 ­4 in human equivalents based on the based on the mouse vascular tumors. Maternal toxicity was observed at the same dose as developmental toxicity in both the rat and rabbit; the studies showed no evidence of a qualitative or quantitative increased susceptibility. In the twogeneration reproduction study, there was evidence of increased quantitative and qualitative susceptibility of offspring. The parental NOAEL level was approximately 27 mg/ kg/ day for males and 30mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption at approximately 108 mg/ kg/ day for males and 124 mg/ kg/ day for females. The offspring NOAEL was approximately 5 mg/ kg/ day in males and 6 mg/ kg/ day in females based on based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival at approximately 27 mg/ kg/ day in males and 30 mg/ kg/ day in females. In the developmental neurotoxicity study, evidence of maternal neurotoxicity (FOB alterations, cholinesterase inhibition) was observed at the same dose as changes in brain morphometric measurements in offspring. 7. DATA GAPS 90­ day inhalation study in the rat with cholinesterase measurements 21­ day dermal toxicity study in the rat with cholinesterase measurements Micronucleus study 36 8. ACUTE TOXICITY Acute Toxicity of Carbaryl Guideline No. Study Type MRIDs # Results Toxicity Category 81­ 1 Acute Oral ­ rat 00148500 LD50 for males = 302.6 mg/ kg; for females = 311.5 mg/ kg; combined = 301.0 mg/ kg II 81­ 2 Acute Dermal rabbit 00148501 LD50 > 2000 mg/ kg III 81­ 3 Acute Inhalation rat 00148502 LC50 > 3.4 mg/ L IV 81­ 4 Primary Eye Irritation 00148503 not a primary eye irritant IV 81­ 5 Primary Skin Irritation 00148504 not a primary skin irritant IV 81­ 6 Dermal Sensitization 00148505 negative 81­ 7 Acute Delayed Neurotoxi city (Hen) * negative at 2000 mg/ kg (approximate LD50) 81­ 8 Acute Neurotoxicity ­ rat 43845201­ 43845204 systemic LOEL = 10 mg/ kg for males and females based on significant inhibition of RBC, plasma, whole blood and brain cholinesterase; NOEL < 10 mg/ kg * Carpenter, C. P., Weil, C. S., Palm, P. E., Woodside, N. W., Nair, J. H. and Smyth, H. F. Mammalian Toxicity of 1­ napthyl­ N­ methyl carbamate (Sevin Insecticide). J. Agric. Food Chem. 9( 1): 30­ 39, 1961. 37 9. SUMMARY OF TOXICOLOGY ENDPOINT SELECTION The doses and toxicological endpoints selected for various exposure scenarios for Carbaryl: EXPOSURE SCENARIO DOSE (mg/ kg/ day) ENDPOINT STUDY Acute Dietary NOAEL = 1 UF = 100 FOB alterations on first day of dosing in maternal animals Developmental Neurotoxicity ­ rat Acute RfD = 0.01 mg/ kg Chronic Dietary LOAEL = 3.1 UF = 300 decrease in brain cholinesterase in females Chronic toxicity dog Chronic RfD = 0.01 mg/ kg/ day Short­ Term Oral Incidental NOAEL = 1 FOB alterations on first day of dosing in maternal animals Developmental Neurotoxicity ­ rat IntermediateTerm Oral Incidental Oral NOAEL= 1.0 increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase subchronic neurotoxicity study ­ rat Short­ Term (Dermal) a NOAEL = 1 FOB alterations on first day of dosing in maternal animals Developmental Neurotoxicity ­ rat IntermediateTerm (Dermal) a Oral NOAEL= 1.0 increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase subchronic neurotoxicity study ­ rat Long­ Term (Dermal) a LOAEL = 3.1 decrease in brain cholinesterase in females chronic toxicity dog Short Term (Inhalation) b NOAEL = 1 FOB alterations on first day of dosing in maternal animals Developmental Neurotoxicity ­ rat Intermediate Term (Inhalation) b Oral NOAEL= 1.0 increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase subchronic neurotoxicity study ­ rat Long Term (Inhalation) LOAEL = 3.1 decrease in brain cholinesterase in females chronic toxicity dog Cancer Q1* = 8.75 x 10 ­4 male mouse hemangiosarcoma tumors carcinogenicity mouse a Since an oral NOAEL/ LOAEL was selected, a dermal absorption factor of 12.7% should be used in route­ to­ route extrapolation. b Since an oral NOAEL was selected, an inhalation factor of 100% should be used in route­ to­ route extrapolation.

epa

2024-06-07T20:31:42.329750

regulations

EPA-HQ-OPP-2002-0138-0010

Supporting & Related Material

TXR NO. 0050634 April 3, 2002 MEMORANDUM SUBJECT: CARBARYL ­ 3 rd Reassessment Report of the FQPA Safety Factor Committee. NOTE: THIS REPORT REPLACES THE PREVIOUS REPORT OF THE FQPA SAFETY FACTOR COMMITTEE DATED APRIL 30, 2001 (HED DOC. NO. 014553). FROM: Carol Christensen, Acting Executive Secretary And Brenda Tarplee, Executive Secretary FQPA Safety Factor Committee Health Effects Division (7509C) THROUGH: Ed Zager, Chairman FQPA Safety Factor Committee Health Effects Division (7509C) TO: Virginia Dobozy, Risk Assessor Reregistration Branch 1 Health Effects Division (7509C) PC Code: 056801 The Health Effects Division (HED) FQPA Safety Factor Committee (SFC) met on January 14, 2002 and February 25, 2002 to re­ evaluate the hazard and exposure data for Carbaryl with regard to making a decision on the additional safety factor for the protection of infants and children. The SFC determined that reliable data demonstrate that the safety of infants and children will be protected by use of an additional safety factor of 3X. This report replaces the previous report of the FQPA Safety Factor Committee dated April 30, 2001 (HED Doc. No. 014553 ). 2 I. HAZARD ASSESSMENT (Correspondence: V. Dobozy to C. Christensen dated February 25, 2002) Since the last FQPA SFC meeting (April 30, 2001), the toxicology data base for Carbaryl was reevaluated by the HED Hazard Identification Assessment Review Committee (HIARC) on December 18, 2001 and February 19, 2002. 1. Adequacy of the Toxicology Database The toxicology data base for Carbaryl is complete for FQPA assessment. There are acceptable guideline developmental studies in the rat and rabbit and a 2­ generation reproduction study in rats. The toxicology data base was reviewed by the Hazard Science Assessment Review Committee (HIARC) on July 7, 1998, April 7, 1999, November 2, 1999, March 1, 2001, December 18, 2001 and February 19, 2002. 2. Determination of Susceptibility There was no evidence of quantitative or qualitative susceptibility following in utero exposures in developmental studies in the rat and rabbit. In the reproduction study, there was evidence of quantitative susceptibility of the offspring. The LOAEL for parental systemic toxicity was based on decreased body weight, weight gain, and food consumption; the NOAEL was 27 mg/ kg/ day in males and 30 mg/ kg/ day in females. In the offspring the LOAEL was based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival; the NOAEL was 5 mg/ kg/ day in males and 6 mg/ kg/ day in females. No adverse effects were observed in the reproductive parameters; the NOAEL was the highest dose tested. In the developmental neurotoxicity study, there was evidence of qualitative susceptibility. For maternal toxicity, the LOAEL was based on decreased body weight gain, alterations in Functional Observational Battery measurements and inhibition of plasma, whole blood and brain cholinesterase activity; the NOAEL was 1 mg/ kg/ day. For developmental neurotoxicity, the LOAEL was based on the morphometric changes seen in the brain of the offsprings; the NOAEL was 1 mg/ kg/ day. 3. Degree of Concern and Residual Uncertainties Since there is evidence of increased susceptibility of the young following exposure to Carbaryl in the 2­ generation reproduction study and in the developmental neurotoxicity study, HIARC performed a Degree of Concern Analysis to: 1) determine the level of concern for the effects observed when considered in the context of all available toxicity data; and 2) identify any residual concerns after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment of this chemical. If residual concerns are identified, HIARC examines whether these residual concerns can 3 be addressed by a special FQPA safety factor and, if so, the size of the factor needed. The results of the HIARC Degree of Concern analyses for Carbaryl follow. A. 2­ Generation Reproduction Study The HIARC concluded that there are no residual concerns related to the 2­ generation reproduction study because the dose­ response for the offspring effects is wellcharacterized and these effects occurred at a dose level which is above that used for establishing the Chronic Reference Dose (cRfD) for chronic dietary risk assessment. The HIARC established the Chronic RfD using the LOAEL of 3.1 mg/ kg/ day in the chronic toxicity study in dogs. Since a NOAEL was not established in this study, an additional uncertainty factor of 3X was applied to the LOAEL (i. e, UFL). The HIARC determined that 3X is adequate to account for the lack of a NOAEL in this case because: 1) the study was well­ conducted and there are sufficient data from subchronic and other chronic studies in other species that support cholinesterase inhibition as the critical effect for Carbaryl; 2.) the data indicate that the dog is more sensitive to the cholinergic effects of Carbaryl and using this species to establish the RfD provides additional protection for the effects seen in the rat (including the reproduction and developmental neurotoxicity studies); 3.) the magnitude of inhibition of plasma cholinesterase inhibition (12­ 23% decrease) seen in this study was comparable to the magnitude of inhibition (22%) seen in the 5­ week study in dogs ­ indicating no cumulative effect following long­ term exposure; 4.) The cholinesterase inhibition seen in females at the LOAEL in this study was not accompanied by clinical signs (response was not judged to be severe); and 5.) no inhibition was seen for any cholinesterase compartment in males at this dose (response was seen in only one sex). The HIARC concluded that the extrapolated NOAEL of 1 mg/ kg/ day used to establish the Chronic RfD for Carbaryl is below the NOAEL for offspring toxicity (5 mg/ kg/ day) in the 2­ generation reproduction study and is protective of chronic dietary exposures to infants and children. B. Developmental Neurotoxicity Study The HIARC concluded that there was a low level of concern for the developmental effects seen in the developmental neurotoxicity study and no residual uncertainties with respect to this study based on the following evidence: ° Any concern for the lack of brain morphometric measurements in the offspring at the mid­ dose (1 mg/ kg/ day) was negated since even at the high dose of 10 mg/ kg/ day, the morphometric changes were minimal and therefore, it is unlikely that adverse effects would be seen at the mid­ dose level (1 mg/ kg/ day ­ 10% of the LOAEL). ° Any concern for the lack of comparative data in adults and offspring for cholinesterase inhibition was negated since no FOB alterations were seen in pups. 4 Other studies in the data base show that when cholinesterase inhibition was seen in adult animals, it usually was accompanied by FOB alterations. Additionally, the results of the National Institute for Environmental Health Sciences study (discussed below) indicate that there is no difference in cholinesterase inhibition in pups and adults. The dose­ related decrease in cholinesterase activity in the brain and blood of dams at gestation day 19 was very similar to the fetal brain cholinesterase levels taken at the same time. The HIARC established the Acute RfD for Carbaryl using the NOAEL of 1 mg/ kg/ day in the developmental neurotoxicity study in rats which is protective of single dose exposures to infants and children. 4. Summary of Open Literature Findings In the scientific literature, there are two relatively recent studies which demonstrated effects on sperm at high doses (50 and 100 mg/ kg/ day) of Carbaryl. The results of these two studies indicated that Carbaryl caused weight reductions in the testes, epididymides, seminal vesicles, prostate and coagulating glands of young rats; changes in testicular enzymes; decreased sperm counts and sperm motility; increased sperm morphological abnormalities; and moderate atrophy of seminiferous tubules of the testes. In a published developmental study in Fisher 344 rats conducted by EPA's Health Effects Research Laboratory, Carbaryl was administered from gestation day 6 through 19 at doses of 78 or 104 mg/ kg/ day. Clinical signs related to cholinesterase inhibition (tremor, motor depression, jaw clonus and lacrimation) were observed in dams but it is unclear if they occurred at both dose levels. There was also increased prenatal mortality at the high dose (104 mg/ kg/ day) and decreased pup weights at the low (78 mg/ kg/ day) doses. In an unpublished developmental neurotoxicity study in SD rats from the National Health and Ecological Effects Research Laboratories at EPA and the National Institute for Environmental Health Sciences/ National Toxicology Program Carbaryl was administered by gavage at doses of 0, 6, 12 or 25 mg/ kg/ day. The chemical or its metabolite 1­ naphthol was not present in pups' plasma above the limit of detection at any exposure concentration (0, 6, 12 or 25 mg/ kg/ day). There was a dose­ related decrease in ChE activity in the brain and blood of dams at GD 19, and fetuses taken at that time also showed a very similar level of inhibition in fetal brain cholinesterase. There was a decrease in the number of live pups/ litter at the high dose. There were no changes in cognitive function. Equivocal changes in Functional Observational Battery parameters were observed in male and female offspring. II. EXPOSURE ASSESSMENT 1. Dietary (Food) Exposure Considerations (Correspondence: V. Dobozy to C. Christensen dated January 7, 2002) 5 Carbaryl is used late in the season at maximum seasonal rates of 6 ­12 lb of active ingredient (a. i.) per acre. Pre­ harvest intervals (PHIs) range from 1­ 29 days, but most PHIs are one week or less. Single application rates are 1­ 5 lb ai/ A with repeated applications on a weekly basis. U. S. tolerances range from 10­ 100 ppm. Codex MRLs have been established for numerous commodities, including fruits, grains, forage/ fodder, and livestock commodities. The limits range from 0.1/ 0.5 for livestock commodities to 100 ppm for forage/ hay. Most fruit and vegetable limits range from 1 to 10 ppm. Carbaryl is registered for use on almost all crop groups and miscellaneous commodities including pome fruit, stone fruit, legumes, cereal grains and fruiting vegetables. Residues are expected in meat and milk. The qualitative nature of the residue of Carbaryl in plants and animals is adequately understood. Based on the results of plant and animal metabolism studies, the HED Metabolism Committee concluded that the Carbaryl residue to be regulated in plants is Carbaryl per se (DP Barcode D221979, S. Hummel, 2/ 8/ 96). The Metabolism Committee also concluded that the residues of concern in meat and milk are the free and conjugated forms of Carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, and 5­ methoxy­ 6­ hydroxy carbaryl (C. Olinger, D255855, 6/ 21/ 99). Residues are primarily surface residues. DEEM analyses are being conducted at the highest level of refinement available (Tier IV). Adequate PDP and FDA monitoring data are available for the vast majority (> 80%) of the commodities. These commodities include those which are considered to be significant in the diets of children such as apples, potatoes, carrots, succulent beans, soybean, orange, orange juice, apple, apple juice, pear, peach, wheat, banana, grape, grape juice and milk. For those commodities not monitored by FDA and PDP, field trial data will be used. These include garden beets, turnips, mustards, dried beans, almonds, pecans, walnuts, field corn grain, rice, flax seed, okra, olive, peanuts, pistachio, and sunflower. Carbaryl residues from field trials were <LOQ in/ on sweet potato, sugar beets, corn grain, flax seed, and peanuts. Quantifiable residues were detected in all other raw agricultural commodities (RACs). For a given crop, residue levels were quite variable overall, probably owing to climactic variations, but were generally consistent within any specific field trial location. Percent of crop treated will also be incorporated. Crops with the highest percent of the crop treated include apples, (30%), avocados (85%), blueberries( 45%), cherries (36%), asparagus (87%), among others. Carbamate market basket data are also available for the commodities, orange, apple, peach, broccoli, lettuce, tomato, bananas, and grapes. Additional data were required for the dermal use of Carbaryl on poultry and its use in poultry houses; however, the registrant has stated that they are no longer supporting these uses. In the previously conducted dietary assessment, the current tolerance for poultry was used, and as a result, poultry was determined to be a significant contributor to the risk estimate. When poultry is not included in the diet, the results of the Critical 6 Exposure Contribution analysis showed no specific commodity comprised a large percentage of the residues found in the tail end of acute exposure. 2. Dietary (Drinking Water) Exposure Considerations (Correspondence: V. Dobozy to C. Christensen dated January 7, 2002) The environmental fate data base for Carbaryl is adequate for the characterization of drinking water exposure. Fate data indicate that parent Carbaryl and its degradate 1­ naphthol are fairly mobile and slightly persistent. In general they are not likely to persist or accumulate in the environment, however, under acidic conditions with limited microbial activity they may persist. Because of the relatively limited persistence of the compound in the environment it is unlikely that non­ targeted monitoring studies will detect the maximum concentrations that occur. Some non­ targeted monitoring data are available but are of limited utility in developing EECs for ecological and human health risk assessment. Therefore modeling was used to estimate surface water and groundwater concentrations that could be expected from normal agricultural use. The results of the modeling are supported by the available monitoring data. For developing surface water, EECs computer modeling with the EPA PRZM3.12 and EXAMS 2.97.7 programs were used to estimate the concentration of Carbaryl in surface water. Index reservoir scenarios corrected for Percent Cropped Area (PCA) for representative crops were used. SCI­ GROW was used to calculate a groundwater screening exposure value to be used in determining the potential risk to human health. 3. Residential Exposure Considerations (Correspondence: V. Dobozy to C. Christensen dated January 7, 2002) Carbaryl is currently registered for many residential uses. Homeowner handler exposure scenarios exist for a variety of use patterns including applications of dusts to vegetables, ornamentals, and pets (dogs & cats); applications of ready­ to­ use products for nuisance insect control; applications of liquid sprays with a variety of hand equipment to gardens, trees, vegetables, and turf; and applications of granular formulations to turf. Carbaryl can be used in outdoor residential areas and to treat pets. Therefore, a number of residential post­ application exposure scenarios exist for toddlers and children. Several chemical­ and scenario­ specific studies designed to quantify exposures to homeowner applicators are available. There are a number of dislodgeable foliar residue studies for Carbaryl that have been used for home gardening activities. Also, there are TTR data from 3 sites (CA, PA, GA) that have been used for the dermal risk assessments (i. e., transferability is >1%). Mouthing behaviors have been addressed using the new 5% factor for wet hands and not the TTRs as stipulated in the latest updates to the Residential SOPs. These data will be used, where appropriate, to calculate residue concentrations 7 and exposures over time instead of using the Agency default assumptions. In addition, the latest Outdoor Residential Exposure Task Force (ORETF) data for homeowner applications to turf have been used which are also the same values that have been incorporated in the Residential SOPs. For any other remaining scenarios not addressed by the Aventis or ORETF data, PHED or the Residential SOPs were used. III. SAFETY FACTOR RECOMMENDATION AND RATIONALE 1. FQPA Safety Factor Recommendations The FQPA SFC recommends that OPP depart from the default 10X additional safety factor and instead use a different additional safety factor of 3X. This recommendation is based on reliable data supporting the findings set forth below. A. Traditional Additional Safety Factor (Addressing Data Deficiencies) The FQPA SFC concurs with the HIARC recommendation for the use of a 3X additional safety factor to address the use of a LOAEL in establishing the Acute and Chronic RfDs, and the toxicity endpoints selected to assess short­ and long­ term residential exposure scenarios (oral, dermal, and inhalation). The rationale as to why reliable data support the safety of using a 3X to address this data deficiency is discussed above in Section I. 3. B. Special FQPA Safety Factors Taking into account the HIARC recommendation regarding the data deficiency, the FQPA SFC recommends that no Special FQPA Safety Factor is necessary to protect the safety of infants and children in assessing Carbaryl exposure and risks. 2. Rationale and Findings Regarding Recommendation on Special FQPA Safety Factor The Committee concluded that no Special FQPA safety factor was needed because: The toxicology database is complete and there is no quantitative or qualitative evidence of increased susceptibility in rat or rabbit fetuses following in utero in the standard developmental studies. Although there is evidence of qualitative susceptibility developmental neurotoxicity study, HIARC concluded there is a low level of concern for the effects in the developmental neurotoxicity study, as discussed in Section I. 3. The RfDs established would account for any uncertainties and are protective of prepre postnatal toxicity following acute and chronic exposures. Similarly, although there is evidence of increased susceptibility in the offspring in the 2­ generation reproduction study, there are no residual uncertainties (Refer to Section I. 3.). The chronic RfD would be protective of the pre­ pre/ post natal toxicity following chronic dietary exposures. The 8 doses/ endpoints selected for residential exposures, are also protective of any pre­ pre/ post natal toxicity resulting from non­ dietary exposures. There are no residual uncertainties identified in the exposure databases. The dietary food exposure assessment utilizes estimates derived from monitoring data (PDP, FDA), the carbamate market basket survey, percent crop treated information (as applicable), and processing data. The dietary drinking water assessment includes a complete environmental fate database for both the parent and the major metabolite (1­ napthol) and uses modeling results based on detailed chemical­ specific data. The modeling results are supported by drinking water monitoring data and do not underestimate the exposure and risks posed by Carbaryl. The residential exposure assessment includes chemical­ specific dislodgeable foliar residue studies (DFRs), ORETF data, a registrant submitted use and usage study, and chemical­ specific total transferable residue (TTR) studies for the handler and post­ application scenarios. In addition, there are human biomonitoring data to support the results of the residential exposure estimate. 3. Application of the FQPA Safety Factors (Population Subgroups / Risk Assessment Scenarios) The FQPA safety factor recommendation is for a 3X traditional safety factor to address data deficiencies and no additional Special FQPA safety factor. The 3X traditional safety factor should be applied to the Chronic RfD and to long­ term residential exposure scenarios (dermal, and inhalation). No other FQPA safety factor would be appropriate for Carbaryl. 9 4. Summary of FQPA Safety Factors Summary of FQPA Safety Factors for Carbaryl LOAEL to NOAEL (UFL) Subchronic to Chronic (UFS) Incomplete Database (UFDB) Special FQPA Safety Factor (Hazard and Exposure) Magnitude of Factor 3X 1X 1X 1X Rationale for the Factor Use of a LOAEL to establish toxicity endpoint (i. e, a NOAEL was not identified in the critical study). Refer to Section I. 3. No subchronic to Chronic extrapolations performed Toxicity Database is complete No residual concerns regarding pre or post­ natal toxicity or completeness of the toxicity or exposure databases Endpoints to which the Factor is Applied Chronic dietary and Long­ term residential exposures (Dermal and Inhalation) Not Applicable Not Applicable Not Applicable

epa

2024-06-07T20:31:42.345411

regulations

EPA-HQ-OPP-2002-0138-0012

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES DP Barcode: D276945 PCCode: 056801 Date: August 17, 2002 MEMORANDUM: SUBJECT: Revised EFED Risk Assessment of Carbaryl in Support of the Reregistration Eligibility Decision (RED) To: Anthony Britten, PM Team Reviewer Betty Shackleford, Product Manager 53 Special Review and Reregistration Division (7508C) FROM: E. Laurence Libelo, Ph. D., Environmental Engineer Thomas Steeger, Ph. D., Senior Biologist Environmental Risk Branch IV Environmental Fate and Effects Division (7507C) THRU: Betsy Behl, Chief Environmental Risk Branch IV/ Environmental Fate and Effects Division (7507C) The Environmental Fate and Effects Division has revised the Environmental Fate and Ecological Risk Assessment chapter in support of the reregistration eligibility decision on carbaryl. The chapter has been abridged from its April 8, 2002, version at the request of the Special Review and Reregistration Division and no longer includes environmental fate data evaluation records contained in the original chapter. Although the data evaluation records were cleared for confidential business information, their presence in the chapter did not contribute significantly to understanding the environmental fate of carbaryl. If interested, the public can access both environmental fate and ecological effect data evaluation records by petitioning the Agency through the Freedom of Information Act. The revised chapter reflects comments made by the registrant (Aventis) during the 30­ day error correction phase of the review process and contains more detailed information on the input files for the Pesticide Root Zone Model (PRZM) used in estimating runoff concentrations of carbaryl. Although the registrant provided constructive comments in their 30­ day responses to the draft risk assessment of carbaryl, the overall concerns and uncertainties originally identified regarding the environmental fate and ecological effects of carbaryl have not changed. Also included with the revised chapter is a review (DP Barcode D279109) of data submitted regarding the Section 24C Special Local Needs use of carbaryl on oyster beds in Willapa Bay and Grays Harbor, Washington, for control of burrowing shrimp. Both the revised environmental fate and ecological effects chapter and the review of the use of carbaryl to control burrowing shrimp are intended to represent EFED's assessment of the risks associated with the uses of carbaryl. While some uses and application rates discussed in the chapter may no longer be supported, the EFED chapter is intended to provide a general overview of the concerns and uncertainties associated with the past and present uses of carbaryl. Environmental Fate and Ecological Risk Assessment For the Reregistration of Carbaryl 1­ Naphthyl methylcarbamate 1­ naphthyl N­ methylcarbamine CAS Registry Number 63­ 25­ 2 PC Code 056801 Prepared by: E. Laurence Libelo, Ph. D., Environmental Engineer Angel Chiri, Ph. D., Entomologist Thomas M. Steeger, Ph. D., Fishery Biologist United States Environmental Protection Agency Office of Pesticide Programs Environmental Fate and Effects Division Environmental Risk Branch IV Ariel Rios Building 1200 Pennsylvania Ave., N. W. Mail Code 7507C Washington, DC 20460 Reviewed by: Elizabeth Behl, Branch Chief Dana Spatz, Senior Chemist i TABLE OF CONTENTS 1.0 Summary and Environmental Risk Conclusions ............................. 1 Risk to Terrestrial Organisms .............................................. 1 Risk to Plants ........................................................... 3 Risk to Endangered Species................................................ 3 Fate and Water Assessment ................................................ 4 2.0 Introduction ........................................................... 7 3.0 Integrated Risk Characterization .......................................... 8 Introduction ............................................................ 8 Aquatic Organisms ....................................................... 9 Terrestrial Organisms ................................................... 12 Endangered Species ..................................................... 15 Endocrine Disruption Concerns ............................................ 15 Uncertainties .......................................................... 16 4.0 Environmental Fate Assessment .......................................... 17 Exposure Characterization ................................................ 17 Persistence ...................................................... 21 Chemical Degradation Processes............................... 21 Hydrolysis .......................................... 21 Photolysis................................................. 21 Microbially­ mediated Processes ............................... 21 Mobility ........................................................ 22 Batch Adsorption/ Desorption ................................. 22 Column Leaching ........................................... 23 Field Dissipation ................................................. 23 Terrestrial Field Dissipation .................................. 23 Forestry Field Dissipation .................................... 24 Aquatic Field Dissipation .................................... 24 Bioaccumulation in Fish ........................................... 24 Foliar Dissipation................................................. 25 Atmospheric Transport ............................................ 25 1­ Naphthol Fate and Transport ...................................... 26 Aquatic Exposure Assessment ............................................. 27 Urban and Suburban .................................................... 29 Estimated Environmental Concentrations for Terrestrial Ecological Risk Assessment................................................ 29 5.0 Drinking Water Assessment ............................................. 30 Water Resources Assessment ............................................. 30 ii Drinking Water Exposure Assessment ................................ 31 Drinking Water Modeling .................................... 31 Water Treatment Effects ......................................................... 32 Groundwater Resources ............................................ 33 Surface Water Resources ........................................... 34 Monitoring Data............................................ 34 NAWQA ........................................... 34 Registrant Monitoring Study ............................ 35 Sacramento­ San Joaquin River Delta ..................... 37 STORET ........................................... 37 6.0 Hazard and Risk Assessment for Aquatic Organisms ........................ 37 Hazard Assessment for Aquatic Organisms .................................. 37 Freshwater Fish .................................................. 37 Amphibians ..................................................... 38 Freshwater Invertebrates ........................................... 38 Estuarine/ Marine Fish ............................................. 39 Estuarine/ Marine Invertebrates ...................................... 39 Aquatic Plants ................................................... 40 1­ Naphthol ...................................................... 40 Risk Assessment for Aquatic Organisms..................................... 40 Freshwater Fish .................................................. 40 Freshwater Aquatic Invertebrates .................................... 41 Estuarine/ Marine Fish ............................................. 41 Estuarine/ Marine Invertebrates ...................................... 44 Reproduction Effects on Fish ....................................... 44 Endangered Aquatic Species ............................................. 45 7.0 Hazard and Risk Assessment for Terrestrial Organisms ..................... 45 Hazard Assessment for Terrestrial Organisms ................................ 45 Avian .......................................................... 45 Mammalian ..................................................... 46 Insects ......................................................... 46 Terrestrial Plants ................................................. 46 Risk Assessment for Terrestrial Organisms................................... 47 Avian Risk ...................................................... 47 Nongranular Formulations .................................... 47 Granular Formulations....................................... 48 Mammalian Risk ................................................. 48 Risk to Herbivores/ Insectivores: Nongranular Formulations ......... 48 Risk Quotients for Herbivores/ Insectivores Based on Less than Maximum Label Use Rates ....................... 48 iii Risk Quotients for Herbivores/ Insectivores Based on Maximum Label Use Rates ............................... 48 Risk to Granivores: Nongranular Uses .......................... 49 Chronic Risk: Nongranular Uses ......................... 50 Risk: Granular Uses................................... 50 Reproduction Effects ............................................. 50 Insects ......................................................... 51 Terrestrial Plants ................................................. 52 Endangered Terrestrial Species ...................................... 52 8.0 Summary of Ecological Incident Data .................................... 53 9.0 References (Non­ MRID) ................................................ 55 Appendix A: Refined Water Memo ............................................. 62 Appendix B: Ecological Risk Assessment ....................................... 147 Appendix C: Toxicity Assessment ............................................. 172 Appendix D: ELL­ FATE ..................................................... 183 Appendix E: Examples of PRZM Standard Pond Input Files ....................... 185 ­1­ 1.0 Summary and Environmental Risk Conclusions Carbaryl is a carbamate insecticide registered for control of a wide range of insect and other arthropod pests on over 100 crop and noncrop use sites, including home and garden uses. Carbaryl is a cholinesterase inhibitor that acts on animals on contact and upon ingestion by competing for binding sites on the enzyme acetyl cholinesterase, thus preventing the breakdown of acetyl choline. Risk to Terrestrial Organisms ° Three different kinds of usage data were considered to assess risk to terrestrial organisms: maximum label rates for 74 uses, maximum reported (based on survey usage data available from the Doane's Agricultural Services for 42 uses) rates, and Quantitative Usage Analysis "average" rates data provided by OPP's Biological and Economic Analysis Division for 70 uses. In most cases the Level of Concern (LOC) exceedance pattern was not significantly affected by the kind of application rate data used to calculate risk quotients. ° Although no avian acute risk LOCs are exceeded for any nongranular carbaryl uses at maximum or less than maximum label application rates, the avian chronic risk LOC is exceeded for most uses. The avian acute LOC is exceeded for 20 g birds for all granular carbaryl uses (risk quotients [RQs]: 0.52 ­ 4.76) and for 180 g birds, it is exceeded for the trees/ ornamentals, turfgrass, and tick control uses (RQ: 0.53). No acute LOCs are exceeded for birds in the 1000 g weight class for any of the granular carbaryl uses. ° At maximum label rates, the mammalian acute risk LOC (0.5) is exceeded for all 74 nongranular uses (0.76 ­ 12.12). The proportion of RQs exceeding the acute LOCs decreases significantly for mammals in all three weight classes feeding on fruits, pods, seeds, and large insects, as well as for the 1000 g mammals feeding on broadleaf/ forage plants and small insects. At maximum reported application rates the acute risk LOC for 15 g mammals feeding on short grass is exceeded for 41 of 42 nongranular carbaryl uses (RQs: 0.60 11.36 and at "average" use rates is exceeded for 63 of 70 uses. ° The mammalian chronic risk LOC (1) is exceeded for practically all nongranular carbaryl uses at maximum label (RQs: 3.0 ­ 48.0), maximum reported (RQs: 1.5 ­ 45.0), and "average" use rates (RQs: 1.5 ­ 15.9). Therefore, almost all nongranular carbaryl uses are expected to pose acute and chronic risks to small mammals. ° At maximum label rates, acute risk LOCs are exceeded for 15 g mammals (RQs: 2.3 ­ 21.1) and 35 g mammals (RQs: 0.99 ­ 9.04) for all granular uses, indicating that all granular carbaryl uses pose an acute risk to the smaller mammalian species. For 1000 g mammals, the acute risk LOC is not exceeded for any use. ° Being highly toxic to honey bees and arthropods in general, carbaryl poses a risk to beneficial insects, including many pests's natural enemies, when directly exposed to carbaryl applications, residues on foliage, or contaminated pollen or nectar. Carbaryl is one of the ­2­ pesticides more often implicated in bee mortality incidents, ranking second and third, respectively, in two separate bee kill surveys undertaken in 1997 by the Washington State Department of Agriculture and the American Beekeeping Federation. Risk to Aquatic Organisms ° Three different application scenarios were considered in assessing risk to aquatic organisms: maximum label rates, maximum reported (based on survey usage data available for 42 uses) rates, and "average" rates. In most cases the Level of Concern (LOC) exceedance pattern was unaffected by the kind of usage data used to calculate risk quotients. ° The acute risk LOC (0.5) for freshwater fish is exceeded for one of five use scenarios modeled (citrus), at maximum label (RQ: 1.10), maximum reported (RQ: 0.93), and "average" (RQ: 0.58) use rates, while the chronic risk LOC for freshwater fish is not exceeded for any scenario, at any use rate. ° The acute risk LOC for estuarine/ marine fish is not exceeded for any use scenario modeled, at any use rate. Because of lack of valid chronic toxicity data, it is not possible to fully assess chronic risk to estuarine/ marine fish at this time. ° Available nonguideline studies suggest that exposure to carbaryl may act as a potential endocrine disruptor in fish. Exposure to sublethal carbaryl levels cause a significant reduction of serum and pituitary levels of gonadotropic hormone and gonadotropin­ releasing hormone in the freshwater murrell and a significant decline in ovarian estrogen levels in freshwater perch, starting on day 15 of exposure. ° Most carbaryl uses are likely to pose an acute risk to both freshwater and estuarine/ marine aquatic invertebrates, especially arthropods. The acute risk LOC (0.5) for freshwater invertebrates is exceeded for all five use scenarios modeled at maximum label (RQs: 5.1 161.2 maximum reported (RQs: 3.3 ­ 136.5), and "average" (RQs: 2.6 ­ 85.3) use rates. The chronic risk LOC (1) is also exceeded for freshwater invertebrates for all 5 use scenarios modeled, at maximum label (RQs: 3.3 ­ 91.3), maximum reported (RQs: 2.0 ­ 74.7), and "average" (RQs: 1.7 ­ 44.7) use rates. ° The acute risk LOC is exceeded for estuarine/ marine invertebrates for the 5 use scenarios modeled at maximum label (RQs: 1.5 ­ 48.1), maximum reported (RQs: 1.0 ­ 40.7), and "average" (RQs: 0.8 ­ 25.4) use rates. Lack of reliable toxicity data precluded the assessment of chronic risk for estuarine/ marine invertebrates. ° Carbaryl directly applied to oyster beds in Washington State poses a severe, albeit localized and temporary, acute risk to fish and nontarget arthropods in and around the target area. The oyster industry is encouraged to continue searching for alternative pest shrimp management measures and more selective carbaryl application regimes, within an IPM context, to minimize impact on non­ target organisms. ­3­ Risk to Plants ° Carbaryl can be used as a fruit thinning agent on apples and pears, and according to the label it may cause injury to tender foliage if applied to wet foliage or during periods of high humidity. It may also cause injury to Boston ivy, Virginia creeper, or maidenhair fern. A few incidents involving injury to vegetable crops (potatoes, tomatoes, cabbage, and broccoli) have been reported. To fully assess carbaryl risk to terrestrial plants, Tier I and, if appropriate, Tier II Seed Germination and Seedling Emergence, as well as Vegetative Vigor studies should be submitted by the registrant. ° Based on the single core green alga study available, the acute risk LOC for aquatic plants is not exceeded for any of the five scenarios modeled even at maximum label rates. However, because four of the required five toxicity studies with aquatic plants are unavailable, these results are insufficient to fully assess carbaryl risk to aquatic plants. Toxicity testing for aquatic plants is required to support carbaryl's registered forestry uses. Risk to Endangered Species ° The endangered species LOC for birds is met or exceeded for most nongranular carbaryl uses at maximum label, QUA average, and maximum reported use rates. The endangered species LOC is exceeded for 20 g birds for all granular uses; it is exceeded for 180 g birds it is exceeded for all granular uses, except cucumber, melons, pumpkin, squash, beans, peas, lentils, cowpeas, southern peas, wheat, millet, and sugar beets; and for 1000 g birds, it is reached for the trees and ornamentals, turfgrass, and tick control granular uses. ° The endangered species LOC for mammals is met or exceeded for all uses at maximum label, QUA average, and maximum reported use rates. ° At less than maximum label rates the endangered species LOC is exceeded for all carbaryl uses for freshwater and marine/ estuarine aquatic invertebrates. At less than maximum label rates, the endangered species LOC is exceeded for freshwater fish only for the citrus use scenario and not exceeded for estuarine/ marine fish for any of the five use scenarios modeled. ­4­ Fate and Water Assessment ° Carbaryl is widely detected in surface water at concentrations up to about 7 : g/ L. In general observed concentrations are generally less then 0.5 : g/ L. It was the second most widely detected insecticide, after diazinon, in the U. S. Geological Survey's National Water Quality Assessment (NAWQA) program. NAWQA reported that about 20 % of surface water samples had detectable carbaryl concentrations. For samples where carbaryl was detected the mean concentration was 0.11 : g/ L and the maximum was 5.5 : g/ L. Urban streams had higher frequency of detection then those draining agricultural areas, and had higher concentrations. A targeted study by the registrant found detectable levels of carbaryl in 9 of 15 sites in agricultural areas and 100% of 4 sites in suburban areas (limit of detection = 0.002 : g/ L). Raw water samples from suburban sites had measured residues greater then the limit of detection but below the level of quantitation (0.03 : g/ L) ranging from 0.002 to 0.023 : g/ L. Concentrations in samples from agricultural sites were lower, with one sample measuring about 0.16 : g/ L, one at 0.031 : g/ L and the rest were below the level of quantitation. While this study was targeted at carbaryl use areas only 20 sites were sampled. It is not known how the selected sites relate to the overall distribution of possible exposures. The concentrations found in this study are similar to those reported n non­ targeted studies. They are not the maximum that occur as evidenced by higher values found in non­ targeted studies. ° Because of the relatively limited persistence of the compound in the environment it is unlikely that non­ targeted monitoring studies will detect the maximum concentrations that occur. Extensive data from targeted studies designed specifically to measure carbaryl in relation to actual application and environmental occurrence is not available. Only the registrant study has tried to target use areas. This study, while useful, is limited in extent and did not measure the concentrations as high as observed in other, non­ targeted studies. Because of the limited number of sites sampled and lack of information on how sampled sites relate to the overall carbaryl use area this study can not be used to estimate the distribution of expected environmental concentrations which actually occur. Targeted monitoring data is limited to this study which found concentrations below those observed in other studies. This lack of extensive targeted data and the limitations inherent in using non­ targeted data to extrapolate to actual environmental concentrations indicate that computer modeling may provided a more representative estimate of actual peak concentrations that occur. ° Computer modeling using the EPA PRZM3.12 and EXAMS 2.97.5 programs were used to estimate the maximum and average concentrations of carbaryl in surface water. Estimated environmental concentrations (EECs) for use in human health risk assessment were developed by modeling with Index Reservoir scenarios corrected for Percent Cropped Area (PCA) for representative crops. Three different application rate scenarios were used in modeling: the maximum allowed on the label for the specific crop, an "average" rate, and 1 Maximum is the highest application rate allowed according to the label for the specific crop. "Average" is the average rate as determined by OPP/ BEAD and reported in the a memo titled Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD. These average rates are presented here, but are not relevant for drinking water exposure estimates as the usage is averaged over a geographic area. The values do not represent a typical rate that a user in a specific area applies. Maximum used is the highest rate of application that is actually reported to be used based on OPP/ BEAD analysis of DoaneS survey data. ­5­ the maximum rate reported to actually be used 1 . EECs varied greatly depending on the geographic location, crop and application rate. EEC values ranged from about 10 : g/ L from sugar beets to about 500 : g/ L from citrus. Chronic EECs ranged from about 1 to 28 : g/ L. With the exception of Florida citrus the calculated EECs are 3­ 5 times as high as concentrations observed in monitoring data. It is highly unlikely that any but the most extensive targeted monitoring would capture the actual peak concentrations, and the results of the modeling provide an conservative, though not unreasonable, estimate of possible concentrations in drinking water. ° The maximum calculated EEC resulted from use on citrus in Florida. A more detailed assessment of the source of water used to provide drinking water and the relationship between the areas where carbaryl is used and surface water supply sources is required to more accurately evaluate possible human exposures. In 1995, seven percent of Florida's population (about one million people) relied on surface water for their drinking water needs (Marella, 1999). A subset of these people get their water from citrus areas. Until more accurate data on land use and related pesticide application is available and can be linked with data on the location and hydraulic characteristics of the water bodies used for water supply it is not possible to provide a more accurate assessment of possible exposures. Also, the Percent Crop Area for citrus may be much lower then the default minor use crop value of 87% so the corresponding concentration may be lower. ° Carbaryl and its degradate 1­ naphthol are fairly mobile and slightly persistent. In general they are not likely to persist or accumulate in the environment. Under acidic conditions with limited microbial activity they may persist. ° Carbaryl dissipates in the environment by abiotic and microbially mediated degradation. The major degradation products are CO2 and 1­ naphthol, which is further degrade to CO2. Carbaryl is stable to hydrolysis in acidic conditions, but hydrolyzes in neutral (half­ life = 12 days) and alkaline environments (pH 9 half­ life = 3.2 hours). Carbaryl is degraded by abiotic photolysis in water with a half­ life of 21 days. Under aerobic conditions the compound degrades rapidly by microbial metabolism, with half­ lives of 4 to 5 days in soil and aquatic environments. In anaerobic environments metabolism is much slower with halflives on the order of 2 to3 months. Carbaryl is considered to be moderately mobile in the environment (Kf =1.7 to 3.5). ° The major metabolite of carbaryl degradation by abiotic and microbially mediated processes is 1­ naphthol. This degradate represented up to 67% of the applied carbaryl in degradation ­6­ studies. It is also formed in the environment by degradation of naphthalene and other polyaeromatic hydrocarbon compounds. Only limited information is available for the environmental transport and fate 1­ naphthol. While guideline studies were not submitted specifically for the degradate, open literature information suggests that it is less persistent and less mobile than parent carbaryl. ° Monitoring data for carbaryl in groundwater suggest that carbaryl is not a major groundwater contaminant though targeted data is not available. Parent carbaryl is detected in about 1 % of well samples in non­ targeted monitoring studies, generally at low concentrations (< 0.1 : g/ L). In the U. S. G. S NAWQA program detections in groundwater were mainly from three setting: wheat (5.8 % of well samples from wheat land use ), orchards and vineyards (1.7 % of well samples from orchard and vineyard land use), and urban (1.8% of urban groundwater samples). 2 Quantitative Usage Analysis for Carbaryl, OPP/ BEAD, 1998 ­7­ 2.0 Introduction Carbaryl (1­ naphthyl N­ methylcarbamate) is a broad­ spectrum carbamate insecticide and acaricide registered for control of over 300 species of insects and mites on over 100 crop and noncrop use sites, including homeowner uses; pet, and poultry uses; and treatment of oyster beds. As other carbamates, carbaryl is a cholinesterase inhibitor that acts on animals on contact and upon ingestion by inactivating the enzyme acetylcholinesterase and blocking the degradation of the neurotransmitter acetylcholine. As a result, the build up of acetylcholine causes an over­ stimulation of the central nervous system. Introduced in 1956, carbaryl was the first carbamate insecticide to be successfully marketed for a wide range of agricultural and household lawn and garden uses. Approximately 2.5 million pounds of carbaryl are applied annually in the U. S. A map showing the widespread use of carbaryl in agriculture is shown in Figure 1. Technical carbaryl is a white crystalline solid that has no appreciable odor. Carbaryl end­ use formulations include aqueous dispersions, baits dusts, emulsifiable concentrates, flowables, granules, oil based flowables, powder, soluble concentrates, suspension concentrates, wettable powders, water based flowables, water dispersible granules, and ready­ to use formulations. Carbaryl can be applied by aircraft, ground equipment, and sprinkler irrigation. The principal registrant is Aventis. For the years of 1987­ 96, carbaryl usage averaged approximately 2.5 million pounds a. i. for over 1.5 million acres treated. Average estimates for major crops treated include alfalfa (120,000 acres), apples (131,000 acres), corn (82,000 acres), hay (91,000 acres), pecans (95,000 acres), soybeans (101,000 acres), and wheat (106,000 acres). Crops with a high percentage of the total planted acreage treated include Chinese cabbages (57%), asparagus (43%), cranberries (39%), Brussels sprouts (33%), okra (32%), pumpkins (31%), and sweet cherries (25%) 2 . Carbaryl is also used for residential and other non­ agricultural uses, being the seventh most commonly used insecticide around the home. ­8­ Figure 1: Carbaryl use in Agriculture (Source USGS http:// water. wr. usgs. gov/ pnsp/ use92/ mapex. html) 3.0 Integrated Risk Characterization Introduction Carbaryl is a widely used insecticide, and as a result of normal agricultural and nonagricultural uses, it is commonly detected in the environment. Carbaryl and its primary degradate 1­ naphthol are fairly mobile and slightly persistent. In general they are not likely to persist or accumulate in the environment. Under acidic conditions with limited microbial activity they may persist. Carbaryl dissipates in the environment by abiotic and microbially mediated degradation. The major degradation products are CO2 and 1­ naphthol which is further degraded to CO2. Carbaryl is stable to hydrolysis in acidic conditions but hydrolyzes in neutral (pH 7 half­ life 12 days) and alkaline (pH 9 half­ life = 5 hours environments. Carbaryl is degraded by photolysis in water with a half­ life of 21 days. Under aerobic conditions the compound degrades rapidly by microbial metabolism with half­ lives of 4 to 5 days in soil and aquatic environments. In anaerobic ­9­ environments metabolism is much slower with half­ lives on the order of 2 to3 months. Carbaryl is mobile in the environment (Kf =1.7 to 3.5). The major metabolite of carbaryl degradation by abiotic and microbially mediated processes is 1­ naphthol. Only limited information is available for the environmental transport and fate 1­ naphthol. While guideline studies were not submitted specifically for the degradate open literature information suggests that it is less persistent and less mobile then parent carbaryl. Carbaryl is commonly detected in surface water monitoring studies. Concentrations are generally low (less than 1 : g/ L), and the maximum reported value is less than 10 : g/ L. In groundwater carbaryl is detected less often and at lower levels (generally less than 0.01 : g/ L). Because of the relatively limited persistence of the compound in the environment it is unlikely that non­ targeted monitoring studies will detect the maximum concentrations that occur. Because only very limited targeted data of uncertain quality exists modeling was used to estimate maximum and average concentrations that may occur. Model results suggest that concentrations in surface water resulting from normal agricultural practices are high enough to adversely effect a variety of aquatic, estuarine and marine species. Aquatic Organisms Most carbaryl uses are not likely to pose acute or chronic risks to freshwater fish, nor an acute risk to estuarine/ marine fish. Most carbaryl uses, however, are likely to pose acute and chronic risks to freshwater invertebrates, and acute risk to estuarine/ marine invertebrates. On an acute basis, carbaryl is highly to slightly toxic to freshwater fish (LC50 = 0.25 ­ 20 ppm), moderately toxic to estuarine/ marine fish (LC50 = 2.6 ppm), very highly toxic to freshwater aquatic invertebrates (LC50 = 1.7 ­ 26 ppb), and very highly toxic to estuarine/ marine aquatic invertebrates, especially mysids. Carbaryl's main degradate, 1­ naphthol, is highly to moderately toxic to freshwater fish (LC50 = 0.75 ­ 1.6 ppm), moderately toxic to estuarine/ marine fish (LC50 = 1.2 ­ 1.8 ppm), highly toxic to freshwater invertebrates (LC50 = 0.7 ppm), and highly toxic to moderately toxic to estuarine/ marine invertebrates (0.21 ­ 2.5 ppm). EECs for 1­ naphthol can not be calculated because of a lack of fate and transport data. Exposure to sublethal carbaryl levels in laboratory studies are known to adversely affect survival of freshwater fish young (NOAEC = 0.25 ppm) and reproduction in freshwater invertebrates (NOAEC = 3.3 ppb). NOAEC values for estuarine/ marine fish and invertebrates have not been established because of missing data on chronic toxicity to estuarine/ marine fish. Although EEC scenarios for aquatic organisms were modeled using three different kinds of application rate data (maximum label, maximum reported Doane, and "average" rates), the LOC exceedances are minimally affected by the type of usage data. The acute risk LOC for freshwater fish is exceeded for one of five use scenarios modeled (citrus) at all three application rates, and the chronic risk LOC is not exceeded for any scenario, at any use rate (Table 1). ­10­ Exposure to certain sublethal carbaryl concentrations can produce deleterious effects in freshwater fish. When the freshwater murrell (Channa punctatus) is exposed to concentrations in the 1666 ­ 3730 ppb range, the resulting inhibition of acetycholinesterase (AChE) can cause thyroid and gonadal dysfunction (Ghosh et al., 1990). However, this study was performed at concentration levels well above the highest peak concentration modeled for carbaryl (Table 5) and, therefore, does not provide an indication as to potential effects under field conditions. In the fathead minnow (Primephales promelas), exposure to concentrations in the 0.008 ­ 0.68 mg/ l (8 ­ 680 ppb) prevented reproduction and decreased survival only at the highest test concentration (Carlson 1972). The NOAEC determined by this study, 0.21 mg/ l (210 ppb), is at the high end of the peak EECs predicted from models for only the citrus scenario (Table 5) and well below the peak EECs predicted for the other four scenarios that were modeled Table 1. Aquatic organisms: acute and chronic Risk LOC exceedances and RQs for nongranular carbaryl uses Acute Risk Chronic Risk Label Max Max Rep "Average" Label Max Max Rep "Average" Freshwater Fish LOC Exceed. 1 1/ 5 1/ 5 1/ 5 0/ 5 0/ 5 0/ 5 RQs 1. 1 0. 93 0. 58 ­­­ ­­­ ­­ Estuarine/ Marine Fish LOC Exceed. 1 0/ 5 0/ 5 0/ 5 no data no data no data RQs ­­­ ­­­ ­­ Freshwater Inverts LOC Exceed. 1 5/ 5 5/ 5 5/ 5 5/ 5 5/ 5 5/ 5 RQ Ranges 1. 5­ 48.9 1. 1­ 4 0.8­ 25.9 3. 3­ 91.3 2. 0­ 74.7 1. 7­ 44.7 Estuarine/ marine Inverts LOC Exceed. 1 5/ 5 5/ 5 5/ 5 no data no data no data RQ Ranges 1. 5­ 48.1 1. 0­ 40.7 0. 8­ 25.4 1 No. use scenarios for which RQ is greater than LOC/ total No. use scenarios examined (acute LOC = 0.5, chronic LOC = 1) At relatively high concentrations, carbaryl can adversely affect amphibians' development and behavior. For instance, Bridges (2000) reports that acute exposure to carbaryl in southern leopard frogs during development, from egg to tadpole, results in a higher rate of deformities relative to control tadpoles. Nearly 18% of the tadpoles exhibited some type of developmental deformity, including both visceral and limb malformities, compared to a single deformed (less than 1%) control tadpole. Activity of plains leopard frog tadpoles exposed to carbaryl diminishes by nearly 90% at 3.5 mg/ L and ceases completely at 7.2 mg/ L (Bridges, 1997). Although under the reported test conditions potential consequences of reduced activity and swimming performance can lead to increased vulnerability to predation, slower growth, and failure to complete metamorphosis, tests concentrations are considerably higher than the highest surface water EECs calculated for carbaryl. Testing at or below maximum EEC is needed to better understand if amphibians are indeed likely to be at risk when exposed to carbaryl at concentrations likely to occur under field conditions. It is also possible that the PRZM/ EXAMS pond modeling may not be conservative enough for amphibians breeding in temporary pools and other short­ lived aquatic habitats exposed to carbaryl ­11­ through runoff and/ or spray drift. EFED is concerned about the behavioral and developmental effects of carbaryl on amphibians; when appropriate test procedures have been developed to examine these effects, EFED will request that carbaryl undergo these studies. The acute risk LOC for estuarine/ marine fish is not exceeded for any use scenario modeled, at any use rate, indicating that, except for the oyster bed use in Washington State, carbaryl uses are unlikely to pose an acute risk to these organisms. The absence of core chronic toxicity data precluded the calculation of an RQ for estuarine/ marine fish. Information from the open literature, however, indicates that exposure to sublethal levels of carbaryl can produce certain adverse effects in some species. According to Weis and Weis (1974), laboratory exposure of the silverside (Menidia menidia) to a single dose of carbaryl (100 ppb) resulted in the temporary disruption of schooling behavior, consisting mainly of a spreading out of the school over a larger area. This change in behavior was observed after 24 h exposure. Returning the fish to carbaryl­ free water did not bring about a return of normal schooling patterns until 72 hours. This effect was attributed to the accumulation of carbaryl degradate1­ naphthol. Aerial carbaryl applications to tideland areas in Washington State, at 7.5 ­ 8 lb ai/ acre, for control of burrowing shrimp in commercial oyster beds are known to pose a significant acute risk to fish inhabiting treated mudflats or trapped in shallow pools. Estimates of potential fish kills range from 15,000 to 96,000 following each treatment (MRID 419826­ 06). Exposure to sublethal carbaryl levels may also inhibit acetylcholinesterase in fish in subtidal areas near treated sites, resulting in a temporary impairment of burying behavior and increasing exposure to predators (Pozorycki, 1999). Along with the burrowing shrimp, other invertebrate populations inhabiting treated mudflats, which constitute a food source for fish, are temporarily reduced or eliminated. There may be up to 100% mortality of Dungenese crab populations following carbaryl applications. However, some invertebrates recolonize the treated areas within two weeks (MRID 419826­ 06), and most populations of invertebrates recover in less than two months (Brooks 1993). Once established, the oyster beds provide a suitable environment for a species­ diverse community, as many plants and invertebrates, which are normally rare or absent in barren mudflats, readily grow on or in between oyster shells (MRID 419826­ 06). Since, on average, tideland areas are treated once every six years, adverse effects on the aquatic biota are temporary. Potential nonchemical pest management methods identified include alternative culture techniques, mechanical control, enhancement of shrimp predators, and electrofishing. Carbaryl application techniques that reduce drift, such as direct injection of carbaryl into the sediment, should be also further explored. In addition, improvements in the forecasting of shrimp infestation and the refinement of current action thresholds may help to decrease the frequency and amount of carbaryl applications without affecting effectiveness. Environmental concentrations of carbaryl resulting from normal agricultural uses have been shown to have effects on invertebrate populations and individuals. Both acute and chronic risk LOCs are exceeded for freshwater invertebrates for all five carbaryl aquatic use scenarios modeled at maximum label, maximum reported, and "average" use rates, indicating that most carbaryl uses are likely to pose acute and chronic risks to freshwater invertebrates. Emergence of aquatic insects, such as damselflies, can also be severely reduced after 10 ­12 days exposure to 100 µg/ L of carbaryl (Hardersen and Wratten, 1998). In a mesocosm study, at carbaryl concentrations above 20 µg/ L ­12­ Daphnia were no longer found and at concentrations greater than 50 µg/ L, all cladocerans were eliminated, resulting in increased algal biomass due to repartitioning of biomass from zooplankton to phytoplankton (Havens, 1995). Studies with the freshwater snail (Pomaca patula) have shown that increased acetyl cholinesterase (AChE) inhibition occurs concurrently with the bioconcentration of carbaryl after 72 hour exposure at 3.2 µg/ g (Mora et al., 2000). The acute LOC for estuarine/ marine invertebrates is exceeded for all five carbaryl use scenarios assessed at maximum label, maximum reported, and "average" application rates, indicating that estuarine/ marine invertebrates inhabiting intertidal zones and estuaries near areas where carbaryl is applied are likely to be at risk. Terrestrial Organisms Three different kinds of nongranular carbaryl usage data were considered for assessing risk to terrestrial animals: maximum label rates, maximum reported (Doane data available for 42 uses) rates, and QUA "average" rates. In most cases the LOC exceedance pattern was not significantly affected by the kind of usage data used to calculate risk quotients. Acute risk quotients indicate that, although none of nongranular carbaryl uses may pose an acute risk to birds, all nongranular uses present a chronic risk to birds. All granular uses are likely to pose an acute risk to 20 g birds, and all granular uses, except for cucurbits, legumes, wheat, millet, and sugar beet, also represent a risk to 180 g birds, while only the trees and ornamentals, turfgrass, and tick control uses pose a risk to 1000 birds. All nongranular and granular uses are likely to pose an acute risk to 15 g and 35 g mammals. All nongranular uses pose a chronic risk to mammals. Table 2 summarizes LOC exceedances as well as the respective RQ ranges for nongranular uses. The Agency is aware of only a few carbaryl­ related mortality incidents for mammals and birds, all involving small numbers of individuals. Although few in number and magnitude, considering that few mortality incidents are actually detected and reported, these known incidents suggest that a certain level of acute risk to birds and mammals from exposure to carbaryl does exist under field conditions. ­13­ Table 2. Avian and Mammalian Acute and Chronic Risk LOC Exceedances and highest RQs for Nongranular Carbaryl Uses at Maximum Label, Maximum Reported, and QUA Average application rates. Acute Risk Chronic Risk Label Max Max Rep "Average" Label Max Max Rep "Average" Birds LOC Exceed. 1 0/ 74 0/ 42 0/ 70 73/ 74 34/ 42 39/ 70 RQs N/ A N/ A N/ A 1.5­ 12.8 1. 0­ 12.0 1. 0­ 4. 2 Mammals LOC Exceed. 1 74/ 74 41/ 42 63/ 70 72/ 74 42/ 42 69/ 70 RQs 0. 76­ 12.12 0.60­ 11.36 0.53­ 4.02 3.0­ 48.0 1. 5­ 45.0 1. 5­ 15.9 1 No. uses for which the highest RQ is greater than LOC/ total No. uses examined (acute LOC for birds = 1; acute LOC for mammals = 0.5, chronic LOC for birds and mammals = 1) Based on a rock dove LD50 of 1,000 mg/ kg and a mallard LD50 greater than 2,000 mg/ kg, technical carbaryl can be classified as slightly to practically nontoxic to birds on an acute basis. LD50 values for carbaryl as low as 16.2 mg/ kg and 56.2 mg/ kg have been reported for the starling and the red­ winged blackbird, respectively (Schafer et al., 1983). Although these data are based on simple screening tests, and are therefore not reliable for risk assessment purposes, they do suggest that passerine birds may be significantly more sensitive to carbaryl exposure than non­ passerine birds. Thus, the registrant is strongly encouraged to submit acute oral toxicity tests with passerine avian species. This risk assessment is using the dove LD50 (lower 95% confidence interval = 1,000 mg/ kg) to calculate acute RQs for granular carbaryl. On a subacute, dietary basis, carbaryl is practically nontoxic to birds. The quail LC50 is greater than 5,000 ppm, and an LC50 greater than 10,000 ppm is reported for the Japanese quail (Coturnix) by Hill and Camardese (1986). On a chronic basis, the NOAEC is 300 ppm for the mallard duck, based on adverse reproduction effects including reduced egg production, decreased fertility, and increased incidence of cracked eggs. For this risk assessment, the quail LC50 (> 5,000 ppm) and the duck NOAEC (300 ppm) are used to calculate the subacute dietary and chronic RQs, respectively. The avian acute risk level of concern (LOC) is not exceeded for any nongranular carbaryl use, at maximum or less than maximum label application rates. The avian chronic risk LOC is exceeded for almost all (73 of 74) uses considered at maximum label rates, for 34 of 42 uses at maximum reported rates, and for39of 70 uses at "average" rates. The avian acute LOC is exceeded for 20 g birds for all granular carbaryl uses (RQs: 0.52 ­ 4.76). For 180 g birds, the acute LOC is exceeded for the trees/ ornamentals, turfgrass, and tick control uses (RQ: 0.53). No acute LOCs are exceeded for birds in the 1000 g weight class for any of the granular carbaryl uses. Carbaryl is moderately toxic to small mammals on an acute oral basis (rat LD50 = 301 mg/ kg) and, based on decreased fetal body weights and increased incomplete ossification of multiple bones in the laboratory rat (LOAEC = 600 ppm, NOAEC = 80 ppm), has the potential for mammalian chronic effects. ­14­ As summarized in Table 2, at maximum label rates the mammalian acute LOC is exceeded for all 74 nongranular carbaryl uses, and the chronic risk LOC is exceeded for 70 of the uses. RQs based on maximum reported rates for 42 uses exceed the acute LOC for 41 uses, while the chronic risk LOC is exceeded for all 42 uses. When "average" rates are used to calculate RQs for 70 nongranular uses, the acute risk LOC is exceeded for 63 uses, and the chronic risk LOC is exceeded for 69 uses, indicating that LOC exceedances are minimally affected when mammalian RQs are calculated using less than maximum label rates. Information available in the open literature suggests potential reproduction effects of carbaryl on mammals. Several field and laboratory studies report significant reproduction effects for several species of mammals, including reduced reproduction, disturbances in spermatogenesis, pathological pregnancy, increased embryonal resorption, increased percentages of infertile females, and males with underdeveloped testicles (Gladenko et al., 1970, Smirnov et al., 1971, Krylova et al., 1975, Pomeroy & Barrett, 1975). Others report only slight effects (Anonymous, 1969, Dougherty et al., 1971, Narotsky and Kavlock, 1995). Some fail to detect any reproduction effects (DeNorscia and Lodge, 1973, Dougherty, 1975, Chapin et al., 1997). Carbaryl is highly toxic to honey bees (LC50 = 1.3 ­ 2.0 µg/ bee), and moderately to highly toxic to a wide range of other beneficial insects, including species that prey on or parasitize many insect pests. Carbaryl has been linked to numerous bee mortality incidents in several states, which is not surprising given its effectiveness as a broad­ spectrum insecticide and its large number of uses. According to surveys conducted by the American Beekeeping Federation and the Washington State Department of Agriculture, carbaryl is one of the pesticides most frequently mentioned as being associated with bee kills (Brandi 1997, Johansen 1997). To minimize risk to bees and other pollinators, all carbaryl­ containing products display the standard pollinator protection language in their labels. As indicated by precautionary label language, carbaryl can cause injury to some terrestrial plants. Carbaryl, used as a fruit thinning agent on apples and pears, may cause fruit deformity under certain environmental conditions, and injury to tender foliage if applied to wet foliage or during periods of high humidity. As indicated in the label, carbaryl may also cause injury to Boston ivy, Virginia creeper, maidenhair fern, and Virginia and sand pines. A few incidents involving carbaryl injury to vegetable crops have been reported. To date, no terrestrial plant toxicity studies have been submitted to the Agency. To fully assess carbaryl risk to terrestrial plants, Tier I and, if appropriate, Tier II Seed Germination and Seedling Emergence, as well as Vegetative Vigor studies should be submitted by the registrant. ­15­ Endangered Species The endangered species LOC for birds (0.1) is met or exceeded for 72 of 74 nongranular carbaryl uses at maximum label use rates, for 18 of 70 carbaryl uses at QUA average use rates, and for 25 of 42 maximum reported use rates. The endangered species LOC is exceeded for 20 g birds for all granular uses. For 180 g birds it is exceeded for all granular uses, except cucumber, melons, pumpkin, squash, beans, peas, lentils, cowpeas, southern peas, wheat, millet, and sugar beets. For 1000 g birds, the endangered species LOC is reached for the trees and ornamentals, turfgrass, and tick control granular uses. The mammalian endangered species LOC for all three mammal weight categories and the grass/ broadleaf plants/ small insects food items is exceeded for all nongranular uses examined, at maximum label rates. At "average" and maximum reported use rates, the endangered species LOC for 15 g mammals feeding on short grass is exceeded for all carbaryl uses. The endangered species LOC is exceeded for 15 ­ 35 g mammals for all granular uses. The endangered species LOC for freshwater fish is exceeded for three (sweet corn, field corn, and citrus) of five use scenarios modeled and for the citrus scenario at less than maximum label rates. For marine/ estuarine fish, the endangered species LOC is met for the citrus scenario only at maximum label rates. The endangered species LOC is exceeded for freshwater and marine/ estuarine aquatic invertebrates for all five use scenarios at maximum and less than maximum label use rates. The uses of carbaryl on field crops (corn, soybeans, sorghum, wheat), forests and pasture/ rangeland were addressed by the US Fish and Wildlife Service (USFWS) in the reinitiation of consultation in September 1989. In their 1989 Biological Opinion, USFWS found jeopardy to a total of 86 species ­ 6 amphibians, 47 freshwater fish, 27 freshwater mussels, and 5 aquatic crustaceans. Reasonable and Prudent Alternatives (RPA) were given for each jeopardized species. Reasonable and Prudent Measures (RPM) were given for 18 non­ jeopardized species to minimize incidental take of these species. Many additional species, especially aquatic species, have been federally listed as endangered/ threatened since the Biological Opinion of 1989 was written, and determination of jeopardy to these species has not been assessed for carbaryl. In addition, endangered insects, birds and mammals were not considered in the 1989 opinion and need to be addressed. Finally, not only are more refined methods to define ecological risks of pesticides being used but also new data, such as that for spray drift, are now available that were not existent in 1989. The RPAs and RPMs in the 1989 Biological Opinion may need to be reassessed and modified based on these new approaches. This can occur once the program is finalized and in place. Endocrine Disruption Concerns EPA is required under the Federal Food, Drugs, and Cosmetics Act (FFDCA), as amended by Food Quality Protection Act (FQPA), to develop a screening program to determine whether ­16­ certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally­ occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific basis for including, as part of the program, the androgen­ and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). When the appropriate screening and or testing protocols being considered under the Agency's Endocrine Disruptor Screening Program have been developed, carbaryl may be subjected to additional screening and or testing to better characterize effects related to endocrine disruption. There are data indicating that carbaryl has the potential for endocrine disruption effects on fish. Serum and pituitary levels of gonadotropic hormone and gonadotropin­ releasing hormone (GnRH) in the freshwater murrell (Channa punctatus) are reduced by exposure to 1.66 ­ 3.73 ppm of carbaryl in laboratory and paddy field tests (Ghosh et al., 1990). The decrease in GnRH levels could be explained by exposure to high estrogen levels, acting through a negative feedback pathway to inhibit GnRH release, and thus the release of gonadotropins (Klotz et al., 1997). Plasma and ovarian estrogen levels in freshwater perch (Anabas testudineus) exposed to 1.66 ppm of carbaryl for 90 days increase until day 15 and then decline, relative to control fish, indicating that long­ term exposure to this chemical may cause an inhibitory effect on fish reproduction (Choudhury et al., 1993). Both the murrell and the perch studies, however, were performed at concentrations well above the highest peak concentration modeled for carbaryl and, therefore, may not reflect risk under field conditions. Furthermore, a number of field and laboratory studies report reproduction effects with mammals, suggesting that the possibility of endocrine disruption effects on wild mammals should be further examined. Uncertainties The absence of valid chronic toxicity data for estuarine/ marine fish, estuarine/ marine invertebrates, and amphibians, as well as the lack of toxicity data for aquatic and terrestrial plants represent uncertainties in the risk assessment for carbaryl that need to be addressed through the submission of additional required data. Additionally, mammalian chronic RQs were based on a rat prenatal development study NOAEC (MRID# 44732901) rather than the more traditional use of a 2­ generation reproduction study. Field studies suggest that exposure to a single carbaryl application may affect reproduction in small mammals. ­17­ Only very limited information is available for the environmental fate and transport of the major carbaryl degradate 1­ Naphthol. Without additional data it is not possible to develop an fate profile for 1­ Naphthol. Concentrations in surface and groundwater can not be estimated without data on the stability and mobility of the degradate compound. 4.0 Environmental Fate Assessment Exposure Characterization Using acceptable and supplemental environmental fate studies submitted by the registrant, along with published scientific literature, a profile of the fate and transport of carbaryl in the environment has been compiled. This information is sufficiently complete to allow the evaluation of the movement and fate of the compound. However, existing data gaps in Soil Photolysis, Terrestrial Field Dissipation, Aquatic Field Dissipation and degradate fate and mobility need to be addressed by the registrant. Carbaryl dissipates in the soil environment by abiotic and microbially mediated degradation. The major degradation products are CO2 and 1­ naphthol, which is further degraded to CO2. Carbaryl is stable to hydrolysis in acidic conditions, but hydrolyzes rapidly in alkaline environments. Carbaryl is degraded by photolysis in water, with a half­ life of 21 days. Under aerobic conditions the compound degrades rapidly by microbial metabolism with half­ lives of 4 to 5 days in soil and aquatic environments. In anaerobic environments metabolism is much slower with half­ lives on the order of 2 to3 months. Carbaryl is mobile in the environment (Kf =1.7 to 3.5). Sorption onto soils is positively correlated with soil organic content, increasing with higher soil organic content. Table 3 summarizes the environmental fate characteristics of carbaryl. An analysis of the significance of the data is presented in this section. Monitoring data for carbaryl in surface water and groundwater show that it is commonly found in surface water and groundwater. In surface water concentrations are generally low (less than 1 : g/ L) and the maximum reported value is less than 10 : g/ L. In groundwater carbaryl is detected less often and at lower levels (generally less than 0.01 : /L). Available monitoring studies and data sets are described below. Because of the relatively limited persistence of the compound in the environment it is unlikely that non­ targeted monitoring studies will detect the maximum concentrations that occur. Because of the limited amount of data available and because of potential problems with extant data (described below) monitoring data are of limited utility in developing EECs for ecological and human health risk assessment. Therefore, EFED used computer modeling to estimate surface water and groundwater concentrations that could be expected from normal agricultural use. For developing surface water EECs EFED used EPA PRZM3.12 and EXAMS 2.97.5 programs to estimate the concentration of carbaryl in surface water. For ecological risk assessment the standard pond scenario was used. For human health risk assessment index reservoir scenarios were used. 3 "Average" is the average rate as determined by OPP/ BEAD and reported in the a memo titled Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD. 4 Maximum used is the highest rate of application that is actually reported to be used based on OPP/ BEAD analysis of DoaneS survey data by Donald Atwood, Personal communication, January 31, 2001. ­18­ Several application rates were used in modeling: the maximum allowed for the specific crop, an "average" rate 3 , and the maximum rate reported to actually be used 4 . The maximum rate was taken from the carbaryl labels. "Average and maximum reported rates were determined by EPA/ BEAD based on data collected by Doane surveys and registrant market analysis. EECs varied greatly depending on the geographic location, crop, and application rate. Modeling "average" and maximum reported use rates yielded EEC values generally 40­ 60% lower than maximum. EFED normally uses the maximum allowed application rates in modeling. In this assessment other, "less then maximum", rates were modeled in order to evaluate how conservative maximum rates modeling estimates are. The average and maximum rates may or may not be representative of actual use rates and are of limited certainty due to the quality and extent of the data available to calculate them. As described in the BEAD chapter the average application rates were derived by dividing total pounds used by the overall use area. The resulting average does not represent the actual average applied to any specific area and is not relevant for fist assessment. The maximum reported rate was determined from DOANES survey results. These data, while the best available, are very limited. The number of farmers surveyed is small, often only one or two per state, and the statistical validity of the results are not known but it is highly unlikely that the survey identified the actual maximum value. The maximum calculated EEC resulted from use on citrus in Florida. For the Index Reservoir scenario using maximum label rates, acute EEC values ranged from about 19 : g/ L from sugar beets to about 500 : g/ L from citrus (Table 6). Chronic EECs ranged from about 2 to 28 : g/ L. These values are higher then concentrations observed in monitoring studies and probably represent conservative estimates of environmental concentrations. Modeling results are higher then monitoring data because of the limited persistence of the compound in most surface waters. It is highly unlikely that any but the most extensive targeted monitoring would capture the actual peak concentrations. The results of the modeling provide a conservative, though not unreasonable, estimate of possible concentrations in drinking water. A more detailed assessment of the source of water used to provide drinking water and the relationship between the areas where carbaryl is used and surface water sources is required to more accurately evaluate possible human exposures. Until more accurate data on land use and related pesticide application is available and can by linked with data on the location and hydraulic characteristics of the water bodies it is not possible to provide more accurate assessment of possible exposures. A more detailed description of modeling is presented below, and model input files are attached in appendix F. ­19­ Figure 2. Generalized carbaryl degradation pathway Table 3: Summary of Environmental Chemistry and Fate Parameters For Carbaryl (See Text for Analysis) Parameter Value Reference Selected Physical/ Chemical Parameters Molecular Weight 201.22 Water Solubility 32 mg/ L (ppm) at 20 o C Suntio, et al., 1988 Vapor pressure 1.36 10 ­7 mm Hg (25 o C) Ferrira and Seiber, 1981 Henry's Law Constant 1.28 x 10 ­8 atm m 3 mol ­1 Suntio, et al., 1988 Octanol/ Water Partition Kow = 229 Windholz et al., 1976 Persistence Hydrolysis t1/ 2 pH 5 pH 7 pH 9 stable 12 days 3.2 hours MRID 00163847, 44759301 Photolysis t½ aqueous 21 days MRID 41982603 Soil photolysis assumed stable No valid data submitted Soil metabolism T½ Aerobic 4 days in one sandy loam soil MRID 42785101 Anaerobic t1/ 2 = 72 days Satisfied by 162­ 3 Aquatic metabolism Aerobic t1/ 2 = 4.9 days MRID 43143401 Anaerobic t1/ 2 = 72 days MRID 42785102 Table 3: Summary of Environmental Chemistry and Fate Parameters For Carbaryl (See Text for Analysis) Parameter Value Reference ­20­ Major Transformation Products Identified in the Fate Studies: 1­ naphthol, CO2 Minor Transformation Products Identified in the Fate Studies: 5­ hydroxy­ l­ naphthyl methylcarbamate (aerobic soil metabolism, anaerobic aquatic ) 1­ naphthyl( hydroxymethyl) carbamate (aerobic soil metabolism, anaerobic aquatic) 1,4­ naphthoquinone (aerobic aquatic metabolism, anaerobic aquatic) (hydroxy) naphthoquinones (degradates of 1­ naphthol) 4­ hydroxy­ 1­ naphthyl methylcarbamate (anaerobic aquatic) 1,5­ naphthalenediol (anaerobic aquatic) 1,4­ naphthalenediol (anaerobic aquatic) Mobility/ Adsorption­ Desorption Batch Equilibrium Kf (Koc) =1.74 (207) ­ sandy loam 2.04 (249) ­ clay loam sediment 3.00 (211) ­ silt loam 3.52 (177) ­ silty clay loam 1/ n values ranged from 0.78­ 0.84 MRID 43259301 Column Leaching slightly mobile in columns (30­ cm length) of sandy loam, silty clay loam, silt loam, and loamy sand soils MRID 433207­ 01 Field Dissipation Terrestrial Dissipation Submitted study not acceptable MRID 419826­ 05 Forestry Dissipation Foliar t1/ 2 = 21 days Leaf Litter t1/ 2 = 75 days Soil t1/ 2 = 65 days MRID 43439801 Aquatic Submitted study not acceptable MRID 4326001 Foliar Dissipation 30 days Default value Bioaccumulation Accumulation in Fish not expected due to low Kow ­21­ Persistence Chemical Degradation Processes Hydrolysis Carbaryl hydrolysis is strongly pH dependant. The compound is stable under acidic conditions and degrades in neutral and alkaline systems with measured half­ lives of 12 days (pH 7) and 3.2 hours (pH 9). Only one major degradate was identified, 1­ naphthol (MRID 44759301). Chapman and Cole (1982) measured half­ lives of 2.0 weeks (pH = 7.0) and 0.07 weeks (pH = 8). Wolfe et al. (1978) reported half­ life values in natural pond waters at pH 6.7 of 30 days and at pH 7.2 of 12 days. They also estimated minimum hydrolysis half­ life in acidic conditions of 1600 days. Armbrust and Crosby (1991) reported hydrolysis half­ lives in filtered seawater of 24 hours at pH 7.9 and 23 hours at pH 8.3. The major degradation product was 1­ naphthol which was stable to further hydrolysis. Photolysis Aqueous Photolysis In an aqueous photolysis study, carbaryl, with an initial concentration of 10.1 mg/ L, degraded in a pH 5 solution with a half­ life of 21 days after correction for dark controls( MRID 41982603). The only degradate identified was 1­ naphthol. Wolfe et al. (1978) reported a photolysis half­ life in distilled water at pH 5.5 of 45 hours. In filtered seawater carbaryl degraded rapidly to 1­ naphthol under artificial sunlight (290­ 360 nm) with a half­ life of 5 hours. The degradation product, 1­ naphthol, was degraded very rapidly with half­ life of less than 1 hour (Armbrust and Crosby, 1991). Soil Photolysis A study of photolysis (MRID 41982604) on soil was submitted; however the study was determined to be invalid. No data on the possible soil photolysis of carbaryl is available. In view of this data gap, it is assumed that the compound is stable to photolysis on soil. Microbially­ mediated Processes Carbaryl is degraded fairly rapidly by microbial processes under aerobic conditions and more slowly under anaerobic conditions. In a guideline study of aerobic soil metabolism carbaryl, with an initial concentration of 11.2 mg/ kg, degraded with a half­ life of 4.0 days in sandy loam soil incubated in the dark at 25 B C (MRID 42785101). The major degradate was 1­ naphthol which further degraded rapidly to non­ detectable levels within 14 days. In an aerobic aquatic metabolism study carbaryl, with an initial concentration of 9.97 mg/ L, degraded with a half­ life of 4.9 days in flooded clay loam sediment in the dark at 25° C (MRID 43143401). 1­ Naphthol was identified as a major nonvolatile degradate. Carbaryl degraded with a half­ life of 72.2 days in anaerobic aquatic sediment with an initial carbaryl concentration of about 10 mg/ L; 1­ naphthol was the major degradate. Minor degradates included 5­ hydroxy­ 1­ naphthyl methylcarbamate, 4­ hydroxy­ 1­ naphthyl methylcarbamate, 1,5­ naphthalenediol, 1,4­ naphthalenediol, 1­ naphthyl( hydroxymethyl) carbamate, and 1,4­ naphthoquinone ­22­ Liu, et al. (1981) studied carbaryl degradation in anaerobic and aerobic fermenters spiked with a mixture of lake sediment, silt loam and domestic activated sludge and buffered to pH 6.8. They reported abiotic degradation half­ lives of 8.3 (aerobic) and 15.3 (anaerobic) days. After correcting for abiotic controls, when carbaryl was used as the sole carbon source they found aerobic and anaerobic metabolism half­ lives of 54 and 11.6 days, respectively. When glucose and peptone were added co­ metabolism aerobic and anaerobic metabolism, half­ lives were 7.6 and 6.1 days respectively. A number of soil microorgamisms have been identified which can degrade carbaryl including Pseudomonas sp (Chapalmadugu and Chaudhry, 1991; Larken and Day, 1986), Rhodoccus sp. (Larkken and Day, 1986), Bacillus sp. (Rajagopal. et al., 1984), Arthrobacter sp. (Hayatsu et al., 1999), and Achromobacter sp (Karns et al., 1986). Some bacteria are capable of complete degradation to CO2 (Chapalamadugu and Chaudhry, 1991) while some stop at 1­ naphthol. In soils it appears that consortia of bacteria are able to degrade parent and 1­ naphthol completely to CO2. Proposed degradation pathways proceed by using the methylcarbarmate side chain as a carbon source, converting the parent to 1­ naphthol. 1­ naphthol is then degraded through intermediates salicylaldehyde, salicylic acid, catechol, and gentisate to CO2 and water (Chapalamadugu and Chaudhry, 1991; Hayatsu et al., 1999). Several studies have shown that bacteria isolated from soil exposed to carbofuran can degrade carbaryl indicating cross adaption by microorganisms allowing degradation of compounds with similar structure (Karns et al., 1986: Chaudhry, et al., 1988). Carbaryl degradation utilizes enzyme systems which may or may not degrade other carbarmate compounds (Chapalamadugu and Chaudhry, 1991). Mobility Carbaryl is considered to be moderately mobile in soils. Based on batch sorption/ desorption studies, the compound has Freundlich Kf values of <3.52. Sorption is dependant on the soil organic matter content and increased with increasing Koc. Batch Adsorption/ Desorption Based on batch equilibrium experiments (MRID 43259301) carbaryl was determined to be moderately mobile to mobile in soils. In silty clay loam, sandy loam, loamy sand, and silt loam soils and clay loam sediment, mobility decreased with increasing soil organic matter content. Adsorption Koc values ranged from 177­ 249. Kf values were 1.74 for the sandy loam soil, 2.04 for the clay loam sediment, 3.00 for the silt loam soil, and 3.52 for the silty clay loam soil. Corresponding Koc values were 207, 249, 211, and 177, respectively, and 1/ n values ranged from 0.78­ 0.84. Mobility decreased with increasing soil organic matter content. Sorption showed significant hystereses with Freundlich desorption constants (Kf( des)) values of 6.72 for sandy loam soil, 6.78 for clay loam sediment, 6.89 for silt loam soil, and 7.66 for silty clay loam soil. 1/ n values ranged from 0.86­ 1.02. Corresponding desorption Koc values were 800, 827, 485, and 385, respectively. Literature data confirms that carbaryl is mobile. Nkedi­ Kizza and Brown (1998) reported Kf of 4.72 (1/ n = 0.80) for soil with an organic content of 590 mg/ Kg. They found that sorption was lower on subsoils and attributed this to a lower organic content. The reported Koc values ranged from 144 to 671. ­23­ Column Leaching In column leaching experiments (MRID 43320701), carbaryl residues were determined to be slightly mobile in columns (30­ cm length) of sandy loam, silty clay loam, silt loam, and loamy sand soils treated with aged carbaryl residues. This disparity with the batch experiments may possibly be explained by the relatively poor extraction recovery, by slow desorption kinetics and by degradation during the aging period. Unextracted [ 14 C] labeled residues in the soils prior to leaching ranged from 19.0% of the recovered in the loamy sand soil to 39.7% in the silty clay loam soil. The study author believed that 50% of the carbaryl applied to the soil had degraded prior to leaching. Field Dissipation Studies of carbaryl dissipation in terrestrial, aquatic and forest environments have been submitted by the registrant. In forest environments carbaryl was found to be moderately persistent in soil (half­ live = 65 days) and leaf litter (half­ live = 75 days). The submitted field and aquatic dissipation studies were determined to be unacceptable, and did not provide useful information on movement and dissipation of carbaryl or its degradation products. Field dissipation studies conducted in the 1960s and 1970s in terrestrial (Fiche/ Master ID 000108961 and 00159337), aquatic (Fiche/ Master ID 001439080, 0124378, 00159337, 00159338, 00159339) and forestry (Fiche/ Master ID 00029738, 00159340, 00159341) environments and submitted in the 1980s have been reexamined. When they were initially reviewed they were not considered acceptable for a number of reasons including: sampling frequency was not sufficient to allow calculation of dissipation rates, degradates were not identified or quantified, soil, sediment and water were not sufficiently characterized, problems with analytical method specificity and validity, insufficient sampling frequency and sampling depth, lack of data on irrigation practices measures. These studies do not meet current levels of scientific validity required to be considered acceptable and do not provide useful information on field dissipation of carbaryl and its degradates. The data requirements for terrestrial and aquatic field dissipation have not been fulfilled, and additional studies are required. Terrestrial Field Dissipation Results of two field dissipation studies conducted in California and North Carolina were submitted (MRID 41982605). Because of inappropriate sampling intervals, poor sample storage stability, lack of degradate monitoring, rainfall and irrigation that were less than evapotranspiration, and irrigation water with high pH, these studies do not provide reliable information on the rate of dissipation of parent carbaryl or formation of degradation products. The requirement for terrestrial field dissipation has not been fulfilled, and additional information is required. Because of problems with submitted studies additional field studies are required. A freezer stability study was reportedly conducted but the results past 90 days were not submitted. There was apparently significant degradation within 90 days. Study samples were analyzed as long as 8 months after collection, making the quality of the data highly questionable. Degradates were not analyzed in either study, and the sampling interval was insufficient to accurately determine the dissipation rate for carbaryl. In the California study >80% of the applied ­24­ carbaryl apparently dissipated between the final carbaryl application and the next sampling interval (4­ 7 days after the final application). In the NC study > 90 % apparently dissipated between application and the next sampling event (7days). However, in both studies dissipation after 7 days suggested a half­ life on the order of weeks. In both studies rainfall and irrigation were less than evapotranspiration so the data can not be used to assess the potential for carbaryl to leach into the subsurface. In the California study, irrigation with water with a pH of 8.0 was applied 1­ 3 days after each pesticide application. Because carbaryl hydrolysis is highly pH dependant ( T1/ 2 at pH 9 = 3.2 hours) this may have resulted in significantly more rapid degradation. Forestry Field Dissipation In a supplemental forestry field dissipation study (MRID 43439801) carbaryl was applied on a pine forest site in Oregon. Carbaryl half­ lives were found to be 21 days on foliage, 75 days in leaf litter and 65 days in soil. At the time of treatment, the trees of primary interest (pine) were 3­ 8 feet tall. Carbaryl concentration was a maximum of 264 ppm in the pine foliage at 2 days posttreatment 28.7 ppm in the leaf litter at 92 days, 0.16 ppm in the upper 15 cm of litter­ covered soil at 62 days, and 1.14 ppm in the upper 15 cm of exposed soil at 2 days. Carbaryl was detected in the leaf litter up to 365 days after treatment, and in the litter­ covered soil up to 302 days after treatment. Carbaryl was <0.003 ppm in water and sediment from a pond and stream located approximately 50 feet from the treated area. This study was determined to provide only supplemental information because degradation products were not identified and their rate of formation and decline was not determined. Aquatic Field Dissipation Results of aquatic field dissipation studies conducted on rice in Texas and Mississippi were submitted (MRID 43263001). The studies were evaluated and found to be unacceptable. They do not provide useable information on the dissipation of carbaryl and 1­ naphthol in aquatic field conditions. Frozen storage stability data were provided for only 6 months, although the water samples were stored for up to 14 months and the soil samples were stored for up to 17.5 months prior to analysis. The data suggest that carbaryl and 1­ naphthol degraded significantly during storage. In the six months of storage carbaryl degraded an average of 34 % in Texas water and 39% in from Mississippi. 1­ naphthol degraded 50% in water from Texas and 69% from Mississippi. Degradation did not appear linear, and it is not possible to extrapolate out to 14 months. It was therefore not possible to evaluate the actual concentrations of carbaryl and 1­ naphthol in the samples or estimate the dissipation rates. Bioaccumulation in Fish Because of the low octanol/ water partition coefficient carbaryl is not expected to significantly bioaccumulate. Reported Kow values range from 65 to 229 (Bracha, and O'Brian, 1966; Mount, M. E. and Oehme, 1981; Windholz et al., 1976). A fish bioaccumulation study reviewed in 1988 (Chib, 1986, Fiche/ Master ID 00159342) suggested that bioaccumulation factors were 14x in ­25­ edible tissue, 75x in visceral tissue and 45x in whole fish. Though the study does not meet current acceptable standards it does support the conclusion that significant bioaccumulation is not expected. No additional data on bioaccumulation is required at this time. Foliar Dissipation The reported rates of carbaryl dissipation from foliar surfaces varies from 1 days to 30 days. In their review of literature data on pesticide foliar persistence, Willis and McDowell (1987) report that carbaryl dissipation rates varied from 1.2 to 29.5 days. In the submitted forestry field dissipation study (MRID 43439801) carbaryl applied to pine needles dissipated with a half­ live of 21 days. For terrestrial risk assessment modeling EFED used 35 days as the dissipation half­ life. Atmospheric Transport Carbaryl has been shown to be transported and deposited by atmospheric processes (Waite, et al., 1995; Foreman, et al., 2000; Sanusi et al., 2000). As with all chemicals applied by aerial or ground spray, spray drift can cause exposure to non­ target organisms downwind. Beyer et al., (1995) studied spray drift from aerial application to rangeland near the Little Missouri River in North Dakota. In 1991 carbaryl was applied to 35130 ha at 560 g/ ha (0.62 lb) A. I. A 152 m nospray buffer zone was maintained. River water samples collected 1 hour after completion of spraying had a mean concentration of 85.1 : g/ l. Concentration decreased over time, and 96 hours after application the mean was 0.1 : g/ l. In 1993 a similar application resulted in a maximum concentration 1 hour after spraying of 12.6 : g/ l decreasing to 5.14 : g/ L after 96 hours. The researchers found that invertebrates in the river were minimally effected while fish brain acetylcholinesterase activity was not effected. Vapor phase transport and particulate transport may carry the compound far from the area of application. In the atmosphere, partitioning between particulate and gas phase is a function of temperature and changes from about 30% vapor phase to about 90% when temperature increases from 283 to 303 K (Sanusi et al., 1999). This suggests that atmospheric transport distance and deposition are a function of temperature. Carbaryl has been detected in air in urban and suburban areas with limited influence from agricultural spraying. It is detected more frequently and generally at higher concentrations at sampling locations in urban areas than in agricultural areas (Foreman et al., 2000). Pesticide concentrations in fog often are higher than those observed in rain water or surface water and may represent a significant, though generally overlooked, route of exposure. Schomburg et al. (1991) reported carbaryl concentrations in fog ranging from 0.069 to 4.0 : g/ L. ­26­ 1­ Naphthol Fate and Transport Limited information is available for the environmental fate and transport of the major carbaryl degradate 1­ Naphthol. 1­ Naphthol was formed in laboratory degradation studies and represented a major portion of the applied mass (maximum of 22 % in aerobic aquatic metabolism, 58% in aerobic soil metabolism and 67% in photolysis). 1­ Naphthol was not persistent in the studies and appears to have degraded more rapidly then the parent. 1­ Naphthol a natural product and is also formed as a degradation product of naphthalene and other polycyclic aromatic hydrocarbons. It appears to degraded more rapidly then the parent in the submitted studies but there is not sufficient information the develop a detailed fate profile. While guideline studies were not submitted specifically for the degradate, literature information suggests that it is less persistent and less mobile than parent carbaryl. Armbrust and Crosby (1991) reported that 1­ Naphthol was stable to hydrolysis in filtered seawater at pH 7.9 and 8.3. Hydrolytic degradation of 1­ naphthol is reported to be due to reaction with dissolved O2 and is highly pH dependant (Karthikeyan and Chorover, 2000). Oxidation increases with pH and ionic strength. Below pH 7 oxidation is minimal and reaches a maximum at about pH 9. Oxidation of 1­ naphthol reportedly results in production of (hydroxy) naphthoquinones and dimer coupled reaction products, though the reaction rates for 1­ naphthol degradation is not well known (Karthikeya and Chorover, 2000). In filtered seawater carbaryl degraded rapidly to 1­ naphthol under artificial sunlight (290­ 360 nm), with half­ life of 5 hours. The degradation product, 1­ naphthol, was degraded very rapidly with half­ life of less than 1 hour (Armbrust and Crosby, 1991). 1­ naphthol is degraded rapidly by microbial processes in aerobic systems. In an aerobic soil metabolism study (MRID 42785101) 1­ naphthol degraded rapidly to non­ detectable levels within 14 days. Armbrust and Crosby (1991) reported that 1­ naphthol degraded in unfiltered seawater to below detectable level within 94 hours. Burgos et al. (1999) found that greater than 90% of aqueous 1­ naphthol was degraded to CO 2 within 10 days. However, they found that sorption to soil greatly reduced the degradation rate; when sorbed degradation was greatly slowed to 25­ 40% degradation in 90 days. No guideline information was submitted on 1­ naphthol sorption. Literature information suggests that it is not strongly sorbed. Sorption to poorly crystalline aluminum hydroxide was pH dependant and appeared to occur only after oxidation (Karthikeyan et al., 1999). Hassett et al. (1981) reported an average 1­ naphthol Koc of 431 (± 40) for 10 of the 16 soils tested. They also found that in other soils with very low organic carbon to clay ratios clay surfaces controlled sorption. Additional data on 1­ naphthol sorption is required to fully characterize mobility. ­27­ Aquatic Exposure Assessment Surface Water Five crop scenarios: apples, field corn, sweet corn, oranges and sugar beets scenarios were used in modeling for surface water EEC. These crops were chosen as representative of the major groups of crops with high carbaryl use and application rates that would result in high potential for surface water contamination. The EEC's generated in this analysis were calculated using PRZM for simulating runoff from an agricultural field and EXAMS for estimating environmental fate and transport within the water body. Modeling was done using the maximum rate on label, average application rate and maximum rate of application reported. Two sets of surface water simulations have been done for carbaryl: for drinking water assessment and for aquatic ecological exposure assessment. The modeling done for drinking water assessment was done using the index reservoir watershed scenario (Jones, et al., 2000) and calculated values were corrected for Percent Crop Area (PCA). For ecological risk assessment modeling was done using the standard farm pond scenario. The standard pond scenario used by EFED simulates a ten­ hectare field draining into a one­ hectare static pond that is two meters deep and has no outlet. It is assumed that evaporation losses and inflow from rainfall and runoff are balanced. The inputs used are similar to those used in modeling drinking water EECs and are shown in Table 4. EECs generated (Table 5) were compared with toxicological information described below to estimate the risk to non­ target aquatic organisms. ­28­ Table 4. PRZM/ EXAMS environmental fate input parameters for Carbaryl Parameter Value Data source Molecular Weight 201.22 Solubility 32 mg/ L (@ 20° C) Suntio, et al., 1988 Vapor Pressure (torr) 1.36 10 ­6 @ 25° C Ferrira and Seiber, 1981 Henry's Law Constant 1.28 x 10 ­8 Suntio, et al. 1988 Hydrolysis Half­ life pH 5 pH 7 pH 9 stable 12 days 3.2 hours MRID 00163847 44759301 Soil Photolysis Half­ life (days) stable no valid data submitted Aquatic Photolysis Half­ life (days) 21 days MRID 41982603 Aerobic Soil Metabolism Half­ life 4. 0 days (n= 1 so use 3x) MRID 42785101 Aerobic Aquatic Metabolism Half­ life 4. 9 days (n = 1 so use 3x) MRID 43143401 Anaerobic Aquatic Metabolism Half­ life 72.2 days MRID 42785102 Soil­ Water Partitioning Coefficient Kads (Koc) 1.74 (207) sandy loam 2.0 (249) clay loam 3.0 (211) silt loam 3.5 (177) silty clay loam (Koc = 209 for SCIGROW) MRID 43259301 There are a number of factors which may limit the accuracy and precision of the PRZM/ EXAMS modeling, including the selection of realistic exposure scenarios, the quality of the input data, the ability of the models to represent the real world and the number of years that were modeled. The scenarios that are selected for use in Tier II EEC calculations were chosen to be representative of uses likely to produce the highest concentrations in the aquatic environment. The EEC's in this analysis are accurate only to the extent that the model represents real environments. The most limiting part of the site selection is the use of the standard pond with no outlet. A standard pond is used because it provides a basis for comparing pesticides in different regions of the country on equal terms. The models also have limitations in their ability to represent some processes such as the handling of spray drift. A second major limitation is the lack of validation at the field level for pesticide runoff. ­29­ Table 5. Tier II surface water estimated environmental concentration (EEC) values derived from PRZM/ EXAMS modeling for use in ecorisk assessment (Calculated using standard pond.) Use Site, Application Method Number of Applications Per Year Application Rate (Pounds A. I. per Application) Surface Water Acute (ppb) (1 in 10 year peak single day concentration) 21 day (ppb) (1 in 10 year) 60 day (ppb) (1 in 10 year) Sweet Corn (OH), air/ ground Maximum "Average" Maximum Reported 8 2 3 2 3.4 1 46 16 14 26 10 8 21 5 4 Field Corn (OH), air/ ground Maximum "Average" Maximum Reported 4 2 2 2 1 1.5 28 12 18 16 6 9.5 10 3 5 Apples (OR), air/ ground Maximum "Average" Maximum Reported 5 2 2 2 1.2 1.6 8.6 4.5 6.0 4.9 2.5 3 4 1 2 Sugar Beets (MN), air/ ground Maximum "Average" Maximum Reported 2 1 1 1.5 1.5 1.2 19 14 11 11 7 5 5 3 2 Oranges (FL), air/ ground Maximum "Average" Maximum Reported 4 2 3 5 3.4 4.3 274 145 232 137 67 112 79 33 55 Urban and Suburban EFED has limited tools for assessing the effects of pesticide use in urban and suburban settings on surface water and groundwater quality. Carbaryl is extensively used in such nonagricultural applications, resulting in widespread surface water contamination. This conclusion is based on monitoring data. In urban and suburban areas small streams are generally greatly affected by surface runoff and water collection into storm sewers. These small streams can provide a significant habitat for aquatic animals, and this habitat can be severely degraded by runoff of urban pesticides. Garden and lawn care products and other outdoor uses contribute to carbaryl presence in storm sewers and streams. Monitoring data show that about 50% of urban streams have measurable concentrations (> 0.01 : g/ L) of carbaryl compared to less than 10% of agricultural sites (Larson, et al., 1999). Additional information is needed to adequately assess the environmental impacts of urban and suburban uses. Targeted surface water and groundwater monitoring studies are required to more adequately understand the movement of the compound in these environments and to provide estimates of the distribution of possible exposures from urban and suburban environments. Estimated Environmental Concentrations for Terrestrial Ecological Risk Assessment For terrestrial EECs, EFED uses the concentration of a chemical on food items derived from the Kenaga nomograph, as modified by Fletcher et al. (1994). The nomograph allows estimation of the concentration of pesticide on food items resulting from application, based on a large set of actual field residue data. The upper limit values from the nomograph represent the 95th percentile ­30­ of residue values from actual field measurements (Hoerger and Kenaga, 1972). Hoerger­ Kenaga pesticide environmental concentration estimates were based on residue data correlated from more than 20 pesticides on more than 60 crops. Representative of many geographic regions (7 states) and a wide array of cultural practices, Hoerger­ Kenaga estimates also considered differences in vegetative yield, surface/ mass ratio and interception factors. In 1994, Fletcher et al. reexamined the Hoerger­ Kenaga simple linear model (y= B 1 x, where x= application rate and y= pesticide residue in ppm) to determine whether the terrestrial EEC's were accurate. They compiled a data set of pesticide day­ 0 and residue­ decay data involving 121 pesticides (85 insecticides, 27 herbicides, and 9 fungicides from 17 different chemical classes) on 118 species of plants. They concluded that Hoerger­ Kenaga estimates needed only minor modifications to elevate the predictive values for forage and fruit categories from 58 to 135 ppm and from 7 to 15 ppm, respectively. Otherwise, the Hoerger­ Kenaga estimates were accurate in predicting the maximum residue values after a 1 lb ai/ acre application. EFED calculates concentration over time assuming first order dissipation from plant surfaces. In the absence of reliable foliar dissipation data a dissipation half­ life of 35 days is used. Published literature shows that carbaryl dissipation rates vary. and are among the highest observed for any pesticide. (Willis and McDowell, 1987). ELL­ FATE, a spreadsheet based first order decay model was used to calculate concentration over time for multiple applications at the label maximum, "average," and maximum reported application rates. A more thorough description of the model calculations and ELL­ FATE outputs are attached in Appendix D. EEC values calculated for different crop applications are presented in Tables 4, 7, 8, and 9, Appendix B. 5.0 Drinking Water Assessment Water Resources Assessment Chemical characteristics and available monitoring data indicate that carbaryl has the potential to enter surface water via leaching and runoff under certain conditions and has limited potential to leach to ground water. Carbaryl tends not to bind tightly to soil, aquifer solids, or sediment. Once the compound has entered surface water, it may be degraded by chemical and biological processes. Abiotic degradation by photolysis (t1/ 2 = 21 days) and hydrolysis in alkaline (t1/ 2 = 3.2 hours at pH 9) and neutral (t1/ 2 = 12 days at pH 7) waters result in fairly rapid degradation in most aqueous environments. Microbially mediated processes also contribute to fairly rapid degradation of the parent to 1­ naphthol and CO2. Aerobic aquatic, soil aerobic and anaerobic metabolism studies (t1/ 2 = 5, 4, and 72 days respectively) suggest that the compound is broken down by a variety of metabolic processes. Under certain limited conditions carbaryl may be expected to persist in the environment. Under low pH conditions the compound is stable to hydrolysis. In anaerobic environments metabolism is fairly slow (t½ = 72 days). Surface water monitoring studies show that carbaryl is the second most widely detected insecticide after diazinon. Carbaryl, at typically low concentrations, is found in greater than 20 % ­31­ of surface samples in NAWQA studies at concentrations up to 5.5 ppb. Carbaryl is detected more frequently in non­ agricultural areas (about 40%) then in agricultural areas (about 5 %). A maximum carbaryl concentration of 8.4 ppb was reported for surface water samples in the California DPR surface water database. Carbaryl is generally not widely detected in groundwater monitoring studies though some studies have found concentrations of up to several hundred ppb. Concentrations as high as 610 µg/ L have been detected in one case but typical groundwater concentrations are much lower. NAWQA studies have found that about 1 % of groundwater samples have measurable levels (> 0.003 : g/ L) of carbaryl, with a maximum concentration of 0.02 µg/ L. Targeted studies designed to measure carbaryl in groundwater are not available. Drinking Water Exposure Assessment Based on chemical properties, existing monitoring data and computer simulation estimates of carbaryl contamination that can be expected in surface water and groundwater as a result of normal use practices have been determined. Carbaryl is the second most commonly detected insecticide in surface water, and can be expected to contaminate drinking water derived from surface water bodies. Targeted and non­ targeted studies regularly detect carbaryl in low concentrations, typically below 1 µg/ L. Monitoring studies suggest that about 20 % of surface water bodies have detectable (> 0.01 : g/ L) levels of the compound. The maximum reported value in surface water was 8.4 µg/ L. Carbaryl is not widely detected in groundwater studies. Drinking water derived from groundwater has been found to have low or non­ detectable levels of carbaryl. For drinking water derived from groundwater, the acute and chronic EEC value of 0.8 µg/ L is based on modeling using SCI­ GROW. It must be noted that carbaryl has an aerobic metabolism half­ life (4 days) which is significantly outside the range of values for which SCI­ GROW may be valid (17­ 1000 days). Because of this there is significant uncertainty in the SCI­ GROW value. EFED currently does not have more advanced groundwater models, and targeted studies specifically designed to evaluate the potential for carbaryl to move to groundwater are not available. Because of its chemical structure carbaryl is somewhat difficult to quantify by gas chromatography. Older studies using GC or GC/ MS generally have poor recovery and quantitation limits. Because of this difficulty in analysis the actual concentration of carbaryl in groundwater and surface waters may be higher than reported. More recent studies using HPLC/ MS should provide better data on the true extent and magnitude of water contamination from the use of carbaryl. Drinking Water Modeling Modeling to support the assessment of drinking water in the human health risk assessment was done for five scenario: Florida citrus, Ohio sweet corn and field corn, Oregon apples and Minnesota sugar beets. These scenarios were selected to represent the range of crops and use rates likely to result in higher environmental concentrations. EECs were calculated using The Pesticide Root Zone Model version 3.12 (PRZM) (Carsel et al., 1997) and EXAMS 2.97.5 (Exposure Analysis Modeling System) (Burns, 1997) were run. PRZM is used to simulate pesticide transport as a result ­32­ of runoff and erosion from an agricultural field and EXAMS estimates environmental fate and transport of pesticides in surface water. Weather and agricultural practices are simulated over 36 years so that the 10­ year exceedance probability at the site can be estimated. A partial list of input parameters for the PRZM/ EXAMS modeling are given in Table 4. Simulations were run using the maximum application rates, average rates, and maximum reported rates. The values generated by the models were multiplied by a default percent crop area factor (PCA) which accounts for the fact that is unlikely for any basin to be completely planted to agricultural crops. For human health assessment, simulations were done using the Index Reservoir scenario in Exams. The Index Reservoir and PCA are described in Jones et al., 2000. The EEC's for the five scenarios simulated are shown in Table 6. Input files for PRZM/ EXAMS modeling is included in Appendix A. The maximum calculated EEC resulted from use on citrus in Florida. For the Index Reservoir scenario using maximum label rates, acute EEC values ranged from about 10 : g/ L from sugar beets to about 500 : g/ L from citrus (Table 6). Chronic EECs ranged from about 2 to 28 : g/ L. These values are higher then concentrations observed in monitoring studies and probably represent conservative estimates of environmental concentrations. It is highly unlikely that any but the most extensive targeted monitoring would capture the actual peak concentrations. The results of the modeling provide a very conservative, though not unreasonable, estimate of possible concentrations in drinking water. A more detailed assessment of the source of water used to provide drinking water and the relationship between the areas where carbaryl is used and surface water sources is required to more accurately evaluate possible human exposures. In Florida, for example, the majority of drinking water is derived from groundwater (> 90%) so high surface water concentrations do not necessary indicate high exposure. Until more accurate data on land use and related pesticide application is available and can by linked with data on the location and hydraulic characteristics of the water bodies it is not possible to provide more accurate assessment of possible exposures. A more detailed description of modeling is presented below, and model input and output files are attached in Appendix A. Water Treatment Effects The Office of Pesticide Programs has completed a preliminary review of the effects of d r i n k i n g w a t e r t r e a t men t o n p e s t i c i d e s i n w a t e r (http:// www. epa. gov/ scipoly/ sap/ 2000/ september/ sept00 sapdw 0907. pdf). This review indicates that standard drinking water treatment, consisting of flocculation/ sedimentation and filtration does not substantially affect concentrations of pesticides in drinking water. Evidence suggests that carbaryl does not react with chlorine or hypoclorite disinfection products in water treatment but is rapidly degraded (T½ = too rapid to measure) by ozone (Mason et al., 1990). Since relatively few water treatment facilities in the U. S. use ozone the limited data available do not indicate that carbaryl is likely to be degraded in the majority of treatment plants. ­33­ Table 6. Drinking Water EECs Crop Number of Applications per Year Pounds A. I. per application Surface Water Acute (ppb) (1 in 10 year peak single day concentration) Surface Water Chronic (ppb) (1 in 10 year annual average concentration) Sweet Corn (OH) (PCA = 0.46) Maximum 1 8 2 37 3.2 Average 2 2 3. 4 45 2.2 Maximum 3 Reported 3 1 15 0.9 Field Corn (OH) (PCA = 0.46) Maximum 1 4 2 30 2.1 Average 2 2 1 13 0.6 Maximum 3 Reported 2 1. 520 1 Apples (OR) (PCA = 0.87) Maximum 1 5 2 144 9 Average 2 2 1. 2 12 0.7 Maximum 3 Reported 2 1. 625 1 Sugar Beats (MN) (PCA = 0.87) Maximum 1 2 1. 519 2 Average 2 1 1. 5 12 1.1 Maximum 3 Reported 1 1. 2 9 0. 9 Oranges (FL) (PCA = 0.87) Maximum 1 4 5 494 28 Average 2 2 3. 4 246 11 Maximum 3 Reported 3 4. 26 411 16 Surface Water Monitoring 5.5 (Maximum Observed Concentration) Groundwater SCIGROW Maximum 1 5 40. 8 0. 8 Groundwater (NAWQA Monitoring Data) 0.02 0.02 1 Maximum application rate on label 2 Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD 3 Maximum rate of application reported in Doanes survey data Groundwater Resources Available evidence from valid scientific studies show that carbaryl has a limited potential to leach to ground water. As a result of normal agricultural use, detections of carbaryl residues have ­34­ been reported in groundwater from several states. As reported in the U. S. EPA. Pesticides in Groundwater Database (Jacoby et al., 1992) carbaryl was detected in 0.4% of wells sampled. Carbaryl was detected in California (2 out of 1433 wells), Missouri (11 out of 325 wells), New York (69 out of 21027 wells) Rhode Island (13 out of 830 wells) and Virginia ( 11 out of 138 wells). The maximum concentration detected was 610 µg/ L in NY, though typically the measured concentrations were significantly lower. The EPA STORET database was queried on May 12, 1999 for reports of measurements of carbaryl in groundwater. The database contained 9389 records indicating that analysis was done for carbaryl. Out of these only 4 reported concentrations above the detection limits. These analyses were all from one well in Cleveland, OK in 1988. The 4 reported concentrations were between 0.8 and 1 ppb. Carbaryl was detected at greater than the detection limit (0.003 µg/ L) in 1.1 % of groundwater samples from 1034 sites across the U. S. by U. S. G. S. NAWQA program. The maximum observed concentration was 0.021 µg/ L. Detections were mainly from three use sites: wheat (5.8 % of well samples from wheat land use ), orchards and vineyards (1.7 % of well samples from orchard and vineyard land use), and urban (1.8% of urban groundwater samples). Data on pesticides in groundwater were reviewed by Kolpin et al. (1998) and updated information is available at: http:// water. wr. usgs. gov/ pnsp/ pestgw/. Surface Water Resources Monitoring Data Carbaryl is widely detected in non­ targeted and targeted monitoring studies. Observed concentrations are generally low (> 0.5 : g/ L). Carbaryl is not very persistent in most surface water conditions suggesting that the wide spread occurrence is a result of its extensive use in a variety of applications. Because of limitation in the analytical methods used there is some uncertainty in the quantitative accuracy of carbaryl analysis. NAWQA Carbaryl is the second most widely detected insecticide after diazinon in the USGS NAWQA program (http:// water. usgs. gov/ nawqa/ nawqa_ home. html). Carbaryl was detected in 46% of 36 NAWQA study units between 1991 and 1998. The reported concentrations are believed to be reliable detections but have greater than average uncertainty in quantification. The data in the NAWQA database are amended with an "E" qualifier to indicate the variability found in the analysis. This suggests that the reported values may not represent the maximum concentrations that exist. Carbaryl (along with diazinon) was one of the two most widely detected insecticides. Out of 5220 surface water samples analyzed 1082, or about 21 percent, were reported as having detections greater than the MDL. The maximum reported concentration was 5.5 µg/ L. For samples ­35­ with positive detections the mean concentration was 0.11 : g/ L, with a standard deviation of 0.43 : g/ L. A significant portion of the total carbaryl applied was transported to streams. In areas with high agricultural use the load measured in surface waters was relatively consistent across the country at about 0.1 percent of the amount used in the basins (Larson et al., 1999) http:// water. wr. usgs. gov/ pnsp/ rep/ wrir984222/ load. html. The estimated carbaryl use on in agricultural applications is about 2.5 million pounds suggesting that 2,500 pounds are delivered to the nations streams draining agricultural areas. Streams draining urban areas showed more frequent detections and higher concentrations than streams draining agricultural or mixed land use areas. For example Kimbrough and Litke (1996) reported that, in the South Platte River Basin Study Unit, between April and December of 1993, carbaryl was detected in 14 urban drainage samples and 6 agricultural drainage samples. Carbaryl had the highest concentration of the four insecticides analyzed with a maximum concentration of 2.5 : g/ L in the urban basin and 1.5 : g/ L in the agricultural basin (http:// webserver. cr. usgs. gov/ nawqa/ splt/ meetings/ KIMB1. html). In the South­ Central Texas Study Unit carbaryl was detected in 12% of streams draining agricultural areas and 52 % draining urban areas (Bush et al., 2000) http:// water. usgs. gov/ pubs/ circ/ circ1212/. Registrant Monitoring Study Aventis Crop Science initiated in February 1999 a surface water monitoring study of carbaryl residues in surface water in areas believed to have high agricultural and residential use, based predominantly on county­ level sales data. A total of 20 sites are monitored, with "medium­ sized watersheds" targeted: 16 sites in agricultural areas and 4 in areas draining suburban areas. Samples of raw water were collected at municipal water treatment facilities. When raw water analyses detected carbaryl, stored finished water samples (collected at the same time) were analyzed. Samples were collected weekly during periods suspected of being "high risk" and monthly the rest of the year in agricultural areas. Suburban sites were sampled weekly. The study was originally envisioned to last for one year, but was extended for an additional year in February, 2000 (amendment 7), and for a third year in February, 2001 (amendment 9). Carbaryl was analyzed by HPLC/ MS/ MS with a limit of detection of 0.002 ppb (2 ppt) and a limit of quantitation (LOQ) of 0.030 ppb (30 ppt). OPP has received two interim reports of monitoring from this study. The first report (MRID 45116201) has been fully reviewed and results are described below. Very recently a second report was received by OPP/ EFED. Results from this latest report (MRID 45394101) have not been reviewed in depth, but are similar to results from year­ one. Carbaryl was widely detected at surface water sites monitored in this study. Samples containing carbaryl were detected in raw drinking water samples collected at all four suburban monitoring locations, and at about three quarters of the agricultural monitoring locations (13 of 16 sites). Carbaryl was not detected as frequently in finished drinking water samples when they were analyzed; however, only a small subset of finished water samples were actually analyzed. This represents a significant flaw in the study design and limited its usefulness for evaluating the effects ­36­ of treatment. Differences in concentrations between raw and finished drinking water are likely attributed more to changes in the concentration of source water than to effects of treatment. Most carbaryl detections in this study were at low levels, below the LOQ of 0.03 ppb. Carbaryl contamination measured in this monitoring study appears to be transient, and therefore it is unlikely that any but the most intensive field sampling would ever detect the actual peak concentration that occurs at a site. The interim study reports have not adequately addressed why concentrations found in this study, which claims to target high carbaryl use areas, are substantially lower than those measured in the untargeted USGS NAWQA studies. That, and the limited number of sites sampled, limit the usefulness of this study. Summary of year­ one monitoring In raw water samples from suburban sites detectable residues in raw water ranged from 0.002 to 0.023 ppb. 11 out of 40 raw water samples from Sweetwater Creek, the source of water for the East Port facility in Douglas, GA had detectable levels ranging from 0.002 to 0.018 ppb. One out of 46 samples from Joe Pool Lake, Ellis Texas had a detection at 0.014 ppb. Jorden Lake in Cary, NC had 2 detections out of 44 samples (0.004 and 0.003 ppb). 11 out of 40 samples from the Cahaba River in Birmingham AL had detections ranging from 0.002 to 0.023 ppb. Finished water sampled from suburban areas were all below the detection limit. In samples from agricultural sites 9 out of 15 water sources had some detectable level of carbaryl. The detections were generally at low levels, with one of about 0.16 ppb and one of 0.031. The rest were below the level of quantitation (< 0.030 ppb). Samples from finished water were generally lower than raw water, though it appears that raw and finished water sampling did not sample the same mass of water. Therefore, the data can not be used to evaluate the effectiveness of water treatment on carbaryl. Because the samples were collected at the same time, the water exiting the treatment plant was temporally different than the water entering and represent different, independent, parcels of water. In several cases finished water had higher concentrations than raw water, and finished water had detectable carbaryl when the raw did not. The highest concentration measured was in finished water (0.18 ppb). Raw water sampled at the same time had much lower concentration (0.010). Non­ targeted monitoring, such as the NAWQA program, has shown that much higher concentrations occur indicating that this study, while useful, can not be used to describe the overall distribution of concentrations that occur throughout the entire use area. This study does not provide sufficient information to allow estimation of actual peak and mean concentrations that actually occur in all use areas. The highest concentration values measured in this study are close to the average values seen in other, non­ targeted, studies. Only limited information was submitted on sampling site selection and how the sites relate to the overall distribution of use areas. Home and garden sites were selected downstream of urban/ suburban areas that were believed to have high use based on county scale sales data. ­37­ Agricultural sites were selected based on county scale sales data, and are believed to be in "major use counties." This study is still ongoing and only interim study results have been submitted. Additional information is needed to evaluate the study results. Additionally, an analysis of how the selected sites relate to the nationwide distribution of carbaryl use areas is required. This should include an explanation of why this study did not observe concentrations as high as those found in other, nontargeted studies, and how the results of this study can be related to concentrations that occur throughout the country. Based on the interim data submitted it appears that this study measured concentrations similar to those observed in non­ targeted studies but did not capture high end or peak values. Until additional information is submitted it is not possible to use these interim results for more then to reinforce the inferences drawn from non­ targeted study data. Sacramento­ San Joaquin River Delta As part of a two year study into the cause of declines in aquatic insects in California's Sacramento­ San Joaquin Delta, toxicity of surface water was measured using ceriodaphnia. When toxicity was found, toxic identification evaluation was done to determine the causative agent. Carbaryl was found to be the primary toxicant at one of 20 sites sampled in 1995, with concentration of 7.0 : g/ L. The toxicity seemed to persist for several days (Werner, et al., 2000). STORET The EPA STORET database ( was queried on May 12, 1999 for reports of measurements of carbaryl in surface water. The database contained 8048 records indicating that analysis was done for carbaryl. Out of these 432 reported concentrations above the detection limits. The maximum value reported was 5.5 µg/ L. Of the reported detections 18 were above 1 ppb. The data is the STORET database is used to give a general indication of the occurrence pattern only. Lack of QA/ QC and analytical methodology limitations limit the usefulness of the STORET data. However, reported detections of carbaryl suggest that the compound is infrequently detected in surface water and at low levels. 6.0 Hazard and Risk Assessment for Aquatic Organisms Hazard Assessment for Aquatic Organisms Freshwater Fish On an acute basis, technical carbaryl is moderately to highly toxic to freshwater fish and to fish that spend a portion of their life cycle in fresh water, such as the Atlantic salmon (LC50 = 0.25 20 ppm). LC50 values for the typical end use products range from 1.4 to 290 ppm, falling in the moderately to practically nontoxic categories. Calculation of acute and chronic risk quotients for freshwater fish are based on an Atlantic salmon LC50 of 250 ppb and a fathead minnow NOAEC of 210 ppb, respectively. ­38­ Amphibians According to an available supplemental study with a 50% carbaryl formulation, the LD50 for the bullfrog (Rana catesbeiana) is greater than 4,000 mg/ kg, or practically nontoxic (MRID 00160000). A single acute exposure of plains leopard frog tadpoles (Rana blairi) to carbaryl concentrations in the 3.5 ­ 7.2 mg/ L range led to a 90% reduction in swimming activity, including sprint speed and sprint distance, activity ceasing completely at 7.2 mg/ L (Bridges 1997). This reduction in activity and swimming performance may result in increased predation rates and, because activity is closely associated with feeding, may result in slowed growth that could lead to failure to complete metamorphosis. Acute exposure to low carbaryl levels may not only affect immediate survival of tadpoles but also impact critical life history functions. On a chronic basis, carbaryl has been shown to have the potential to adversely affect amphibians. In a recent study, nearly 18% of southern leopard frog (Rana sphenocephala) tadpoles exposed to carbaryl during development exhibited some type of developmental deformity, including both visceral and limb malformations, compared to a single deformed (< 1%) control tadpole demonstrating that carbaryl exposure can result in amphibian deformities (Bridges, 2000). Although the length of the larval period was the same for all experimental groups, tadpoles exposed throughout the egg stage were smaller than their corresponding controls. Because exposure to nonpersistent chemicals may last for only a short period of time, it is important to examine the long­ term effects that short­ term exposure has on larval amphibians and the existence of any sensitive life stage. Any delay in metamorphosis or decrease in size at metamorphosis can impact demographic processes of the population, potentially leading to declines or local extinction. Freshwater Invertebrates Carbaryl is very highly toxic to aquatic invertebrates (1.7 ­ 26 ppb) on an acute basis. This compound also has a very strong potential for chronic effects to invertebrates (NOAEC = 3.3 ppb). Field studies that evaluated populations of damselflies (Xanthocnemis zealandica) after exposure to 100 µg/ L carbaryl showed a 90% reduction in emergence success after 10­ 12 days exposure (Hardersen and Wratten, 1998). Studying natural plankton communities in enclosed mesocosms, Havens (1995) reports a decline in total zooplankton biomass and individuals across the range of carbaryl treatments (0 ­ 100 ug/ L). Furthermore, at carbaryl concentrations greater than 20 µg/ L Daphnia was no longer found and that at concentrations above 50 ug/ L all cladocerans were eliminated, resulting in an increase in algal biomass, representing a repartitioning of biomass from zooplankton to phytoplankton. Hanazato (1995) exposed Daphnia ambigua to carbaryl and a kairomone released by the predator Chaoborus (phantom midge) simultaneously. Daphnia developed helmets in response to the kairomone, but not in response to carbaryl at 1­ 3 µg/ L. However, carbaryl enhanced the development of high helmets and prolonged the maintenance period of the helmets in the presence of the kairomone, suggesting that at low concentrations carbaryl can alter predator­ prey interactions by inducing helmet formation and vulnerability to predation in Daphnia. In related mesocosms studies, exposure to carbaryl at 1 ppm killed all plankton species, including Chaoborus larvae (Hanazato, 1989). However, this concentration is well above the maximum EECs modeled for carbaryl, and is unlikely that such high levels of this chemical would ­39­ be found under field conditions. Mora et al. (2000) studying the relationship between toxicokinetics of carbaryl and effects on acetylcholinesterase (ACHase) activity in the snail, Pomaca patula, observed increased enzyme inhibition, along with the bioconcentration of carbaryl, after 72 hours of exposure to sublethal levels (3.2 ug/ g). The transfer of snails to carbaryl­ free water was followed by rapid monophasic elimination with a half­ life of 1.0 hour, although ACHase activity levels never returned to control values. The risk assessment for freshwater invertebrates is based on a stonefly LC50 of 1.7 ppb and a water flea NOAEC of 1.5 ppb, respectively. Estuarine/ Marine Fish Carbaryl is categorized as moderately toxic to estuarine/ marine fish on an acute basis, based on a minnow LC50 of 2.6 ppm. Laboratory exposure to a single dose of carbaryl at 100 ppb can adversely affect schooling behavior in the silverside (Weis and Weis, 1974). Exposure to carbaryl at 10 ppb caused retardation of fin regeneration during the first week of the study in the killifish (Fundulus heteroclitus) (Weis and Weis 1975). Field exposure to a maximum carbaryl water concentration of 1.2 ppm affected burying behavior in caged English sole young (Pozorycki, 1999). The acute risk assessment for estuarine/ marine fish is based on a sheepshead minnow LC50 of 2.6 ppm. At present, the chronic NOAEC for marine/ estuarine fish has not been established, therefore additional chronic toxicity studies are required. Guideline 72­ 4( a) is not fulfilled. Estuarine/ Marine Invertebrates Technical carbaryl is categorized as very highly toxic to estuarine/ marine shrimp species and moderately toxic to oysters on an acute basis. The mysid LC50 falls in the 5.7 ­ 9.6 ppb range and the oyster LC50 is 2.7 ppm. Typical end­ use carbaryl products are considered very highly toxic to mysids and slightly toxic to oysters. Carbaryl applied to oyster beds in Washington State tidelands at 7.5 ­ 8 lb ai/ acre to control ghost and mud shrimp has been shown to be lethal to many nontarget invertebrate species. The acute risk assessment for estuarine/ marine invertebrates is based on a mysid LC50 of 5.7 ppb. There is insufficient data to assess the chronic risk for estuarine/ marine invertebrates. Additional chronic toxicity studies are required. Guideline 72­ 4( b) is not fulfilled. ­40­ Aquatic Plants Data based on a single available core toxicity study with the green alga Pseudokirchneria subcapitata (formerly Selenastrum capricornutum) indicates that the LC50 and NOAEC are, respectively, 1.1 ppm and 0.37 ppm . Toxicity testing for the following four aquatic plants is required to support carbaryl's registered forestry uses; duckweed (Lemna gibba), marine diatom (Skeletonema costatum), freshwater blue­ green algae (Anabaena flos­ aquae), and a freshwater diatom. Guideline 122­ 2 is not fulfilled. 1­ Naphthol 1­ naphthol, the major metabolite of carbaryl degradation by abiotic and microbially mediated processes is moderately to highly toxic to aquatic organisms on an acute basis. LC50 values range from 0.75 to 1.6 ppm for freshwater fish, from 1.2 to 1.8 ppm for estuarine/ marine fish, from 0.70 to 0.73 ppm for freshwater invertebrates, and from 0.21 to 2.5 ppm for estuarine/ marine invertebrates. Risk Assessment for Aquatic Organisms A detailed analyses of risk quotients (RQs) in relation to their corresponding levels of concern (LOCs) is presented in Appendix B. A summary of the acute and chronic LOC exceedances for aquatic organisms, based on maximum label rates, is presented in Tables 7 and 8. Freshwater Fish Carbaryl is highly to slightly toxic to freshwater fish (LC50 = 0.25 ­ 20 ppm) on an acute basis. The acute risk LOC (0.5) for freshwater fish is exceeded for one of five use scenarios modeled (citrus), at maximum label (RQ: 1.10), "average" (RQ: 0.58), and maximum reported (RQ: 0.93) use rates, and not exceeded for the other four scenarios (sweet corn, field corn, apples, sugar beets). The chronic risk LOC is not exceeded for any of the five use scenarios modeled (Table 7). These data suggest that carbaryl uses may present a risk to freshwater fish only under situations that combine high application rates and runoff into water bodies, such as ponds or lagoons, where the chemical may reach toxic levels. Sublethal effects have been documented in the literature showing that in fish the inhibition of acetycholinesterase (AChE) can effect thyroid and gonadal dysfunction in the freshwater murrell, Channa punctatus, resulting in ACh accumulation. At the 0.21 ppm concentration level carbaryl was found to reduce pituitary and serum gonadotropin levels accompanied by inhibition of hypothalamic gonadotropin releasing hormone (GnRH) (Bhattacharya, 1993). These test concentration are at the upper end of the water EECs modeled for carbaryl (citrus scenario). ­41­ Freshwater Aquatic Invertebrates Acute and chronic risk LOCs are exceeded for freshwater invertebrates for all five carbaryl use aquatic scenarios modeled using maximum label use rates (acute RQs = 5.06 ­ 161.18, chronic RQs = 3.27 ­ 91.33), maximum reported rates (acute RQs = 3.30 ­ 136.47, chronic RQs = 2.00 74.67 and "average" rates (acute RQs = 2.65 ­ 85.29, chronic RQs = 1.67 ­ 44.67), indicating that most carbaryl uses are likely to pose acute and chronic risks to freshwater invertebrates, especially to arthropods. Although carbamates and OP's breakdown rapidly in the environment, studies pertaining to agricultural regions where these insecticides are applied for extended periods of the year have shown that nontarget aquatic invertebrates may be exposed to high levels of ChE inhibiting compounds for a period of up to several months (Gruber and Munn, 1998). In general, due to its rapid metabolism and rapid degradation, carbaryl should not pose a significant bioaccumulation. Table 7. Summary of acute and chronic risk LOC exceedances, based on maximum label application rates, for freshwater organisms 1 Organism Use site Scenarios Risk Quotients Equal or Exceed Level of Concern for: Acute Risk (RQs) Acute Restricted Use Acute Endangered Species Chronic Risk Fish Sweet Corn NO YES YES NO Field Corn NO YES YES NO Apples NO NO NO NO Sugar Beets NO NO YES NO Citrus YES (1.1) YES YES NO Aquatic Invertebrates Sweet Corn YES (27.1) YES YES YES (17.3) Field Corn YES (16.5) YES YES YES (10.7) Apples YES (5. 1) YES YES YES (3. 3) Sugar Beets YES (11.2) YES YES YES (7.3) Citrus YES (161.2) YES YES YES (91.3) 1 Levels of concern (LOCs) for aquatic organisms Acute Risk 0.5 Acute Restricted Use 0. 1 Acute Endangered species 0.05 Chronic Risk 1 Estuarine/ Marine Fish Carbaryl is moderately toxic to estuarine/ marine fish (LC50 = 2.6 ppm); however, no acute LOCs are exceeded for any of the five use scenarios modeled, at any use rate (Table 8). Thus, most carbaryl uses are unlikely to pose an acute risk to marine/ estuarine fish. Although a NOAEC based on core data has not been established, evidence from the open literature indicates that exposure to 5 Also referred in the literature as Callianassa californiensis. ­42­ low carbaryl levels may produce adverse physiological and behavioral effects in estuarine/ marine fish. Laboratory exposure of Menidia menidia to a single dose of carbaryl (100 ppb) resulted in the disruption of schooling behavior, as carbaryl­ exposed groups consistently occupied twice the space of control groups, which was attributed to the accumulation of the carbaryl degradate 1­ naphthol (Weis and Weis, 1974). Exposing the killifish (Fundulus heteroclitus) to carbaryl at 10 ppb in the laboratory caused retardation of fin regeneration during the first week of the study (Weis and Weis 1975). According to Pozorycki (1999), field studies with caged juvenile English sole (Pleuronectes vetulus) indicated that brain acetylcholinesterase (AChE) activity decreases following carbaryl application, affecting the ability to bury in sediments. Mean brain AChE inhibition was 26% in fish placed on treated mudflats and 24% in fish placed subtidally, but maximum individual values approached 50%. AChE inhibition at 50­ 60% was noted as a threshold value below which burying decreased sharply. Maximum carbaryl water concentration measured by HPLC was 1.2 µg/ ml at the cage sites. Sediment concentrations on treated mudflats were as high as 23 µg/ g 24 hrs after application. Chronic toxicity studies with an estuarine/ marine fish species is required. There is one carbaryl use in particular that represents a potential acute and chronic risk to estuarine/ marine fish. Since 1963, carbaryl has been used to treat two tideland areas of Washington State for the control of two species of burrowing shrimp in commercial oyster beds. The acute risk to fish inhabiting treated mudflats or trapped in shallow pools is extremely high, often resulting in fish kills. Exposure to sublethal carbaryl levels has also been shown to inhibit acetylcholinesterase in fish in subtidal areas adjacent to the treated sites resulting in a significant, although reversible, impairment of burying behavior, thus increasing their exposure to predators. Carbaryl is applied aerially, at the rate of 7.5 ­ 8 lb ai/ acre (maximum label rate) over oyster seed beds and bare mudflats on a combined total of 800 acres of tidelands in Willapa Bay and Grays Harbor, Washington, to control burrowing shrimp populations (Neotrypaea 5 californiensis and Upogebia pugettensis). Applications are made when shrimp population densities meet the established action threshold of 10 burrow holes per square meter. On average, oyster beds are treated once every six years (Feldman et al. 2000). Unchecked, these shrimp can adversely affect oyster production by making the substrate unsuitable for oyster culture and by competing with these bivalves for food resources (Hulburt et al. 1989). ­43­ Table 8. Summary of acute risk LOC exceedances, based on maximum label application rates, for marine/ estuarine organisms 1 Organism Use site Scenarios Risk Quotients Equal or Exceed Level of Concern for: Acute Risk (RQs) Acute Restricted Use Acute Endangered Species Chronic Risk Fish Sweet Corn NO NO NO No Data Field Corn NO NO NO No Data Apples NO NO NO No Data Sugar Beets NO NO NO No Data Citrus NO YES YES No Data Aquatic Invertebrates Sweet Corn YES (27.1) YES YES No Data Field Corn YES (16.5) YES YES No Data Apples YES (5.1) YES YES No Data Sugar Beets YES (11.2) YES YES No Data Citrus YES (161.2) YES YES No Data 1 Levels of concern (LOCs) for aquatic organisms Acute Risk 0.5 Acute Restricted Use 0. 1 Acute Endangered species 0.05 Chronic Risk 1 In addition to providing a substantial portion of U. S. oyster production, these estuaries are also important nurseries for several valuable fisheries. Estimates of potential fish kills in the treated area range from 15,000 to 96,000. Species killed following carbaryl applications include staghorn sculpin (Leptocottus armatus), saddleback gunnels (Pholis ornata), English and sand sole (Parophrys vetulus and Psettichthys melanostictus), shiner perch (Cymatogaster aggregata), starry flounder (Platichthys stellatus), bay gobies (Lepidogobius lepidus), and three­ spine sticklebacks (Gasterosteus aculeatus) (Feldman 2001). Furthermore, fish inhabiting subtidal channels or migrating over treated mudflats with the flood tide may exhibit a marked reduction in brain acetylcholinesterase (AChE) activity. Field studies with caged juvenile English sole (Pleuronectes vetulus) indicated that mean brain AChE inhibition was 26% in fish placed on treated mudflats and 24% in fish placed subtidally, maximum individual values approaching 50%. The maximum carbaryl water concentration was 1.2 ppm at the cage sites, while sediment concentrations on treated mudflats were as high as 23 ppm 24 hours following application. In treated mudflats, invertebrates that are a source of food for these fish had carbaryl concentrations as high as 76 ppm. It was estimated that AChE inhibition of up to 50% was possible due to the additive exposure to carbaryl in water and prey items, resulting in temporary impairment of burying behavior and increased exposure to predators (Hulburt et al. 1989). Recovery of burying behavior occurred after removal of the exposure. Several potential nonchemical pest management methods have been identified, including alternative culture techniques, mechanical control, enhancement of shrimp predators, electrofishing, ­44­ and modification of carbaryl application. Results have shown significant short term impacts to arthropods on a species specific basis (Brooks, 1993). Additional mitigation measures may include alternative carbaryl application techniques that reduce dispersion to nontarget areas, such as direct injection of carbaryl into the sediment. Subsurface injection has shown to be effective in controlling burrowing shrimp and uses 66% less chemical than aerial application (Durfey and Simpson, 1995). Applying a layer of oyster shells (shell pavement) is a promising technique that can reduce ghost shrimp densities under certain conditions, but this approach can be disruptive to the oyster culture and remains untested on a commercial scale. To date, the complexity of the oyster culture and the ecology of the burrowing shrimp has disrupted attempts to develop and adopt practical and costeffective alternative control methods (Feldman et al., 2000). Estuarine/ Marine Invertebrates The acute LOC for estuarine/ marine invertebrates is exceeded for all five carbaryl use scenarios assessed at maximum label application rates (acute RQs = 1.51 ­ 48.07), at maximum reported use rates (acute RQs = 1.05 ­ 40.70), and at "average" rates (acute RQs = 0.79 ­ 25.44) indicating that some carbaryl uses may pose an acute risk to estuarine/ marine invertebrates inhabiting intertidal zones and estuaries located downstream from treated areas. It is not possible to evaluate chronic risk to estuarine/ marine invertebrates at this time due to the unavailability of data. As for fish, carbaryl applications to control burrowing shrimp in Washington State tidelands is known to represent a significant acute risk to estuarine/ marine invertebrates inhabiting treated tideland areas. There may be up to 100% mortality of Dungenese crab (Cancer magister) populations following carbaryl applications (Hulburt et al. 1989). In addition, the populations of some salmonid arthropod prey species are significantly reduced following application, while other species are more tolerant. Most populations recover within 51 days, but some do not recover (Brooks 1993). Once established, oyster beds do provide an enhanced environment for many plants and invertebrates that grow on the oyster shells or in between them, and which are normally rare or absent in barren mudflats. Reproduction Effects on Fish There is information indicating that carbaryl has the potential to adversely affect reproduction in fish. Carlson (1972) reports that when the fathead minnow (Primephales promelas) was exposed to 5 concentrations of carbaryl in the 0.008­ 0.68 mg/ l range for 9 months and throughout a life cycle, the 0.68 mg/ l (680 ppb) concentration prevented reproduction and decreased survival. At this high concentration, the mean number of eggs per female and the mean number of eggs per spawning were significantly less than for the control group, and no hatching occurred. In addition, the ovaries contained flaccid eggs and appeared to be in a resorptive state. However, this test concentration is higher than the highest peak EECs derived from PRZM/ EXAMS, and it is therefore unlikely that fish will be exposed to such high carbaryl levels for extended periods under field conditions. ­45­ Ghosh et al. (1990) report that serum and pituitary levels of gonadotropic hormone (GtH) and gonadotropin­ releasing hormone (GnRH) in C. punctatus were significantly reduced by exposure to nonlethal levels (1.66 ­ 3.73 ppm) of carbaryl in laboratory and paddy field tests, indicating that at these doses carbaryl may cause reproductive effects to fish. It must be pointed out, however, that the test doses selected for this study are one order of magnitude higher than the highest peak concentrations derived from PRZM/ EXAMS modeling. The decrease in GnRH levels could indicate constant exposure to elevated levels of estrogen acting through a negative feedback pathway to inhibit GnRH release, and the subsequent release of gonadotropins (Klotz et al. 1997). In a related study, freshwater perch (Anabas testudineus) were exposed to nonlethal carbaryl levels (1.66 ppm) for 90 days, covering the pre­ spawning and spawning phases of the annual reproductive cycle. Plasma and ovarian estrogen levels in treated fish increased significantly until day 15, after which they declined significantly relative to the control, until the end of the experiment, indicating that at short­ term exposures nonlethal levels of carbaryl have no inhibitory effect, while long­ term exposure has an inhibitory effect on fish reproduction (Choudhury et al. 1993). However, this study was also performed at carbaryl concentrations well above the highest concentration modeled for carbaryl (Table 5) and, therefore, does not provide an indication as to potential effects under field conditions. Endangered Aquatic Species The endangered species level of concern for freshwater fish is exceeded for three (sweet corn, field corn, and citrus) of five use scenarios modeled and for the citrus scenario at less than maximum label rates. For marine/ estuarine fish, the endangered species LOC is met for the citrus scenario only at maximum label rates. The endangered species LOC is exceeded for freshwater and marine/ estuarine aquatic invertebrates for all five use scenarios at maximum label, maximum reported, and "average" application rates. 7.0 Hazard and Risk Assessment for Terrestrial Organisms Hazard Assessment for Terrestrial Organisms Avian Carbaryl is slightly toxic to practically nontoxic to avian species on an acute basis. LD50 values are greater than 2,000 mg/ kg in pheasants, greater than 2,564 mg/ kg in mallards, and fall in the 1,000 ­ 1,790 mg/ kg range for a passerine species (rock doves). LD50 values as low as 16.2 mg/ kg and 56.2 mg/ kg, based on simple screening tests, have been reported for the starling and the red­ winged blackbird, respectively (Schafer et al., 1983). At a subacute level, carbaryl is categorized as practically nontoxic to birds, with LC50 values greater than 5,000 ppm. However, chronic reproduction effects (egg production) from carbaryl exposure have been noted in the mallard duck at the 1000 and 3000 ppm levels (LOAEC = 1000 ppm, NOAEC = 300 ppm). Other reproduction effects, at the 3000 ppm level, include cracked eggs, fertility, embryonic mortality, and hatching success. ­46­ According to DeRosa et al. (1976), significant amounts of carbaryl were detected in the egg yolks of adult Coturnix quail (Coturnix coturnix japonica) following pesticide ingestion, with treatment levels of 20, 40, and 400 ppm resulting in pesticide residues of 1.58, 2.03, and 3.15 ppm, respectively in the egg yolk. In addition, egg production was significantly reduced, although egg viability was not affected, and agonistic behavior decreased in males, while increasing in the females. The rock dove acute oral LD50 of 1000 mg/ kg is used to assess risk for granular uses, whereas the quail subacute dietary LD50 of >5000 ppm and the mallard duck reproduction NOAEC of 300 ppm are used to assess, respectively, acute and chronic risk for nongranular uses. Mammalian With a rat LD50 of 301 mg/ kg, carbaryl is categorized as moderately toxic to small mammals on an acute oral basis. However, NOAEC and LOAEC values of 80 and 600 ppm, respectively, based on decreased fetal body weights and increased incomplete ossification of multiple bones in the laboratory rat suggest that carbaryl has the potential for chronic effects on small mammals. The rat LD50 of 301 mg/ kg and a rat NOAEC of 80 ppm are the toxicity endpoints used in the risk assessment for carbaryl. Insects Technical carbaryl is highly toxic to bees on an acute contact basis (LD50 = 1.3 µg/ bee). The topical LD50 for alfalfa leaf­ cutter bee (Megachile pacifica = M. rotundata) is 262.4 µg/ g (MRID 05015678: Lee & Brindley, 1974). Nongranular carbaryl formulations can be highly toxic to bees exposed to direct application, i. e. when bees are actively visiting blooming crops or weeds. Residual toxicity varies with the crops and weather conditions. Exposing leafcutting bees (Megachilidae), alkali bees (Halictidae), and honey bees (Apidae) to 24 hr residues from 80% WP carbaryl applied at the rate of 1 lb/ acre resulted, respectively, in a 85%, 78%, and 69% mortality rate (Johansen 1972). Carbaryl is also moderately to highly toxic to predaceous arthropods, including lace bugs (Nabidae) (MRID 05010807), big eyed bugs (Geocoridae: Geocoris) (MRID 05010807), lady beetles (Coccinellidae: Coccinella, Cryptolaemus, Hippodamia, Lindorus, Rhodolia, Stethorus) (MRIDs 05013372, 05003978, 05005640), ground beetles (Carabidae: Scarites, Pterostichus, Bembidion, Harpalus) (MRID 05008149), hymenopterous parasitoids (Aphytis, Metaphycus, Spalangia, Leptomastix) (MRID 05003978, 05005640), predaceous mites (Amblyseius, Typhlodromus) (MRIDs 05004148, 05013359, 05009346), and spiders (MRID 05010807). In laboratory tests, field­ weathered carbaryl residues have been shown to kill the parasitic wasp Aphytis holoxanthus, a natural enemy of the Florida red scale, for a period of up to 22 days post­ treatment under spring conditions in Florida (Rehman et al., 1999). Terrestrial Plants ­47­ Although carbaryl is primarily an insecticide, it can also be used as a fruit thinning agent on apples and pears. However, the product's label cautions that if applied to wet foliage or during periods of high humidity, it may cause injury to tender foliage. The label also cautions against using carbaryl on Boston ivy, Virginia creeper, or maidenhair fern due to potential injury. Several incidents involving injury to vegetable crops (potatoes, tomatoes, cabbage, and broccoli) in New York and Pennsylvania have been reported. Tier I and, if appropriate, Tier II Seed Germination and Seedling Emergence, as well as Vegetative Vigor studies are required. Risk Assessment for Terrestrial Organisms To assess acute risk to birds from exposure to nongranular carbaryl, estimated environmental concentrations (EECs) in food items following product application were compared to LC50 values. EECs were calculated using three separate sets of usage data: maximum label use rates, maximum reported (based on Doane usage data available for 42 uses) use rates, and "average" use rates (used mainly for comparison purposes). To assess chronic risk to birds, EECs were compared to NOAEC values. To assess acute risk to birds from exposure to granular carbaryl, the number of LD50 values per square foot was used as the risk quotient for birds in three separate weight classes (20, 180, and 1000 g). Acute risk to mammals (herbivores/ insectivores and granivores) from exposure to nongranular carbaryl was assessed for three separate body weight and food consumption classes (15g, 35g, and 1000 g mammals and daily food consumption rates equal to 95%, 66%, and 15% of their body weight, respectively) by comparing EECs in food items following product application to LD50 values. Chronic risk to mammals was assessed for the same three weight classes by comparing EECs to NOAEC values. To assess exposure to granular carbaryl, the number of LD50 values per square foot was used to calculate RQs for mammals in the three weight classes. Avian Risk Nongranular Formulations Carbaryl is slightly to practically nontoxic to avian species on an acute, and practically nontoxic on a subacute basis. However, it has been shown to have chronic reproduction effects (number of eggs produced) to the mallard at 1000 ppm and higher exposure levels (NOAEC = 300 ppm). A detailed analyses of avian risk quotients (RQs) in relation to their corresponding levels of concern (LOCs) is presented in Appendix B. The avian acute risk level of concern (LOC) is not exceeded for any nongranular carbaryl use at maximum nor less than maximum label application rates. The avian chronic risk LOC is exceeded for almost all (73 of 74) nongranular uses considered at maximum label rates, for 34 of 42 uses at maximum reported rates, and for 39 of 70 uses at "average" rates. (Appendix B, Tables 4, 5a, and 5b). Thus, although no nongranular uses are likely to present an acute risk to birds, most uses are expected to pose a significant chronic risk (i. e. reproduction effects) to birds. ­48­ Granular Formulations The avian acute, restricted use, and endangered species LOCs are exceeded (RQs: 0.52 4.76 for birds in the 20 g weight class, for all (about 40) granular carbaryl uses. The acute risk LOC is also exceeded (RQ: 0.53) for birds in the 180 g weight class for the trees/ ornamentals, turfgrass, and tick control uses. No acute LOCs are exceeded for birds in the 1000 g weight class for any of the granular carbaryl uses (Appendix B, Table 6). The avian endangered species LOC is exceeded for 20 g and 180 g birds for most uses. Mammalian Risk Risk to Herbivores/ Insectivores: Nongranular Formulations Risk Quotients for Herbivores/ Insectivores Based on Less than Maximum Label Use Rates In addition to maximum label use rates, mammalian acute and chronic RQs were also calculated for nongranular carbaryl using QUA average use rates data available for 70 uses (Appendix B, Table 10a) and maximum reported (Doane data) use rates data available for 42 uses (Appendix B, Table 10b). As summarized in Table 10a, when RQs are based on QUA average rates, the acute risk LOC is exceeded for 63 of the 70 uses (RQs = 0.53 ­ 4.02), whereas the restricted use LOC is exceeded for 69 uses (not exceeded only for cabbage), and the endangered species LOC is exceeded for all 70 uses. The chronic risk LOC is exceeded for 69 of the 70 uses (RQs: 1.5 ­ 15.9). When RQs are calculated using maximum reported application rates, the acute risk LOC is exceeded for 41 of the 42 uses (RQs: 0.60 ­ 11.36), while the restricted use, endangered species, and chronic (RQs: 1.5 ­ 45) risk LOCs are exceeded for all 42 uses (Table 10b). Risk Quotients for Herbivores/ Insectivores Based on Maximum Label Use Rates Carbaryl is moderately toxic to small mammals on an acute oral basis (rat LD50 = 301 mg/ kg), and has the potential for mammalian chronic effects (LOAEC = 600 ppm , NOAEC = 80 ppm, based on decreased fetal body weights and increased incomplete ossification of multiple bones in the laboratory rat). A detailed analysis of mammalian RQs in relation to their corresponding levels of concern (LOCs) is presented in Appendix B. Food items: short grass ­ The mammalian acute risk LOC is exceeded for all registered nongranular carbaryl uses, at maximum label application rates, for small (15 and 35 g) short grass feeders with a daily food consumption equal to 95% and 66% of their body weight, with RQ values ranging from 0.76 to 12.12 and from 0.53 to 8.42, respectively (Appendix B, Table 7). Similarly, the acute risk LOC for 1000 g herbivores with a daily food consumption equal to 15% of their body ­49­ weight is exceeded for all uses (RQs: 0.56 ­ 1.91), except rice, sunflower, sugar beets, wheat, millet, flax, pasture, grasses, noncropland, alfalfa, clover, rangeland, and forested areas. Food items: broadleaf/ forage plants and small insects ­ At maximum label application rates, the acute risk LOC is exceeded for all nongranular carbaryl uses, except rangeland, for 15 g (RQs: 0.80 ­ 6.82) and 35 g (0.55 ­ 4.74) small mammals feeding on broadleaf/ forage plants and small insects. For 1000 g mammals consuming 15 % of their body weight, the acute risk LOC is reached or exceeded for only the citrus, olives, pome fruits, stone fruits, tree nuts, sweet corn, asparagus, small fruits and berries, and turfgrass uses (RQs: 0.52 ­ 1.08), although the restricted use and/ or the endangered species LOCs are exceeded for most other uses. Food items: fruits, pods, seeds, and large insects ­ For small mammals consuming 95% of their body weight in fruits, pods, seeds, and large insects, the acute risk LOC is exceeded for the citrus, olives, tree nuts, sweet corn, turfgrass uses (RQs: 0.62 ­ 0.76). Most other registered uses (pome and stone fruits, field corn, asparagus, cucurbits, trees and ornamentals, solanaceous crops, sweet potatoes, peanuts, tobacco, leafy vegetables, Brassica crops, roots and tubers, sorghum, small fruits and berries), however, exceed the acute restricted use LOC, while rice, sunflower, sugar beets, wheat, millet, flax, pasture, grasses, noncropland, alfalfa, and clover exceed the acute endangered species LOC. For mammals consuming 66% of their body weight the acute risk LOC is exceeded only for use on citrus in California (RQ: 0.53); the acute restricted use LOC is exceeded for the following uses: citrus, olives, pome and stone fruits, tree nuts, sweet corn, asparagus, solanaceous crops, sweet potatoes, peanuts, tobacco, small fruits, berries, and turfgrass (RQs: 0.22 ­ 0.49 ); and the acute endangered species LOC is reached or exceeded for field corn, cucurbits, trees and ornamentals, leafy vegetables, Brassica crops, roots and tubers, sorghum, legumes, alfalfa, and clover (RQs: 0.11 ­ 0.18). For mammals that consume 15% of their body weight, neither acute risk nor acute restricted use LOC is exceeded for any registered uses, although the acute endangered species LOC is reached or exceeded for a few uses (citrus, olives, tree nuts, sweet corn, and turfgrass), with RQs in the 0.1 0.12 range. Risk to Granivores: Nongranular Uses Neither the acute risk nor the acute restricted use LOC is exceeded for granivores for any of the nongranular carbaryl uses. However, the acute endangered species LOC is reached or exceeded for the citrus, olives, pome and stone fruits, tree nuts, sweet corn, and turfgrass use sites (RQs: 0.10 0.16 as well as for the citrus, olives, tree nuts, sweet corn, and turfgrass use sites (RQs: 0.10 0.12 for granivores with daily food consumption equal to 21% and 15% of their body weight, respectively. No acute LOCs are exceeded for granivores which consume daily 3% of their body weight. Chronic Risk: Nongranular Uses ­50­ At maximum label application rates, the mammalian chronic LOC (1) is exceeded for all registered uses of nongranular carbaryl for all food item groups, with chronic RQ values in the 3.0 48.0 range (for short grasses), 1.4 ­ 22.0 range (for tall grasses), and 1.7 ­ 27.0 range (for broadleaf/ forage plants, small insects). The mammalian chronic LOC is exceeded for the fruits/ pods/ seeds/ large insects food items for the following uses: citrus, olives, pome and stone fruits, tree nuts, field and sweet corn, asparagus, solanaceous vegetable crops, sweet potatoes, peanuts, tobacco, small fruits and berries, and turfgrass (chronic RQs = 1.0 ­ 3.0). These data are summarized in Appendix B, Table 9. Risk: Granular Uses At maximum application rates, RQs exceed the acute risk LOC for 15 g mammals (RQs: 2.26 ­ 20.71) and 35 g mammals (RQs: 0.97 ­ 8.87) for all 40 registered granular uses. For the 1000 g mammal category, the acute restricted use LOC is exceeded for the trees/ ornamentals, turfgrass, and tick control uses. Reproduction Effects Field and laboratory studies conducted in the 1970s, some of them in former Soviet Union countries, suggest that exposure to carbaryl may affect reproduction in mammals. For instance, in a field study undertaken by Smirnov et al. (1971), the vegetation around colonies of ground squirrels (Rhombomys opimus Licht.) was treated with carbaryl at 0.5 g/ m 2 (4.45 lb/ acre) within a radius of 15 m. Carbaryl residues in plants around dens and in food stored in dens were, respectively, above 0.03 mg/ kg and 0.02 mg/ kg four months after treatment. The percentage of lactating females was 5. 9% in the treated area and 31. 6% for control females. In the treated areas, 41. 2% of all females were inactive in mid­ May, while 28.9% of females were inactive in the untreated colonies. Rates of fetal resorption were 41.9% in the test group and 1.08% in the control group. The average number of embryos per female was 6 in the treated group and 7. 4 in the control group. Exposure to a single field application of 0.1­ 5 kg/ ha of carbaryl in areas spanning several climatic zones of the former USSR resulted in adverse effects in lemmings, voles, moles, pikas, and gerbils, including disturbances in spermatogenesis, pathological pregnancy, increased embryonal resorption, increased percentages of infertile females, males with underdeveloped testicles, reduction of the number of embryos per pregnancy and changes in population structures (Krylova et al., 1975). In the year of treatment, carbaryl residues were present in livers (1.4­ 3 mg/ kg), testes (3.6­ 12.5 mg/ kg), uteri (2­ 5 mg/ kg) and embryos (1.9­ 3.3 mg/ kg), as well as in these species' natural food (1.5 mg/ kg). Carbaryl was found in grass (0.08 mg/ kg) for as long as 2 years after treatment. During the year of treatment, there was a significant reduction of only the mole population in the treated areas, but during the following 1­ 3 years there were significant reductions in the populations of all five species. Pomeroy and Barrett (1975) report that a population of cotton rats (Sigmodon hispidus) inhabiting a plot that had been treated with a single application of carbaryl had a lower peak population density than in a nontreated, control plot. During winter, reproduction ceased, and the ­51­ cotton rats lost weight in the treated area, whereas rats in the nontreated area maintained or gained weight. Also, a population of house mice that was present in the study area continued to reproduce in the treated plot, although at a reduced rate, further indicating the potential to disrupt mammal reproduction. Pregnant dogs treated with carbaryl via diet at 0, 2.0, 5.0, and 12.5 mg/ kg/ day from day 1 of gestation until their pups were weaned at 6 weeks of age resulted in a slight increase in stillbirths and a slight reduction in survival until weaning, although no teratogenic effects were observed (Anonymous, 1969). Dietary exposure to carbaryl at levels up to 2000 ppm did not affect reproduction in house mice (DeNorscia and Lodge, 1973). According to Gladenko et al. (1970), a considerable reduction of fecundity and litter size was observed in rats fed daily 10 mg of carbaryl for 138 days, and pesticide residues were detected in embryos. Narotsky and Kavlock (1995) report that carbaryl fed to pregnant rats showed a slight potential for developmental toxicity. Chapin et al. (1997), however, found no changes in sex organ structure or reproductive function of male or female rats treated as juveniles with carbaryl at 0, 6, 12, or 25 mg/ kg/ day. Feeding 2 or 20 mg/ kg of carbaryl to pregnant rhesus monkeys (Macacca mulatta) throughout gestation did not produce teratologic effect, although treatment apparently caused a higher rate of abortion as compared with controls (Dougherty et al., 1971). In a related study, pregnant rhesus monkeys received either 0.2, 2 or 20 mg/ kg of carbaryl per day by stomach tube from day 20 to day 28 of gestation. Females were observed during pregnancy, and offspring were followed for one year following birth. None of the pregnant monkeys showed signs of toxicity. There were no statistical differences between controls and monkeys receiving up to 20 milligrams of carbaryl in terms of birth weights, gestation lengths, or infant growth rates. There were no significant differences observed in plasma or red blood cell cholinesterase concentrations. Examination of aborted animals, still births and live infants revealed no teratogenic signs (Dougherty, 1975). Insects Although EFED does not assess risk to nontarget insects at present, data from acceptable guideline and nonguideline studies are used to recommend appropriate label precautions. Technical carbaryl is highly toxic to honey bees (LC50 = 1.3 ­ 2.0 ug/ bee) and carbaryl­ containing products should be applied only under the conditions specified by the pollinator protection label language. An important factor in determining the degree of carbaryl hazard to honey bees is the formulation type. Certain formulations, such as baits and granulars, present little or no hazard to bees due to the low potential for exposure, whereas other formulations, such as dusts, wettable powders, and flowables may pose a hazard from direct contact as well as from extended residual toxicity. The honey bee is a beneficial arthropod that plays a major role in pollinating wild plants and crop plants including fruits, vegetables, and herbs. Toxic compounds present in air, soil and water not only can hit the foraging bee, but can also be concentrated and stored in the beehive before being consumed by emerging broods or overwintering bees. Sublethal doses of carbaryl can disturb the ­52­ reproductive behavior, dispersal behavior, feeding behavior, and locomotion of bees, all of which can lead to disorders in population dynamics. Carbaryl has often been implicated in bee kills, which is not surprising considering that this chemical is an effective wide­ spectrum insecticide with multiple agricultural and urban uses. For instance, carbaryl was one of three insecticides responsible for most of the 114 bee kill incidents reported for Washington State during the 1992­ 1996 period (Johansen, 1997). The other two chemicals were chlorpyrifos and micro­ encapsulated methyl parathion. Similarly, in 1997 the American Beekeeping Federation ranked carbaryl as third in importance among pesticides reported as responsible for most bee mortality incidents in the U. S. (Brandi, 1997). Bee kill incidents involving carbaryl in several states, including North Carolina, South Dakota, and Washington have been reported to the Agency. Carbaryl, being moderately to highly toxic to a wide range of predaceous and parasitic arthropods, many of which are natural enemies of insects and mites injurious to agriculture, is expected to pose an acute risk to such organisms. Terrestrial Plants Although primarily an insecticide/ acaricide, carbaryl can have adverse effects in some terrestrial plants. Carbaryl is used as a fruit thinning agent on apples and pears, but precautionary label language cautions that it may cause fruit deformity under certain environmental conditions, and applications to wet foliage or during periods of high humidity may cause injury to tender foliage. Carbaryl may also cause injury to Boston ivy, Virginia creeper, maidenhair fern, and Virginia and sand pines. Plant incidents classified as probable include damage to potatoes, tomatoes, cabbage, broccoli in Pennsylvania and Florida (I009305­ 001, I010017­ 016). The registrant should submit a Tier I Seed Germination and Seedling Emergence, as well as Vegetative Vigor Studies. If 25% or greater detrimental effects are found in one or more plant species in the Tier I study, Tier II Seed Germination/ Seedling Emergence and Vegetative Vigor studies should be also submitted. Guideline 122­ 1 is not fulfilled. Endangered Terrestrial Species The endangered species LOC for birds is met or exceeded for 72 of 74 nongranular carbaryl uses at maximum label use rates, for 18 of 70 carbaryl uses at QUA average use rates, and for 25 of 42 maximum reported use rates. The endangered species LOC is exceeded for 20 g birds for all granular uses. For 180 g birds it is exceeded for all granular uses, except cucumber, melons, pumpkin, squash, beans, peas, lentils, cowpeas, southern peas, wheat, millet, and sugar beets. For 1000 g birds, the endangered species LOC is reached for the trees and ornamentals, turfgrass, and tick control granular uses. The endangered species LOC for all three mammal weight categories and the grass/ broadleaf plants/ small insects food items is exceeded for all nongranular uses examined, at maximum label rates. At "average" and maximum reported use rates, the endangered species LOC ­53­ for 15 g mammals feeding on short grass is exceeded for all nongranular uses. At maximum label rates, the endangered species LOC is exceeded for small (15 and 35 g) mammals for all granular uses, whereas for 1000 g mammals, it is exceeded only for the trees/ ornamentals, turfgrass, and tick control granular uses. The endangered species LOC for freshwater fish is exceeded for three (sweet corn, field corn, and citrus) of five use scenarios modeled and for the citrus scenario at less than maximum label rates. For marine/ estuarine fish, the endangered species LOC is met for the citrus scenario only at maximum label rates. The endangered species LOC is exceeded for freshwater and marine/ estuarine aquatic invertebrates for all five use scenarios at maximum and less than maximum label use rates. Although no RQs are calculated for insects, considering its toxicity to arthropods and broadspectrum uses, carbaryl is expected to pose a risk to endangered species of insects and other terrestrial arthropods. The Agency has developed a program (the "Endangered Species Protection Program") to identify pesticides whose use may cause adverse impacts on endangered and threatened species, and to implement mitigation measures that will eliminate the adverse impacts. At present, the program is being implemented on an interim basis as described in a Federal Register notice (54 FR 27984­ 28008, July 3, 1989), and is providing information to pesticide users to help them protect these species on a voluntary basis. As currently planned, the final program will call for label modifications referring to required limitations on pesticide uses, typically as depicted in countyspecific bulletins or by other site­ specific mechanisms as specified by state partners. A final program, which may be altered from the interim program, will be described in a future Federal Register notice. The Agency is not imposing label modifications at this time through the RED. Rather, any requirements for product use modifications will occur in the future under the Endangered Species Protection Program. 8.0 Summary of Ecological Incident Data Based on information available in the USEPA Ecological Incident Information System (EIIS), carbaryl does not rank high in the list of pesticides responsible for bird or mammal mortality. Three bird kill incidents, involving blackbirds, ducks, starlings, and grackles in Virginia, New Jersey, and South Carolina have been reported and classified as probable. Likewise, there are only two incidents involving small mammals (grey and ground squirrels, mole, rabbit) in South Carolina and Virginia. On the other hand, numerous bee kill incidents have been recorded for carbaryl in several states, including North Carolina, South Dakota, and Washington. In addition, several incidents on vegetable crops, including damage to potatoes, tomatoes, cabbage, broccoli classified as probable, have been recorded in New York, Pennsylvania, and Florida (I009305­ 001, I010017­ 016). The number of documented incidents in the EIIS is believed to be a small fraction of the total mortality caused by pesticides. Mortality incidents must be seen, reported, investigated and the ­54­ information submitted to EPA in order to be recorded in the data base (the states submit this information on a voluntary basis). Often incidents may not be noted because the carcasses either decayed in the field, were removed by scavengers, or were located in out­ of­ the­ way or hard­ to­ see locations. For example, poisoned birds may fly off­ site before dying, some species of fish may sink and the bodies of young fish can quickly decompose in the environment prior to any notice of a problem. An incident may also go unreported because the finder may not be aware of the significance of the issue or may not know the appropriate authorities for an investigation. Furthermore, limited resources may hamper investigations and preclude any confirmatory analysis of tissue and residues. ­55­ 9.0 References (Non­ MRID) Armbrust, Kevin L., and Donald Crosby, 1991. Fate of Carbaryl, 1­ Naphthol, and Atrazine in Seawater. Pacific Science, 45: 314­ 320. Anonymous, 1969. Sevin: Safety evaluation by feeding to female beagles from day one of gestation through weaning of the offspring. Woodward Research Corporation, Herndon, Virginia, 25 pp. Barret, G. W., 1988. Effects of sevin on small­ mammal populations in agricultural and old­ field ecosystems. J. Mammal. 69( 4): 731­ 739. Barrett, M.., 1997, Proposal For a Method to Determine Screening Concentration Estimates for Drinking Water Derived from Groundwater Studies, EFED/ OPP. Beyer, D. W., M. S. Farmer and P. J. Sikoski, 1995. Effects of rangeland aerial application on Sevin­ 4­ Oil ® on fish and aquatic invertebrate drift in the Little Missouri River, North Dakota. Arch. Environ. Contam. Toxicol., 28: 27­ 34. Bhattacharya, S. 1993. Target and non­ target effects of anticholinesterase pesticides in fish. Proceedings of the Second European Conference on Ecotoxicology. May 1992. Sloof, W; de Kruijf, H (eds). pp. 859­ 866. Bracha, P. and R. O'Brian, 1966. J. Econ. Entomol. 59: 1255. Brandi, G., 1997. Pesticide ­ bee kill survey. The American Beekeeping Federation, Inc. Bridges, C. M., 1997. Tadpole swimming performance and activity affected by acute exposure to sublethal levels of carbaryl. Environ. Toxicol. Chem. 16: 1935­ 1939. Bridges, C. M., 2000. Long term effects of pesticide exposure at various stages of the southern leopard frog (Rana sphenocephala). Arch. Environ. Contam. Toxicol. 39: 91­ 96. Brooks, K. M., 1993. Impact on benthic invertebrate communities caused by serial application of carbaryl to control burrowing shrimp in Willapa Bay, WA. J. Shellfish Res. 12: 146. Burgos, William D., Duane F. Berry, Alok Bhandair, and John T. Novak, 1999. Impact of SoilChemical Interactions on the Bioavailability of Naphthalene and 1­ Naphthol. Water Research, 33: 3789­ 3795. Burns, L. A., 1997. EXAMS 2.97.5 Users Manual. National Exposure Research Lab, Office of Research and Development, U. S. Environmental Protection Agency, Athens, Georgia. Carlson, A. R., 1972. Effects of long­ term exposure to carbaryl (Sevin), on survival, growth, and ­56­ reproduction of the fathead minnow (Primephales promelas). J. Fish. Res. Board Can. 29( 5): 583­ 587. Carsel, R. F., Imhoff, J. C., Hummel, P. R., Cheplick, J. M. and Donigan, A. S., 1997. PRZM 3.1 Users Manual. National Exposure Research Lab, Office of Research and Development, U. S. Environmental Protection Agency, Athens, Georgia. Chapalmadugu, S. and G. Rasul Chaudhry, 1991. Hydrolysis of Carbaryl by a Pseudomonas sp and Construction of a Microbial Consortium that Completely Metabolize Carbaryl. Appl. Environ. Microbiol, 57: 744­ 750. Chapin, R. E., Harris M. R., Davis, B. J., Hawkins, E. A., Purdue, W. A., Collins B. J., Maundy, M. A., and Smialowicz. R. J. 1997. The effect of perinatal/ juvenile pesticide exposure on adult neural, immune, and reproductive function. II. carbaryl. Toxicologist 36( 1 Pt 2): 344. Chapman, R. A. and C. M. Cole, 1982. Observations on the Influence of Water and Soil pH on the Persistance of Insecticides. J. Environ. Sci. Hlth., B17: 487­ 504. Chaudhry, G. R., A. N. Ali, and W. B. Wheeler, 1988. Isolation of a methyl parathion­ degrading Pseudomonas sp. that possesses DNA homologous to the opd gene from a Flavobacterium sp. Appl. Environ. Microbiol., 54: 288­ 293. Chib, J., 1986. Seven brand carbaryl insecticide: bioaccumulation and fate of carbaryl in bluegill sunfish (Lepomis macrochirus): Project No. 801R10; File No. 34540. Unpublished study by Union Carbide Agricultural Projects Co., Inc. and Analytical Biochemistry Laboratory, Inc. Choudhury, C., A. K. Ray, and S. Bhattacharya, 1993. Nonlethal concentrations of pesticide impair ovarian function ion the freshwater perch, Anabas testudineus. Environ. Biol. Fishes. 36( 3): 319­ 324. Crisp, T. M., E. D. Clegg, R. L. Cooper, W. P. Wood, D. G. Anderson, K. P. Baetcke, J. L. Hoffmann, M. S. Morrow, D. J. Rodier, J. E. Schaeffer, L. W. Touart, M.. G. Zeeman, and Y. M. Patel, 1998. Environmental endocrine disruption: An effects assessment and analysis. Env. Health Perspectives 106 (Suppl. 1): 11­ 56. DeRosa, C. T., D. H. Taylor, M. P. Farrell, and S. K. Seilkop, 1976. Effects of sevin on the reproductive biology of the Coturnix. Poult Sci 55( 6): , 2133­ 41. DeNorscia, R. M. and J. R. Lodge, 1973. Dietary carbaryl and reproduction in mice. J. Anim. Sci. 37( 1): 243­ 244. Dougherty, W. J., L. Golberg, and F. Coulston, 1971. The effect of carbaryl on reproduction in the monkey (Macacca mulatta). Toxicol. and Applied Pharmacol. (19): 365. ­57­ Dougherty, W. J., 1975. Carbaryl Manuscript. The Albany Medical College of Union University, Institute of Comparative and Human Toxicology, Albany, New York, pp 2­ 16. Feldman, K. L, B. R. Dumbauld, T. H. DeWitt, and D. C. Doty, 2000. Oyster, crabs, and burrowing shrimp: Review of an environmental conflict over aquatic resources and pesticide use in Washington State's (USA) coastal estuaries. Estuaries 23( 2): 141­ 176. Fletcher, J. S., Nellessen, and T. G. Pfleeger, 1994. Literature Review and Evaluation of the EPA Food­ chain (Kenaga) Nomogram, an Instrument for Estimating Pesticide Residues on Plants. Environ. Tox. Chem. 13: 1383­ 1391. Foreman, W. T., M. S. Majewski, D. A. Goolsby, F. W. Wiebe and R. H. Coupe, 2000. Pesticides in the Atmosphere of the Mississippi River Valley, Part II ­ Air. Sci. Total Environ. 248: 213­ 266. Ghosh, P. and S. Bhattacharya, 1990. Impairment of the regulation of gonadal function in Channa punctatus by Metacid­ 50 and Carbaryl under laboratory and field conditions. Biomed. Environ. Sci. 3( 1): 106­ 112. Gladenko, I., V. D. Shulyak, and T. K. Trifonova, 1970. Effect of gamma­ BHC and sevin on reproduction. Veterinariya (Moscow). 47( 6): 91­ 93. Gruber, S. J. and M. D. Munn, 1998. Organophosphate and carbamate insecticides in agricultural waters and cholinesterase (ChE) inhibition in common carp (Cyprinus carpio). Arch. Environ. Contam. Toxicol. 35: 391­ 396. Hardersen, S. and S. D. Wratten, 1998. The effects of carbaryl exposure of the penultimate larval instars of Xathocnemis zealandica on emergence and fluctuating asymmetry. Ecotoxicology 7: 297­ 304. Havens, K. E., 1995. Insecticide (carbaryl, 1­ napthyl­ N­ methylcarbamate) effects on a freshwater plankton community: zooplankton, size, biomass, and algal abundance. Water Air Soil Pollut. 84: 1­ 10. Hanazato, T. and M. Yasuno. 1989. Environ. Pollut. 56( 1): 1­ 10. Hanazato, T., 1995. Combined effect of the insecticide carbaryl and the Chaoborus kairomone on helmet development in Daphnia ambigua. Hydrobiologia, 310 (2): 95­ 100. Hassett, J. J., W. L. Banwart, S. G. Wood, and J. C. Means. 1981. Sorption of ­naphthol: Implications concerning the limits of hydrophobic sorption. Soil Sci. Soc. Am. J 45( 1): 38­ 42. Hayatsu, M., M. Hirano, and T Nagata, 1999. Involvement of Two Plasmids in the Degradation ­58­ of Carbaryl by Arthrobacter sp. Strain RC100. Appl. Environ. Microbiol., 65: 1015­ 1019. Hetrick, James, Ronald Parker, Rodolfo Pisigan and Nelson Thurman. 2000. Progress Report on Estimating concentrations in Drinking Water and Assessing Water Treatment Effects on Pesticide Removal and Transformation: A Consultation. Briefing Document for a Presentation to the FIFRA Scientific Advisory Panel, Friday September 29, 2000. www. epa. gov/ scipoly/ sap/ 2000/ september/ sept00_ sap_ dw_ 0907. pdf Hill, Elwood F. and Michael B. Camardese, 1986. Lethal dietary toxicities of environmental contaminants and pesticides to Coturnix. United States Department of the Interior, Fish and Wildlife Service. Fish and Wildlife Technical Report 2. Washington, D. C. Hoerger, F. and E. E. Kenaga, 1972. Pesticide Residues on Plants: Correlation of Representative Data as a Basis for Estimation of their Magnitude in the Environment. In F. Coulston and F. Korte, eds., Environmental Quality and Safety: Chemistry, Toxicology, and Technology, Georg Thieme Publ, Stuttgart, West Germany, pp. 9­ 28. Hurlburt, E.; McMillan, R.; Vialle, M. (1989) Supplemental Environmental Impact Statement: Use of the Insecticide Carbaryl to Control Ghost and Mud Shrimp in Oyster Beds of Willapa Bay and Grays Harbor: Lab Project Number: CARBARYL SEIS. Unpublished study prepared by Washington Department of Fisheries and Washington Department of Ecology. 144 p. Jacoby, H., C. Hoheisel, J. Karrie, S. Lees, L. Davies­ Hilliard, P. Hannon, R. Bingham, E. Behl, D. Wells, and E. Waldman, 1992. Pesticides in groundwater database: a compilation of monitoring studies: 1971­ 1991 National Summary. EPA 734­ 12­ 92­ 001. Johansen, C. A. (1972) Toxicity of field­ weathered insecticide residues to four kinds of bees. Environmental Entomology 1( 3): 393­ 394. Johansen, E., 1997. Pollinating insects and labeling issues in 1997. Washington State Department of Agriculture . Jones, R. David, Jim Breithaupt, Jim Carleton, Laurence Libelo, Jim Lin, Robert Matzner, Ron Parker, William Feeland, Nelson Thurman and Ian Kennedy, 2000. Draft Guidance for Use of the Index Reservoir and Percent Crop Area Factor in Drinking Water Assessments. EPA/ OPP Draft dated March 3, 2000. Karns, J. S., W. W. Mulbry, J. O. Nelson and P. C. Kearney, 1986. Metabolism on Carbofuran by a Pure Bacterial Culture. Pestic. Biochem. Physiol., 25: 211­ 217. Karthikeyan, K. G., Jon Chorover, Jackie M. Bortiatynski, and Patrick G. Hatcher, 1999. Interaction of 1­ Naphthol and Its Oxidation Products with Aluminum Hydroxide. Environ. Sci. Technol., 33: 4009­ 4015. ­59­ Karthikeyan, K. G. and Jon Chorover, 2000. Effects of Solution Chemistry on the Oxidative Transformation of 1­ Naphthol and Its Complexation with Humic Acid. Environ. Sci. Technol. 34: 2939­ 2946. Klotz, D. M., S. F. Arnold, and J. A. McLachlan, 1997. Inhibition of 17 beta­ estradiol and progesterone activity in human breast and endometrial cancer cells by carbamate insecticides. Life Sciences 60( 17): 1467­ 1475. Kolpin, Dana W., Jack E. Barbash and Robert Gilliom, 1998. Occurrence of Pesticides in Shallow Groundwater of the United States: Initial Results of the National Water­ Quality Assessment Program. Environ. Sci. Technol. 32: 588­ 566. Krylova, T. V., S. A. Shilova, D. G. Krylov, A. V. Denisova, and A. A Smirnov, 1975. Consequences of using a pesticide affecting the reproductive function of mammals. Zool. ZH 54( 12): 1874­ 1879. Larken, M. j. and M. J. Day, 1986. The metabolism of Carbaryl by Three Bacterial Isolates. Pseudomonas spp. (NCIB 12042 & 12043) and Rhodococcus sp. (NCIB 12038) from Garden Soil. J. Appl. Bacteriol., 60: 233­ 242. Larson, Steven J., Robert Gilliom, and Paul Capel, 1999. Pesticides in Streams of the United States­­ Initial Results from the National Water­ Quality Assessment Program. U. S. G. S. Water­ Resources Investigations Report 98­ 4222. Liu, D., K. Thompson, and W. M. J. Strachan, 1981. Biodegradation on Carbaryl in Simulated Aquatic Environment. Bulletin of Environmental Contamination and Toxicology, 27: 412­ 417. Marella, R. L., 1999, Water Withdrawals, Use, Discharge, and Trends in Florida, 1995: U. S. Geological Survey Water­ Resources Investigations Report 99­ 4002, 90p. Mason, Yael (Zelicovizt), Ehud Choshen, and Chaim Rav­ Acha, 1990. Carbarmate Insecticides: Removal from Water By Chlorination and Ozonation. Wat. Res., 24: 11­ 21. Mora, B. R., Martinez­ Tabche, L., Sanchez­ Hildalgo, E., Hernandez, G. C., Ruiz, M. C. and Murrieta, F. F. 2000. Relationship between toxicokinetics of carbaryl and effect on acetylcholinesterase activity in Pomacea patula snail. Ecotoxicol. Environ. Saf. 46: 234­ 239. Mount, M. E. and F. W. Oehme, 1981. Residue Rev. 80: 1­ 64. Narotsky, M. G. and R. J. Kavlock, 1995. A multidisciplinary approach to toxicological screening: II. Developmental toxicity. J. Toxicol. Environ. Health 45( 2): 145­ 71. ­60­ Nkedi­ Kizza, P., and K. D. Brown, 1998. Sorption, Degradation, and Mineralization of Carbaryl in Soils, for Single­ Pesticide and Multiple­ Pesticide Systems. J. Environ. Qual., 27: 1318­ 1324. Pomeroy, S. E. and G. W. Barrett, 1975. Dynamics of enclosed small mammal populations in relation to an experimental pesticide application. Am. Midl. Nat. 93 (1): 91­ 106. Pozorycki, S. V. 1999. Sublethal effects of estuarine carbaryl application on juvenile English sole (Pleuronectes vetulus). Diss. Abstr. Int. Pt. B. Sci. & Eng. 60: 2424. Rajagopal, B. S., V. R. Rao, G. Nagendrappa and N. Sethunathan, 1984. Metabolism of Carbaryl and Carbofuran by Soil Enrichment and Bacterial Cultures. Can. J. Microbiol., 30: 1458­ 1466. Rehman, Su, H. W. Browning, H. N. Nigg, and J. M. Harrison, 1999. Residual effects of carbaryl and dicofol on Aphytis holoxanthus DeBach (Hymenoptera: Aphelinidae). Biological Control. 16( 3): 252­ 257. Sanusi, Astrid, Maurice Millet, Philippe Mirabel and Henri Wortham, 1999. Gas­ particle partitioning of pesticides in atmospheric samples. Atm. Environ. 33: 4941­ 4951. Sanusi, Astrid, Maurice Millet, Philippe Mirabel and Henri Wortham, 2000. Comparison of Atmospheric Pesticide Concentrations at Three Sampling Sites: Local, Regional and Long­ Range Transport. Sci. Total. Environ. 263: 263­ 277. Schafer, Jr.,, E. W., W. A. Bowles, Jr., and J. Hurlbut, 1983. The acute oral toxicity, repellency, and hazard potential of 998 chemicals to one or more species of wild and domestic birds. Arch. Environ. Contam. Toxicol. 12: 355­ 382. Schomburg, C. J., D. E. Glotfelty, and J. N. Seiber, 1991. Pesticide occurrence and distribution in fog collected near Monetery California. Environ. Sci. Technol. 25: 155­ 160. Smirnov, A. A., V. S. Lobachev, and A. V. Denisova, 1971. Effect of carbaryl on the reproductive capacity of Rhombomys opimus Licht. in carbaryl­ treated areas. Biol. Nauki. 3: 29­ 33. Sonnenschein, C. and A. M. Soto, 1998. An updated review of environmental estrogen and androgen mimics and antagonists. J. Steroid Biochem. and Molecular Biol. 65( 1­ 6): 143­ 150. Syslo, Stephanie, Amer Al­ Mudallal, Ron Bloom, Laurence Libelo, Thuy Nugyen, Rudy Pisigan and Kevin Poff, 1999. Proposed Interim Guidance for the Selection of ChemicalSpecific Input Values for EFED Models. EPA/ OPP/ EFED memo dated July 15, 1999. ­61­ Waite, D. T., R. Grover, N. D. Westcott, D. G. Irvine, L. A. Kerr and H. Sommerstad, 1995. Atmospheric Deposition of Pesticides in a Small Southern Saskatchewan Watershed. Environ. Toxicol. and Chem., 14: 1171­ 1175. Weis, P. and J. S. Weis, 1974. Schooling behavior of Menidia menidia in the presence of the insecticide Sevin (carbaryl). Marine Biol. 28: 261­ 263. Weis, J. S. and P. Weis, 1975. Retardation of fin regeneration in Fundulus by several insecticides. Trans. Am. Fish. Soc. 104( 1): 135­ 137. Werner, Ingborg, Linda A. Denovic, Valeri Conner, Victor De Vlaming, Howard Bailey and David E. Hinton, 2000. Insecticide­ Caused Toxicity to Ceriodaphnia dubia (Cladocera) in the Sacramento­ San Joaquin River Delta, California. Environmental Toxicology and Chemistry, 19: 215­ 227. Willis, Guye H., and Leslie. L. McDowell, 1987. Pesticide Persistence on Foliage. in Reviews of Environmental Contamination and Toxicology. 100: 23­ 73. Windholz, M., et al., eds. 1976. The Merck Index, 9th ed. Merck and Co., Inc.: Rathway, NJ. Wolfe, N. L., R. G. Zepp and D. F. Paris, 1978. Carbaryl, Propham and Chlorpropham: A Comparison of the Rates of Hydrolysis and Photolysis with the Rate of Biolysis. Water Research, 12: 565­ 571. ­62­ Appendix A: Refined Water Memo UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 PC Code: 056801 DP Bar Code: D267276 DATE: July 23, 2001 MEMORANDUM SUBJECT: Refined Estimated Environmental Concentrations for Carbaryl FROM: E. Laurence Libelo, Ph. D., Environmental Engineer Environmental Risk Branch IV Environmental Fate and Effects Division (7507C) THROUGH: Elizabeth Behl, Chief Environmental Risk Branch IV, EFED (7507C) TO: Anthony E. Britten, Chemical Review Manager Betty Shackleford, Branch Chief Reregistration Branch III Special Review and Reregistration Division (7508C) Virginia Dobozy, Ph. D., HED/ RRBI This memo presents refined surface water and groundwater Estimated Environmental Concentrations (EECs) for use in calculating human exposure to carbaryl. These values were determined using available monitoring data, modeling with PRZM/ EXAMS for surface water, and SCI­ GROW for groundwater. EEC values are shown in Table 1. Because of uncertainties in available monitoring data EFED recommends using modeling results in assessing Carbaryl risks. Background: Chemical characteristics and available monitoring data indicate that carbaryl has the potential to enter surface water via leaching and runoff under certain conditions and has limited potential to leach to ground water. Carbaryl tends not to partition to soil, aquifer solids, or ­63­ sediment. Once the compound has entered surface water, it may be degraded by chemical and biological processes. Abiotic degradation by photolysis (t1/ 2 = 21 days) and hydrolysis in alkaline (t1/ 2 = 3.2 hours at pH 9) and neutral (t1/ 2 = 12 days at pH 7) waters result in fairly rapid degradation in most aqueous environments. Microbially mediated processes also contribute to fairly rapid degradation of the parent to 1­ naphthol and CO2. Aerobic aquatic, soil aerobic and anaerobic metabolism studies (t1/ 2 = 5, 4, and 72 days respectively) suggest that the compound is broken down by a variety of metabolic processes. Under certain conditions carbaryl can be expected to persist in the environment. Under low pH conditions the compound is stable to hydrolysis. In anaerobic environments metabolism is fairly slow (t½ = 72 days). This suggests that carbaryl may leach to ground water and persist in some aquifers. Monitoring studies show that carbaryl is a commonly detected contaminant in surface water. Carbaryl, at typically low concentrations, is found in greater than 20 % of surface samples with concentrations up to 7 ppb. Carbaryl is generally not widely detected in groundwater monitoring studies though some studies have found concentrations of up to several hundred ppb. Concentrations as high as 610 µg/ L have been detected in one case but typical groundwater concentrations are much lower. NAWQA studies have found that about 1 % of groundwater samples have measurable levels (> 0.003 : g/ L) of carbaryl, with a maximum concentration of 0.02 µg/ L. Targeted studies designed to measure carbaryl in groundwater are not available. Based on chemical properties, existing monitoring data and computer simulation estimates of carbaryl contamination that can be expected in surface water and groundwater as a result of normal agricultural practices have been determined. Carbaryl is commonly found in surface water, and can be expected to contaminate drinking water derived from surface water bodies. Targeted and non­ targeted studies regularly detect carbaryl in low concentrations, typically below 1 µg/ L. Carbaryl use in urban and suburban areas results in higher frequency of surface water contamination. Monitoring data suggest that carbaryl concentrations resulting from non­ agricultural uses are higher then from agricultural uses. However, at this time EFED does not have methods for evaluating EECs from non­ agricultural uses. Carbaryl is not widely detected in groundwater studies. For drinking water derived from groundwater, the acute and chronic EEC value of 0.8 µg/ L is based on modeling using SCIGROW It must be noted that carbaryl has an aerobic metabolism half­ life (4 days) which is significantly outside the range of values for which SCI­ GROW may be valid (17­ 1000 days). Because of this there is significant uncertainty in the SCI­ GROW value. EFED currently does not have more advanced groundwater models, and targeted studies specifically designed to evaluate the potential for carbaryl to move to groundwater are not available. Because of its chemical structure carbaryl is somewhat difficult to quantify by gas chromatography. Older studies using GC or GC/ MS generally have poor recovery and 6 Maximum is the highest application rate allowed according to the label for the specific crop "Average" is the average rate as determined by OPP/ BEAD and reported in the a memo titled Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD Maximum used is the highest rate of application that is actually reported to be used based on OPP/ BEAD analysis of Doanes survey data ­64­ quantitation limits. Because of this difficulty in analysis the actual concentration of carbaryl in groundwater and surface waters may be higher than reported. More recent studies using HPLC/ MS should provide better data on the true extent and magnitude of water contamination from the use of carbaryl. Surface Water Modeling Surface water EECs derived from computer modeling are higher than generally seen in monitoring studies. Carbaryl is often detected in surface water, and it is very unlikely that monitoring data represents actual maximum concentrations or that all occurrences have been sampled. Because Carbaryl is fairly reactive in the environment it is difficult to design a sampling program that can identify the peak concentrations. Therefore EFED recommends using modeling data in human health risk assessment. Modeling to support the assessment of drinking water in the human health risk assessment was done for five crop scenario: Florida citrus, Ohio sweet corn and field corn, Oregon apples and Minnesota sugar beets. Three different application rate scenarios were used in modeling: the maximum allowed on the label for the specific crop, an "average" rate, and the maximum rate reported to actually be used 6 . EECs were calculated using The Pesticide Root Zone Model version 3.12 (PRZM) (Carsel et al., 1997) and EXAMS 2.97.5 (Exposure Analysis Modeling System) (Burns, 1997). PRZM is used to simulate pesticide transport as a result of runoff and erosion from an agricultural field and EXAMS estimates environmental fate and transport of pesticides in surface water. Weather and agricultural practices are simulated over 36 years so that the 10­ year exceedance probability at the site can be estimated. A partial list of input parameters for the PRZM/ EXAMS modeling are given in Table 2. The values generated by the models were multiplied by a default percent crop area factor (PCA) which accounts for the fact that is unlikely for any basin to be completely planted to agricultural crops. For human health assessment, simulations were done using the Index Reservoir scenario in Exams. The Index Reservoir and PCA are described in Jones et al., 2000. The EEC's for the five scenarios simulated are shown in Table 1. Input files for PRZM/ EXAMS modeling are attached. Corn: Runoff from use on sweet and field corn was modeled using a Ohio corn scenario located in the Scioto River valley of Central Ohio. The soil is a Cardington silt loam, a fine, illitic, mesic Aquic Hapludalfs in MLRA M­ 111. The Cardington silt loam is a very deep, moderately well drained soil formed in loamy till of medium lime content. Soils are located on 0­ 15 percent ­65­ convex SE facing slopes on summits, shoulders, and back slopes on Wisconsin Age ground and end moraines. Permeability is slow and runoff is negligible to very high. An intermittent perched water table is present between 1­ 2 feet from November and April in most years. The MAP is 36 inches and the MAT is 51 o F. Most areas are cultivated. Major crops are corn, soybeans, small grains, and hay. Some areas are in pasture. The soil is characterized as Group C hydrologic soil. The soil distribution includes Central and North­ Central Ohio. The series is of large extent, approximately 250,000 acres. The series was established in Licking County Ohio in 1930. A PCA of 0.46 was used to correct calculated values for percent area cropped. Apples: Runoff from application on apples was modeled using a standard input scenario for an orchard in Washington County, Oregon. The soil at the site is a Cornelius silt loam soil, a finesilty mixed, mesic Ultic Haploxeralf on a 15% slope in MLRA 2. Seventy­ six acres of pears and 238 acres of apples were grown in Washington County in 1987 (US Department of Commerce, 1989b). The weather data is from weather station W24232 in Salem, Oregon. The weather data file is also part of the PIRANHA shell, and is used to represent the weather for MLRA 2. The site was selected to represent orchards in the western United States that are reasonable likely to result in high exposures to aquatic organisms. The pond used the standard Richard Lee pond that is distributed with EXAMS modified for the Index Reservoir. Additional adjustments were made to the standard pond by changing the water temperature to that which was more appropriate for the region being simulated. The temperature in the pond each month was set to the average monthly air temperature over all 36 years calculated from the meteorological file that was used in the simulation. The default PCA of 0.87 was used. Sugar beets: Runoff from application on sugar beets was modeled using a standard scenario modified for the Index Reservoir in Polk Co. MN. MN has the highest sugar beet acreage and Polk Co. is the highest in the state. The soil at the site is Bearden silty clay loam, a benchmark, hydrologic group C soil with about 800K mapped acres in MLRA 56. The chemical was applied is two aerial applications of 1.5 lb a. i. per acre 14 days apart. Application timing information provided by the University of Minnesota Agricultural Extension Service, Polk County, MN, EFED does not have a PCA for sugar beets so the default value of 0.87 was used. Citrus Use on citrus was modeled using the EFED standard citrus scenario in Oceola County, Florida. The soil is a Adamsville sand, a hyperthermic, uncoated Aquic Quartzipsamment in MLRA 156A. The Adamsville sand is a somewhat poorly drained, rapidly permeable soil that formed in thick sandy marine sediments occurring in Central and Southern Florida on slopes of 0­ 5 percent. The soil is typical of soils used either for rangeland or citrus production. ­66­ Adamsville sand ranges from a Hydrologic Group A soil to a Hydrologic Group C soil, depending on the water table. For the purpose of this modeling, EFED assumed the curve numbers from the PIC of the Adamsville sand as a Group C soil. The default PCA of 0.87 was used. EECs varied greatly depending on the geographic location, crop and application rate. Calculated EECs range up to about 500 : g/ L. The maximum calculated EEC resulted from use on citrus in Florida. Modeling "average" and maximum reported use rates gave EEC values generally 40­ 60% lower than calculated with maximum rate. EECs calculated by modeling are slightly higher than concentrations observed in monitoring data. Because most available monitoring data is not from targeted studies and is limited spatially and temporally it is not reasonable to expect that it represents the maximum environmental concentrations that exist. Therefore modeling results probably are a better estimate of actual concentrations that may occur in the environment. ­67­ Table 1. Carbaryl Drinking Water EECs Crop Number of Applications per Year Pounds A. I. per application Surface Water Acute (ppb) (1 in 10 year peak single day concentration) Surface Water Chronic (ppb) (1 in 10 year annual average concentration) Sweet Corn (OH) (PCA = 0.46) Maximum 1 8 2 37 3.2 Average 2 2 3. 4 45 2.2 Maximum 3 Reported 3 1 15 0.9 Field Corn (OH) (PCA = 0.46) Maximum 1 4 2 30 2.1 Average 2 2 1 13 0.6 Maximum 3 Reported 2 1. 520 1 Apples (OR) (PCA = 0.87) Maximum 1 5 2 144 9 Average 2 2 1. 2 12 0.7 Maximum 3 Reported 2 1. 625 1 Sugar Beets (MN) (PCA = 0.87) Maximum 1 2 1. 519 2 Average 2 1 1. 5 12 1.1 Maximum 3 Reported 1 1. 2 9 0. 9 Citrus (FL) (PCA = 0.87) Maximum 1 4 5 494 28 Average 2 2 3. 4 246 11 Maximum 3 Reported 3 4. 26 411 16 Surface Water Monitoring 5.5 (Maximum Observed Concentration) Groundwater SCIGROW Maximum 1 5 40. 8 0. 8 Groundwater (NAWQA Monitoring Data) 0.02 0.02 1 Maximum application rate on label 2 Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD 3 Maximum rate of application reported in DoaneS survey data ­68­ Surface Water Monitoring Carbaryl is widely detected in surface waters in non­ targeted and targeted monitoring studies. Observed concentrations are generally low (> 0.5 : g/ L). Carbaryl is not very persistent in most surface water conditions suggesting that the wide spread occurrence is a result of its extensive use in a variety of applications. Because of limitation in the analytical methods used there is some question as to the accuracy of carbaryl analysis. Poor analytical methods probably have resulted in lower detection rates and lower concentrations than actually present. NAWQA Carbaryl is second most widely detected incesticide (after diazanon) the USGS NAWQA program (http:// water. usgs. gov/ nawqa/ nawqa_ home. html). Carbaryl was detected in 46% of 36 NAWQA study units between 1991 and 1998. The reported concentrations are believed to be reliable detections but have greater than average uncertainty in quantification. Carbaryl analytical results are fairly poor, with a typical mean percent recovery of 24% ( F = 15) in laboratory quality control samples, and a method detection limit (MDL) of 0.003 ug/ L. This suggests that the reported values do not represent the maximum concentrations that exist, and that surface water contamination may be more widespread than the data show. Out of 5220 surface water samples analyzed 1082, or about 21 percent, were reported as having detections greater than the MDL. The maximum reported concentration was 5.5 µg/ L. For samples with positive detections the mean concentration was 0.11 : g/ L, with a standard deviation of 0.43 : g/ L. A significant portion of the total carbaryl applied was transported to streams. In areas with high agricultural use the load measured in surface waters was relatively consistent across the country at about 0.1 percent of the amount used in the basins (Larson et al., 1999) http:// water. wr. usgs. gov/ pnsp/ rep/ wrir984222/ load. html. The estimated annual carbaryl use on in agricultural applications is about 4 million pounds suggesting that 400,000 pounds are delivered each year to the nations streams draining agricultural areas. Streams draining urban areas showed more frequent detections and higher concentrations than streams draining agricultural or mixed land use areas. For example Kimbrough and Litke (1996) reported that, in the South Platte River Basin Study Unit, between April and December of 1993, carbaryl was detected in 14 urban drainage samples and 6 agricultural drainage samples. Carbaryl had the highest concentration of the four insecticides analyzed with a maximum concentration of 2.5 : g/ L in the urban basin and 1.5 : g/ L in the agricultural basin (http:// webserver. cr. usgs. gov/ nawqa/ splt/ meetings/ KIMB1. html). In the South­ Central Texas Study Unit carbaryl was detected in 12% of streams draining agricultural areas and 52 % draining urban areas (Bush et al., 2000) http:// water. usgs. gov/ pubs/ circ/ circ1212/. ­69­ Registrant Monitoring Study Aventis Crop Science submitted interim results of an on­ going surface water monitoring study. Carbaryl residues in surface water were measured at drinking water facilities in areas believed to have high agricultural and residential use (MRID 45116201). In this study 16 sites were in agricultural areas and 4 in areas draining suburban areas. Samples of raw water were collected at municipal water treatment facilities for 8­ 12 months. When raw water showed positive detections for carbaryl, finished water samples collected at the same time were analyzed. Samples were collected weekly during periods suspected of being "high risk" and monthly the rest of the year in agricultural areas. Suburban sites were sampled weekly. In this study carbaryl was analyzed by HPLC/ MS with a limit of detection of 0.002 ppb and a limit of quantitation (LOQ) of 0.030 ppb. Most carbaryl detections in this study were below the LOQ. In raw water samples from suburban sites detectable residues in raw water ranged from 0.002 to 0.023 ppb. 11 out of 40 raw water samples from Sweetwater Creek, the source of water for the East Port facility in Douglas, GA had detectable levels ranging from 0.002 to 0.018 ppb. One out of 46 samples from Joe Pool Lake, Ellis Texas had a detection at 0.014 ppb. Jorden Lake in Cary, NC had 2 detections out of 44 samples (0.004 and 0.003 ppb). 11 out of 40 samples from the Cahaba River in Birmingham AL had detections ranging from 0.002 to 0.023 ppb. Finished water sampled from suburban areas were all below the detection limit. In samples from agricultural sites 9 out of 15 water sources had some detectable level of carbaryl. The detections were generally at low levels, with one of about 0.16 ppb and one of 0.031. The rest were below the level of quantitation (< 0.03 ppb). Samples from finished water were generally lower than raw water, though it appears that raw and finished water sampling did not sample the same mass of water. Therefore, the data can not be used to evaluate the effectiveness of water treatment on carbaryl. Because the samples were collected at the same time, the water exiting the treatment plant was temporally different than the water entering and represent different, independent, parcels of water. In several cases finished water had higher concentrations than raw water, and finished water had detectable carbaryl when the raw did not. The highest concentration measured was in finished water (0.16 ppb). Raw water sampled at the same time had much lower concentration (0.010). This illustrates that carbaryl contamination is transient, and that it is unlikely that any but the most intensive sampling would ever detect the actual peak concentration. That, and the limited number of sites sampled, limit the usefulness of this study. Non­ targeted monitoring, such as the NAWQA program, has shown that much higher concentrations occur indicating that this study, while useful, can not be used to describe the overall distribution of concentrations that occur throughout the entire use area. This study does not provide sufficient information to allow estimation of actual peak and mean concentrations that actually occur in all use areas. The highest concentration values measured in this study are close to the average values seen in other, non­ targeted, studies. ­70­ Only limited information was submitted on sampling site selection and how the sites relate to the overall distribution of use areas. Home and garden sites were selected downstream of urban/ suburban areas that were believed to have high use based on county scale sales data. Agricultural sites were selected based on county scale sales data, and are believed to be in "major use counties." This study is still ongoing and only interim study results have been submitted. Additional information is needed to evaluate the study results. Additionally, an analysis of how the selected sites relate to the nationwide distribution of use areas is required. This should include an explanation of why this study did not observe concentrations as high as those found in other, non­ targeted studies, and how the results of this study can be related to concentrations that occur throughout the country. Based on the interim data submitted it appears that this study measured concentrations similar to those observed in non­ targeted studies and did not capture high end or peak values. This study appears to be well designed though limited but until additional information is submitted it is not possible to use the interim results for more then to reinforce the inferences drawn from non­ targeted study data. STORET The EPA STORET database ( was queried on May 12, 1999 for reports of measurements of carbaryl in surface water. The database contained 8048 records indicating that analysis was done for carbaryl. Out of these 432 reported concentrations above the detection limits. The maximum value reported was 5.5 µg/ L. Of the reported detections 18 were above 1 ppb. The data is the STORET database is used to give a general indication of the occurrence pattern only. Lack of QA/ QC and analytical methodology limitations limit the usefulness of the STORET data. However, reported detections of carbaryl suggest that the compound is infrequently detected in surface water and at low levels. Groundwater Available evidence from valid scientific studies show that carbaryl has a limited potential to leach to ground water, and as a result of normal agricultural use, detections of carbaryl residues have been reported in groundwater from several states. As reported in the U. S. EPA. Pesticides in Groundwater Database (Jacoby et al., 1992) carbaryl was detected in 0.4% of wells sampled. Carbaryl was detected in California (2 out of 1433 wells), Missouri (11 out of 325 wells), New York (69 out of 21027 wells) Rhode Island (13 out of 830 wells) and Virginia (11 out of 138 wells). The maximum concentration detected was 610 µg/ L in NY, though typically the measured concentrations were significantly lower. The EPA STORET database was queried on May 12, 1999 for reports of measurements of carbaryl in groundwater. The database contained 9389 records indicating that analysis was done for carbaryl. Out of these only 4 reported concentrations above the detection limits. These analyses were all from one well in Cleveland, OK in 1988. The 4 reported concentrations were between 0.8 and 1 ppb. ­71­ Carbaryl was detected at greater than the detection limit (0.003 µg/ L) in 1.1 % of groundwater samples from 1034 sites across the U. S. by U. S. G. S. NAWQA program. The maximum observed concentration was 0.021 µg/ L. Detections were from mainly from three use sites: wheat (5.8 % of well samples from wheat land use ), orchards and vineyards (1.7 % of well samples from orchard and vineyard land use), and urban (1.8% of urban groundwater samples). Limitations in analytical methodology (described elsewhere) apply to groundwater sample analysis also suggesting that there actual maximum concentrations and extent of contamination may be significantly higher. Data on pesticides in groundwater were reviewed by Kolpin et al. (1998) and updated information is available at: http:// water. wr. usgs. gov/ pnsp/ ja/ est32/. For drinking water derived from groundwater an acute and chronic EEC value of 0.8 µg/ L should be used based on modeling using SCIGROW. Carbaryl is not frequently detected in groundwater monitoring studies. However, targeted studies specifically designed to evaluate the potential for carbaryl to move to groundwater are not available. SCI­ GROW is used to calculate a groundwater screening exposure value to be used in determining the potential risk to human health from drinking water contaminated by use of pesticides. In the case of Carbaryl the chemical properties of the compound are outside the range of values for which SCI­ GROW was developed. The EEC value calculated using SCI­ GROW should therefore be used with caution since it may significantly underestimate possible groundwater concentrations. SCI­ GROW input parameters are shown in Table 2 and a copy of the output is attached.. Water Treatment Effects The Office of Pesticide Programs has completed a review of the effects of drinking water treatment on pesticides in water (http:// www. epa. gov/ scipoly/ sap/ 2000/ september/ sept00 sap__ dw 0907. pdf). This review indicates that standard drinking water treatment, consisting of flocculation/ sedimentation and filtration does not substantially affect concentrations of pesticides in drinking water. Evidence suggests that carbaryl does not react with chlorine or hypoclorite disinfection products in water treatment but is rapidly degraded (T½ = too rapid to measure) by ozone (Mason et al., 1990). ­72­ Table 2. PRZM/ EXAMS environmental fate input parameters for Carbaryl Parameter Value Data source Molecular Weight 201.22 Solubility 32 mg/ L (@ 20° C) Suntio, et al., 1988 Vapor Pressure (torr) 1.36 10 ­6 @ 25° C Ferrira and Seiber, 1981 Henry's Law Constant 1.28 x 10 ­8 Suntio, et al. 1988 Hydrolysis Half­ life pH 5 pH 7 pH 9 stable stable 5 hours MRID 00163847 44759301 Soil Photolysis Half­ life (days) stable no valid data submitted Aquatic Photolysis Half­ life (days) 21 days MRID 41982603 Aerobic Soil Metabolism Half­ life 4.0 days (n= 1 so use 3x) MRID 42785101 Aerobic Aquatic Metabolism Half­ life 4.9 days (n = 1 so use 3x) MRID 43143401 Anaerobic Aquatic Metabolism Half­ life 72.2 days MRID 42785102 Soil­ Water Partitioning Coefficient Kads (Koc) 1.74 (207) sandy loam 2.0 (249) clay loam 3.0 (211) silt loam 3.5 (177) silty clay loam (Koc = 211 for SCIGROW) MRID 43259301 References Cited: Bush, Peter W., Ann F. Ardis, Lynne Fahlquist, Patricia B. Ging, C. Evan Hornig, and Jennifer Lanning­ Rush, 2000. Water Quality in South­ Central Texas, 1996­ 98. Water­ Resources Circular 1212. U. S. Geological Survey. Burns, L. A., 1997. EXAMS 2.97.5 Users Manual. National Exposure Research Lab, Office of ­73­ Research and Development, U. S. Environmental Protection Agency, Athens, Georgia. Carsel, R. F., Imhoff, J. C., Hummel, P. R., Cheplick, J. M. and Donigan, A. S., 1997. PRZM 3.1 Users Manual. National Exposure Research Lab, Office of Research and Development, U. S. Environmental Protection Agency, Athens, Georgia. Ferreira, G. A. and J. N. Seiber, 1981. J. Agric. Food Chem., 29: 93­ 99 Jacoby, H., C. Hoheisel, J. Karrie, S. Lees, L. Davies­ Hilliard, P. Hannon, R. Bingham, E. Behl, D. Wells, and E. Waldman. 1992. Pesticides in Ground Water Database ­ A Compilation of Monitoring Studies: 1971­ 1991, EPA 734­ 12­ 92­ 001, September 1992. Jones, R. David, Jim Breithaupt, Jim Carleton, Laurence Libelo, Jim Lin, Robert Matzner, Ron Parker, William Feeland, Nelson Thurman and Ian Kennedy, 2000. Draft Guidance for Use of the Index Reservoir and Percent Crop Area Factor in Drinking Water Assessments. EPA/ OPP Draft dated March 3, 2000. Kimbrough, R. A., and Litke, D. W., 1996. Environ. Sci. and Technol., 30: 908­ 916. Kolpin, Dana W., Jack E. Barbash and Robert Gilliom, 1998. Environ. Sci. Technol. 32: 588­ 566. Larson, Steven J., Robert Gilliom, and Paul Capel, 1999. Pesticides in Streams of the United States­­ Initial Results from the National Water­ Quality Assessment Program. U. S. G. S. WaterResources Investigations Report 98­ 4222. Suntio, L. R., et al., 1988. Rev. Environ. Contam. Toxicol., 103: 1­ 59. ­74­ APPENDIX A1: PRZM Input Files Maximum Application Rate Ohio Sweet Corn, Index Reservoir *** PRZM3 Input File for INDEX RESERVOIR, IROHCORN1. inp converted 3/ 30/ 2000 *** *** Modeler: S. Abel *** *** Modified for CARBARYL by Laurence Libelo, 6/ 20/ 00 *** Manning's N values for cornstalk residue, fallow surface, 1 ton/ acre *** *** Cardington silt loam is not one of the benchmark soils *** *** Benchmark soils include: blount; crosby; pewamo; miami; brookston; glynwood *** *** miamian; morley; bennington; and fincastle *** *** IR Spray Drift: Aerial: 0.16; Orchard air blast: 0.063; Ground spray: 0.064 *** *** Application efficiency: 0.95 aerial; 0.99 spray blast and ground spray *** *** PCA for corn = 0.46 *** CARBARYL Location: OH Crop: corn MLRA 111 *** ­ RECORD 3 *** 0.72 0.30 0 15.00 1 3 *** ­ RECORED 4 *** 4 *** ­ RECORD 7 *** 0.37 0.43 0.50 172.8 5.80 3 6.00 600.0 *** ­ RECORD 8 *** 1 *** ­ RECORD 9 *** 1 0.25 90.00 100.00 3 91 85 88 0.00 100.00 *** ­ RECORD 9A *** 1 3 *** ­ RECORD 9B, C, D 0101 1605 1110 0.50 0.25 0.30 0.02 0.02 0.02 *** ­ RECORD 10 *** 36 *** ­ RECORD 11 * 160548 260948 111048 1 160549 260949 111049 1 160550 260950 111050 1 160551 260951 111051 1 160552 260952 111052 1 160553 260953 111053 1 160554 260954 111054 1 160555 260955 111055 1 160556 260956 111056 1 160557 260957 111057 1 160558 260958 111058 1 160559 260959 111059 1 160560 260960 111060 1 160561 260961 111061 1 160562 260962 111062 1 160563 260963 111063 1 160564 260964 111064 1 160565 260965 111065 1 160566 260966 111066 1 160567 260967 111067 1 160568 260968 111068 1 160569 260969 111069 1 ­75­ 160570 260970 111070 1 160571 260971 111071 1 160572 260972 111072 1 160573 260973 111073 1 160574 260974 111074 1 160575 260975 111075 1 160576 260976 111076 1 160577 260977 111077 1 160578 260978 111078 1 160579 260979 111079 1 160580 260980 111080 1 160581 260981 111081 1 160582 260982 111082 1 160583 260983 111083 1 *** ­ RECORD 12 *** Application: aerial Application 8 apps @ 2 lb a. i./ acre *** ­ RECORD 13 *** 288 1 0 0 *** ­ RECORD ­ 15 *** Carbaryl Chemical Kd: 3.0 (Silt Loam Soil); ASM T1/ 2 = 12 days; AnSM T1/ 2 = 24 days *** ­ RECORD 16 *** 300448 0 2 0.00 2.24 0.95 0.16 140548 0 2 0.00 2.24 0.95 0.16 280548 0 2 0.00 2.24 0.95 0.16 110648 0 2 0.00 2.24 0.95 0.16 250648 0 2 0.00 2.24 0.95 0.16 090748 0 2 0.00 2.24 0.95 0.16 230748 0 2 0.00 2.24 0.95 0.16 060848 0 2 0.00 2.24 0.95 0.16 300449 0 2 0.00 2.24 0.95 0.16 140549 0 2 0.00 2.24 0.95 0.16 280549 0 2 0.00 2.24 0.95 0.16 110649 0 2 0.00 2.24 0.95 0.16 250649 0 2 0.00 2.24 0.95 0.16 090749 0 2 0.00 2.24 0.95 0.16 230749 0 2 0.00 2.24 0.95 0.16 060849 0 2 0.00 2.24 0.95 0.16 300450 0 2 0.00 2.24 0.95 0.16 140550 0 2 0.00 2.24 0.95 0.16 280550 0 2 0.00 2.24 0.95 0.16 110650 0 2 0.00 2.24 0.95 0.16 250650 0 2 0.00 2.24 0.95 0.16 090750 0 2 0.00 2.24 0.95 0.16 230750 0 2 0.00 2.24 0.95 0.16 060850 0 2 0.00 2.24 0.95 0.16 300451 0 2 0.00 2.24 0.95 0.16 140551 0 2 0.00 2.24 0.95 0.16 280551 0 2 0.00 2.24 0.95 0.16 110651 0 2 0.00 2.24 0.95 0.16 250651 0 2 0.00 2.24 0.95 0.16 090751 0 2 0.00 2.24 0.95 0.16 230751 0 2 0.00 2.24 0.95 0.16 060851 0 2 0.00 2.24 0.95 0.16 300452 0 2 0.00 2.24 0.95 0.16 140552 0 2 0.00 2.24 0.95 0.16 280552 0 2 0.00 2.24 0.95 0.16 110652 0 2 0.00 2.24 0.95 0.16 250652 0 2 0.00 2.24 0.95 0.16 090752 0 2 0.00 2.24 0.95 0.16 230752 0 2 0.00 2.24 0.95 0.16 ­76­ 060852 0 2 0.00 2.24 0.95 0.16 300453 0 2 0.00 2.24 0.95 0.16 140553 0 2 0.00 2.24 0.95 0.16 280553 0 2 0.00 2.24 0.95 0.16 110653 0 2 0.00 2.24 0.95 0.16 250653 0 2 0.00 2.24 0.95 0.16 090753 0 2 0.00 2.24 0.95 0.16 230753 0 2 0.00 2.24 0.95 0.16 060853 0 2 0.00 2.24 0.95 0.16 300454 0 2 0.00 2.24 0.95 0.16 140554 0 2 0.00 2.24 0.95 0.16 280554 0 2 0.00 2.24 0.95 0.16 110654 0 2 0.00 2.24 0.95 0.16 250654 0 2 0.00 2.24 0.95 0.16 090754 0 2 0.00 2.24 0.95 0.16 230754 0 2 0.00 2.24 0.95 0.16 060854 0 2 0.00 2.24 0.95 0.16 300455 0 2 0.00 2.24 0.95 0.16 140555 0 2 0.00 2.24 0.95 0.16 280555 0 2 0.00 2.24 0.95 0.16 110655 0 2 0.00 2.24 0.95 0.16 250655 0 2 0.00 2.24 0.95 0.16 090755 0 2 0.00 2.24 0.95 0.16 230755 0 2 0.00 2.24 0.95 0.16 060855 0 2 0.00 2.24 0.95 0.16 300456 0 2 0.00 2.24 0.95 0.16 140556 0 2 0.00 2.24 0.95 0.16 280556 0 2 0.00 2.24 0.95 0.16 110656 0 2 0.00 2.24 0.95 0.16 250656 0 2 0.00 2.24 0.95 0.16 090756 0 2 0.00 2.24 0.95 0.16 230756 0 2 0.00 2.24 0.95 0.16 060856 0 2 0.00 2.24 0.95 0.16 300457 0 2 0.00 2.24 0.95 0.16 140557 0 2 0.00 2.24 0.95 0.16 280557 0 2 0.00 2.24 0.95 0.16 110657 0 2 0.00 2.24 0.95 0.16 250657 0 2 0.00 2.24 0.95 0.16 090757 0 2 0.00 2.24 0.95 0.16 230757 0 2 0.00 2.24 0.95 0.16 060857 0 2 0.00 2.24 0.95 0.16 300458 0 2 0.00 2.24 0.95 0.16 140558 0 2 0.00 2.24 0.95 0.16 280558 0 2 0.00 2.24 0.95 0.16 110658 0 2 0.00 2.24 0.95 0.16 250658 0 2 0.00 2.24 0.95 0.16 090758 0 2 0.00 2.24 0.95 0.16 230758 0 2 0.00 2.24 0.95 0.16 060858 0 2 0.00 2.24 0.95 0.16 300459 0 2 0.00 2.24 0.95 0.16 140559 0 2 0.00 2.24 0.95 0.16 280559 0 2 0.00 2.24 0.95 0.16 110659 0 2 0.00 2.24 0.95 0.16 250659 0 2 0.00 2.24 0.95 0.16 090759 0 2 0.00 2.24 0.95 0.16 230759 0 2 0.00 2.24 0.95 0.16 060859 0 2 0.00 2.24 0.95 0.16 300460 0 2 0.00 2.24 0.95 0.16 140560 0 2 0.00 2.24 0.95 0.16 280560 0 2 0.00 2.24 0.95 0.16 110660 0 2 0.00 2.24 0.95 0.16 ­77­ 250660 0 2 0.00 2.24 0.95 0.16 090760 0 2 0.00 2.24 0.95 0.16 230760 0 2 0.00 2.24 0.95 0.16 060860 0 2 0.00 2.24 0.95 0.16 300461 0 2 0.00 2.24 0.95 0.16 140561 0 2 0.00 2.24 0.95 0.16 280561 0 2 0.00 2.24 0.95 0.16 110661 0 2 0.00 2.24 0.95 0.16 250661 0 2 0.00 2.24 0.95 0.16 090761 0 2 0.00 2.24 0.95 0.16 230761 0 2 0.00 2.24 0.95 0.16 060861 0 2 0.00 2.24 0.95 0.16 300462 0 2 0.00 2.24 0.95 0.16 140562 0 2 0.00 2.24 0.95 0.16 280562 0 2 0.00 2.24 0.95 0.16 110662 0 2 0.00 2.24 0.95 0.16 250662 0 2 0.00 2.24 0.95 0.16 090762 0 2 0.00 2.24 0.95 0.16 230762 0 2 0.00 2.24 0.95 0.16 060862 0 2 0.00 2.24 0.95 0.16 300463 0 2 0.00 2.24 0.95 0.16 140563 0 2 0.00 2.24 0.95 0.16 280563 0 2 0.00 2.24 0.95 0.16 110663 0 2 0.00 2.24 0.95 0.16 250663 0 2 0.00 2.24 0.95 0.16 090763 0 2 0.00 2.24 0.95 0.16 230763 0 2 0.00 2.24 0.95 0.16 060863 0 2 0.00 2.24 0.95 0.16 300464 0 2 0.00 2.24 0.95 0.16 140564 0 2 0.00 2.24 0.95 0.16 280564 0 2 0.00 2.24 0.95 0.16 110664 0 2 0.00 2.24 0.95 0.16 250664 0 2 0.00 2.24 0.95 0.16 090764 0 2 0.00 2.24 0.95 0.16 230764 0 2 0.00 2.24 0.95 0.16 060864 0 2 0.00 2.24 0.95 0.16 300465 0 2 0.00 2.24 0.95 0.16 140565 0 2 0.00 2.24 0.95 0.16 280565 0 2 0.00 2.24 0.95 0.16 110665 0 2 0.00 2.24 0.95 0.16 250665 0 2 0.00 2.24 0.95 0.16 090765 0 2 0.00 2.24 0.95 0.16 230765 0 2 0.00 2.24 0.95 0.16 060865 0 2 0.00 2.24 0.95 0.16 300466 0 2 0.00 2.24 0.95 0.16 140566 0 2 0.00 2.24 0.95 0.16 280566 0 2 0.00 2.24 0.95 0.16 110666 0 2 0.00 2.24 0.95 0.16 250666 0 2 0.00 2.24 0.95 0.16 090766 0 2 0.00 2.24 0.95 0.16 230766 0 2 0.00 2.24 0.95 0.16 060866 0 2 0.00 2.24 0.95 0.16 300467 0 2 0.00 2.24 0.95 0.16 140567 0 2 0.00 2.24 0.95 0.16 280567 0 2 0.00 2.24 0.95 0.16 110667 0 2 0.00 2.24 0.95 0.16 250667 0 2 0.00 2.24 0.95 0.16 090767 0 2 0.00 2.24 0.95 0.16 230767 0 2 0.00 2.24 0.95 0.16 060867 0 2 0.00 2.24 0.95 0.16 300468 0 2 0.00 2.24 0.95 0.16 ­78­ 140568 0 2 0.00 2.24 0.95 0.16 280568 0 2 0.00 2.24 0.95 0.16 110668 0 2 0.00 2.24 0.95 0.16 250668 0 2 0.00 2.24 0.95 0.16 090768 0 2 0.00 2.24 0.95 0.16 230768 0 2 0.00 2.24 0.95 0.16 060868 0 2 0.00 2.24 0.95 0.16 300469 0 2 0.00 2.24 0.95 0.16 140569 0 2 0.00 2.24 0.95 0.16 280569 0 2 0.00 2.24 0.95 0.16 110669 0 2 0.00 2.24 0.95 0.16 250669 0 2 0.00 2.24 0.95 0.16 090769 0 2 0.00 2.24 0.95 0.16 230769 0 2 0.00 2.24 0.95 0.16 060869 0 2 0.00 2.24 0.95 0.16 300470 0 2 0.00 2.24 0.95 0.16 140570 0 2 0.00 2.24 0.95 0.16 280570 0 2 0.00 2.24 0.95 0.16 110670 0 2 0.00 2.24 0.95 0.16 250670 0 2 0.00 2.24 0.95 0.16 090770 0 2 0.00 2.24 0.95 0.16 230770 0 2 0.00 2.24 0.95 0.16 060870 0 2 0.00 2.24 0.95 0.16 300471 0 2 0.00 2.24 0.95 0.16 140571 0 2 0.00 2.24 0.95 0.16 280571 0 2 0.00 2.24 0.95 0.16 110671 0 2 0.00 2.24 0.95 0.16 250671 0 2 0.00 2.24 0.95 0.16 090771 0 2 0.00 2.24 0.95 0.16 230771 0 2 0.00 2.24 0.95 0.16 060871 0 2 0.00 2.24 0.95 0.16 300472 0 2 0.00 2.24 0.95 0.16 140572 0 2 0.00 2.24 0.95 0.16 280572 0 2 0.00 2.24 0.95 0.16 110672 0 2 0.00 2.24 0.95 0.16 250672 0 2 0.00 2.24 0.95 0.16 090772 0 2 0.00 2.24 0.95 0.16 230772 0 2 0.00 2.24 0.95 0.16 060872 0 2 0.00 2.24 0.95 0.16 300473 0 2 0.00 2.24 0.95 0.16 140573 0 2 0.00 2.24 0.95 0.16 280573 0 2 0.00 2.24 0.95 0.16 110673 0 2 0.00 2.24 0.95 0.16 250673 0 2 0.00 2.24 0.95 0.16 090773 0 2 0.00 2.24 0.95 0.16 230773 0 2 0.00 2.24 0.95 0.16 060873 0 2 0.00 2.24 0.95 0.16 300474 0 2 0.00 2.24 0.95 0.16 140574 0 2 0.00 2.24 0.95 0.16 280574 0 2 0.00 2.24 0.95 0.16 110674 0 2 0.00 2.24 0.95 0.16 250674 0 2 0.00 2.24 0.95 0.16 090774 0 2 0.00 2.24 0.95 0.16 230774 0 2 0.00 2.24 0.95 0.16 060874 0 2 0.00 2.24 0.95 0.16 300475 0 2 0.00 2.24 0.95 0.16 140575 0 2 0.00 2.24 0.95 0.16 280575 0 2 0.00 2.24 0.95 0.16 110675 0 2 0.00 2.24 0.95 0.16 250675 0 2 0.00 2.24 0.95 0.16 090775 0 2 0.00 2.24 0.95 0.16 ­79­ 230775 0 2 0.00 2.24 0.95 0.16 060875 0 2 0.00 2.24 0.95 0.16 300476 0 2 0.00 2.24 0.95 0.16 140576 0 2 0.00 2.24 0.95 0.16 280576 0 2 0.00 2.24 0.95 0.16 110676 0 2 0.00 2.24 0.95 0.16 250676 0 2 0.00 2.24 0.95 0.16 090776 0 2 0.00 2.24 0.95 0.16 230776 0 2 0.00 2.24 0.95 0.16 060876 0 2 0.00 2.24 0.95 0.16 300477 0 2 0.00 2.24 0.95 0.16 140577 0 2 0.00 2.24 0.95 0.16 280577 0 2 0.00 2.24 0.95 0.16 110677 0 2 0.00 2.24 0.95 0.16 250677 0 2 0.00 2.24 0.95 0.16 090777 0 2 0.00 2.24 0.95 0.16 230777 0 2 0.00 2.24 0.95 0.16 060877 0 2 0.00 2.24 0.95 0.16 300478 0 2 0.00 2.24 0.95 0.16 140578 0 2 0.00 2.24 0.95 0.16 280578 0 2 0.00 2.24 0.95 0.16 110678 0 2 0.00 2.24 0.95 0.16 250678 0 2 0.00 2.24 0.95 0.16 090778 0 2 0.00 2.24 0.95 0.16 230778 0 2 0.00 2.24 0.95 0.16 060878 0 2 0.00 2.24 0.95 0.16 300479 0 2 0.00 2.24 0.95 0.16 140579 0 2 0.00 2.24 0.95 0.16 280579 0 2 0.00 2.24 0.95 0.16 110679 0 2 0.00 2.24 0.95 0.16 250679 0 2 0.00 2.24 0.95 0.16 090779 0 2 0.00 2.24 0.95 0.16 230779 0 2 0.00 2.24 0.95 0.16 060879 0 2 0.00 2.24 0.95 0.16 300480 0 2 0.00 2.24 0.95 0.16 140580 0 2 0.00 2.24 0.95 0.16 280580 0 2 0.00 2.24 0.95 0.16 110680 0 2 0.00 2.24 0.95 0.16 250680 0 2 0.00 2.24 0.95 0.16 090780 0 2 0.00 2.24 0.95 0.16 230780 0 2 0.00 2.24 0.95 0.16 060880 0 2 0.00 2.24 0.95 0.16 300481 0 2 0.00 2.24 0.95 0.16 140581 0 2 0.00 2.24 0.95 0.16 280581 0 2 0.00 2.24 0.95 0.16 110681 0 2 0.00 2.24 0.95 0.16 250681 0 2 0.00 2.24 0.95 0.16 090781 0 2 0.00 2.24 0.95 0.16 230781 0 2 0.00 2.24 0.95 0.16 060881 0 2 0.00 2.24 0.95 0.16 300482 0 2 0.00 2.24 0.95 0.16 140582 0 2 0.00 2.24 0.95 0.16 280582 0 2 0.00 2.24 0.95 0.16 110682 0 2 0.00 2.24 0.95 0.16 250682 0 2 0.00 2.24 0.95 0.16 090782 0 2 0.00 2.24 0.95 0.16 230782 0 2 0.00 2.24 0.95 0.16 060882 0 2 0.00 2.24 0.95 0.16 300483 0 2 0.00 2.24 0.95 0.16 140583 0 2 0.00 2.24 0.95 0.16 280583 0 2 0.00 2.24 0.95 0.16 ­80­ 110683 0 2 0.00 2.24 0.95 0.16 250683 0 2 0.00 2.24 0.95 0.16 090783 0 2 0.00 2.24 0.95 0.16 230783 0 2 0.00 2.24 0.95 0.16 060883 0 2 0.00 2.24 0.95 0.16 *** ­ Record 17 *** 0.0 3 0 *** ­ RECORD 18 *** 0.0 0.0 0.00 *** ­ RECORD 19 *** Soil Series: Cardington silt loam; Hydrogic Group C *** ­ RECORD 20 *** 100.00 0 0 0 0 0 0 0 0 0 *** ­ RECORD 26 *** 0.00 0.00 00.00 *** ­ RECORD 33 *** 2 *** RECORD 34,36,37 1 22.000 1.600 0.294 0.000 0.000 0.000 0.058 0.058 0.000 0.200 0.294 0.086 1.160 3.0 2 78.000 1.650 0.147 0.000 0.000 0.000 0.029 0.029 0.000 1.000 0.147 0.087 0.174 3.0 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­ 7 YEAR PRCP TSER 0 0 RUNF TSER 0 0 INFL TSER 1 1 ESLS TSER 0 0 1. E3 RFLX TSER 0 0 1. E5 EFLX TSER 0 0 1. E5 RZFX TSER 0 0 1. E5 ­81­ Average Application Rate Ohio Sweet Corn, Index Reservoir *** PRZM3 Input File for INDEX RESERVOIR, IROHCORN1. inp converted 3/ 30/ 2000 *** *** Modeler: S. Abel *** *** Modified for CARBARYL by Laurence Libelo, 6/ 20/ 00 *** Use rate changed to QUA (July 21, 1998 QUA Report) AVERAGE VALUES on 2/ 28/ 01 *** *** Manning's N values for cornstalk residue, fallow surface, 1 ton/ acre *** *** Cardington silt loam is not one of the benchmark soils *** *** Benchmark soils include: blount; crosby; pewamo; miami; brookston; glynwood *** *** miamian; morley; bennington; and fincastle *** *** IR Spray Drift: Aerial: 0.16; Orchard air blast: 0.063; Ground spray: 0.064 *** *** Application efficiency: 0.95 aerial; 0.99 spray blast and ground spray *** *** PCA for corn = 0.46 *** CARBARYL Location: OH Crop: corn MLRA 111 *** ­ RECORD 3 *** 0.72 0.30 0 15.00 1 3 *** ­ RECORED 4 *** 4 *** ­ RECORD 7 *** 0.37 0.43 0.50 172.8 5.80 3 6.00 600.0 *** ­ RECORD 8 *** 1 *** ­ RECORD 9 *** 1 0.25 90.00 100.00 3 91 85 88 0.00 100.00 *** ­ RECORD 9A *** 1 3 *** ­ RECORD 9B, C, D 0101 1605 1110 0.50 0.25 0.30 0.02 0.02 0.02 *** ­ RECORD 10 *** 36 *** ­ RECORD 11 * 160548 260948 111048 1 160549 260949 111049 1 160550 260950 111050 1 160551 260951 111051 1 160552 260952 111052 1 160553 260953 111053 1 160554 260954 111054 1 160555 260955 111055 1 160556 260956 111056 1 160557 260957 111057 1 160558 260958 111058 1 160559 260959 111059 1 160560 260960 111060 1 160561 260961 111061 1 160562 260962 111062 1 160563 260963 111063 1 160564 260964 111064 1 160565 260965 111065 1 160566 260966 111066 1 160567 260967 111067 1 160568 260968 111068 1 160569 260969 111069 1 ­82­ 160570 260970 111070 1 160571 260971 111071 1 160572 260972 111072 1 160573 260973 111073 1 160574 260974 111074 1 160575 260975 111075 1 160576 260976 111076 1 160577 260977 111077 1 160578 260978 111078 1 160579 260979 111079 1 160580 260980 111080 1 160581 260981 111081 1 160582 260982 111082 1 160583 260983 111083 1 *** ­ RECORD 12 *** Application by ground spray Rate = "average" from QUA memo (July 21, 1998) ­ 3 apps @ 1.1 lb a. i./ acre *** Application: X Application Method. 2 apps @ 8 lb a. i./ acre (8.9 kgs/ hectare *** ­ RECORD 13 *** 108 1 0 0 *** ­ RECORD ­ 15 *** Carbaryl Chemical Kd: 3.0 (Silt Loam Soil); ASM T1/ 2 = 12 days; AnSM T1/ 2 = 24 days *** ­ RECORD 16 *** 300448 0 2 0.00 1.23 0.95 0.064 140548 0 2 0.00 1.23 0.95 0.064 280548 0 2 0.00 1.23 0.95 0.064 300449 0 2 0.00 1.23 0.95 0.064 140549 0 2 0.00 1.23 0.95 0.064 280549 0 2 0.00 1.23 0.95 0.064 300450 0 2 0.00 1.23 0.95 0.064 140550 0 2 0.00 1.23 0.95 0.064 280550 0 2 0.00 1.23 0.95 0.064 300451 0 2 0.00 1.23 0.95 0.064 140551 0 2 0.00 1.23 0.95 0.064 280551 0 2 0.00 1.23 0.95 0.064 300452 0 2 0.00 1.23 0.95 0.064 140552 0 2 0.00 1.23 0.95 0.064 280552 0 2 0.00 1.23 0.95 0.064 300453 0 2 0.00 1.23 0.95 0.064 140553 0 2 0.00 1.23 0.95 0.064 280553 0 2 0.00 1.23 0.95 0.064 300454 0 2 0.00 1.23 0.95 0.064 140554 0 2 0.00 1.23 0.95 0.064 280554 0 2 0.00 1.23 0.95 0.064 300455 0 2 0.00 1.23 0.95 0.064 140555 0 2 0.00 1.23 0.95 0.064 280555 0 2 0.00 1.23 0.95 0.064 300456 0 2 0.00 1.23 0.95 0.064 140556 0 2 0.00 1.23 0.95 0.064 280556 0 2 0.00 1.23 0.95 0.064 300457 0 2 0.00 1.23 0.95 0.064 140557 0 2 0.00 1.23 0.95 0.064 280557 0 2 0.00 1.23 0.95 0.064 300458 0 2 0.00 1.23 0.95 0.064 140558 0 2 0.00 1.23 0.95 0.064 280558 0 2 0.00 1.23 0.95 0.064 300459 0 2 0.00 1.23 0.95 0.064 140559 0 2 0.00 1.23 0.95 0.064 280559 0 2 0.00 1.23 0.95 0.064 ­83­ 300460 0 2 0.00 1.23 0.95 0.064 140560 0 2 0.00 1.23 0.95 0.064 280560 0 2 0.00 1.23 0.95 0.064 300461 0 2 0.00 1.23 0.95 0.064 140561 0 2 0.00 1.23 0.95 0.064 280561 0 2 0.00 1.23 0.95 0.064 300462 0 2 0.00 1.23 0.95 0.064 140562 0 2 0.00 1.23 0.95 0.064 280562 0 2 0.00 1.23 0.95 0.064 300463 0 2 0.00 1.23 0.95 0.064 140563 0 2 0.00 1.23 0.95 0.064 280563 0 2 0.00 1.23 0.95 0.064 300464 0 2 0.00 1.23 0.95 0.064 140564 0 2 0.00 1.23 0.95 0.064 280564 0 2 0.00 1.23 0.95 0.064 300465 0 2 0.00 1.23 0.95 0.064 140565 0 2 0.00 1.23 0.95 0.064 280565 0 2 0.00 1.23 0.95 0.064 300466 0 2 0.00 1.23 0.95 0.064 140566 0 2 0.00 1.23 0.95 0.064 280566 0 2 0.00 1.23 0.95 0.064 300467 0 2 0.00 1.23 0.95 0.064 140567 0 2 0.00 1.23 0.95 0.064 280567 0 2 0.00 1.23 0.95 0.064 300468 0 2 0.00 1.23 0.95 0.064 140568 0 2 0.00 1.23 0.95 0.064 280568 0 2 0.00 1.23 0.95 0.064 300469 0 2 0.00 1.23 0.95 0.064 140569 0 2 0.00 1.23 0.95 0.064 280569 0 2 0.00 1.23 0.95 0.064 300470 0 2 0.00 1.23 0.95 0.064 140570 0 2 0.00 1.23 0.95 0.064 280570 0 2 0.00 1.23 0.95 0.064 300471 0 2 0.00 1.23 0.95 0.064 140571 0 2 0.00 1.23 0.95 0.064 280571 0 2 0.00 1.23 0.95 0.064 300472 0 2 0.00 1.23 0.95 0.064 140572 0 2 0.00 1.23 0.95 0.064 280572 0 2 0.00 1.23 0.95 0.064 300473 0 2 0.00 1.23 0.95 0.064 140573 0 2 0.00 1.23 0.95 0.064 280573 0 2 0.00 1.23 0.95 0.064 300474 0 2 0.00 1.23 0.95 0.064 140574 0 2 0.00 1.23 0.95 0.064 280574 0 2 0.00 1.23 0.95 0.064 300475 0 2 0.00 1.23 0.95 0.064 140575 0 2 0.00 1.23 0.95 0.064 280575 0 2 0.00 1.23 0.95 0.064 300476 0 2 0.00 1.23 0.95 0.064 140576 0 2 0.00 1.23 0.95 0.064 280576 0 2 0.00 1.23 0.95 0.064 300477 0 2 0.00 1.23 0.95 0.064 140577 0 2 0.00 1.23 0.95 0.064 280577 0 2 0.00 1.23 0.95 0.064 300478 0 2 0.00 1.23 0.95 0.064 140578 0 2 0.00 1.23 0.95 0.064 280578 0 2 0.00 1.23 0.95 0.064 300479 0 2 0.00 1.23 0.95 0.064 140579 0 2 0.00 1.23 0.95 0.064 280579 0 2 0.00 1.23 0.95 0.064 300480 0 2 0.00 1.23 0.95 0.064 ­84­ 140580 0 2 0.00 1.23 0.95 0.064 280580 0 2 0.00 1.23 0.95 0.064 300481 0 2 0.00 1.23 0.95 0.064 140581 0 2 0.00 1.23 0.95 0.064 280581 0 2 0.00 1.23 0.95 0.064 300482 0 2 0.00 1.23 0.95 0.064 140582 0 2 0.00 1.23 0.95 0.064 280582 0 2 0.00 1.23 0.95 0.064 300483 0 2 0.00 1.23 0.95 0.064 140583 0 2 0.00 1.23 0.95 0.064 280583 0 2 0.00 1.23 0.95 0.064 *** ­ Record 17 *** 0.0 3 0 *** ­ RECORD 18 *** 0.0 0.0 0.00 *** ­ RECORD 19 *** Soil Series: Cardington silt loam; Hydrogic Group C *** ­ RECORD 20 *** 100.00 0 0 0 0 0 0 0 0 0 *** ­ RECORD 26 *** 0.00 0.00 00.00 *** ­ RECORD 33 *** 2 *** RECORD 34,36,37 1 22.000 1.600 0.294 0.000 0.000 0.000 0.058 0.058 0.000 0.200 0.294 0.086 1.160 3.0 2 78.000 1.650 0.147 0.000 0.000 0.000 0.029 0.029 0.000 1.000 0.147 0.087 0.174 3.0 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­ 7 YEAR PRCP TSER 0 0 RUNF TSER 0 0 INFL TSER 1 1 ESLS TSER 0 0 1. E3 RFLX TSER 0 0 1. E5 EFLX TSER 0 0 1. E5 RZFX TSER 0 0 1. E5 ­85­ Maximum Reported Application Rate Ohio Sweet Corn, Index Reservoir *** PRZM3 Input File for INDEX RESERVOIR, IROHCORN1. inp converted 3/ 30/ 2000 *** *** Modeler: S. Abel *** *** Modified for CARBARYL by Laurence Libelo, 6/ 20/ 00 *** Manning's N values for cornstalk residue, fallow surface, 1 ton/ acre *** *** Cardington silt loam is not one of the benchmark soils *** *** Benchmark soils include: blount; crosby; pewamo; miami; brookston; glynwood *** *** miamian; morley; bennington; and fincastle *** *** IR Spray Drift: Aerial: 0.16; Orchard air blast: 0.063; Ground spray: 0.064 *** *** Application efficiency: 0.95 aerial; 0.99 spray blast and ground spray *** *** PCA for corn = 0.46 *** CARBARYL Location: OH Crop: corn MLRA 111 *** ­ RECORD 3 *** 0.72 0.30 0 15.00 1 3 *** ­ RECORED 4 *** 4 *** ­ RECORD 7 *** 0.37 0.43 0.50 172.8 5.80 3 6.00 600.0 *** ­ RECORD 8 *** 1 *** ­ RECORD 9 *** 1 0.25 90.00 100.00 3 91 85 88 0.00 100.00 *** ­ RECORD 9A *** 1 3 *** ­ RECORD 9B, C, D 0101 1605 1110 0.50 0.25 0.30 0.02 0.02 0.02 *** ­ RECORD 10 *** 36 *** ­ RECORD 11 * 160548 260948 111048 1 160549 260949 111049 1 160550 260950 111050 1 160551 260951 111051 1 160552 260952 111052 1 160553 260953 111053 1 160554 260954 111054 1 160555 260955 111055 1 160556 260956 111056 1 160557 260957 111057 1 160558 260958 111058 1 160559 260959 111059 1 ­86­ 160560 260960 111060 1 160561 260961 111061 1 160562 260962 111062 1 160563 260963 111063 1 160564 260964 111064 1 160565 260965 111065 1 160566 260966 111066 1 160567 260967 111067 1 160568 260968 111068 1 160569 260969 111069 1 160570 260970 111070 1 160571 260971 111071 1 160572 260972 111072 1 160573 260973 111073 1 160574 260974 111074 1 160575 260975 111075 1 160576 260976 111076 1 160577 260977 111077 1 160578 260978 111078 1 160579 260979 111079 1 160580 260980 111080 1 160581 260981 111081 1 160582 260982 111082 1 160583 260983 111083 1 *** ­ RECORD 12 *** Max reported application ­ 3 apps @ 1 lb A. I./ acre *** Application: aerial Application Method. 2 apps @ 8 lb a. i./ acre (8.9 kgs/ hectare *** ­ RECORD 13 *** 108 1 0 0 *** ­ RECORD ­ 15 *** Carbaryl Chemical Kd: 3.0 (Silt Loam Soil); ASM T1/ 2 = 12 days; AnSM T1/ 2 = 24 days *** ­ RECORD 16 *** 300448 0 2 0.00 1.12 0.95 0.16 140548 0 2 0.00 1.12 0.95 0.16 280548 0 2 0.00 1.12 0.95 0.16 300449 0 2 0.00 1.12 0.95 0.16 140549 0 2 0.00 1.12 0.95 0.16 280549 0 2 0.00 1.12 0.95 0.16 300450 0 2 0.00 1.12 0.95 0.16 140550 0 2 0.00 1.12 0.95 0.16 280550 0 2 0.00 1.12 0.95 0.16 300451 0 2 0.00 1.12 0.95 0.16 140551 0 2 0.00 1.12 0.95 0.16 280551 0 2 0.00 1.12 0.95 0.16 300452 0 2 0.00 1.12 0.95 0.16 140552 0 2 0.00 1.12 0.95 0.16 280552 0 2 0.00 1.12 0.95 0.16 300453 0 2 0.00 1.12 0.95 0.16 140553 0 2 0.00 1.12 0.95 0.16 280553 0 2 0.00 1.12 0.95 0.16 ­87­ 300454 0 2 0.00 1.12 0.95 0.16 140554 0 2 0.00 1.12 0.95 0.16 280554 0 2 0.00 1.12 0.95 0.16 300455 0 2 0.00 1.12 0.95 0.16 140555 0 2 0.00 1.12 0.95 0.16 280555 0 2 0.00 1.12 0.95 0.16 300456 0 2 0.00 1.12 0.95 0.16 140556 0 2 0.00 1.12 0.95 0.16 280556 0 2 0.00 1.12 0.95 0.16 300457 0 2 0.00 1.12 0.95 0.16 140557 0 2 0.00 1.12 0.95 0.16 280557 0 2 0.00 1.12 0.95 0.16 300458 0 2 0.00 1.12 0.95 0.16 140558 0 2 0.00 1.12 0.95 0.16 280558 0 2 0.00 1.12 0.95 0.16 300459 0 2 0.00 1.12 0.95 0.16 140559 0 2 0.00 1.12 0.95 0.16 280559 0 2 0.00 1.12 0.95 0.16 300460 0 2 0.00 1.12 0.95 0.16 140560 0 2 0.00 1.12 0.95 0.16 280560 0 2 0.00 1.12 0.95 0.16 300461 0 2 0.00 1.12 0.95 0.16 140561 0 2 0.00 1.12 0.95 0.16 280561 0 2 0.00 1.12 0.95 0.16 300462 0 2 0.00 1.12 0.95 0.16 140562 0 2 0.00 1.12 0.95 0.16 280562 0 2 0.00 1.12 0.95 0.16 300463 0 2 0.00 1.12 0.95 0.16 140563 0 2 0.00 1.12 0.95 0.16 280563 0 2 0.00 1.12 0.95 0.16 300464 0 2 0.00 1.12 0.95 0.16 140564 0 2 0.00 1.12 0.95 0.16 280564 0 2 0.00 1.12 0.95 0.16 300465 0 2 0.00 1.12 0.95 0.16 140565 0 2 0.00 1.12 0.95 0.16 280565 0 2 0.00 1.12 0.95 0.16 300466 0 2 0.00 1.12 0.95 0.16 140566 0 2 0.00 1.12 0.95 0.16 280566 0 2 0.00 1.12 0.95 0.16 300467 0 2 0.00 1.12 0.95 0.16 140567 0 2 0.00 1.12 0.95 0.16 280567 0 2 0.00 1.12 0.95 0.16 300468 0 2 0.00 1.12 0.95 0.16 140568 0 2 0.00 1.12 0.95 0.16 280568 0 2 0.00 1.12 0.95 0.16 300469 0 2 0.00 1.12 0.95 0.16 140569 0 2 0.00 1.12 0.95 0.16 280569 0 2 0.00 1.12 0.95 0.16 300470 0 2 0.00 1.12 0.95 0.16 140570 0 2 0.00 1.12 0.95 0.16 280570 0 2 0.00 1.12 0.95 0.16 300471 0 2 0.00 1.12 0.95 0.16 ­88­ 140571 0 2 0.00 1.12 0.95 0.16 280571 0 2 0.00 1.12 0.95 0.16 300472 0 2 0.00 1.12 0.95 0.16 140572 0 2 0.00 1.12 0.95 0.16 280572 0 2 0.00 1.12 0.95 0.16 300473 0 2 0.00 1.12 0.95 0.16 140573 0 2 0.00 1.12 0.95 0.16 280573 0 2 0.00 1.12 0.95 0.16 300474 0 2 0.00 1.12 0.95 0.16 140574 0 2 0.00 1.12 0.95 0.16 280574 0 2 0.00 1.12 0.95 0.16 300475 0 2 0.00 1.12 0.95 0.16 140575 0 2 0.00 1.12 0.95 0.16 280575 0 2 0.00 1.12 0.95 0.16 300476 0 2 0.00 1.12 0.95 0.16 140576 0 2 0.00 1.12 0.95 0.16 280576 0 2 0.00 1.12 0.95 0.16 300477 0 2 0.00 1.12 0.95 0.16 140577 0 2 0.00 1.12 0.95 0.16 280577 0 2 0.00 1.12 0.95 0.16 300478 0 2 0.00 1.12 0.95 0.16 140578 0 2 0.00 1.12 0.95 0.16 280578 0 2 0.00 1.12 0.95 0.16 300479 0 2 0.00 1.12 0.95 0.16 140579 0 2 0.00 1.12 0.95 0.16 280579 0 2 0.00 1.12 0.95 0.16 300480 0 2 0.00 1.12 0.95 0.16 140580 0 2 0.00 1.12 0.95 0.16 280580 0 2 0.00 1.12 0.95 0.16 300481 0 2 0.00 1.12 0.95 0.16 140581 0 2 0.00 1.12 0.95 0.16 280581 0 2 0.00 1.12 0.95 0.16 300482 0 2 0.00 1.12 0.95 0.16 140582 0 2 0.00 1.12 0.95 0.16 280582 0 2 0.00 1.12 0.95 0.16 300483 0 2 0.00 1.12 0.95 0.16 140583 0 2 0.00 1.12 0.95 0.16 280583 0 2 0.00 1.12 0.95 0.16 *** ­ Record 17 *** 0.0 3 0 *** ­ RECORD 18 *** 0.0 0.0 0.00 *** ­ RECORD 19 *** Soil Series: Cardington silt loam; Hydrogic Group C *** ­ RECORD 20 *** 100.00 0 0 0 0 0 0 0 0 0 *** ­ RECORD 26 *** 0.00 0.00 00.00 *** ­ RECORD 33 *** 2 *** RECORD 34,36,37 ­89­ 1 22.000 1.600 0.294 0.000 0.000 0.000 0.058 0.058 0.000 0.200 0.294 0.086 1.160 3.0 2 78.000 1.650 0.147 0.000 0.000 0.000 0.029 0.029 0.000 1.000 0.147 0.087 0.174 3.0 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­ 7 YEAR PRCP TSER 0 0 RUNF TSER 0 0 INFL TSER 1 1 ESLS TSER 0 0 1. E3 RFLX TSER 0 0 1. E5 EFLX TSER 0 0 1. E5 RZFX TSER 0 0 1. E5 ­90­ Maximum Application Rate Ohio Corn, Index Reservoir *** PRZM3 Input File for INDEX RESERVOIR, IROHCORN1. inp converted 3/ 30/ 2000 *** *** Modeler: S. Abel *** *** Modified for CARBARYL by Laurence Libelo, 6/ 20/ 00 *** Manning's N values for cornstalk residue, fallow surface, 1 ton/ acre *** *** Cardington silt loam is not one of the benchmark soils *** *** Benchmark soils include: blount; crosby; pewamo; miami; brookston; glynwood *** *** miamian; morley; bennington; and fincastle *** *** IR Spray Drift: Aerial: 0.16; Orchard air blast: 0.063; Ground spray: 0.064 *** *** Application efficiency: 0.95 aerial; 0.99 spray blast and ground spray *** *** PCA for corn = 0.46 *** CARBARYL Location: OH Crop: corn MLRA 111 *** ­ RECORD 3 *** 0.72 0.30 0 15.00 1 3 *** ­ RECORED 4 *** 4 *** ­ RECORD 7 *** 0.37 0.43 0.50 172.8 5.80 3 6.00 600.0 *** ­ RECORD 8 *** 1 *** ­ RECORD 9 *** 1 0.25 90.00 100.00 3 91 85 88 0.00 100.00 *** ­ RECORD 9A *** 1 3 *** ­ RECORD 9B, C, D 0101 1605 1110 0.50 0.25 0.30 0.02 0.02 0.02 *** ­ RECORD 10 *** 36 *** ­ RECORD 11 * 160548 260948 111048 1 160549 260949 111049 1 160550 260950 111050 1 160551 260951 111051 1 160552 260952 111052 1 160553 260953 111053 1 160554 260954 111054 1 160555 260955 111055 1 160556 260956 111056 1 160557 260957 111057 1 160558 260958 111058 1 ­91­ 160559 260959 111059 1 160560 260960 111060 1 160561 260961 111061 1 160562 260962 111062 1 160563 260963 111063 1 160564 260964 111064 1 160565 260965 111065 1 160566 260966 111066 1 160567 260967 111067 1 160568 260968 111068 1 160569 260969 111069 1 160570 260970 111070 1 160571 260971 111071 1 160572 260972 111072 1 160573 260973 111073 1 160574 260974 111074 1 160575 260975 111075 1 160576 260976 111076 1 160577 260977 111077 1 160578 260978 111078 1 160579 260979 111079 1 160580 260980 111080 1 160581 260981 111081 1 160582 260982 111082 1 160583 260983 111083 1 *** ­ RECORD 12 *** Application: X Application Method. 4 apps @ 2 lb a. i./ acre *** ­ RECORD 13 *** 144 1 0 0 *** ­ RECORD ­ 15 *** Carbaryl Chemical Kd: 3.0 (Silt Loam Soil); ASM T1/ 2 = 12 days; AnSM T1/ 2 = 24 days *** ­ RECORD 16 *** 300448 0 2 0.00 2.24 0.95 0.16 140548 0 2 0.00 2.24 0.95 0.16 280548 0 2 0.00 2.24 0.95 0.16 110648 0 2 0.00 2.24 0.95 0.16 300449 0 2 0.00 2.24 0.95 0.16 140549 0 2 0.00 2.24 0.95 0.16 280549 0 2 0.00 2.24 0.95 0.16 110649 0 2 0.00 2.24 0.95 0.16 300450 0 2 0.00 2.24 0.95 0.16 140550 0 2 0.00 2.24 0.95 0.16 280550 0 2 0.00 2.24 0.95 0.16 110650 0 2 0.00 2.24 0.95 0.16 300451 0 2 0.00 2.24 0.95 0.16 140551 0 2 0.00 2.24 0.95 0.16 280551 0 2 0.00 2.24 0.95 0.16 110651 0 2 0.00 2.24 0.95 0.16 300452 0 2 0.00 2.24 0.95 0.16 ­92­ 140552 0 2 0.00 2.24 0.95 0.16 280552 0 2 0.00 2.24 0.95 0.16 110652 0 2 0.00 2.24 0.95 0.16 300453 0 2 0.00 2.24 0.95 0.16 140553 0 2 0.00 2.24 0.95 0.16 280553 0 2 0.00 2.24 0.95 0.16 110653 0 2 0.00 2.24 0.95 0.16 300454 0 2 0.00 2.24 0.95 0.16 140554 0 2 0.00 2.24 0.95 0.16 280554 0 2 0.00 2.24 0.95 0.16 110654 0 2 0.00 2.24 0.95 0.16 300455 0 2 0.00 2.24 0.95 0.16 140555 0 2 0.00 2.24 0.95 0.16 280555 0 2 0.00 2.24 0.95 0.16 110655 0 2 0.00 2.24 0.95 0.16 300456 0 2 0.00 2.24 0.95 0.16 140556 0 2 0.00 2.24 0.95 0.16 280556 0 2 0.00 2.24 0.95 0.16 110656 0 2 0.00 2.24 0.95 0.16 300457 0 2 0.00 2.24 0.95 0.16 140557 0 2 0.00 2.24 0.95 0.16 280557 0 2 0.00 2.24 0.95 0.16 110657 0 2 0.00 2.24 0.95 0.16 300458 0 2 0.00 2.24 0.95 0.16 140558 0 2 0.00 2.24 0.95 0.16 280558 0 2 0.00 2.24 0.95 0.16 110658 0 2 0.00 2.24 0.95 0.16 300459 0 2 0.00 2.24 0.95 0.16 140559 0 2 0.00 2.24 0.95 0.16 280559 0 2 0.00 2.24 0.95 0.16 110659 0 2 0.00 2.24 0.95 0.16 300460 0 2 0.00 2.24 0.95 0.16 140560 0 2 0.00 2.24 0.95 0.16 280560 0 2 0.00 2.24 0.95 0.16 110660 0 2 0.00 2.24 0.95 0.16 300461 0 2 0.00 2.24 0.95 0.16 140561 0 2 0.00 2.24 0.95 0.16 280561 0 2 0.00 2.24 0.95 0.16 110661 0 2 0.00 2.24 0.95 0.16 300462 0 2 0.00 2.24 0.95 0.16 140562 0 2 0.00 2.24 0.95 0.16 280562 0 2 0.00 2.24 0.95 0.16 110662 0 2 0.00 2.24 0.95 0.16 300463 0 2 0.00 2.24 0.95 0.16 140563 0 2 0.00 2.24 0.95 0.16 280563 0 2 0.00 2.24 0.95 0.16 110663 0 2 0.00 2.24 0.95 0.16 300464 0 2 0.00 2.24 0.95 0.16 140564 0 2 0.00 2.24 0.95 0.16 280564 0 2 0.00 2.24 0.95 0.16 ­93­ 110664 0 2 0.00 2.24 0.95 0.16 300465 0 2 0.00 2.24 0.95 0.16 140565 0 2 0.00 2.24 0.95 0.16 280565 0 2 0.00 2.24 0.95 0.16 110665 0 2 0.00 2.24 0.95 0.16 300466 0 2 0.00 2.24 0.95 0.16 140566 0 2 0.00 2.24 0.95 0.16 280566 0 2 0.00 2.24 0.95 0.16 110666 0 2 0.00 2.24 0.95 0.16 300467 0 2 0.00 2.24 0.95 0.16 140567 0 2 0.00 2.24 0.95 0.16 280567 0 2 0.00 2.24 0.95 0.16 110667 0 2 0.00 2.24 0.95 0.16 300468 0 2 0.00 2.24 0.95 0.16 140568 0 2 0.00 2.24 0.95 0.16 280568 0 2 0.00 2.24 0.95 0.16 110668 0 2 0.00 2.24 0.95 0.16 300469 0 2 0.00 2.24 0.95 0.16 140569 0 2 0.00 2.24 0.95 0.16 280569 0 2 0.00 2.24 0.95 0.16 110669 0 2 0.00 2.24 0.95 0.16 300470 0 2 0.00 2.24 0.95 0.16 140570 0 2 0.00 2.24 0.95 0.16 280570 0 2 0.00 2.24 0.95 0.16 110670 0 2 0.00 2.24 0.95 0.16 300471 0 2 0.00 2.24 0.95 0.16 140571 0 2 0.00 2.24 0.95 0.16 280571 0 2 0.00 2.24 0.95 0.16 110671 0 2 0.00 2.24 0.95 0.16 300472 0 2 0.00 2.24 0.95 0.16 140572 0 2 0.00 2.24 0.95 0.16 280572 0 2 0.00 2.24 0.95 0.16 110672 0 2 0.00 2.24 0.95 0.16 300473 0 2 0.00 2.24 0.95 0.16 140573 0 2 0.00 2.24 0.95 0.16 280573 0 2 0.00 2.24 0.95 0.16 110673 0 2 0.00 2.24 0.95 0.16 300474 0 2 0.00 2.24 0.95 0.16 140574 0 2 0.00 2.24 0.95 0.16 280574 0 2 0.00 2.24 0.95 0.16 110674 0 2 0.00 2.24 0.95 0.16 300475 0 2 0.00 2.24 0.95 0.16 140575 0 2 0.00 2.24 0.95 0.16 280575 0 2 0.00 2.24 0.95 0.16 110675 0 2 0.00 2.24 0.95 0.16 300476 0 2 0.00 2.24 0.95 0.16 140576 0 2 0.00 2.24 0.95 0.16 280576 0 2 0.00 2.24 0.95 0.16 110676 0 2 0.00 2.24 0.95 0.16 300477 0 2 0.00 2.24 0.95 0.16 ­94­ 140577 0 2 0.00 2.24 0.95 0.16 280577 0 2 0.00 2.24 0.95 0.16 110677 0 2 0.00 2.24 0.95 0.16 300478 0 2 0.00 2.24 0.95 0.16 140578 0 2 0.00 2.24 0.95 0.16 280578 0 2 0.00 2.24 0.95 0.16 110678 0 2 0.00 2.24 0.95 0.16 300479 0 2 0.00 2.24 0.95 0.16 140579 0 2 0.00 2.24 0.95 0.16 280579 0 2 0.00 2.24 0.95 0.16 110679 0 2 0.00 2.24 0.95 0.16 300480 0 2 0.00 2.24 0.95 0.16 140580 0 2 0.00 2.24 0.95 0.16 280580 0 2 0.00 2.24 0.95 0.16 110680 0 2 0.00 2.24 0.95 0.16 300481 0 2 0.00 2.24 0.95 0.16 140581 0 2 0.00 2.24 0.95 0.16 280581 0 2 0.00 2.24 0.95 0.16 110681 0 2 0.00 2.24 0.95 0.16 300482 0 2 0.00 2.24 0.95 0.16 140582 0 2 0.00 2.24 0.95 0.16 280582 0 2 0.00 2.24 0.95 0.16 110682 0 2 0.00 2.24 0.95 0.16 300483 0 2 0.00 2.24 0.95 0.16 140583 0 2 0.00 2.24 0.95 0.16 280583 0 2 0.00 2.24 0.95 0.16 110683 0 2 0.00 2.24 0.95 0.16 *** ­ Record 17 *** 0.0 3 0 *** ­ RECORD 18 *** 0.0 0.0 0.00 *** ­ RECORD 19 *** Soil Series: Cardington silt loam; Hydrogic Group C *** ­ RECORD 20 *** 100.00 0 0 0 0 0 0 0 0 0 *** ­ RECORD 26 *** 0.00 0.00 00.00 *** ­ RECORD 33 *** 2 *** RECORD 34,36,37 1 22.000 1.600 0.294 0.000 0.000 0.000 0.058 0.058 0.000 0.200 0.294 0.086 1.160 3.0 2 78.000 1.650 0.147 0.000 0.000 0.000 0.029 0.029 0.000 1.000 0.147 0.087 0.174 3.0 0 YEAR 10 YEAR 10 YEAR 10 1 ­95­ 1 1 ­­­­ 7 YEAR PRCP TSER 0 0 RUNF TSER 0 0 INFL TSER 1 1 ESLS TSER 0 0 1. E3 RFLX TSER 0 0 1. E5 EFLX TSER 0 0 1. E5 RZFX TSER 0 0 1. E5 ­96­ Average Reported Application Rate Ohio Corn, Index Reservoir *** PRZM3 Input File for INDEX RESERVOIR, IROHCORN1. inp converted 3/ 30/ 2000 *** *** Modeler: S. Abel *** *** Modified for CARBARYL by Laurence Libelo, 6/ 20/ 00 *** Manning's N values for cornstalk residue, fallow surface, 1 ton/ acre *** *** Cardington silt loam is not one of the benchmark soils *** *** Benchmark soils include: blount; crosby; pewamo; miami; brookston; glynwood *** *** miamian; morley; bennington; and fincastle *** *** IR Spray Drift: Aerial: 0.16; Orchard air blast: 0.063; Ground spray: 0.064 *** *** Application efficiency: 0.95 aerial; 0.99 spray blast and ground spray *** *** PCA for corn = 0.46 *** CARBARYL Location: OH Crop: corn MLRA 111 *** ­ RECORD 3 *** 0.72 0.30 0 15.00 1 3 *** ­ RECORED 4 *** 4 *** ­ RECORD 7 *** 0.37 0.43 0.50 172.8 5.80 3 6.00 600.0 *** ­ RECORD 8 *** 1 *** ­ RECORD 9 *** 1 0.25 90.00 100.00 3 91 85 88 0.00 100.00 *** ­ RECORD 9A *** 1 3 *** ­ RECORD 9B, C, D 0101 1605 1110 0.50 0.25 0.30 0.02 0.02 0.02 *** ­ RECORD 10 *** 36 *** ­ RECORD 11 * 160548 260948 111048 1 160549 260949 111049 1 160550 260950 111050 1 160551 260951 111051 1 160552 260952 111052 1 160553 260953 111053 1 160554 260954 111054 1 160555 260955 111055 1 160556 260956 111056 1 ­97­ 160557 260957 111057 1 160558 260958 111058 1 160559 260959 111059 1 160560 260960 111060 1 160561 260961 111061 1 160562 260962 111062 1 160563 260963 111063 1 160564 260964 111064 1 160565 260965 111065 1 160566 260966 111066 1 160567 260967 111067 1 160568 260968 111068 1 160569 260969 111069 1 160570 260970 111070 1 160571 260971 111071 1 160572 260972 111072 1 160573 260973 111073 1 160574 260974 111074 1 160575 260975 111075 1 160576 260976 111076 1 160577 260977 111077 1 160578 260978 111078 1 160579 260979 111079 1 160580 260980 111080 1 160581 260981 111081 1 160582 260982 111082 1 160583 260983 111083 1 *** ­ RECORD 12 *** Average app rate ­ 2 apps @ 1 lb A. I./ acre *** Application: aerial Application at max label rate 4 apps @ 2 lb a. i./ acre *** ­ RECORD 13 *** 72 1 0 0 *** ­ RECORD ­ 15 *** Carbaryl Chemical Kd: 3.0 (Silt Loam Soil); ASM T1/ 2 = 12 days; AnSM T1/ 2 = 24 days *** ­ RECORD 16 *** 300448 0 2 0.00 1.12 0.95 0.16 140548 0 2 0.00 1.12 0.95 0.16 300449 0 2 0.00 1.12 0.95 0.16 140549 0 2 0.00 1.12 0.95 0.16 300450 0 2 0.00 1.12 0.95 0.16 140550 0 2 0.00 1.12 0.95 0.16 300451 0 2 0.00 1.12 0.95 0.16 140551 0 2 0.00 1.12 0.95 0.16 300452 0 2 0.00 1.12 0.95 0.16 140552 0 2 0.00 1.12 0.95 0.16 300453 0 2 0.00 1.12 0.95 0.16 140553 0 2 0.00 1.12 0.95 0.16 300454 0 2 0.00 1.12 0.95 0.16 ­98­ 140554 0 2 0.00 1.12 0.95 0.16 300455 0 2 0.00 1.12 0.95 0.16 140555 0 2 0.00 1.12 0.95 0.16 300456 0 2 0.00 1.12 0.95 0.16 140556 0 2 0.00 1.12 0.95 0.16 300457 0 2 0.00 1.12 0.95 0.16 140557 0 2 0.00 1.12 0.95 0.16 300458 0 2 0.00 1.12 0.95 0.16 140558 0 2 0.00 1.12 0.95 0.16 300459 0 2 0.00 1.12 0.95 0.16 140559 0 2 0.00 1.12 0.95 0.16 300460 0 2 0.00 1.12 0.95 0.16 140560 0 2 0.00 1.12 0.95 0.16 300461 0 2 0.00 1.12 0.95 0.16 140561 0 2 0.00 1.12 0.95 0.16 300462 0 2 0.00 1.12 0.95 0.16 140562 0 2 0.00 1.12 0.95 0.16 300463 0 2 0.00 1.12 0.95 0.16 140563 0 2 0.00 1.12 0.95 0.16 300464 0 2 0.00 1.12 0.95 0.16 140564 0 2 0.00 1.12 0.95 0.16 300465 0 2 0.00 1.12 0.95 0.16 140565 0 2 0.00 1.12 0.95 0.16 300466 0 2 0.00 1.12 0.95 0.16 140566 0 2 0.00 1.12 0.95 0.16 300467 0 2 0.00 1.12 0.95 0.16 140567 0 2 0.00 1.12 0.95 0.16 300468 0 2 0.00 1.12 0.95 0.16 140568 0 2 0.00 1.12 0.95 0.16 300469 0 2 0.00 1.12 0.95 0.16 140569 0 2 0.00 1.12 0.95 0.16 300470 0 2 0.00 1.12 0.95 0.16 140570 0 2 0.00 1.12 0.95 0.16 300471 0 2 0.00 1.12 0.95 0.16 140571 0 2 0.00 1.12 0.95 0.16 300472 0 2 0.00 1.12 0.95 0.16 140572 0 2 0.00 1.12 0.95 0.16 300473 0 2 0.00 1.12 0.95 0.16 140573 0 2 0.00 1.12 0.95 0.16 300474 0 2 0.00 1.12 0.95 0.16 140574 0 2 0.00 1.12 0.95 0.16 300475 0 2 0.00 1.12 0.95 0.16 140575 0 2 0.00 1.12 0.95 0.16 300476 0 2 0.00 1.12 0.95 0.16 140576 0 2 0.00 1.12 0.95 0.16 300477 0 2 0.00 1.12 0.95 0.16 140577 0 2 0.00 1.12 0.95 0.16 300478 0 2 0.00 1.12 0.95 0.16 140578 0 2 0.00 1.12 0.95 0.16 300479 0 2 0.00 1.12 0.95 0.16 ­99­ 140579 0 2 0.00 1.12 0.95 0.16 300480 0 2 0.00 1.12 0.95 0.16 140580 0 2 0.00 1.12 0.95 0.16 300481 0 2 0.00 1.12 0.95 0.16 140581 0 2 0.00 1.12 0.95 0.16 300482 0 2 0.00 1.12 0.95 0.16 140582 0 2 0.00 1.12 0.95 0.16 300483 0 2 0.00 1.12 0.95 0.16 140583 0 2 0.00 1.12 0.95 0.16 *** ­ Record 17 *** 0.0 3 0 *** ­ RECORD 18 *** 0.0 0.0 0.00 *** ­ RECORD 19 *** Soil Series: Cardington silt loam; Hydrogic Group C *** ­ RECORD 20 *** 100.00 0 0 0 0 0 0 0 0 0 *** ­ RECORD 26 *** 0.00 0.00 00.00 *** ­ RECORD 33 *** 2 *** RECORD 34,36,37 1 22.000 1.600 0.294 0.000 0.000 0.000 0.058 0.058 0.000 0.200 0.294 0.086 1.160 3.0 2 78.000 1.650 0.147 0.000 0.000 0.000 0.029 0.029 0.000 1.000 0.147 0.087 0.174 3.0 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­ 7 YEAR PRCP TSER 0 0 RUNF TSER 0 0 INFL TSER 1 1 ESLS TSER 0 0 1. E3 RFLX TSER 0 0 1. E5 EFLX TSER 0 0 1. E5 RZFX TSER 0 0 1. E5 ­100­ Maximum Reported Application Rate Ohio Corn, Index Reservoir *** PRZM3 Input File for INDEX RESERVOIR, IROHCORN1. inp converted 3/ 30/ 2000 *** *** Modeler: S. Abel *** *** Modified for CARBARYL by Laurence Libelo, 6/ 20/ 00 *** Manning's N values for cornstalk residue, fallow surface, 1 ton/ acre *** *** Cardington silt loam is not one of the benchmark soils *** *** Benchmark soils include: blount; crosby; pewamo; miami; brookston; glynwood *** *** miamian; morley; bennington; and fincastle *** *** IR Spray Drift: Aerial: 0.16; Orchard air blast: 0.063; Ground spray: 0.064 *** *** Application efficiency: 0.95 aerial; 0.99 spray blast and ground spray *** *** PCA for corn = 0.46 *** CARBARYL Location: OH Crop: corn MLRA 111 *** ­ RECORD 3 *** 0.72 0.30 0 15.00 1 3 *** ­ RECORED 4 *** 4 *** ­ RECORD 7 *** 0.37 0.43 0.50 172.8 5.80 3 6.00 600.0 *** ­ RECORD 8 *** 1 *** ­ RECORD 9 *** 1 0.25 90.00 100.00 3 91 85 88 0.00 100.00 *** ­ RECORD 9A *** 1 3 *** ­ RECORD 9B, C, D 0101 1605 1110 0.50 0.25 0.30 0.02 0.02 0.02 *** ­ RECORD 10 *** 36 *** ­ RECORD 11 * 160548 260948 111048 1 160549 260949 111049 1 160550 260950 111050 1 160551 260951 111051 1 160552 260952 111052 1 160553 260953 111053 1 160554 260954 111054 1 160555 260955 111055 1 160556 260956 111056 1 160557 260957 111057 1 ­101­ 160558 260958 111058 1 160559 260959 111059 1 160560 260960 111060 1 160561 260961 111061 1 160562 260962 111062 1 160563 260963 111063 1 160564 260964 111064 1 160565 260965 111065 1 160566 260966 111066 1 160567 260967 111067 1 160568 260968 111068 1 160569 260969 111069 1 160570 260970 111070 1 160571 260971 111071 1 160572 260972 111072 1 160573 260973 111073 1 160574 260974 111074 1 160575 260975 111075 1 160576 260976 111076 1 160577 260977 111077 1 160578 260978 111078 1 160579 260979 111079 1 160580 260980 111080 1 160581 260981 111081 1 160582 260982 111082 1 160583 260983 111083 1 *** ­ RECORD 12 *** Max reported app rate ­ 2 apps @ 1.5 lb A. I./ acre *** Application: aerial Application at max label rate 4 apps @ 2 lb a. i./ acre *** ­ RECORD 13 *** 72 1 0 0 *** ­ RECORD ­ 15 *** Carbaryl Chemical Kd: 3.0 (Silt Loam Soil); ASM T1/ 2 = 12 days; AnSM T1/ 2 = 24 days *** ­ RECORD 16 *** 300448 0 2 0.00 1.68 0.95 0.16 140548 0 2 0.00 1.68 0.95 0.16 300449 0 2 0.00 1.68 0.95 0.16 140549 0 2 0.00 1.68 0.95 0.16 300450 0 2 0.00 1.68 0.95 0.16 140550 0 2 0.00 1.68 0.95 0.16 300451 0 2 0.00 1.68 0.95 0.16 140551 0 2 0.00 1.68 0.95 0.16 300452 0 2 0.00 1.68 0.95 0.16 140552 0 2 0.00 1.68 0.95 0.16 300453 0 2 0.00 1.68 0.95 0.16 140553 0 2 0.00 1.68 0.95 0.16 300454 0 2 0.00 1.68 0.95 0.16 140554 0 2 0.00 1.68 0.95 0.16 ­102­ 300455 0 2 0.00 1.68 0.95 0.16 140555 0 2 0.00 1.68 0.95 0.16 300456 0 2 0.00 1.68 0.95 0.16 140556 0 2 0.00 1.68 0.95 0.16 300457 0 2 0.00 1.68 0.95 0.16 140557 0 2 0.00 1.68 0.95 0.16 300458 0 2 0.00 1.68 0.95 0.16 140558 0 2 0.00 1.68 0.95 0.16 300459 0 2 0.00 1.68 0.95 0.16 140559 0 2 0.00 1.68 0.95 0.16 300460 0 2 0.00 1.68 0.95 0.16 140560 0 2 0.00 1.68 0.95 0.16 300461 0 2 0.00 1.68 0.95 0.16 140561 0 2 0.00 1.68 0.95 0.16 300462 0 2 0.00 1.68 0.95 0.16 140562 0 2 0.00 1.68 0.95 0.16 300463 0 2 0.00 1.68 0.95 0.16 140563 0 2 0.00 1.68 0.95 0.16 300464 0 2 0.00 1.68 0.95 0.16 140564 0 2 0.00 1.68 0.95 0.16 300465 0 2 0.00 1.68 0.95 0.16 140565 0 2 0.00 1.68 0.95 0.16 300466 0 2 0.00 1.68 0.95 0.16 140566 0 2 0.00 1.68 0.95 0.16 300467 0 2 0.00 1.68 0.95 0.16 140567 0 2 0.00 1.68 0.95 0.16 300468 0 2 0.00 1.68 0.95 0.16 140568 0 2 0.00 1.68 0.95 0.16 300469 0 2 0.00 1.68 0.95 0.16 140569 0 2 0.00 1.68 0.95 0.16 300470 0 2 0.00 1.68 0.95 0.16 140570 0 2 0.00 1.68 0.95 0.16 300471 0 2 0.00 1.68 0.95 0.16 140571 0 2 0.00 1.68 0.95 0.16 300472 0 2 0.00 1.68 0.95 0.16 140572 0 2 0.00 1.68 0.95 0.16 300473 0 2 0.00 1.68 0.95 0.16 140573 0 2 0.00 1.68 0.95 0.16 300474 0 2 0.00 1.68 0.95 0.16 140574 0 2 0.00 1.68 0.95 0.16 300475 0 2 0.00 1.68 0.95 0.16 140575 0 2 0.00 1.68 0.95 0.16 300476 0 2 0.00 1.68 0.95 0.16 140576 0 2 0.00 1.68 0.95 0.16 300477 0 2 0.00 1.68 0.95 0.16 140577 0 2 0.00 1.68 0.95 0.16 300478 0 2 0.00 1.68 0.95 0.16 140578 0 2 0.00 1.68 0.95 0.16 300479 0 2 0.00 1.68 0.95 0.16 140579 0 2 0.00 1.68 0.95 0.16 ­103­ 300480 0 2 0.00 1.68 0.95 0.16 140580 0 2 0.00 1.68 0.95 0.16 300481 0 2 0.00 1.68 0.95 0.16 140581 0 2 0.00 1.68 0.95 0.16 300482 0 2 0.00 1.68 0.95 0.16 140582 0 2 0.00 1.68 0.95 0.16 300483 0 2 0.00 1.68 0.95 0.16 140583 0 2 0.00 1.68 0.95 0.16 *** ­ Record 17 *** 0.0 3 0 *** ­ RECORD 18 *** 0.0 0.0 0.00 *** ­ RECORD 19 *** Soil Series: Cardington silt loam; Hydrogic Group C *** ­ RECORD 20 *** 100.00 0 0 0 0 0 0 0 0 0 *** ­ RECORD 26 *** 0.00 0.00 00.00 *** ­ RECORD 33 *** 2 *** RECORD 34,36,37 1 22.000 1.600 0.294 0.000 0.000 0.000 0.058 0.058 0.000 0.200 0.294 0.086 1.160 3.0 2 78.000 1.650 0.147 0.000 0.000 0.000 0.029 0.029 0.000 1.000 0.147 0.087 0.174 3.0 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­ 7 YEAR PRCP TSER 0 0 RUNF TSER 0 0 INFL TSER 1 1 ESLS TSER 0 0 1. E3 RFLX TSER 0 0 1. E5 EFLX TSER 0 0 1. E5 RZFX TSER 0 0 1. E5 ­104­ Maximum Application Rate: Oregon Apples, Index Reservoir *** PRZM 3.1 Input Data File; ORAPPLEX. INP; Modified April 5, 1998 *** *** Modified for Carbaryl by Laurence Libelo, 6/ 21/ 00 *** Modified for Index Res. by Laurence Libelo, 3/ 7/ 01 *** Crops simulated: Apples, Crabapples, and Quince *** *** Location Washington County, Oregon; Meadow/ Orchard Scenario; MLRA: A2 *** *** Manning's N: Assume sparse grass under mature trees (ca. 20 feet) *** *** Temperature data read *** *** This file is for scenario standardization; Reference chemical is Atrazine *** *** See ORAPPLEX. wpd for scenario details *** Carbaryl Cornelius silt loam, 15% slope, Hydrologic Group: C 0.740 0.150 2 17.000 1 3 9.2 10.3 11.8 13.6 15.30 15.3 14.2 12.5 10.9 9.4 8.6 9.1 4 0.43 3.30 1.0 172.8 5.4 2 15.00 464 1 1 0.25 17.0 100.000 3 91 71 71 0.0 600 1 3 0103 0105 0112 0.01 0.01 0.01 0.015 0.015 0.015 36 010448 150548 151248 1 010449 150549 151249 1 010450 150550 151250 1 010451 150551 151251 1 010452 150552 151252 1 010453 150553 151253 1 010454 150554 151254 1 010455 150555 151255 1 010456 150556 151256 1 010457 150557 151257 1 010458 150558 151258 1 010459 150559 151259 1 010460 150560 151260 1 010461 150561 151261 1 010462 150562 151262 1 010463 150563 151263 1 010464 150564 151264 1 010465 150565 151265 1 010466 150566 151266 1 010467 150567 151267 1 ­105­ 010468 150568 151268 1 010469 150569 151269 1 010470 150570 151270 1 010471 150571 151271 1 010472 150572 151272 1 010473 150573 151273 1 010474 150574 151274 1 010475 150575 151275 1 010476 150576 151276 1 010477 150577 151277 1 010478 150578 151278 1 010479 150579 151279 1 010480 150580 151280 1 010481 150581 151281 1 010482 150582 151282 1 010483 150583 151283 1 Aerial Application: 5 apps of 2 lb a. i./ acre (2.2 kg/ ha), Aerial @ 95% eff. w/ 16% drift 180 1 0 0 Chemical Kd: 3.0 (silt Loam soil); AeSM: T1/ 2: 12 days; AnSM: T1/ 2 = 24 days *** Record 16: Application information; set specific to carbaryl *** 100348 0 2 0.00 2.24 0.95 0.16 140348 0 2 0.00 2.24 0.95 0.16 180348 0 2 0.00 2.24 0.95 0.16 220348 0 2 0.00 2.24 0.95 0.16 260348 0 2 0.00 2.24 0.95 0.16 100349 0 2 0.00 2.24 0.95 0.16 140349 0 2 0.00 2.24 0.95 0.16 180349 0 2 0.00 2.24 0.95 0.16 220349 0 2 0.00 2.24 0.95 0.16 260349 0 2 0.00 2.24 0.95 0.16 100350 0 2 0.00 2.24 0.95 0.16 140350 0 2 0.00 2.24 0.95 0.16 180350 0 2 0.00 2.24 0.95 0.16 220350 0 2 0.00 2.24 0.95 0.16 260350 0 2 0.00 2.24 0.95 0.16 100351 0 2 0.00 2.24 0.95 0.16 140351 0 2 0.00 2.24 0.95 0.16 180351 0 2 0.00 2.24 0.95 0.16 220351 0 2 0.00 2.24 0.95 0.16 260351 0 2 0.00 2.24 0.95 0.16 100352 0 2 0.00 2.24 0.95 0.16 140352 0 2 0.00 2.24 0.95 0.16 180352 0 2 0.00 2.24 0.95 0.16 220352 0 2 0.00 2.24 0.95 0.16 260352 0 2 0.00 2.24 0.95 0.16 100353 0 2 0.00 2.24 0.95 0.16 140353 0 2 0.00 2.24 0.95 0.16 ­106­ 180353 0 2 0.00 2.24 0.95 0.16 220353 0 2 0.00 2.24 0.95 0.16 260353 0 2 0.00 2.24 0.95 0.16 100354 0 2 0.00 2.24 0.95 0.16 140354 0 2 0.00 2.24 0.95 0.16 180354 0 2 0.00 2.24 0.95 0.16 220354 0 2 0.00 2.24 0.95 0.16 260354 0 2 0.00 2.24 0.95 0.16 100355 0 2 0.00 2.24 0.95 0.16 140355 0 2 0.00 2.24 0.95 0.16 180355 0 2 0.00 2.24 0.95 0.16 220355 0 2 0.00 2.24 0.95 0.16 260355 0 2 0.00 2.24 0.95 0.16 100356 0 2 0.00 2.24 0.95 0.16 140356 0 2 0.00 2.24 0.95 0.16 180356 0 2 0.00 2.24 0.95 0.16 220356 0 2 0.00 2.24 0.95 0.16 260356 0 2 0.00 2.24 0.95 0.16 100357 0 2 0.00 2.24 0.95 0.16 140357 0 2 0.00 2.24 0.95 0.16 180357 0 2 0.00 2.24 0.95 0.16 220357 0 2 0.00 2.24 0.95 0.16 260357 0 2 0.00 2.24 0.95 0.16 100358 0 2 0.00 2.24 0.95 0.16 140358 0 2 0.00 2.24 0.95 0.16 180358 0 2 0.00 2.24 0.95 0.16 220358 0 2 0.00 2.24 0.95 0.16 260358 0 2 0.00 2.24 0.95 0.16 100359 0 2 0.00 2.24 0.95 0.16 140359 0 2 0.00 2.24 0.95 0.16 180359 0 2 0.00 2.24 0.95 0.16 220359 0 2 0.00 2.24 0.95 0.16 260359 0 2 0.00 2.24 0.95 0.16 100360 0 2 0.00 2.24 0.95 0.16 140360 0 2 0.00 2.24 0.95 0.16 180360 0 2 0.00 2.24 0.95 0.16 220360 0 2 0.00 2.24 0.95 0.16 260360 0 2 0.00 2.24 0.95 0.16 100361 0 2 0.00 2.24 0.95 0.16 140361 0 2 0.00 2.24 0.95 0.16 180361 0 2 0.00 2.24 0.95 0.16 220361 0 2 0.00 2.24 0.95 0.16 260361 0 2 0.00 2.24 0.95 0.16 100362 0 2 0.00 2.24 0.95 0.16 140362 0 2 0.00 2.24 0.95 0.16 180362 0 2 0.00 2.24 0.95 0.16 220362 0 2 0.00 2.24 0.95 0.16 260362 0 2 0.00 2.24 0.95 0.16 100363 0 2 0.00 2.24 0.95 0.16 140363 0 2 0.00 2.24 0.95 0.16 ­107­ 180363 0 2 0.00 2.24 0.95 0.16 220363 0 2 0.00 2.24 0.95 0.16 260363 0 2 0.00 2.24 0.95 0.16 100364 0 2 0.00 2.24 0.95 0.16 140364 0 2 0.00 2.24 0.95 0.16 180364 0 2 0.00 2.24 0.95 0.16 220364 0 2 0.00 2.24 0.95 0.16 260364 0 2 0.00 2.24 0.95 0.16 100365 0 2 0.00 2.24 0.95 0.16 140365 0 2 0.00 2.24 0.95 0.16 180365 0 2 0.00 2.24 0.95 0.16 220365 0 2 0.00 2.24 0.95 0.16 260365 0 2 0.00 2.24 0.95 0.16 100366 0 2 0.00 2.24 0.95 0.16 140366 0 2 0.00 2.24 0.95 0.16 180366 0 2 0.00 2.24 0.95 0.16 220366 0 2 0.00 2.24 0.95 0.16 260366 0 2 0.00 2.24 0.95 0.16 100367 0 2 0.00 2.24 0.95 0.16 140367 0 2 0.00 2.24 0.95 0.16 180367 0 2 0.00 2.24 0.95 0.16 220367 0 2 0.00 2.24 0.95 0.16 260367 0 2 0.00 2.24 0.95 0.16 100368 0 2 0.00 2.24 0.95 0.16 140368 0 2 0.00 2.24 0.95 0.16 180368 0 2 0.00 2.24 0.95 0.16 220368 0 2 0.00 2.24 0.95 0.16 260368 0 2 0.00 2.24 0.95 0.16 100369 0 2 0.00 2.24 0.95 0.16 140369 0 2 0.00 2.24 0.95 0.16 180369 0 2 0.00 2.24 0.95 0.16 220369 0 2 0.00 2.24 0.95 0.16 260369 0 2 0.00 2.24 0.95 0.16 100370 0 2 0.00 2.24 0.95 0.16 140370 0 2 0.00 2.24 0.95 0.16 180370 0 2 0.00 2.24 0.95 0.16 220370 0 2 0.00 2.24 0.95 0.16 260370 0 2 0.00 2.24 0.95 0.16 100371 0 2 0.00 2.24 0.95 0.16 140371 0 2 0.00 2.24 0.95 0.16 180371 0 2 0.00 2.24 0.95 0.16 220371 0 2 0.00 2.24 0.95 0.16 260371 0 2 0.00 2.24 0.95 0.16 100372 0 2 0.00 2.24 0.95 0.16 140372 0 2 0.00 2.24 0.95 0.16 180372 0 2 0.00 2.24 0.95 0.16 220372 0 2 0.00 2.24 0.95 0.16 260372 0 2 0.00 2.24 0.95 0.16 100373 0 2 0.00 2.24 0.95 0.16 140373 0 2 0.00 2.24 0.95 0.16 ­108­ 180373 0 2 0.00 2.24 0.95 0.16 220373 0 2 0.00 2.24 0.95 0.16 260373 0 2 0.00 2.24 0.95 0.16 100374 0 2 0.00 2.24 0.95 0.16 140374 0 2 0.00 2.24 0.95 0.16 180374 0 2 0.00 2.24 0.95 0.16 220374 0 2 0.00 2.24 0.95 0.16 260374 0 2 0.00 2.24 0.95 0.16 100375 0 2 0.00 2.24 0.95 0.16 140375 0 2 0.00 2.24 0.95 0.16 180375 0 2 0.00 2.24 0.95 0.16 220375 0 2 0.00 2.24 0.95 0.16 260375 0 2 0.00 2.24 0.95 0.16 100376 0 2 0.00 2.24 0.95 0.16 140376 0 2 0.00 2.24 0.95 0.16 180376 0 2 0.00 2.24 0.95 0.16 220376 0 2 0.00 2.24 0.95 0.16 260376 0 2 0.00 2.24 0.95 0.16 100377 0 2 0.00 2.24 0.95 0.16 140377 0 2 0.00 2.24 0.95 0.16 180377 0 2 0.00 2.24 0.95 0.16 220377 0 2 0.00 2.24 0.95 0.16 260377 0 2 0.00 2.24 0.95 0.16 100378 0 2 0.00 2.24 0.95 0.16 140378 0 2 0.00 2.24 0.95 0.16 180378 0 2 0.00 2.24 0.95 0.16 220378 0 2 0.00 2.24 0.95 0.16 260378 0 2 0.00 2.24 0.95 0.16 100379 0 2 0.00 2.24 0.95 0.16 140379 0 2 0.00 2.24 0.95 0.16 180379 0 2 0.00 2.24 0.95 0.16 220379 0 2 0.00 2.24 0.95 0.16 260379 0 2 0.00 2.24 0.95 0.16 100380 0 2 0.00 2.24 0.95 0.16 140380 0 2 0.00 2.24 0.95 0.16 180380 0 2 0.00 2.24 0.95 0.16 220380 0 2 0.00 2.24 0.95 0.16 260380 0 2 0.00 2.24 0.95 0.16 100381 0 2 0.00 2.24 0.95 0.16 140381 0 2 0.00 2.24 0.95 0.16 180381 0 2 0.00 2.24 0.95 0.16 220381 0 2 0.00 2.24 0.95 0.16 260381 0 2 0.00 2.24 0.95 0.16 100382 0 2 0.00 2.24 0.95 0.16 140382 0 2 0.00 2.24 0.95 0.16 180382 0 2 0.00 2.24 0.95 0.16 220382 0 2 0.00 2.24 0.95 0.16 260382 0 2 0.00 2.24 0.95 0.16 100383 0 2 0.00 2.24 0.95 0.16 140383 0 2 0.00 2.24 0.95 0.16 ­109­ 180383 0 2 0.00 2.24 0.95 0.16 220383 0 2 0.00 2.24 0.95 0.16 260383 0 2 0.00 2.24 0.95 0.16 *** Record 17: Filtra., disposit. foliar pest. after harvest, and plant uptake *** 0.0 3 0.0 *** Record 18: Foliar dissipation parameters *** 0.0 0.0 0.50 Cornelius silt loam, 15% slope, Hydrologic Group: C 148.0 0 0 0 0 0 0 0 0 0 *** Record 26: Soil volatilization constants *** 0.0 0.0 0.0 *** Record 33 *** 5 *** Record 34 *** 1 15.0 1.30 0.329 0.0 0.0 0.0 *** Record 36: Soil half­ life rate constants; repeat for each horizon *** 0.058 0.058 0.0 *** Record 37: *** 0.1 0.329 0.099 2.30 3.0 *** Record 39: Omitted; parent/ daughter transformation rates *** 2 13.0 1.38 0.338 0.0 0.0 0.0 0.029 0.029 0.0 1.0 0.338 0.108 1.11 3.0 3 15.0 1.58 0.340 0.0 0.0 0.0 0.029 0.029 0.0 1.0 0.340 0.110 0.21 3.0 4 55.0 1.52 0.358 0.0 0.0 0.0 0.029 0.029 0.0 5.0 0.358 0.148 0.145 3.0 5 50.0 1.46 0.202 0.0 0.0 0.0 0.029 0.029 0.0 5.0 0.202 0.142 0.07 3.0 0 YEAR 5 YEAR 5 YEAR 5 1 1 1 ­­­­ 6 YEAR PRCP TSER 0 0 RUNF TSER 0 0 ESLS TSER 0 0 1.0E3 RFLX TSER 0 0 1.0E5 EFLX TSER 0 0 1.0E5 RZFX TSER 0 0 1.0E5 ­110­ Average Application Rate: Oregon Apples, Index Reservoir *** PRZM 3.1 Input Data File; ORAPPLEX. INP; Modified April 5, 1998 *** *** Modified for Carbaryl by Laurence Libelo, 6/ 21/ 00 *** *** Use rate changed to QUA (July 21, 1998 QUA Report) AVERAGE VALUES on 2/ 28/ 01 *** *** Crops simulated: Apples, Crabapples, and Quince *** *** Location Washington County, Oregon; Meadow/ Orchard Scenario; MLRA: A2 *** *** Manning's N: Assume sparse grass under mature trees (ca. 20 feet) *** *** Temperature data read *** *** This file is for scenario standardization; Reference chemical is Atrazine *** *** See ORAPPLEX. wpd for scenario details *** Carbaryl Cornelius silt loam, 15% slope, Hydrologic Group: C 0.740 0.150 2 17.000 1 3 9.2 10.3 11.8 13.6 15.30 15.3 14.2 12.5 10.9 9.4 8.6 9.1 4 0.43 3.30 1.0 10.0 5.4 2 15.00 354.0 1 1 0.25 17.0 100.000 3 91 71 71 0.0 600 1 3 0103 0105 0112 0.01 0.01 0.01 0.015 0.015 0.015 36 010448 150548 151248 1 010449 150549 151249 1 010450 150550 151250 1 010451 150551 151251 1 010452 150552 151252 1 010453 150553 151253 1 010454 150554 151254 1 010455 150555 151255 1 010456 150556 151256 1 010457 150557 151257 1 010458 150558 151258 1 010459 150559 151259 1 010460 150560 151260 1 010461 150561 151261 1 010462 150562 151262 1 010463 150563 151263 1 010464 150564 151264 1 010465 150565 151265 1 010466 150566 151266 1 ­111­ 010467 150567 151267 1 010468 150568 151268 1 010469 150569 151269 1 010470 150570 151270 1 010471 150571 151271 1 010472 150572 151272 1 010473 150573 151273 1 010474 150574 151274 1 010475 150575 151275 1 010476 150576 151276 1 010477 150577 151277 1 010478 150578 151278 1 010479 150579 151279 1 010480 150580 151280 1 010481 150581 151281 1 010482 150582 151282 1 010483 150583 151283 1 Use rate changed to QUA (July 21, 1998 QUA Report) AVERAGE VALUES on 2/ 28/ 01 2 apps@ 1.2 lb/ app *** *** Aerial Application: 5 apps of 2 lb a. i./ acre (3.3 kg/ ha), Aerial @ 95% eff. w/ 16% drift 72 1 0 0 Chemical Kd: 3.0 (silt Loam soil); AeSM: T1/ 2: 12 days; AnSM: T1/ 2 = 24 days *** Record 16: Application information; set specific to carbaryl *** 300448 0 2 0.00 1.34 0.95 0.16 140548 0 2 0.00 1.34 0.95 0.16 300449 0 2 0.00 1.34 0.95 0.16 140549 0 2 0.00 1.34 0.95 0.16 300450 0 2 0.00 1.34 0.95 0.16 140550 0 2 0.00 1.34 0.95 0.16 300451 0 2 0.00 1.34 0.95 0.16 140551 0 2 0.00 1.34 0.95 0.16 300452 0 2 0.00 1.34 0.95 0.16 140552 0 2 0.00 1.34 0.95 0.16 300453 0 2 0.00 1.34 0.95 0.16 140553 0 2 0.00 1.34 0.95 0.16 300454 0 2 0.00 1.34 0.95 0.16 140554 0 2 0.00 1.34 0.95 0.16 300455 0 2 0.00 1.34 0.95 0.16 140555 0 2 0.00 1.34 0.95 0.16 300456 0 2 0.00 1.34 0.95 0.16 140556 0 2 0.00 1.34 0.95 0.16 300457 0 2 0.00 1.34 0.95 0.16 140557 0 2 0.00 1.34 0.95 0.16 300458 0 2 0.00 1.34 0.95 0.16 140558 0 2 0.00 1.34 0.95 0.16 300459 0 2 0.00 1.34 0.95 0.16 140559 0 2 0.00 1.34 0.95 0.16 ­112­ 300460 0 2 0.00 1.34 0.95 0.16 140560 0 2 0.00 1.34 0.95 0.16 300461 0 2 0.00 1.34 0.95 0.16 140561 0 2 0.00 1.34 0.95 0.16 300462 0 2 0.00 1.34 0.95 0.16 140562 0 2 0.00 1.34 0.95 0.16 300463 0 2 0.00 1.34 0.95 0.16 140563 0 2 0.00 1.34 0.95 0.16 300464 0 2 0.00 1.34 0.95 0.16 140564 0 2 0.00 1.34 0.95 0.16 300465 0 2 0.00 1.34 0.95 0.16 140565 0 2 0.00 1.34 0.95 0.16 300466 0 2 0.00 1.34 0.95 0.16 140566 0 2 0.00 1.34 0.95 0.16 300467 0 2 0.00 1.34 0.95 0.16 140567 0 2 0.00 1.34 0.95 0.16 300468 0 2 0.00 1.34 0.95 0.16 140568 0 2 0.00 1.34 0.95 0.16 300469 0 2 0.00 1.34 0.95 0.16 140569 0 2 0.00 1.34 0.95 0.16 300470 0 2 0.00 1.34 0.95 0.16 140570 0 2 0.00 1.34 0.95 0.16 300471 0 2 0.00 1.34 0.95 0.16 140571 0 2 0.00 1.34 0.95 0.16 300472 0 2 0.00 1.34 0.95 0.16 140572 0 2 0.00 1.34 0.95 0.16 300473 0 2 0.00 1.34 0.95 0.16 140573 0 2 0.00 1.34 0.95 0.16 300474 0 2 0.00 1.34 0.95 0.16 140574 0 2 0.00 1.34 0.95 0.16 300475 0 2 0.00 1.34 0.95 0.16 140575 0 2 0.00 1.34 0.95 0.16 300476 0 2 0.00 1.34 0.95 0.16 140576 0 2 0.00 1.34 0.95 0.16 300477 0 2 0.00 1.34 0.95 0.16 140577 0 2 0.00 1.34 0.95 0.16 300478 0 2 0.00 1.34 0.95 0.16 140578 0 2 0.00 1.34 0.95 0.16 300479 0 2 0.00 1.34 0.95 0.16 140579 0 2 0.00 1.34 0.95 0.16 300480 0 2 0.00 1.34 0.95 0.16 140580 0 2 0.00 1.34 0.95 0.16 300481 0 2 0.00 1.34 0.95 0.16 140581 0 2 0.00 1.34 0.95 0.16 300482 0 2 0.00 1.34 0.95 0.16 140582 0 2 0.00 1.34 0.95 0.16 300483 0 2 0.00 1.34 0.95 0.16 140583 0 2 0.00 1.34 0.95 0.16 ­113­ *** Record 17: Filtra., disposit. foliar pest. after harvest, and plant uptake *** 0.0 3 0.0 *** Record 18: Foliar dissipation parameters *** 0.0 0.0 0.50 Cornelius silt loam, 15% slope, Hydrologic Group: C 148.0 0 0 0 0 0 0 0 0 0 *** Record 26: Soil volatilization constants *** 0.0 0.0 0.0 *** Record 33 *** 5 *** Record 34 *** 1 15.0 1.30 0.329 0.0 0.0 0.0 *** Record 36: Soil half­ life rate constants; repeat for each horizon *** 0.058 0.058 0.0 *** Record 37: *** 0.1 0.329 0.099 2.30 3.0 *** Record 39: Omitted; parent/ daughter transformation rates *** 2 13.0 1.38 0.338 0.0 0.0 0.0 0.029 0.029 0.0 1.0 0.338 0.108 1.11 3.0 3 15.0 1.58 0.340 0.0 0.0 0.0 0.029 0.029 0.0 1.0 0.340 0.110 0.21 3.0 4 55.0 1.52 0.358 0.0 0.0 0.0 0.029 0.029 0.0 5.0 0.358 0.148 0.145 3.0 5 50.0 1.46 0.202 0.0 0.0 0.0 0.029 0.029 0.0 5.0 0.202 0.142 0.07 3.0 0 YEAR 5 YEAR 5 YEAR 5 1 1 1 ­­­­ 6 YEAR PRCP TSER 0 0 RUNF TSER 0 0 ESLS TSER 0 0 1.0E3 RFLX TSER 0 0 1.0E5 EFLX TSER 0 0 1.0E5 RZFX TSER 0 0 1.0E5 ­114­ Maximum Reported Application Rate: Oregon Apples, Index Reservoir *** PRZM 3.1 Input Data File; ORAPPLEX. INP; Modified April 5, 1998 *** *** Modified for Carbaryl by Laurence Libelo, 6/ 21/ 00 *** Modified for Index Res. by Laurence Libelo, 3/ 7/ 01 *** Crops simulated: Apples, Crabapples, and Quince *** *** Location Washington County, Oregon; Meadow/ Orchard Scenario; MLRA: A2 *** *** Manning's N: Assume sparse grass under mature trees (ca. 20 feet) *** *** Temperature data read *** *** This file is for scenario standardization; Reference chemical is Atrazine *** *** See ORAPPLEX. wpd for scenario details *** Carbaryl Cornelius silt loam, 15% slope, Hydrologic Group: C 0.740 0.150 2 17.000 1 3 9.2 10.3 11.8 13.6 15.30 15.3 14.2 12.5 10.9 9.4 8.6 9.1 4 0.43 3.30 1.0 172.8 5.4 2 15.00 464 1 1 0.25 17.0 100.000 3 91 71 71 0.0 600 1 3 0103 0105 0112 0.01 0.01 0.01 0.015 0.015 0.015 36 010448 150548 151248 1 010449 150549 151249 1 010450 150550 151250 1 010451 150551 151251 1 010452 150552 151252 1 010453 150553 151253 1 010454 150554 151254 1 010455 150555 151255 1 010456 150556 151256 1 010457 150557 151257 1 010458 150558 151258 1 010459 150559 151259 1 010460 150560 151260 1 010461 150561 151261 1 010462 150562 151262 1 010463 150563 151263 1 010464 150564 151264 1 010465 150565 151265 1 010466 150566 151266 1 010467 150567 151267 1 ­115­ 010468 150568 151268 1 010469 150569 151269 1 010470 150570 151270 1 010471 150571 151271 1 010472 150572 151272 1 010473 150573 151273 1 010474 150574 151274 1 010475 150575 151275 1 010476 150576 151276 1 010477 150577 151277 1 010478 150578 151278 1 010479 150579 151279 1 010480 150580 151280 1 010481 150581 151281 1 010482 150582 151282 1 010483 150583 151283 1 Max reported rate ­ 2 apps @ 1.6 lb A. I./ acre *** Aerial Application: 5 apps of 2 lb a. i./ acre (2.2 kg/ ha), Aerial @ 95% eff. w/ 16% drift 72 1 0 0 Chemical Kd: 3.0 (silt Loam soil); AeSM: T1/ 2: 12 days; AnSM: T1/ 2 = 24 days *** Record 16: Application information; set specific to carbaryl *** 300448 0 2 0.00 1.79 0.95 0.16 140548 0 2 0.00 1.79 0.95 0.16 300449 0 2 0.00 1.79 0.95 0.16 140549 0 2 0.00 1.79 0.95 0.16 300450 0 2 0.00 1.79 0.95 0.16 140550 0 2 0.00 1.79 0.95 0.16 300451 0 2 0.00 1.79 0.95 0.16 140551 0 2 0.00 1.79 0.95 0.16 300452 0 2 0.00 1.79 0.95 0.16 140552 0 2 0.00 1.79 0.95 0.16 300453 0 2 0.00 1.79 0.95 0.16 140553 0 2 0.00 1.79 0.95 0.16 300454 0 2 0.00 1.79 0.95 0.16 140554 0 2 0.00 1.79 0.95 0.16 300455 0 2 0.00 1.79 0.95 0.16 140555 0 2 0.00 1.79 0.95 0.16 300456 0 2 0.00 1.79 0.95 0.16 140556 0 2 0.00 1.79 0.95 0.16 300457 0 2 0.00 1.79 0.95 0.16 140557 0 2 0.00 1.79 0.95 0.16 300458 0 2 0.00 1.79 0.95 0.16 140558 0 2 0.00 1.79 0.95 0.16 300459 0 2 0.00 1.79 0.95 0.16 140559 0 2 0.00 1.79 0.95 0.16 300460 0 2 0.00 1.79 0.95 0.16 140560 0 2 0.00 1.79 0.95 0.16 ­116­ 300461 0 2 0.00 1.79 0.95 0.16 140561 0 2 0.00 1.79 0.95 0.16 300462 0 2 0.00 1.79 0.95 0.16 140562 0 2 0.00 1.79 0.95 0.16 300463 0 2 0.00 1.79 0.95 0.16 140563 0 2 0.00 1.79 0.95 0.16 300464 0 2 0.00 1.79 0.95 0.16 140564 0 2 0.00 1.79 0.95 0.16 300465 0 2 0.00 1.79 0.95 0.16 140565 0 2 0.00 1.79 0.95 0.16 300466 0 2 0.00 1.79 0.95 0.16 140566 0 2 0.00 1.79 0.95 0.16 300467 0 2 0.00 1.79 0.95 0.16 140567 0 2 0.00 1.79 0.95 0.16 300468 0 2 0.00 1.79 0.95 0.16 140568 0 2 0.00 1.79 0.95 0.16 300469 0 2 0.00 1.79 0.95 0.16 140569 0 2 0.00 1.79 0.95 0.16 300470 0 2 0.00 1.79 0.95 0.16 140570 0 2 0.00 1.79 0.95 0.16 300471 0 2 0.00 1.79 0.95 0.16 140571 0 2 0.00 1.79 0.95 0.16 300472 0 2 0.00 1.79 0.95 0.16 140572 0 2 0.00 1.79 0.95 0.16 300473 0 2 0.00 1.79 0.95 0.16 140573 0 2 0.00 1.79 0.95 0.16 300474 0 2 0.00 1.79 0.95 0.16 140574 0 2 0.00 1.79 0.95 0.16 300475 0 2 0.00 1.79 0.95 0.16 140575 0 2 0.00 1.79 0.95 0.16 300476 0 2 0.00 1.79 0.95 0.16 140576 0 2 0.00 1.79 0.95 0.16 300477 0 2 0.00 1.79 0.95 0.16 140577 0 2 0.00 1.79 0.95 0.16 300478 0 2 0.00 1.79 0.95 0.16 140578 0 2 0.00 1.79 0.95 0.16 300479 0 2 0.00 1.79 0.95 0.16 140579 0 2 0.00 1.79 0.95 0.16 300480 0 2 0.00 1.79 0.95 0.16 140580 0 2 0.00 1.79 0.95 0.16 300481 0 2 0.00 1.79 0.95 0.16 140581 0 2 0.00 1.79 0.95 0.16 300482 0 2 0.00 1.79 0.95 0.16 140582 0 2 0.00 1.79 0.95 0.16 300483 0 2 0.00 1.79 0.95 0.16 140583 0 2 0.00 1.79 0.95 0.16 *** Record 17: Filtra., disposit. foliar pest. after harvest, and plant uptake *** 0.0 3 0.0 ­117­ *** Record 18: Foliar dissipation parameters *** 0.0 0.0 0.50 Cornelius silt loam, 15% slope, Hydrologic Group: C 148.0 0 0 0 0 0 0 0 0 0 *** Record 26: Soil volatilization constants *** 0.0 0.0 0.0 *** Record 33 *** 5 *** Record 34 *** 1 15.0 1.30 0.329 0.0 0.0 0.0 *** Record 36: Soil half­ life rate constants; repeat for each horizon *** 0.058 0.058 0.0 *** Record 37: *** 0.1 0.329 0.099 2.30 3.0 *** Record 39: Omitted; parent/ daughter transformation rates *** 2 13.0 1.38 0.338 0.0 0.0 0.0 0.029 0.029 0.0 1.0 0.338 0.108 1.11 3.0 3 15.0 1.58 0.340 0.0 0.0 0.0 0.029 0.029 0.0 1.0 0.340 0.110 0.21 3.0 4 55.0 1.52 0.358 0.0 0.0 0.0 0.029 0.029 0.0 5.0 0.358 0.148 0.145 3.0 5 50.0 1.46 0.202 0.0 0.0 0.0 0.029 0.029 0.0 5.0 0.202 0.142 0.07 3.0 0 YEAR 5 YEAR 5 YEAR 5 1 1 1 ­­­­ 6 YEAR PRCP TSER 0 0 RUNF TSER 0 0 ESLS TSER 0 0 1.0E3 RFLX TSER 0 0 1.0E5 EFLX TSER 0 0 1.0E5 RZFX TSER 0 0 1.0E5 ­118­ Maximum Application Rate: Sugar beets, Index Reservoir *** PRZM2 Version 3.12 Input Data File *** *** MNSUGAR1. inp Index Reservoir Scenario created on 12/ 13/ 99 *** *** Modified for CABRBARYL 6/ 21/ 00 by Laurence Libelo *** *** Bearden soil is a Benchmark soil with ca. 800K mapped acres in MLRA *** *** Sugar beets, conventional tillage *** *** Highest acreage sugarbeet state is MN; highest county in MN is Polk *** *** Manning's N value set to 0.02 for residues applied to fallow surfaces *** *** Application timing information provided by Russ Severson (?), *** University of Minnesota Agricultural Extension Service, Polk County, MN, *** (218) 281­ 8696 *** PCA for sugarbeets not available, use default PCA of 0.87 *** Chemical: Carbaryl Bearden Silty Clay Loam; HYGP: C; MLRA F­ 56, Polk County, Minnesota 0.760 0.500 0 12.00 1 3 4 0.28 0.12 0.50 172.80 3 3.00 600.0 1 1 0.10 20.00 80.00 3 91 82 91 0.00 100.00 1 3 0101 1605 1110 0.43 0.18 0.43 0.02 0.02 0.02 36 160548 061048 161048 1 160549 061049 161049 1 160550 061050 161050 1 160551 061051 161051 1 160552 061052 161052 1 160553 061053 161053 1 160554 061054 161054 1 160555 061055 161055 1 160556 061056 161056 1 160557 061057 161057 1 160558 061058 161058 1 160559 061059 161059 1 160560 061060 161060 1 160561 061061 161061 1 160562 061062 161062 1 160563 061063 161063 1 160564 061064 161064 1 160565 061065 161065 1 ­119­ 160566 061066 161066 1 160567 061067 161067 1 160568 061068 161068 1 160569 061069 161069 1 160570 061070 161070 1 160571 061071 161071 1 160572 061072 161072 1 160573 061073 161073 1 160574 061074 161074 1 160575 061075 161075 1 160576 061076 161076 1 160577 061077 161077 1 160578 061078 161078 1 160579 061079 161079 1 160580 061080 161080 1 160581 061081 161081 1 160582 061082 161082 1 160583 061083 161083 1 Application Schedule: 2 aerial app @ 1.5 lb a. i./ acre (1.68 kg/ ha, 95% app. eff, 16% spray drift 72 1 0 0 Carbaryl: Kd: 3.0; AeSM: T1/ 2 = 12 days; AnSM: T1/ 2 = 24 days 300448 0 2 0.00 1.68 0.95 0.16 140548 0 2 0.00 1.68 0.95 0.16 300449 0 2 0.00 1.68 0.95 0.16 140549 0 2 0.00 1.68 0.95 0.16 300450 0 2 0.00 1.68 0.95 0.16 140550 0 2 0.00 1.68 0.95 0.16 300451 0 2 0.00 1.68 0.95 0.16 140551 0 2 0.00 1.68 0.95 0.16 300452 0 2 0.00 1.68 0.95 0.16 140552 0 2 0.00 1.68 0.95 0.16 300453 0 2 0.00 1.68 0.95 0.16 140553 0 2 0.00 1.68 0.95 0.16 300454 0 2 0.00 1.68 0.95 0.16 140554 0 2 0.00 1.68 0.95 0.16 300455 0 2 0.00 1.68 0.95 0.16 140555 0 2 0.00 1.68 0.95 0.16 300456 0 2 0.00 1.68 0.95 0.16 140556 0 2 0.00 1.68 0.95 0.16 300457 0 2 0.00 1.68 0.95 0.16 140557 0 2 0.00 1.68 0.95 0.16 300458 0 2 0.00 1.68 0.95 0.16 140558 0 2 0.00 1.68 0.95 0.16 300459 0 2 0.00 1.68 0.95 0.16 140559 0 2 0.00 1.68 0.95 0.16 300460 0 2 0.00 1.68 0.95 0.16 140560 0 2 0.00 1.68 0.95 0.16 300461 0 2 0.00 1.68 0.95 0.16 140561 0 2 0.00 1.68 0.95 0.16 ­120­ 300462 0 2 0.00 1.68 0.95 0.16 140562 0 2 0.00 1.68 0.95 0.16 300463 0 2 0.00 1.68 0.95 0.16 140563 0 2 0.00 1.68 0.95 0.16 300464 0 2 0.00 1.68 0.95 0.16 140564 0 2 0.00 1.68 0.95 0.16 300465 0 2 0.00 1.68 0.95 0.16 140565 0 2 0.00 1.68 0.95 0.16 300466 0 2 0.00 1.68 0.95 0.16 140566 0 2 0.00 1.68 0.95 0.16 300467 0 2 0.00 1.68 0.95 0.16 140567 0 2 0.00 1.68 0.95 0.16 300468 0 2 0.00 1.68 0.95 0.16 140568 0 2 0.00 1.68 0.95 0.16 300469 0 2 0.00 1.68 0.95 0.16 140569 0 2 0.00 1.68 0.95 0.16 300470 0 2 0.00 1.68 0.95 0.16 140570 0 2 0.00 1.68 0.95 0.16 300471 0 2 0.00 1.68 0.95 0.16 140571 0 2 0.00 1.68 0.95 0.16 300472 0 2 0.00 1.68 0.95 0.16 140572 0 2 0.00 1.68 0.95 0.16 300473 0 2 0.00 1.68 0.95 0.16 140573 0 2 0.00 1.68 0.95 0.16 300474 0 2 0.00 1.68 0.95 0.16 140574 0 2 0.00 1.68 0.95 0.16 300475 0 2 0.00 1.68 0.95 0.16 140575 0 2 0.00 1.68 0.95 0.16 300476 0 2 0.00 1.68 0.95 0.16 140576 0 2 0.00 1.68 0.95 0.16 300477 0 2 0.00 1.68 0.95 0.16 140577 0 2 0.00 1.68 0.95 0.16 300478 0 2 0.00 1.68 0.95 0.16 140578 0 2 0.00 1.68 0.95 0.16 300479 0 2 0.00 1.68 0.95 0.16 140579 0 2 0.00 1.68 0.95 0.16 300480 0 2 0.00 1.68 0.95 0.16 140580 0 2 0.00 1.68 0.95 0.16 300481 0 2 0.00 1.68 0.95 0.16 140581 0 2 0.00 1.68 0.95 0.16 300482 0 2 0.00 1.68 0.95 0.16 140582 0 2 0.00 1.68 0.95 0.16 300483 0 2 0.00 1.68 0.95 0.16 140583 0 2 0.00 1.68 0.95 0.16 0.0 3 0.00 0.0 0.00 0.50 Bearden Silty Clay Loam; Hydrologic Group C; 100.00 0 0 0 0 0 0 0 0 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 ­121­ 4 1 10.00 1.400 0.377 0.000 0.000 0.58 0.58 0.00 0.10 0.377 0.207 1.160 3.0 2 8.00 1.400 0.377 0.000 0.000 0.029 0.029 0.00 1.00 0.377 0.207 1.160 3.0 3 54.00 1.500 0.292 0.000 0.000 0.029 0.029 0.00 2.00 0.292 0.132 1.160 3.0 4 28.00 1.800 0.285 0.000 0.000 0.029 0.029 0.00 2.0 0.285 0.125 0.174 3.0 0 YEAR 5 YEAR 5 YEAR 5 1 1 1 ­­­­ 1 YEAR *** PRCP TSER 0 0*** RUNF TCUM 0 0 *** ESLS TSER 0 0 1.0E3*** *** RFLX TSER 0 0 1.0E5*** *** EFLX TSER 0 0 1.0E5*** *** RZFX TSER 0 0 1.0E5*** ­122­ Average Application Rate: Sugar beets, Index Reservoir *** PRZM2 Version 3.12 Input Data File *** *** MNSUGAR1. inp Index Reservoir Scenario created on 12/ 13/ 99 *** *** Modified for CABRBARYL 6/ 21/ 00 by Laurence Libelo *** *** Use rate changed to QUA (July 21, 1998 QUA Report) AVERAGE VALUES on 2/ 28/ 01 *** *** Bearden soil is a Benchmark soil with ca. 800K mapped acres in MLRA *** *** Sugar beets, conventional tillage *** *** Highest acreage sugarbeet state is MN; highest county in MN is Polk *** *** Manning's N value set to 0.02 for residues applied to fallow surfaces *** *** Application timing information provided by Russ Severson (?), *** University of Minnesota Agricultural Extension Service, Polk County, MN, *** (218) 281­ 8696 *** PCA for sugarbeets not available, use default PCA of 0.87 *** Chemical: Carbaryl Bearden Silty Clay Loam; HYGP: C; MLRA F­ 56, Polk County, Minnesota 0.760 0.500 0 12.00 1 3 4 0.28 0.12 0.50 172.80 3 3.00 600.0 1 1 0.10 20.00 80.00 3 91 82 91 0.00 100.00 1 3 0101 1605 1110 0.43 0.18 0.43 0.02 0.02 0.02 36 160548 061048 161048 1 160549 061049 161049 1 160550 061050 161050 1 160551 061051 161051 1 160552 061052 161052 1 160553 061053 161053 1 160554 061054 161054 1 160555 061055 161055 1 160556 061056 161056 1 160557 061057 161057 1 160558 061058 161058 1 160559 061059 161059 1 160560 061060 161060 1 160561 061061 161061 1 160562 061062 161062 1 160563 061063 161063 1 160564 061064 161064 1 ­123­ 160565 061065 161065 1 160566 061066 161066 1 160567 061067 161067 1 160568 061068 161068 1 160569 061069 161069 1 160570 061070 161070 1 160571 061071 161071 1 160572 061072 161072 1 160573 061073 161073 1 160574 061074 161074 1 160575 061075 161075 1 160576 061076 161076 1 160577 061077 161077 1 160578 061078 161078 1 160579 061079 161079 1 160580 061080 161080 1 160581 061081 161081 1 160582 061082 161082 1 160583 061083 161083 1 Application Schedule: 1 aerial app @ 1.5 lb a. i./ acre (1.68 kg/ ha, 95% app. eff, 5% spray drift *** *** Application Schedule: 2 aerial app @ 1.5 lb a. i./ acre (1.68 kg/ ha, 95% app. eff, 16% spray drift 36 1 0 0 Carbaryl: Kd: 3.0; AeSM: T1/ 2 = 12 days; AnSM: T1/ 2 = 24 days 300448 0 2 0.00 1.68 0.95 0.16 300449 0 2 0.00 1.68 0.95 0.16 300450 0 2 0.00 1.68 0.95 0.16 300451 0 2 0.00 1.68 0.95 0.16 300452 0 2 0.00 1.68 0.95 0.16 300453 0 2 0.00 1.68 0.95 0.16 300454 0 2 0.00 1.68 0.95 0.16 300455 0 2 0.00 1.68 0.95 0.16 300456 0 2 0.00 1.68 0.95 0.16 300457 0 2 0.00 1.68 0.95 0.16 300458 0 2 0.00 1.68 0.95 0.16 300459 0 2 0.00 1.68 0.95 0.16 300460 0 2 0.00 1.68 0.95 0.16 300461 0 2 0.00 1.68 0.95 0.16 300462 0 2 0.00 1.68 0.95 0.16 300463 0 2 0.00 1.68 0.95 0.16 300464 0 2 0.00 1.68 0.95 0.16 300465 0 2 0.00 1.68 0.95 0.16 300466 0 2 0.00 1.68 0.95 0.16 300467 0 2 0.00 1.68 0.95 0.16 300468 0 2 0.00 1.68 0.95 0.16 300469 0 2 0.00 1.68 0.95 0.16 300470 0 2 0.00 1.68 0.95 0.16 300471 0 2 0.00 1.68 0.95 0.16 300472 0 2 0.00 1.68 0.95 0.16 ­124­ 300473 0 2 0.00 1.68 0.95 0.16 300474 0 2 0.00 1.68 0.95 0.16 300475 0 2 0.00 1.68 0.95 0.16 300476 0 2 0.00 1.68 0.95 0.16 300477 0 2 0.00 1.68 0.95 0.16 300478 0 2 0.00 1.68 0.95 0.16 300479 0 2 0.00 1.68 0.95 0.16 300480 0 2 0.00 1.68 0.95 0.16 300481 0 2 0.00 1.68 0.95 0.16 300482 0 2 0.00 1.68 0.95 0.16 300483 0 2 0.00 1.68 0.95 0.16 0.0 3 0.00 0.0 0.00 0.50 Bearden Silty Clay Loam; Hydrologic Group C; 100.00 0 0 0 0 0 0 0 0 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4 1 10.00 1.400 0.377 0.000 0.000 0.58 0.58 0.00 0.10 0.377 0.207 1.160 3.0 2 8.00 1.400 0.377 0.000 0.000 0.029 0.029 0.00 1.00 0.377 0.207 1.160 3.0 3 54.00 1.500 0.292 0.000 0.000 0.029 0.029 0.00 2.00 0.292 0.132 1.160 3.0 4 28.00 1.800 0.285 0.000 0.000 0.029 0.029 0.00 2.0 0.285 0.125 0.174 3.0 0 YEAR 5 YEAR 5 YEAR 5 1 1 1 ­­­­ 1 YEAR *** PRCP TSER 0 0*** RUNF TCUM 0 0 *** ESLS TSER 0 0 1.0E3*** *** RFLX TSER 0 0 1.0E5*** *** EFLX TSER 0 0 1.0E5*** *** RZFX TSER 0 0 1.0E5*** ­125­ Maximum Reported Application Rate: Sugar beets, Index Reservoir *** PRZM2 Version 3.12 Input Data File *** *** MNSUGAR1. inp Index Reservoir Scenario created on 12/ 13/ 99 *** *** Modified for CABRBARYL 6/ 21/ 00 by Laurence Libelo *** *** Use rate changed to QUA (July 21, 1998 QUA Report) AVERAGE VALUES on 2/ 28/ 01 *** *** Bearden soil is a Benchmark soil with ca. 800K mapped acres in MLRA *** *** Sugar beets, conventional tillage *** *** Highest acreage sugarbeet state is MN; highest county in MN is Polk *** *** Manning's N value set to 0.02 for residues applied to fallow surfaces *** *** Application timing information provided by Russ Severson (?), *** University of Minnesota Agricultural Extension Service, Polk County, MN, *** (218) 281­ 8696 *** PCA for sugarbeets not available, use default PCA of 0.87 *** Chemical: Carbaryl Bearden Silty Clay Loam; HYGP: C; MLRA F­ 56, Polk County, Minnesota 0.760 0.500 0 12.00 1 3 4 0.28 0.12 0.50 172.80 3 3.00 600.0 1 1 0.10 20.00 80.00 3 91 82 91 0.00 100.00 1 3 0101 1605 1110 0.43 0.18 0.43 0.02 0.02 0.02 36 160548 061048 161048 1 160549 061049 161049 1 160550 061050 161050 1 160551 061051 161051 1 160552 061052 161052 1 160553 061053 161053 1 160554 061054 161054 1 160555 061055 161055 1 160556 061056 161056 1 160557 061057 161057 1 160558 061058 161058 1 160559 061059 161059 1 160560 061060 161060 1 160561 061061 161061 1 160562 061062 161062 1 160563 061063 161063 1 160564 061064 161064 1 160565 061065 161065 1 ­126­ 160566 061066 161066 1 160567 061067 161067 1 160568 061068 161068 1 160569 061069 161069 1 160570 061070 161070 1 160571 061071 161071 1 160572 061072 161072 1 160573 061073 161073 1 160574 061074 161074 1 160575 061075 161075 1 160576 061076 161076 1 160577 061077 161077 1 160578 061078 161078 1 160579 061079 161079 1 160580 061080 161080 1 160581 061081 161081 1 160582 061082 161082 1 160583 061083 161083 1 Maximum raported application rate: 1 app @ 1.2 lb A. I./ acre *** Application Schedule: 2 aerial app @ 1.5 lb a. i./ acre (1.68 kg/ ha, 95% app. eff, 16% spray drift 36 1 0 0 Carbaryl: Kd: 3.0; AeSM: T1/ 2 = 12 days; AnSM: T1/ 2 = 24 days 300448 0 2 0.00 1.34 0.95 0.16 300449 0 2 0.00 1.34 0.95 0.16 300450 0 2 0.00 1.34 0.95 0.16 300451 0 2 0.00 1.34 0.95 0.16 300452 0 2 0.00 1.34 0.95 0.16 300453 0 2 0.00 1.34 0.95 0.16 300454 0 2 0.00 1.34 0.95 0.16 300455 0 2 0.00 1.34 0.95 0.16 300456 0 2 0.00 1.34 0.95 0.16 300457 0 2 0.00 1.34 0.95 0.16 300458 0 2 0.00 1.34 0.95 0.16 300459 0 2 0.00 1.34 0.95 0.16 300460 0 2 0.00 1.34 0.95 0.16 300461 0 2 0.00 1.34 0.95 0.16 300462 0 2 0.00 1.34 0.95 0.16 300463 0 2 0.00 1.34 0.95 0.16 300464 0 2 0.00 1.34 0.95 0.16 300465 0 2 0.00 1.34 0.95 0.16 300466 0 2 0.00 1.34 0.95 0.16 300467 0 2 0.00 1.34 0.95 0.16 300468 0 2 0.00 1.34 0.95 0.16 300469 0 2 0.00 1.34 0.95 0.16 300470 0 2 0.00 1.34 0.95 0.16 300471 0 2 0.00 1.34 0.95 0.16 300472 0 2 0.00 1.34 0.95 0.16 300473 0 2 0.00 1.34 0.95 0.16 300474 0 2 0.00 1.34 0.95 0.16 300475 0 2 0.00 1.34 0.95 0.16 ­127­ 300476 0 2 0.00 1.34 0.95 0.16 300477 0 2 0.00 1.34 0.95 0.16 300478 0 2 0.00 1.34 0.95 0.16 300479 0 2 0.00 1.34 0.95 0.16 300480 0 2 0.00 1.34 0.95 0.16 300481 0 2 0.00 1.34 0.95 0.16 300482 0 2 0.00 1.34 0.95 0.16 300483 0 2 0.00 1.34 0.95 0.16 0.0 3 0.00 0.0 0.00 0.50 Bearden Silty Clay Loam; Hydrologic Group C; 100.00 0 0 0 0 0 0 0 0 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4 1 10.00 1.400 0.377 0.000 0.000 0.58 0.58 0.00 0.10 0.377 0.207 1.160 3.0 2 8.00 1.400 0.377 0.000 0.000 0.029 0.029 0.00 1.00 0.377 0.207 1.160 3.0 3 54.00 1.500 0.292 0.000 0.000 0.029 0.029 0.00 2.00 0.292 0.132 1.160 3.0 4 28.00 1.800 0.285 0.000 0.000 0.029 0.029 0.00 2.0 0.285 0.125 0.174 3.0 0 YEAR 5 YEAR 5 YEAR 5 1 1 1 ­­­­ 1 YEAR *** PRCP TSER 0 0*** RUNF TCUM 0 0 *** ESLS TSER 0 0 1.0E3*** *** RFLX TSER 0 0 1.0E5*** *** EFLX TSER 0 0 1.0E5*** *** RZFX TSER 0 0 1.0E5*** ­128­ Maximum Application Rate: Florida Citrus, Index Reservoir PRZM3 Input File, flcit. inp (Jan 28 2000) *** original file source unknown *** *** Source of crop and soil data unknown *** *** modified for carbaryl by Laurence Libelo, 6/ 21/ 00 *** Location: Osceola County, FL.; Crop: citrus; MLRA 156A 0.77 0.15 0 25.00 1 1 4 0.10 0.13 1.00 172.8 3 1.00 600.0 1 1 0.10 100.00 80.00 3 94 84 89 0.00 100.00 1 3 0101 21 9 2209 0.10 0.10 0.10 .023 .023 .023 36 110548 170748 10848 1 110549 170749 10849 1 110550 170750 10850 1 110551 170751 10851 1 110552 170752 10852 1 110553 170753 10853 1 110554 170754 10854 1 110555 170755 10855 1 110556 170756 10856 1 110557 170757 10857 1 110558 170758 10858 1 110559 170759 10859 1 110560 170760 10860 1 110561 170761 10861 1 110562 170762 10862 1 110563 170763 10863 1 110564 170764 10864 1 110565 170765 10865 1 110566 170766 10866 1 110567 170767 10867 1 110568 170768 10868 1 110569 170769 10869 1 110570 170770 10870 1 110571 170771 10871 1 110572 170772 10872 1 110573 170773 10873 1 110574 170774 10874 1 110575 170775 10875 1 110576 170776 10876 1 110577 170777 10877 1 110578 170778 10878 1 110579 170779 10879 1 110580 170780 10880 1 ­129­ 110581 170781 10881 1 110582 170782 10882 1 110583 170783 10883 1 Application: 4 aerial appls @ 5 lb a. i./ ac/ year (5.6 kg/ ha) @95% eff, w/ 16% drift 144 1 0 0 CARBARYL on FL Cirtus 300448 0 2 0.00 5.60 0.95 0.16 140548 0 2 0.00 5.60 0.95 0.16 280548 0 2 0.00 5.60 0.95 0.16 110648 0 2 0.00 5.60 0.95 0.16 300449 0 2 0.00 5.60 0.95 0.16 140549 0 2 0.00 5.60 0.95 0.16 280549 0 2 0.00 5.60 0.95 0.16 110649 0 2 0.00 5.60 0.95 0.16 300450 0 2 0.00 5.60 0.95 0.16 140550 0 2 0.00 5.60 0.95 0.16 280550 0 2 0.00 5.60 0.95 0.16 110650 0 2 0.00 5.60 0.95 0.16 300451 0 2 0.00 5.60 0.95 0.16 140551 0 2 0.00 5.60 0.95 0.16 280551 0 2 0.00 5.60 0.95 0.16 110651 0 2 0.00 5.60 0.95 0.16 300452 0 2 0.00 5.60 0.95 0.16 140552 0 2 0.00 5.60 0.95 0.16 280552 0 2 0.00 5.60 0.95 0.16 110652 0 2 0.00 5.60 0.95 0.16 300453 0 2 0.00 5.60 0.95 0.16 140553 0 2 0.00 5.60 0.95 0.16 280553 0 2 0.00 5.60 0.95 0.16 110653 0 2 0.00 5.60 0.95 0.16 300454 0 2 0.00 5.60 0.95 0.16 140554 0 2 0.00 5.60 0.95 0.16 280554 0 2 0.00 5.60 0.95 0.16 110654 0 2 0.00 5.60 0.95 0.16 300455 0 2 0.00 5.60 0.95 0.16 140555 0 2 0.00 5.60 0.95 0.16 280555 0 2 0.00 5.60 0.95 0.16 110655 0 2 0.00 5.60 0.95 0.16 300456 0 2 0.00 5.60 0.95 0.16 140556 0 2 0.00 5.60 0.95 0.16 280556 0 2 0.00 5.60 0.95 0.16 110656 0 2 0.00 5.60 0.95 0.16 300457 0 2 0.00 5.60 0.95 0.16 140557 0 2 0.00 5.60 0.95 0.16 280557 0 2 0.00 5.60 0.95 0.16 110657 0 2 0.00 5.60 0.95 0.16 300458 0 2 0.00 5.60 0.95 0.16 140558 0 2 0.00 5.60 0.95 0.16 280558 0 2 0.00 5.60 0.95 0.16 110658 0 2 0.00 5.60 0.95 0.16 ­130­ 300459 0 2 0.00 5.60 0.95 0.16 140559 0 2 0.00 5.60 0.95 0.16 280559 0 2 0.00 5.60 0.95 0.16 110659 0 2 0.00 5.60 0.95 0.16 300460 0 2 0.00 5.60 0.95 0.16 140560 0 2 0.00 5.60 0.95 0.16 280560 0 2 0.00 5.60 0.95 0.16 110660 0 2 0.00 5.60 0.95 0.16 300461 0 2 0.00 5.60 0.95 0.16 140561 0 2 0.00 5.60 0.95 0.16 280561 0 2 0.00 5.60 0.95 0.16 110661 0 2 0.00 5.60 0.95 0.16 300462 0 2 0.00 5.60 0.95 0.16 140562 0 2 0.00 5.60 0.95 0.16 280562 0 2 0.00 5.60 0.95 0.16 110662 0 2 0.00 5.60 0.95 0.16 300463 0 2 0.00 5.60 0.95 0.16 140563 0 2 0.00 5.60 0.95 0.16 280563 0 2 0.00 5.60 0.95 0.16 110663 0 2 0.00 5.60 0.95 0.16 300464 0 2 0.00 5.60 0.95 0.16 140564 0 2 0.00 5.60 0.95 0.16 280564 0 2 0.00 5.60 0.95 0.16 110664 0 2 0.00 5.60 0.95 0.16 300465 0 2 0.00 5.60 0.95 0.16 140565 0 2 0.00 5.60 0.95 0.16 280565 0 2 0.00 5.60 0.95 0.16 110665 0 2 0.00 5.60 0.95 0.16 300466 0 2 0.00 5.60 0.95 0.16 140566 0 2 0.00 5.60 0.95 0.16 280566 0 2 0.00 5.60 0.95 0.16 110666 0 2 0.00 5.60 0.95 0.16 300467 0 2 0.00 5.60 0.95 0.16 140567 0 2 0.00 5.60 0.95 0.16 280567 0 2 0.00 5.60 0.95 0.16 110667 0 2 0.00 5.60 0.95 0.16 300468 0 2 0.00 5.60 0.95 0.16 140568 0 2 0.00 5.60 0.95 0.16 280568 0 2 0.00 5.60 0.95 0.16 110668 0 2 0.00 5.60 0.95 0.16 300469 0 2 0.00 5.60 0.95 0.16 140569 0 2 0.00 5.60 0.95 0.16 280569 0 2 0.00 5.60 0.95 0.16 110669 0 2 0.00 5.60 0.95 0.16 300470 0 2 0.00 5.60 0.95 0.16 140570 0 2 0.00 5.60 0.95 0.16 280570 0 2 0.00 5.60 0.95 0.16 110670 0 2 0.00 5.60 0.95 0.16 300471 0 2 0.00 5.60 0.95 0.16 140571 0 2 0.00 5.60 0.95 0.16 280571 0 2 0.00 5.60 0.95 0.16 ­131­ 110671 0 2 0.00 5.60 0.95 0.16 300472 0 2 0.00 5.60 0.95 0.16 140572 0 2 0.00 5.60 0.95 0.16 280572 0 2 0.00 5.60 0.95 0.16 110672 0 2 0.00 5.60 0.95 0.16 300473 0 2 0.00 5.60 0.95 0.16 140573 0 2 0.00 5.60 0.95 0.16 280573 0 2 0.00 5.60 0.95 0.16 110673 0 2 0.00 5.60 0.95 0.16 300474 0 2 0.00 5.60 0.95 0.16 140574 0 2 0.00 5.60 0.95 0.16 280574 0 2 0.00 5.60 0.95 0.16 110674 0 2 0.00 5.60 0.95 0.16 300475 0 2 0.00 5.60 0.95 0.16 140575 0 2 0.00 5.60 0.95 0.16 280575 0 2 0.00 5.60 0.95 0.16 110675 0 2 0.00 5.60 0.95 0.16 300476 0 2 0.00 5.60 0.95 0.16 140576 0 2 0.00 5.60 0.95 0.16 280576 0 2 0.00 5.60 0.95 0.16 110676 0 2 0.00 5.60 0.95 0.16 300477 0 2 0.00 5.60 0.95 0.16 140577 0 2 0.00 5.60 0.95 0.16 280577 0 2 0.00 5.60 0.95 0.16 110677 0 2 0.00 5.60 0.95 0.16 300478 0 2 0.00 5.60 0.95 0.16 140578 0 2 0.00 5.60 0.95 0.16 280578 0 2 0.00 5.60 0.95 0.16 110678 0 2 0.00 5.60 0.95 0.16 300479 0 2 0.00 5.60 0.95 0.16 140579 0 2 0.00 5.60 0.95 0.16 280579 0 2 0.00 5.60 0.95 0.16 110679 0 2 0.00 5.60 0.95 0.16 300480 0 2 0.00 5.60 0.95 0.16 140580 0 2 0.00 5.60 0.95 0.16 280580 0 2 0.00 5.60 0.95 0.16 110680 0 2 0.00 5.60 0.95 0.16 300481 0 2 0.00 5.60 0.95 0.16 140581 0 2 0.00 5.60 0.95 0.16 280581 0 2 0.00 5.60 0.95 0.16 110681 0 2 0.00 5.60 0.95 0.16 300482 0 2 0.00 5.60 0.95 0.16 140582 0 2 0.00 5.60 0.95 0.16 280582 0 2 0.00 5.60 0.95 0.16 110682 0 2 0.00 5.60 0.95 0.16 300483 0 2 0.00 5.60 0.95 0.16 140583 0 2 0.00 5.60 0.95 0.16 280583 0 2 0.00 5.60 0.95 0.16 110683 0 2 0.00 5.60 0.95 0.16 0. 1 ­132­ 0.00 0.000 0.50 Soil Series: Adamsville sand; Hydrogic Group C *** Kd for sandy loam = 1.7 100.00 0 0 0 0 0 0 0 0 0 00.0 0.00 00.00 3 1 10.000 1.440 0.086 0.000 0.000 0.000 .058 .058 0.000 0.100 0.086 0.036 0.580 1.7 2 10.000 1.440 0.086 0.000 0.000 0.000 .029 .029 0.000 1.000 0.086 0.036 0.580 1.7 3 80.000 1.580 0.030 0.000 0.000 0.000 .029 .029 0.000 5.000 0.030 0.023 0.116 1.7 0 WATR YEAR 10 PEST YEAR 10 CONC YEAR 10 1 6 11 ­­­­ 1 DAY RUNF TSER 0 0 1. E0 ­133­ Average Application Rate: Florida Citrus, Index Reservoir PRZM3 Input File, flcit. inp (Jan 28 2000) *** original file source unknown *** *** Source of crop and soil data unknown *** *** modified for carbaryl by Laurence Libelo, 6/ 21/ 00 *** Location: Osceola County, FL.; Crop: citrus; MLRA 156A 0.77 0.15 0 25.00 1 1 4 0.10 0.13 1.00 172.8 3 1.00 600.0 1 1 0.10 100.00 80.00 3 94 84 89 0.00 100.00 1 3 0101 21 9 2209 0.10 0.10 0.10 .023 .023 .023 36 110548 170748 10848 1 110549 170749 10849 1 110550 170750 10850 1 110551 170751 10851 1 110552 170752 10852 1 110553 170753 10853 1 110554 170754 10854 1 110555 170755 10855 1 110556 170756 10856 1 110557 170757 10857 1 110558 170758 10858 1 110559 170759 10859 1 110560 170760 10860 1 110561 170761 10861 1 110562 170762 10862 1 110563 170763 10863 1 110564 170764 10864 1 110565 170765 10865 1 110566 170766 10866 1 110567 170767 10867 1 110568 170768 10868 1 110569 170769 10869 1 110570 170770 10870 1 110571 170771 10871 1 110572 170772 10872 1 110573 170773 10873 1 110574 170774 10874 1 110575 170775 10875 1 110576 170776 10876 1 110577 170777 10877 1 110578 170778 10878 1 110579 170779 10879 1 110580 170780 10880 1 ­134­ 110581 170781 10881 1 110582 170782 10882 1 110583 170783 10883 1 Application = average ­ 2 aps @ 3.4 lb A. I./ acre *** Application: 4 aerial appls @ 5 lb a. i./ ac/ year (5.6 kg/ ha) @95% eff, w/ 16% drift 72 1 0 0 CARBARYL on FL Cirtus 300448 0 2 0.00 3.81 0.95 0.16 170548 0 2 0.00 3.81 0.95 0.16 300449 0 2 0.00 3.81 0.95 0.16 170549 0 2 0.00 3.81 0.95 0.16 300450 0 2 0.00 3.81 0.95 0.16 170550 0 2 0.00 3.81 0.95 0.16 300451 0 2 0.00 3.81 0.95 0.16 170551 0 2 0.00 3.81 0.95 0.16 300452 0 2 0.00 3.81 0.95 0.16 170552 0 2 0.00 3.81 0.95 0.16 300453 0 2 0.00 3.81 0.95 0.16 170553 0 2 0.00 3.81 0.95 0.16 300454 0 2 0.00 3.81 0.95 0.16 170554 0 2 0.00 3.81 0.95 0.16 300455 0 2 0.00 3.81 0.95 0.16 170555 0 2 0.00 3.81 0.95 0.16 300456 0 2 0.00 3.81 0.95 0.16 170556 0 2 0.00 3.81 0.95 0.16 300457 0 2 0.00 3.81 0.95 0.16 170557 0 2 0.00 3.81 0.95 0.16 300458 0 2 0.00 3.81 0.95 0.16 170558 0 2 0.00 3.81 0.95 0.16 300459 0 2 0.00 3.81 0.95 0.16 170559 0 2 0.00 3.81 0.95 0.16 300460 0 2 0.00 3.81 0.95 0.16 170560 0 2 0.00 3.81 0.95 0.16 300461 0 2 0.00 3.81 0.95 0.16 170561 0 2 0.00 3.81 0.95 0.16 300462 0 2 0.00 3.81 0.95 0.16 170562 0 2 0.00 3.81 0.95 0.16 300463 0 2 0.00 3.81 0.95 0.16 170563 0 2 0.00 3.81 0.95 0.16 300464 0 2 0.00 3.81 0.95 0.16 170564 0 2 0.00 3.81 0.95 0.16 300465 0 2 0.00 3.81 0.95 0.16 170565 0 2 0.00 3.81 0.95 0.16 300466 0 2 0.00 3.81 0.95 0.16 170566 0 2 0.00 3.81 0.95 0.16 300467 0 2 0.00 3.81 0.95 0.16 170567 0 2 0.00 3.81 0.95 0.16 300468 0 2 0.00 3.81 0.95 0.16 170568 0 2 0.00 3.81 0.95 0.16 300469 0 2 0.00 3.81 0.95 0.16 ­135­ 170569 0 2 0.00 3.81 0.95 0.16 300470 0 2 0.00 3.81 0.95 0.16 170570 0 2 0.00 3.81 0.95 0.16 300471 0 2 0.00 3.81 0.95 0.16 170571 0 2 0.00 3.81 0.95 0.16 300472 0 2 0.00 3.81 0.95 0.16 170572 0 2 0.00 3.81 0.95 0.16 300473 0 2 0.00 3.81 0.95 0.16 170573 0 2 0.00 3.81 0.95 0.16 300474 0 2 0.00 3.81 0.95 0.16 170574 0 2 0.00 3.81 0.95 0.16 300475 0 2 0.00 3.81 0.95 0.16 170575 0 2 0.00 3.81 0.95 0.16 300476 0 2 0.00 3.81 0.95 0.16 170576 0 2 0.00 3.81 0.95 0.16 300477 0 2 0.00 3.81 0.95 0.16 170577 0 2 0.00 3.81 0.95 0.16 300478 0 2 0.00 3.81 0.95 0.16 170578 0 2 0.00 3.81 0.95 0.16 300479 0 2 0.00 3.81 0.95 0.16 170579 0 2 0.00 3.81 0.95 0.16 300480 0 2 0.00 3.81 0.95 0.16 170580 0 2 0.00 3.81 0.95 0.16 300481 0 2 0.00 3.81 0.95 0.16 170581 0 2 0.00 3.81 0.95 0.16 300482 0 2 0.00 3.81 0.95 0.16 170582 0 2 0.00 3.81 0.95 0.16 300483 0 2 0.00 3.81 0.95 0.16 170583 0 2 0.00 3.81 0.95 0.16 0. 1 0.00 0.000 0.50 Soil Series: Adamsville sand; Hydrogic Group C *** Kd for sandy loam = 1.7 100.00 0 0 0 0 0 0 0 0 0 00.0 0.00 00.00 3 1 10.000 1.440 0.086 0.000 0.000 0.000 .058 .058 0.000 0.100 0.086 0.036 0.580 1.7 2 10.000 1.440 0.086 0.000 0.000 0.000 .029 .029 0.000 1.000 0.086 0.036 0.580 1.7 3 80.000 1.580 0.030 0.000 0.000 0.000 .029 .029 0.000 5.000 0.030 0.023 0.116 1.7 0 WATR YEAR 10 PEST YEAR 10 CONC YEAR 10 1 6 11 ­­­­­ ­136­ 1 DAY RUNF TSER 0 0 1. E0 ­137­ Maximum Reported Application Rate: Florida Citrus, Index Reservoir PRZM3 Input File, flcit. inp (Jan 28 2000) *** original file source unknown *** *** Source of crop and soil data unknown *** *** modified for carbaryl by Laurence Libelo, 6/ 21/ 00 *** Location: Osceola County, FL.; Crop: citrus; MLRA 156A 0.77 0.15 0 25.00 1 1 4 0.10 0.13 1.00 172.8 3 1.00 600.0 1 1 0.10 100.00 80.00 3 94 84 89 0.00 100.00 1 3 0101 21 9 2209 0.10 0.10 0.10 .023 .023 .023 36 110548 170748 10848 1 110549 170749 10849 1 110550 170750 10850 1 110551 170751 10851 1 110552 170752 10852 1 110553 170753 10853 1 110554 170754 10854 1 110555 170755 10855 1 110556 170756 10856 1 110557 170757 10857 1 110558 170758 10858 1 110559 170759 10859 1 110560 170760 10860 1 110561 170761 10861 1 110562 170762 10862 1 110563 170763 10863 1 110564 170764 10864 1 110565 170765 10865 1 110566 170766 10866 1 110567 170767 10867 1 110568 170768 10868 1 110569 170769 10869 1 110570 170770 10870 1 110571 170771 10871 1 110572 170772 10872 1 110573 170773 10873 1 110574 170774 10874 1 110575 170775 10875 1 110576 170776 10876 1 110577 170777 10877 1 110578 170778 10878 1 110579 170779 10879 1 ­138­ 110580 170780 10880 1 110581 170781 10881 1 110582 170782 10882 1 110583 170783 10883 1 Application = maximum reported 3 aps @ 4.26 lb A. I./ acre *** Application: 4 aerial appls @ 5 lb a. i./ ac/ year (5.6 kg/ ha) @95% eff, w/ 16% drift 108 1 0 0 CARBARYL on FL Cirtus 300448 0 2 0.00 4.77 0.95 0.16 140548 0 2 0.00 4.77 0.95 0.16 280548 0 2 0.00 4.77 0.95 0.16 300449 0 2 0.00 4.77 0.95 0.16 140549 0 2 0.00 4.77 0.95 0.16 280549 0 2 0.00 4.77 0.95 0.16 300450 0 2 0.00 4.77 0.95 0.16 140550 0 2 0.00 4.77 0.95 0.16 280550 0 2 0.00 4.77 0.95 0.16 300451 0 2 0.00 4.77 0.95 0.16 140551 0 2 0.00 4.77 0.95 0.16 280551 0 2 0.00 4.77 0.95 0.16 300452 0 2 0.00 4.77 0.95 0.16 140552 0 2 0.00 4.77 0.95 0.16 280552 0 2 0.00 4.77 0.95 0.16 300453 0 2 0.00 4.77 0.95 0.16 140553 0 2 0.00 4.77 0.95 0.16 280553 0 2 0.00 4.77 0.95 0.16 300454 0 2 0.00 4.77 0.95 0.16 140554 0 2 0.00 4.77 0.95 0.16 280554 0 2 0.00 4.77 0.95 0.16 300455 0 2 0.00 4.77 0.95 0.16 140555 0 2 0.00 4.77 0.95 0.16 280555 0 2 0.00 4.77 0.95 0.16 300456 0 2 0.00 4.77 0.95 0.16 140556 0 2 0.00 4.77 0.95 0.16 280556 0 2 0.00 4.77 0.95 0.16 300457 0 2 0.00 4.77 0.95 0.16 140557 0 2 0.00 4.77 0.95 0.16 280557 0 2 0.00 4.77 0.95 0.16 300458 0 2 0.00 4.77 0.95 0.16 140558 0 2 0.00 4.77 0.95 0.16 280558 0 2 0.00 4.77 0.95 0.16 300459 0 2 0.00 4.77 0.95 0.16 140559 0 2 0.00 4.77 0.95 0.16 280559 0 2 0.00 4.77 0.95 0.16 300460 0 2 0.00 4.77 0.95 0.16 140560 0 2 0.00 4.77 0.95 0.16 280560 0 2 0.00 4.77 0.95 0.16 300461 0 2 0.00 4.77 0.95 0.16 140561 0 2 0.00 4.77 0.95 0.16 280561 0 2 0.00 4.77 0.95 0.16 ­139­ 300462 0 2 0.00 4.77 0.95 0.16 140562 0 2 0.00 4.77 0.95 0.16 280562 0 2 0.00 4.77 0.95 0.16 300463 0 2 0.00 4.77 0.95 0.16 140563 0 2 0.00 4.77 0.95 0.16 280563 0 2 0.00 4.77 0.95 0.16 300464 0 2 0.00 4.77 0.95 0.16 140564 0 2 0.00 4.77 0.95 0.16 280564 0 2 0.00 4.77 0.95 0.16 300465 0 2 0.00 4.77 0.95 0.16 140565 0 2 0.00 4.77 0.95 0.16 280565 0 2 0.00 4.77 0.95 0.16 300466 0 2 0.00 4.77 0.95 0.16 140566 0 2 0.00 4.77 0.95 0.16 280566 0 2 0.00 4.77 0.95 0.16 300467 0 2 0.00 4.77 0.95 0.16 140567 0 2 0.00 4.77 0.95 0.16 280567 0 2 0.00 4.77 0.95 0.16 300468 0 2 0.00 4.77 0.95 0.16 140568 0 2 0.00 4.77 0.95 0.16 280568 0 2 0.00 4.77 0.95 0.16 300469 0 2 0.00 4.77 0.95 0.16 140569 0 2 0.00 4.77 0.95 0.16 280569 0 2 0.00 4.77 0.95 0.16 300470 0 2 0.00 4.77 0.95 0.16 140570 0 2 0.00 4.77 0.95 0.16 280570 0 2 0.00 4.77 0.95 0.16 300471 0 2 0.00 4.77 0.95 0.16 140571 0 2 0.00 4.77 0.95 0.16 280571 0 2 0.00 4.77 0.95 0.16 300472 0 2 0.00 4.77 0.95 0.16 140572 0 2 0.00 4.77 0.95 0.16 280572 0 2 0.00 4.77 0.95 0.16 300473 0 2 0.00 4.77 0.95 0.16 140573 0 2 0.00 4.77 0.95 0.16 280573 0 2 0.00 4.77 0.95 0.16 300474 0 2 0.00 4.77 0.95 0.16 140574 0 2 0.00 4.77 0.95 0.16 280574 0 2 0.00 4.77 0.95 0.16 300475 0 2 0.00 4.77 0.95 0.16 140575 0 2 0.00 4.77 0.95 0.16 280575 0 2 0.00 4.77 0.95 0.16 300476 0 2 0.00 4.77 0.95 0.16 140576 0 2 0.00 4.77 0.95 0.16 280576 0 2 0.00 4.77 0.95 0.16 300477 0 2 0.00 4.77 0.95 0.16 140577 0 2 0.00 4.77 0.95 0.16 280577 0 2 0.00 4.77 0.95 0.16 300478 0 2 0.00 4.77 0.95 0.16 140578 0 2 0.00 4.77 0.95 0.16 280578 0 2 0.00 4.77 0.95 0.16 ­140­ 300479 0 2 0.00 4.77 0.95 0.16 140579 0 2 0.00 4.77 0.95 0.16 280579 0 2 0.00 4.77 0.95 0.16 300480 0 2 0.00 4.77 0.95 0.16 140580 0 2 0.00 4.77 0.95 0.16 280580 0 2 0.00 4.77 0.95 0.16 300481 0 2 0.00 4.77 0.95 0.16 140581 0 2 0.00 4.77 0.95 0.16 280581 0 2 0.00 4.77 0.95 0.16 300482 0 2 0.00 4.77 0.95 0.16 140582 0 2 0.00 4.77 0.95 0.16 280582 0 2 0.00 4.77 0.95 0.16 300483 0 2 0.00 4.77 0.95 0.16 140583 0 2 0.00 4.77 0.95 0.16 280583 0 2 0.00 4.77 0.95 0.16 0. 1 0.00 0.000 0.50 Soil Series: Adamsville sand; Hydrogic Group C *** Kd for sandy loam = 1.7 100.00 0 0 0 0 0 0 0 0 0 00.0 0.00 00.00 3 1 10.000 1.440 0.086 0.000 0.000 0.000 .058 .058 0.000 0.100 0.086 0.036 0.580 1.7 2 10.000 1.440 0.086 0.000 0.000 0.000 .029 .029 0.000 1.000 0.086 0.036 0.580 1.7 3 80.000 1.580 0.030 0.000 0.000 0.000 .029 .029 0.000 5.000 0.030 0.023 0.116 1.7 0 WATR YEAR 10 PEST YEAR 10 CONC YEAR 10 1 6 11 ­­­­ 1 DAY RUNF TSER 0 0 1. E0 APPENDIX A2: Results of Scigrow Run for Carbaryl RUN No. 1 FOR Carbaryl INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APPL (#/ AC) APPL. URATE SOIL SOIL AEROBIC RATE NO. (#/ AC/ YR) KOC METABOLISM (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 5.000 4 20.000 211.0 12.0 ­141­ GROUND­ WATER SCREENING CONCENTRATIONS IN PPB ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .829154 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ A= 7.000 B= 216.000 C= .845 D= 2.334 RILP= 1.408 F= ­1.382 G= .041 URATE= 20.000 GWSC= .829154 ­142­ Appendix B: Ecological Risk Assessment ECOLOGICAL RISK ASSESSMENT Risk characterization integrates the results of exposure and ecotoxicity data to evaluate the likelihood of adverse ecological effects, using for this purpose the risk quotient (RQ) method. RQs are calculated by dividing estimated environmental concentrations (EECs) of the pesticide by acute and chronic toxicity values. Although EECs are primarily based on the maximum label application rates for that pesticide, EECs based on QUA average and maximum reported (Doane data) use rates were also considered in this assessment. The 74 carbaryl registered uses and application specifications (methods, maximum label use rates, number of applications, and interval between applications) used in the risk assessment for terrestrial organisms are summarized in Table 1. RQs are compared to levels of concern (LOC) criteria used by OPP for determining potential risk to nontarget organisms and the subsequent need for possible regulatory action. The criteria indicate that a pesticide used as directed has the potential to cause adverse effects on nontarget organisms. Levels of concern currently address the following risk presumption categories: (1) acute ­­ potential for acute risk; regulatory action may be warranted in addition to restricted use classification, (2) acute restricted use ­­ potential for acute risk, but may be mitigated through restricted use classification, (3) acute endangered species ­ potential for acute risk to endangered species; regulatory action may be warranted, and (4) chronic risk ­ the potential for chronic risk is high, and regulatory action may be warranted. Currently, EFED does not perform assessments for chronic risk to plants, acute or chronic risks to nontarget insects, or chronic risk from granular/ bait formulations to birds or mammals. Risk presumptions and the corresponding risk quotients and levels of concern are summarized in Table 2. In addition, the Agency considers any incident data that is submitted concerning adverse effects on nontarget species. ­143­ Table 1. Uses, application rates, and application intervals used in the risk assessment for carbaryl 1 Uses Non­ granular Formulations Granular/ Bait Use/ Crop Appl Rate (lb ai/ A) No. Appl Interval (days) Max lb/ year Rate (lb ai/ A) Asparagus 2 5 3 10 2 Broccoli, Brussels sprouts, cauliflower, collards, cabbage, mustard greens, lettuce, parsley, spinach, celery, Swiss chard, (beets, carrots, potato, radish, horseradish, parsnip, rutabaga, salsify 2 37 62 Corn (field, pop) 2 4 14 8 ­­­­ Sorghum 2 3 7 6 ­­­­ Rice (tadpole shrimp) 1. 5 2 7 4 ­­­­ Corn (sweet) 2 8 3 16 2 Flax, millet, wheat, pasture, grasses, noncropland, 1.5 2 14 3 ­­­­ Cucurbits (melons, cucumbers, squash, pumpkin) 1 6 7 6 ­­­­ Alfalfa, clover 1. 5 8 30 12 ­­­­ Rangeland 1 1 ­­­­ 1 ­­­­ Solanaceous crops (tomato, pepper, eggplant), tobacco 2 4 7 8 2 Legumes (beans, peas, lentils, cowpeas, soybean) 1.5 4 7 6 ­­­­ Peanuts, sweet potatoes 2 4 7 8 ­­­­ Sugar beets 1. 5 2 14 4 1.5 Small fruits & berries (grape, blueberry, caneberry, cranberry, strawberry) 2 5 7 10 ­­­­ Strawberry ­­­­ ­­­­ ­­­­ ­­­­­ 2 Sunflower 1. 5 2 7 3 ­­­­ Citrus (orange, lemon, grapefruit) 5, 16 4 14 20 ­­­­ Olives 7. 5 2 14 15 ­­­­ Pome fruits (apple, pear) 3 5 14 15 ­­­­ Stone fruits (peach, apricot, cherry, nectarine, plum/ prune) 4 3 14 14 ­­­­ Tree nuts (almond, chestnut, filbert, pecan, pistachios, walnut) 5 3 7 15 ­­­­ Forested areas (non­ urban) 1 2 7 2 ­­­­ Trees and ornamentals 1 6 7 6 9. 1 Turfgrass 8 2 7 16 9.1 Ticks ­­­­­ ­­­­­ 9. 1 Oyster beds 1 ­­­­­ 10 1 Aerial and ground application methods for all uses ­144­ Table 2. Risk presumptions for terrestrial animals Risk Presumption Risk Quotient (RQ) Level of Concern (LOC) Birds Acute Risk EEC 1 /LC50 or LD50/ sqft 2 or LD50/ day 3 0.5 Acute Restricted Use EEC/ LC50 or LD50/ sqft or LD50/ day (or LD50 < 50 mg/ kg) 0.2 Acute Endangered Species EEC/ LC50 or LD50/ sqft or LD50/ day 0.1 Chronic Risk EEC/ NOAEC 1 Wild Mammals Acute Risk EEC/ LC50 or LD50/ sqft or LD50/ day 0.5 Acute Restricted Use EEC/ LC50 or LD50/ sqft or LD50/ day (or LD50 < 50 mg/ kg) 0.2 Acute Endangered Species EEC/ LC50 or LD50/ sqft or LD50/ day 0.1 Chronic Risk EEC/ NOAEC 1 1 abbreviation for Estimated Environmental Concentration (ppm) on avian/ mammalian food items 2 mg/ ft 2 3 mg of toxicant consumed/ day LD50 * wt. of bird LD50 * wt. of bird Risk presumptions for aquatic animals Risk Presumption RQ LOC Acute Risk EEC 1 /LC50 or EC50 0.5 Acute Restricted Use EEC/ LC50 or EC50 0.1 Acute Endangered Species EEC/ LC50 or EC50 0.05 Chronic Risk EEC/ NOAEC 1 1 EEC = (ppm or ppb) in water Risk presumptions for plants Risk Presumption RQ LOC Plant Inhabiting Terrestrial and Semi­ Aquatic Areas Acute Risk EEC 1 /EC25 1 Acute Endangered Species EEC/ EC05 or NOAEC 1 Aquatic Plants Acute Risk EEC 2 /EC50 1 Acute Endangered Species EEC/ EC05 or NOAEC 1 1 EEC = lbs a. i./ A 2 EEC = (ppb or ppm) in water ­145­ Exposure and Risk to Nontarget Terrestrial Animals For nongranular pesticide applications (e. g., liquid, dust), the estimated environmental concentrations (EECs) on food items following product application are compared to LC50 values to assess risk. The predicted 0­ day maximum and mean residues of a pesticide that may be expected to occur on selected avian or mammalian food items immediately following a direct single application at 1 lb a. i./ A are tabulated in Table 3. Table 3. Estimated environmental concentrations (EECs) on avian and mammalian food items (ppm) following a single application at 1 lb a. i./ A) Food Items EEC (ppm) Predicted Maximum Residue 1 EEC (ppm) Predicted Mean Residue 1 Short grass 240 85 Tall grass 110 36 Broadleaf/ forage plants and small insects 135 45 Fruits, pods, seeds, and large insects 15 7 1 Predicted maximum and mean residues are for a 1 lb a. i./ a application rate and are based on Hoerger and Kenaga (1972) as modified by Fletcher et al. (1994). The following toxicity endpoints are used in the risk assessment of carbaryl: Avian acute oral LD50 rock dove = 1000 mg/ kg Avian subacute dietary LC50 bobwhite quail = >5000 ppm Avian chronic (reproduction) NOAEC mallard duck = 300 ppm Mammalian acute oral LD50 rat = 301 mg/ kg Mammalian chronic (reproduction) NOAEC rat = 80 ppm Freshwater fish acute LC50 salmon = 0.25 ppm Freshwater fish acute (TEP) LC50 trout = 1.2 ppm Freshwater fish chronic NOAEC minnow = 0.21 ppm Freshwater invertebrate acute LC50 stonefly = 1.7 ppb Freshwater invertebrate chronic NOAEC waterflea = 1.5 ppb Estuarine/ marine fish acute LC50 minnow = 2.6 ppm Estuarine/ marine mollusc acute EC50 oyster = 2.7 ppm Estuarine/ marine shrimp EC50 mysid = 5.7 ppb Estuarine/ marine fish chronic NOAEC no data Estuarine/ marine aquatic invertebrate chronic NOAEC no data ­146­ Avian Acute and Chronic Risk Risk from Exposure to Nongranular Products Since the avian LC50 is greater than 5,000 ppm (Appendix C), with zero mortality observed at this concentration for the four avian species tested, carbaryl is classified as practically nontoxic to birds, and the avian LC50 value for carbaryl can be considered a NOAEC value. Therefore, for the avian risk assessment, acute RQs for nongranular carbaryl are compared to an acute risk LOC of 1, rather than to the established avian risk LOCs shown in Table 2. On this basis, no avian acute risk LOCs are exceeded for nongranular carbaryl at maximum label application rates (Table 4). Based on an avian NOAEC of 300 ppm and maximum label application rates, the avian chronic risk LOC is exceeded for most nongranular uses (Table 4). For birds feeding on short grasses, the avian chronic risk LOC is exceeded for all uses, except rangeland. For tall grass feeders, the avian chronic LOC is exceeded for all uses, except sugar beets, wheat, millet, flax, pasture, grasses, noncropland, rangeland, and non­ urban forested areas. For birds feeding on broadleaf/ forage plants and small insects the avian chronic LOC is exceeded for all uses except for rangeland and non­ urban forested areas. The chronic LOC for birds feeding on fruits, pods, seeds, and large insects is not exceeded for any of the carbaryl uses. In addition to maximum label use rates, avian acute and chronic RQs were also calculated for nongranular carbaryl using QUA average use rates (Table 5a) for 70 use sites, as well as maximum reported (Doane data) use rates for 42 use sites (Table 5b). The acute risk LOCs are not exceeded for any nongranular carbaryl use at less than maximum label use rates. When RQs are based on average application rates, the chronic risk LOC is exceeded for 39 of 70 uses. For RQs based on maximum reported use rates, the chronic risk LOC is met or exceeded for 34 of 42 uses (Table 5b). ­147­ Table 4. Avian acute and chronic RQs for multiple applications of nongranular carbaryl (broadcast) based on a bobwhite quail LC50 of >5000 ppm, a mallard duck NOAEC of 300 ppm, and maximum label application rates. Uses Appl. Rate No. Appl. Interval Food Items Maximum EEC 1 (ppm) LC50 (ppm) NOAEC (ppm) Acute RQ (EEC/ LC50) Chron. RQ (EEC/ NOAEC) Citrus (orange, lemon, grapefruit) 5 lb ai/ A 4 appl 14 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 3320.98 1522.12 1868.05 207.56 >5000 300 <0.66 <0.30 <0.37 <0.04 11.07 5.07 6.23 0.69 Citrus (California) 16 lb ai/ A 1 appl Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 3840.00 1760.00 2160.00 240.00 >5000 300 <0.77 <0.35 <0.43 <0.05 12.80 5.87 7.20 0.80 Olives 7.5 lb ai/ A 2 appl 14 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 3164.15 1450.23 1779.83 197.76 >5000 300 <0.63 <0.29 <0.36 <0.04 10.55 4.83 5.93 0.66 Pome fruits (apple, pear) 3 lb ai/ A 5 appl 14 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 2230.10 1022.13 1254.43 139.38 >5000 300 <0.45 <0.20 <0.25 <0.03 7.43 3.41 4.18 0.46 Stone fruits (peaches, apricot, cherry, nectarine, plum/ prune) 4 lb ai/ A 3 appl 14 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 2238.92 1026.17 1259.39 139.93 >5000 300 <0.45 <0.21 <0.25 <0.03 7.46 3.42 4.20 0.47 Tree nuts (almond, chestnut, filbert, pecan, pistachios, walnut) 5 lb ai/ A 3 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 3154.09 1445.62 1774.18 197.13 >5000 300 <0.63 <0.29 <0.35 <0.04 10.51 4.82 5.91 0.66 Corn (field, pop) 2 lb ai/ A 4 appl 14 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 1328.39 608.85 747.22 83.02 >5000 300 <0.27 <0.12 <0.15 <0.02 4.43 2.03 2.49 0.28 Corn (sweet) 2 lb ai/ A 8 appl 3 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 3148.03 1442.85 1770.77 196.75 >5000 300 <0.63 <0.29 <0.35 <0.04 10.49 4.81 5.90 0.66 Rice, sunflower 1. 5 lb ai/ A 2 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 673.40 308.64 378.79 42.09 >5000 300 <0.13 <0.06 <0.08 <0.01 2.24 1.03 1.26 0.14 Sugar beets, wheat, millet, flax, pasture, grasses, noncropland 1.5 lb ai/ A 2 appl 14 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 632.83 290.05 355.97 39.55 >5000 300 <0.13 <0.06 <0.07 <0.01 2.11 0.97 1.19 0.13 Asparagus 2 lb ai/ A 5 appl 3 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 2138.64 980.21 1202.99 133.67 >5000 300 <0.43 <0.20 <0.24 <0.03 7.13 3.27 4.01 0.45 ­148­ Broccoli, Brussels sprouts, cabbage, cauliflower, collards, mustard greens, celery, lettuce, parsley, spinach, beets, potato, carrot, horseradish, parsnip, rutabaga, salsify, sorghum 2 lb ai/ A 3 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 1261.64 578.25 709.67 78.85 >5000 300 <0.25 <0.12 <0.14 <0.02 4.21 1.93 2.37 0.26 Table 4. Avian acute and chronic RQs for multiple applications of nongranular carbaryl (broadcast) based on a bobwhite quail LC50 of >5000 ppm, a mallard duck NOAEC of 300 ppm, and maximum label application rates. Uses Appl. Rate No. Appl. Interval Food Items Maximum EEC 1 (ppm) LC50 (ppm) NOAEC (ppm) Acute RQ (EEC/ LC50) Chron. RQ (EEC/ NOAEC) Cucurbits (cucumbers, melons, squash, pumpkin), trees and ornamentals 1 lb ai/ A 6 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 1047.00 479.88 588.94 65.44 >5000 300 <0.21 <0.10 <0.12 <0.01 3.49 1.60 1.96 0.22 Solanaceous (tomato, pepper, eggplant), peanuts, tobacco, sweet potato 2 lb ai/ A 4 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 1578.32 723.40 887.80 98.64 >5000 300 <0.32 <0.14 <0.18 <0.02 5.26 2.41 2.96 0.33 Legumes (beans, peas, lentils, cowpeas, soybeans) 1.5 lb ai/ A 4 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 1183.74 542.55 665.85 73.98 >5000 300 <0.24 <0.11 <0.13 <0.01 3.95 1.81 2.22 0.25 Small fruits & berries (grapes, blueberry, caneberry, cranberry, strawberry) 2 lb ai/ A 5 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 1854.01 849.75 1042.88 115.88 >5000 300 <0.37 <0.17 <0.21 <0.02 6.18 2.83 3.48 0.39 Alfalfa, clover 1. 5 lb ai/ A 8 appl 30 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 796.72 365.16 448.15 49.79 >5000 300 <0.16 <0.07 <0.09 <0.01 2.66 1.22 1.49 0.17 Rangeland 1 lb ai/ A 1 appl Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 240.00 110.00 135.00 15.00 >5000 300 <0.05 <0.02 <0.03 <0.00 0.80 0.37 0.45 0.05 Forested areas (non­ urban) 1 lb ai/ A 2 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 448.93 205.76 252.52 28.06 >5000 300 <0.09 <0.04 <0.05 <0.01 1.5 0.69 0.84 0.09 Turfgrass 8 lb ai/ A 2 appl 7 days Short grass Tall grass Broadleaf plants, sm. ins. Fruit, seeds, lg. insects 3591.46 1646.08 2020.19 224.47 5000 300 <0.72 <0.33 <0.40 <0.04 11.97 5.49 6.73 0.75 1 Predicted maximum residues are for a 1 lb a. i./ a application rate and are based on Hoerger and Kenaga (1972) as modified by Fletcher et al. (1994). ­149­ Table 5a. Avian acute and chronic risk quotients 1 for multiple applications of nongranular carbaryl based on a bobwhite quail LC50 of >5000 ppm and, a mallard duck NOAEC of 300 ppm, and QUA average application rates for 70 uses Use site (Appl. Rate [lb ai/ A], No. Applications, Interval) Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Use Site Acute RQ (EEC/ LC50 ) Chronic RQ (EEC/ NOAEC) Alfalfa (1. 1, 1) Almonds (2. 1, 1) Apples (1. 2, 1) Asparagus (0. 9, 1) Beans, Dry (0. 5, 1) Beans, Lima, Fresh (0. 9, 1) Beans, Snap, Fresh (0. 9, 2, 7) Beans, Snap, Processed (0. 7, 2, 7) Beets (0. 5, 1) Blackberries (1. 7, 1) Blueberries (1. 7, 1) Broccoli (0. 8, 1) Brussels Sprouts (0. 9, 1) Chinese Cabbage (0. 2, 1) Fresh Cabbage (1. 0, 2, 7) Cantaloupes (0. 8, 1) Carrots (0. 9, 2, 7) Cauliflower (1.1, 1) Celery (1. 0, 2, 7) Cherries (1. 9, 1) Citrus, other (1. 8, 2, 14) Corn, Field (1. 0, 1) Cranberries (2. 0, 1) Cucumbers (1.1, 1) Cucumbers, Processed (0. 6, 2, 7) Eggplant (1. 0, 2, 7) Flax (1. 1, 1) Grapefruit (1. 4, 2, 14) Grapes (1. 4, 2, 7) Hay (0. 8, 1) Hazelnuts (2.5, 1) Lemons (2. 7, 1) Lettuce (1. 1, 1) Lots/ Farmsteads (0.4, 2, 14) Melons (0. 7, 1) <0.05 <0.10 <0.06 <0.04 <0.02 <0.04 <0.08 <0.06 <0.02 <0.08 <0.08 <0.04 <0.04 <0.01 <0.09 <0.04 <0.08 <0.05 <0.09 <0.09 <0.15 <0.05 <0.10 <0.05 <0.05 <0.09 <0.05 <0.12 <0.13 <0.04 <0.12 <0.13 <0.05 <0.04 <0.03 0.88 1.68 0.96 0.72 0.40 0.72 1.35 1.05 0.40 1.36 1.36 0.64 0.72 0.16 1.50 0.64 1.35 0.88 1.50 1.52 2.53 0.80 1.60 0.88 0.90 1.50 0.88 1.97 2.10 0.64 2.00 2.16 0.88 0.75 0.56 Nectarines (3.8, 1) Okra (1. 9, 1) Olives (5. 3, 1) Oranges (3. 4, 1) Pasture (0. 9, 1) Peaches (1.0, 3, 7) Peanuts (0. 8, 1) Pears (1. 0, 1, 2 Pears, Dry (1. 0, 1) Peas, Green (1. 5, 1) Pecans (1.4, 2) Peppers, Bell (0. 9, 2) Peppers, Sweet (1. 3, 1) Pistachios (3.6, 1) Plums (3. 8, 1) Potatoes (0. 8, 2) Pumpkins (2. 0, 2) Raspberries (2. 8, 1) Rice (1. 1, 1) Sorghum (1. 1, 1) Soybeans (0. 9, 1) Squash (1. 4, 1) Strawberries (1. 4, 2) Sugar Beets (1. 3, 1) Sunflower (0. 7, 1) Sweet Corn, Fresh (1. 3, 3, 3) Sweet Potatoes (1. 6, 1) Tobacco (1.1, 2,7) Tomatoes, Fresh (0. 7, 3, 7) Tomatoes, Processed (1. 2, 1) Walnuts (1. 9, 1) Watermelons (0. 5, 1) Wheat, Spring (0. 6, 1) Wheat, Winter (0. 8, 1) Woodland (0. 7, 1) <0.18 <0.09 <0.25 <0.16 <0.04 <0.13 <0.04 <0.08 <0.05 <0.07 <0.13 <0.08 <0.06 <0.17 <0.18 <0.07 <0.18 <0.13 <0.05 <0.05 <0.04 <0.07 <0.13 <0.06 <0.02 <0.18 <0.08 <0.09 <0.09 <0.06 <0.09 <0.02 <0.03 <0.04 <0.02 3.04 1.52 4.24 2.72 0.72 2.10 0.64 1.41 0.80 1.20 2.10 1.35 1.04 2.88 3.04 1.20 2.99 2.24 0.88 0.88 0.72 1.12 2.10 1.04 0.32 2.94 1.28 1.50 1.47 0.96 1.52 0.40 0.48 0.64 0.32 1 Only the highest RQs ­­ i. e. those based on short grass EECs ­­ are included in this table. ­150­ Table 5b. Avian highest acute and chronic risk quotients 1 for multiple applications of nongranular carbaryl based on a bobwhite quail LC50 of >5000 ppm and, a mallard duck NOAEC of 300 ppm, and maximum reported use rates (Doane data) for 42 use sites Use site [appl. rate (lb ai/ A), No. appl] Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Use Site [appl. rate (lb ai/ A) No. appl] Acute RQ (EEC/ LC50 ) Chronic RQ (EEC/ NOAEC) Alfalfa (1. 5, 1) Almonds (4, 1) Apples (3. 2, 1) Apricots (4, 1) Asparagus (4, 1) Beans, Lima, (1. 3, 1) Beans, snap (1. 6, 1) Cabbage (2, 1) Canola (0. 5, 1) Cantaloupe (1. 2, 1) Carrots (0. 8, 1) Cauliflower (1, 1) Celery (2, 1) Cherries (5, 1) Corn, Field (1. 5, 2, 14) Cucumbers (1, 1) Grapefruit (12.8, 1) Grapes (2. 5, 1) Lemons (8, 1) Lettuce (1, 1) Oranges (15, 1) <0.07 <0.19 <0.15 <0.19 <0.19 <0.06 <0.08 <0.10 <0.02 <0.06 <0.04 <0.05 <0.10 <0.24 <0.13 <0.05 <0.61 <0.12 <0.38 <0.05 <0.72 1.2 3.2 2.6 3.2 3.2 1.0 1.3 1.6 0.4 1.0 0.6 0.8 1.6 4.0 2.1 0.8 10.2 2.0 6.4 0.8 12.0 Peaches (5,1) Peanuts (2, 1) Pears (2, 1) Pecans (3, 2, 7) Peppers (2, 1) Pistachios (5, 1) Plums (4, 1) Potatoes (1. 5, 1) Pumpkins (1. 5, 1) Rice (1. 3, 1) Sorghum (0. 5, 1) Squash (1. 2, 1) Sugar Beets (1. 2, 1) Sunflower (1, 1) Strawberries (2, 1) Sweet Corn (1. 5, 2, 3) Tobacco (2, 1) Tomatoes (2, 1) Walnuts (4, 1) Watermelons (2, 1) Wheat (1,1) <0.24 <0.10 <0.10 <0.27 <0.10 <0.24 <0.19 <0.07 <0.07 <0.06 <0.02 <0.06 <0.06 <0.05 <0.10 <0.14 <0.10 <0.10 <0.19 <0.10 <0.05 4.0 1.6 1.6 4.5 1.6 4.0 3.2 1.2 1.2 1.0 0.4 1.0 1.0 0.8 1.6 2.3 1.6 1.6 3.2 1.6 0.8 1 Only the highest RQs ­­ i. e. those based on short grass EECs ­­ are included in this table. Risk from Exposure to Granular Products Birds may be exposed to granular pesticides by ingesting granules when foraging for food or grit. Birds may also be exposed by other routes, such as by walking on exposed granules or by drinking water contaminated with granules. The number of lethal doses (LD50) that are available within one square foot immediately after application (LD50/ ft2) is used as the risk quotient for granular/ bait products. Risk quotients are calculated for birds in three separate weight classes: 1000 g (e. g. waterfowl), 180 g (e. g. upland gamebirds), and 20 g (e. g., songbirds). Based on a rock dove LD50 of 1,000 mg/ kg and a mallard LD50 greater than 2,000 mg/ kg, technical carbaryl can be classified as slightly to practically nontoxic to birds on an acute basis. LD50 values for carbaryl as low as 16.2 mg/ kg and 56.2 mg/ kg have been reported for the starling and the red­ winged blackbird, respectively (Schafer et al., 1983). Although these data are based on simple screening tests, and are therefore not reliable for risk assessment purposes, they do suggest that passerine birds may be significantly more sensitive to carbaryl exposure than non­ passerine birds. The registrant is strongly encouraged to submit acute oral toxicity tests with passerine avian species. ­151­ The acute RQs for granular carbaryl are based on a rock dove LD50 of 1,000 (Table 6). The avian acute, restricted use, and endangered species LOCs are exceeded for birds in the 20 g weight class, for all granular carbaryl uses. Although for most uses the acute LOC is not exceeded for birds in the two higher weight classes, for the trees/ ornamentals, turfgrass, and tick control uses the avian acute risk LOC is also exceeded for birds in the 180 g weight class. No acute LOCs are exceeded for birds in the 1000 g weight class for any of the granular carbaryl uses. Table 6. Avian acute risk quotients for granular carbaryl (broadcast, unincorporated) based on LD50 for rock dove (1,000 mg/ kg) Uses Rate in lb ai/ A LD50 (mg/ kg) Body Weight (g) Acute RQ 1 (LD50/ ft 2 ) Asparagus, Brassica crops (broccoli, Brussels sprouts, cabbage, cauliflower, collards, etc.), corn (field, sweet), sorghum, Solanaceous crops (tomato, pepper, eggplant), Leafy vegetables (celery, endive, lettuce, parsley, spinach, etc.), Roots and tubers (garden beets, carrots, radishes, potatoes, etc.), strawberries 2 1000 1000 1000 20 180 1000 1.04 0.16 0.02 Cucurbits (cucumber, melon, pumpkin, squash) 1 1000 1000 1000 20 180 1000 0.52 0.06 0.01 Legumes ( beans, peas, lentils, cowpeas, southern peas) , wheat, millet, sugar beets 1.5 1000 1000 1000 20 180 1000 0.78 0.09 0.02 Trees and ornamentals, turfgrass, tick control 9. 15 1000 1000 1000 20 180 1000 4.76 0.53 0.10 1 RQ = App. Rate (lb ai/ a) * (453,590 mg/ lb/ 43,560 ft 2 /a) LD50 mg/ kg * Weight of Animal (kg) Mammalian acute and chronic risk Estimating the potential for adverse effects to wild mammals is based upon EFED's draft 1995 SOP of mammalian risk assessments and methods used by Hoerger and Kenaga (1972) as modified by Fletcher et al. (1994). The concentration of carbaryl in the diet that is expected to be acutely lethal to 50% of the test population (LC50 ) is determined by dividing the LD50 value (usually rat LD50) by the % (decimal of) body weight consumed. A risk quotient is then determined by dividing the EEC by the derived LC50 value. Risk quotients are calculated for three separate weight classes of mammals (15, 35, and 1000 g), each presumed to consume four different kinds of food (grass, forage, insects, and seeds). The acute risk quotients for broadcast applications of nongranular products are tabulated below. Risk from Exposure to Nongranular Products Short grass ­152­ The mammalian acute risk LOC is exceeded for all registered nongranular carbaryl uses, at maximum label application rates, for short grass feeders with a daily food consumption equal to 95% and 66% of their body weight, with RQ values ranging from 0.76 to 12.12 and from 0.53 to 8.42, respectively (Table 7). The acute risk LOC for herbivores consuming daily 15% of their body weight are exceeded for all uses (RQs: 0.56 ­ 1.91), except for the rice, sugar beets, wheat, millet, flax, pasture, grasses, noncropland, alfalfa, clover, and rangeland use site scenarios. Broadleaf/ forage plans and small insects The acute risk LOC is exceeded for all nongranular carbaryl uses for small mammals feeding on broadleaf/ forage plants and small insects, with RQs in the 0.80 ­ 6.82 range for mammals with a daily food consumption equal to 95% of their body weights. It is also exceeded for all uses, except rangeland, for mammals consuming 66% of their body weights (RQs: 0.55 to 4.74). For mammals consuming 15 % of their body weight, the acute risk LOC is reached or exceeded for citrus, olives, pome fruits, stone fruits, tree nuts, sweet corn, asparagus, small fruits, berries, and turfgrass (RQs: 0.52 ­ 1.08). RQs equal or exceed the acute restricted use or the endangered species LOCs for most other uses. Fruit, pods, seeds, and large insects For small mammals consuming 95% of these food items, the acute risk LOC is exceeded for citrus, olives, tree nuts, sweet corn, and turfgrass (RQs: 0.62 ­ 0.76). For mammals consuming 66% of their body weight the acute risk LOC is exceeded only for citrus in California (RQ: 0.53). For mammals that consume 15% of their body weight, the acute risk LOC is not exceeded for any use. ­153­ Table 7. Mammalian (herbivore/ insectivore) acute risk quotients for multiple applications of nongranular carbaryl (broadcast) based on a rat LD50 of 301 mg/ kg and maximum label use rates. Uses, Application Rate, No. Applications, Interval Body Weight (g) % Body Weight Con_ sumed LC50 (LD50/% Body Wt Con_ sumed EEC: Short Grass (ppm) EEC: Forage & Small Insects (ppm) EEC: Fruit, Seeds, Lg Insects (ppm) Acute RQ: Short Grass Acute RQ: Forage & Small Insects Acute RQ: Large Insects Citrus, 5 lb ai/ A, 4 appl, 14 days 15 35 1000 95 66 15 316.84 456.06 2006.67 3320.98 3320.98 3320.98 1868.05 1868.05 1868.05 207.56 207.56 207.56 10.48 7.28 1.65 5.90 4.10 0.93 0.66 0.46 0.10 Citrus (California), 16 lb ai/ A, 1 appl 15 35 1000 95 66 15 316.84 456.06 2006.67 3840.00 3840.00 3840.00 2160.00 2160.00 2160.00 240.00 240.00 240.00 12.12 8.42 1.91 6.82 4.74 1.08 0.76 0.53 0.12 Olives, 7.5 lb ai/ A 2 appl, 14 days 15 35 1000 95 66 15 316.84 456.06 2006.67 3164.15 3164.15 3164.15 1779.83 1779.83 1779.83 197.76 197.76 197.76 9.99 6.94 1.58 5.62 3.90 0.89 0.62 0.43 0.10 Pome fruits (apples, etc.), 3 lb ai/ A, 5 appl, 14 days 15 35 1000 95 66 15 316.84 456.06 2006.67 2230.10 2230.10 2230.10 1254.43 1254.43 1254.43 139.38 139.38 139.38 7.04 4.89 1.11 3.96 2.75 0.63 0.44 0.31 0.07 Stone fruits (peaches, etc.), 4 lb ai/ A, 3 appl, 14 days 15 35 1000 95 66 15 316.84 456.06 2006.67 2238.92 2238.92 2238.92 1259.39 1259.39 1259.39 139.93 139.93 139.93 7.07 4.91 1.12 3.97 2.76 0.63 0.44 0.31 0.07 Tree nuts (pistachios, etc.), 5 lb ai/ A, 3 appl, 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 3154.09 3154.09 3154.09 1774.18 1774.18 1774.18 197.13 197.13 197.13 9.95 6.92 1.57 5.60 3.89 0.88 0.62 0.43 0.10 Corn, field, 2 lb ai/ A 4 appl, 14 days 15 35 1000 95 66 15 316.84 456.06 2006.67 1328.39 1328.39 1328.39 747.22 747.22 747.22 83.02 83.02 83.02 4.19 2.91 0.66 2.36 1.64 0.37 0.26 0.18 0.04 Corn, sweet, 2 lb ai/ A 8 appl, 3 days 15 35 1000 95 66 15 316.84 456.06 2006.67 3148.03 3148.03 3148.03 1770.77 1770.77 1770.77 196.75 196.75 196.75 9.94 6.90 1.57 5.59 3.88 0.88 0.62 0.43 0.10 Rice (tadpole shrimp), sunflower, 1.5 lb ai/ A, 2 appl, 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 673.40 673.40 673.40 378.79 378.79 378.79 42.09 42.09 42.09 2.13 1.48 0.34 1.20 0.83 0.19 0.13 0.09 0.02 Sugar beets, wheat, millet, flax, pasture, grasses, noncropland 1.5 lb ai/ A, 2 appl, 14 days 15 35 1000 95 66 15 316.84 456.06 2006.67 632.83 632.83 632.83 355.97 355.97 355.97 39.55 39.55 39.55 2.00 1.39 0.32 1.12 0.78 0.18 0.12 0.09 0.02 Asparagus, 2 lb ai/ A, 5 appl, 3 days 15 35 1000 95 66 15 316.84 456.06 2006.67 2138.64 2138.64 2138.64 1202.99 1202.99 1202.99 133.67 133.67 133.67 6.75 4.69 1.07 3.80 2.64 0.60 0.42 0.29 0.07 Cucurbits (cucumbers melons, squash, etc.), trees & ornamentals, 1 lb ai/ A, 6 appl, 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 1047.00 1047.00 1047.00 588.94 588.94 588.94 65.44 65.44 65.44 3.30 2.30 0.56 1.86 1.29 0.29 0.21 0.14 0.03 ­154­ Solanaceous (peppers, tomatoes, eggplant), sweet potatoes, peanuts, tobacco, 2 lb ai/ A, 4 appl, 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 1578.32 1578.32 1578.32 887.80 887.80 887.80 98.64 98.64 98.64 4.98 3.46 0.79 2.80 1.95 0.44 0.31 0.22 0.05 Table 7. Mammalian (herbivore/ insectivore) acute risk quotients for multiple applications of nongranular carbaryl (broadcast) based on a rat LD50 of 301 mg/ kg and maximum label use rates. Uses, Application Rate, No. Applications, Interval Body Weight (g) % Body Weight Con_ sumed LC50 (LD50/% Body Wt Con_ sumed EEC: Short Grass (ppm) EEC: Forage & Small Insects (ppm) EEC: Fruit, Seeds, Lg Insects (ppm) Acute RQ: Short Grass Acute RQ: Forage & Small Insects Acute RQ: Large Insects Leafy veg (celery, lettuce, etc.), Brassica (broccoli, cabbage, etc.), roots & tubers (carrots, potatoes, etc.), sorghum, 2 lb ai/ A, 3 appl, 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 1261.64 1261.64 1261.64 709.67 709.67 709.67 78.85 78.85 78.85 3.98 2.77 0.63 2.24 1.56 0.35 0.25 0.17 0.04 Legumes (beans, peas, lentils, cowpeas), 1.5 lb ai/ A, 4 appl, 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 1183.74 1183.74 1183.74 665.85 665.85 665.85 73.98 73.98 73.98 3.74 2.60 0.59 2.10 1.46 0.33 0.23 0.16 0.04 Small fruits & berries (grapes, strawberries, etc.), 2 lb ai/ A, 5 appl 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 1854.01 1854.01 1854.01 1042.88 1042.88 1042.88 115.88 115.88 115.88 5.85 4.07 0.92 3.29 2.29 0.52 0.37 0.25 0.06 Alfalfa, clover, 1.5 lb ai/ A, 10 appl, 30 days 15 35 1000 95 66 15 316.84 456.06 2006.67 796.72 796.72 796.72 448.15 448.15 448.15 49.79 49.79 49.79 2.53 1.76 0.40 1.42 0.99 0.22 0.16 0.11 0.02 Rangeland, 1 lb ai/ A, 1 appl 15 35 1000 95 66 15 316.84 456.06 2006.67 240.00 240.00 240.00 135.00 135.00 135.00 15.00 15.00 15.00 0.76 0.53 0.12 0.43 0.30 0.07 0.05 0.03 0.01 Forested areas non urban), 1 lb ai/ A, 2 appl, 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 448.93 448.93 448.93 252.52 252.52 252.52 28.06 28.06 28.06 1.42 0.98 0.22 0.80 0.55 0.13 0.09 0.06 0.01 Turfgrass, 8 lb ai/ A, 2 appl, 7 days 15 35 1000 95 66 15 316.84 456.06 2006.67 3591.46 3591.46 3591.46 2020.19 2020.19 2020.19 224.47 224.47 224.47 11.34 7.87 1.79 6.38 4.43 1.01 0.71 0.49 0.11 Although neither the acute risk nor the acute restricted use LOC is exceeded for granivores for any of the nongranular carbaryl uses, the acute endangered species LOC is reached or exceeded for citrus, olives, pome and stone fruits, tree nuts, sweet corn, and turfgrass (RQs: 0.10 ­ 0.16), and for citrus, olives, tree nuts, sweet corn, and turfgrass (RQs: 0.10 ­ 0.12), for granivores with daily food consumption equal to 21% and 15% of their body weight, respectively (Table 8). No acute LOCs are exceeded for granivores which consume daily 3% of their body weight. ­155­ Table 8. Mammalian (granivore) acute risk quotients for multiple applications of nongranular carbaryl (broadcast) based on a rat LD50 of 301 mg/ kg and maximum label use rates. Uses, Application Rate, No. Applications, Interval Body Weight (g) % Body Weight Consumed LC50 (LD50 ÷ % Body Weight Consumed) EEC: Seeds (ppm) Acute RQ: Seeds Citrus, 5 lb ai/ A, 4 appl, 14 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 207.56 207.56 207.56 0.14 0.10 0.02 Citrus (California), 16 lb ai/ A, 1 appl 15 35 1000 21 15 3 1433.33 2000.67 10033.33 240.00 240.00 240.00 0.16 0.12 0.00 Olives, 7.5 lb ai/ A, 2 appl, 14 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 197.76 197.76 197.76 0.14 0.10 0.02 Pome fruits (apple, pear, etc.), 3 lb ai/ A, 3 appl, 14 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 139.38 139.38 139.38 0.10 0.07 0.01 Stone fruits (peach, apricot, etc.), 4 lb ai/ A, 3 appl, 14 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 139.93 139.93 139.93 0.10 0.07 0.01 Tree nuts (pistachios, etc.), 5 lb ai/ A, 3 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 197.13 197.13 197.13 0.13 0.10 0.02 Corn, field, 2 lb ai/ A, 4 appl, 14 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 83.02 83.02 83.02 0.06 0.04 0.02 Corn, sweet, 2 lb ai/ A, 8 appl, 3 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 196.75 196.75 196.75 0.13 0.10 0.00 Rice, sunflower, 1.5 lb ai/ A, 2 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 42.09 42.09 42.09 0.03 0.02 0.00 Sugar beets, wheat & millet, flax, pasture, grasses, noncropland, 1.5 lb ai/ A, 2 appl, 14 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 39.55 39.55 39.55 0.03 0.02 0.00 Asparagus, 4 lb ai/ A, 2 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 133.67 133.67 133.67 0.09 0.07 0.01 Brassica crops (broccoli, cabbage, etc.), leafy veg (celery, lettuce, etc.), Roots & tubers (beets, carrot, potato, etc.), sorghum, 2 lb ai/ A, 3 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 78.85 78.85 78.85 0.05 0.04 0.01 Cucurbits (cucumbers, melons, squash, etc.), trees and ornamentals, 1 lb ai/ A, 6 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 65.44 65.44 65.44 0.04 0.03 0.01 Solanaceous (pepper, tomato, eggplant), sweet potato, peanuts, tobacco, 2 lb ai/ A, 4 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 98.64 98.64 98.64 0.07 0.05 0.01 ­156­ Legumes (beans, peas, lentils, cowpeas), 1.5 lb ai/ A, 4 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 73.98 73.98 73.98 0.05 0.04 0.01 Table 8. Mammalian (granivore) acute risk quotients for multiple applications of nongranular carbaryl (broadcast) based on a rat LD50 of 301 mg/ kg and maximum label use rates. Uses, Application Rate, No. Applications, Interval Body Weight (g) % Body Weight Consumed LC50 (LD50 ÷ % Body Weight Consumed) EEC: Seeds (ppm) Acute RQ: Seeds Small fruits & berries (grapes, strawberries, etc.), 2 lb ai/ A, 5 appl 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 115.88 115.88 115.88 0.08 0.06 0.01 Alfalfa, clover, 1.5 lb ai/ A, 10 appl, 30 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 49.79 49.79 49.79 0.03 0.02 0.00 Rangeland, 1 lb ai/ A, 1 appl 15 35 1000 21 15 3 1433.33 2000.67 10033.33 15.00 15.00 15.00 0.01 0.01 0.00 Forested areas (non­ urban), 1 lb ai/ A, 2 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 28.06 28.06 28.06 0.02 0.01 0.00 Turfgrass, 8 lb ai/ A, 2 appl, 7 days 15 35 1000 21 15 3 1433.33 2000.67 10033.33 224.47 224.47 224.47 0.15 0.11 0.02 Assummarized inTable9,at maximumlabelapplicationrates, themammalianchronicLOC (1) is exceeded for all registered uses of nongranular carbaryl for all food item groups, with chronic RQ values in the range of: 3.0 ­ 48.0 (for short grasses), 1.4 ­ 22.0 (for tall grasses), and 1.7 ­ 27.0 (for broadleaf/ forage plants, small insects). The mammalian chronic LOC is exceeded for the fruits/ pods/ seeds/ large insects food items for the following uses: citrus, olives, pome and stone fruits, tree nuts, field and sweet corn, asparagus, solanaceous vegetable crops, sweet potatoes, peanuts, tobacco, small fruits and berries, and turfgrass (chronic RQs = 1.0 ­ 3.0). ­157­ Table 9. Mammalian chronic risk quotients for multiple applications of nongranular carbaryl (broadcast) based on a developmental rat NOAEC of 80 ppm and maximum label application rates Site, Application Rate, Number of Applications, Interval Food Items Peak Mean EEC (ppm) Chronic RQ (EEC)/ NOAEC) Citrus, 5 lb ai/ A, 4 appl, 14 days Short Grass Tall Grass Broad Leaf Seed Fruit 3320.98 1522.12 1868.05 207.56 41.51 19.03 23.35 2.59 Citrus (California), 16 lb ai/ A, 1 appl Short Grass Tall Grass Broad Leaf Seed Fruit 3840.00 1760.00 2160.00 240.00 48.00 22.00 27.00 3.00 Olives, 7.5 lb ai/ A, 2 appl, 14 days Short Grass Tall Grass Broad Leaf Seed Fruit 3164.15 1450.23 1779.83 197.76 39.55 18.13 22.25 2.47 Pome fruits (apples, etc.), 3 lb ai/ A, 5 appl, 14 days Short Grass Tall Grass Broad Leaf Seed Fruit 2230.10 1022.13 1254.43 139.38 27.88 12.78 15.68 1.74 Stone fruits (peaches, etc.), 4 lb ai/ A, 3 appl, 14 days Short Grass Tall Grass Broad Leaf Seed Fruit 2238.92 1026.17 1259.39 139.93 27.99 12.83 15.74 1.75 Tree nuts (pistachios, etc.), 5 lb ai/ A, 3 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 3154.09 1445.62 1774.18 197.13 39.43 18.07 22.18 2.46 Corn, field, 2 lb ai/ A, 4 appl, 14 days Short Grass Tall Grass Broad Leaf Seed Fruit 1328.39 608.85 747.22 83.02 16.60 7.61 9.34 1.04 Corn, sweet, 2 lb ai/ A, 8 appl, 3 days Short Grass Tall Grass Broad Leaf Seed Fruit 3148.03 1442.85 1770.77 196.75 39.35 18.04 22.13 2.46 Rice, sunflower, 1.5 lb ai/ A, 2 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 673.40 308.64 378.79 42.09 8.42 3.86 4.73 0.53 Asparagus, 2 lb ai/ A, 5 appl, 3 days Short Grass Tall Grass Broad Leaf Seed Fruit 2138.64 980.21 1202.99 133.67 26.73 12.25 15.04 1.67 Brassica crops (broccoli, cabbage, etc.), leafy veg (celery, lettuce, etc.), roots & tubers (beets, carrots, potatoes, etc.), sorghum, 2 lb ai/ A, 3 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 1261.64 578.25 709.67 78.85 15.77 7.23 8.87 0.99 ­158­ Table 9. Mammalian chronic risk quotients for multiple applications of nongranular carbaryl (broadcast) based on a developmental rat NOAEC of 80 ppm and maximum label application rates Site, Application Rate, Number of Applications, Interval Food Items Peak Mean EEC (ppm) Chronic RQ (EEC)/ NOAEC) Cucurbits (cucumbers melons, squash, etc.), trees and ornamentals, 1 lb ai/ A, 6 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 1047.00 479.88 588.94 65.44 13.09 6.00 7.36 0.82 Solanaceous (peppers, tomatoes, eggplant), sweet potatoes, peanuts, tobacco, 2 lb ai/ A, 4 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 1578.32 723.40 887.80 98.64 19.73 9.04 11.10 1.23 Legumes (beans, peas, lentils, cowpeas), 1.5 lb ai/ A, 4 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 1183.74 542.55 665.85 73.98 14.80 6.78 8.32 0.92 Sugar beets, wheat, millet, flax, pasture, grasses, noncropland 1.5 lb ai/ A, 2 appl, 14 days Short Grass Tall Grass Broad Leaf Seed Fruit 632.83 290.05 355.97 39.55 7.91 3.63 4.45 0.49 Small fruits & berries (grapes, strawberries, etc.), 2 lb ai/ A, 5 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 1854.01 849.75 1042.88 115.88 23.18 10.62 13.04 1.45 Alfalfa, clover, 1.5 lb ai/ A, 8 appl, 30 days Short Grass Tall Grass Broad Leaf Seed Fruit 796.72 365.16 448.15 49.79 9.96 4.56 5.60 0.62 Rangeland, 1 lb ai/ A, 1 appl Short Grass Tall Grass Broad Leaf Seed Fruit 240.00 110.00 135.00 15.00 3.00 1.38 1.69 0.19 Forested areas (non­ urban), 1 lb ai/ A, 2 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 448.93 205.76 252.52 28.06 5.61 2.57 3.16 0.35 Turfgrass, 8 lb ai/ A, 2 appl, 7 days Short Grass Tall Grass Broad Leaf Seed Fruit 3591.46 1646.08 2020.19 224.47 44.89 20.58 25.25 2.81 In addition to maximum label use rates, mammalian acute and chronic RQs were also calculated for nongranular carbaryl using QUA average use rates data available for for 70 uses (Table 10a) and maximum reported (Doane data) use rates data available for 42 uses (Table 10b). As summarized in Table 10a, when RQs are based on QUA average rates, the acute risk LOC is exceeded for 63 uses, whereas the restricted use LOC is exceeded for 69 uses (not exceeded only ­159­ for Chinese cabbage), and the endangered species LOC is exceeded for all 70 uses. The chronic risk LOC is exceeded for 69 uses (not exceeded only for Chinese cabbage). Table 10a. Mammalian (herbivores) highest acute and chronic risk quotients 1 for nongranular carbaryl based on a rat LD50 of 301 mg/ kg ppm, a developmental rat NOAEC of 80 ppm, and QUA average application rates for 70 uses Use site Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Use Site Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Alfalfa Almonds Apples Asparagus Beans, Dry Beans, Lima, Fresh Beans, Snap, Fresh Beans, Snap, Processed Beets Blackberries Blueberries Broccoli Brussels Sprouts Chinese Cabbage Fresh Cabbage Cantaloupes Carrots Cauliflower Celery Cherries Citrus, other Corn, Field Cranberries Cucumbers Cucumbers, Processed Eggplant Flax Grapefruit Grapes Hay Hazelnuts Lemons Lettuce Lots/ Farmsteads Melons 0.84 1.59 0.91 0.68 0.38 0.68 1.28 0.99 0.38 1.28 1.28 0.60 0.68 0.15 1.42 0.60 1.28 0.84 1.42 1.44 2.40 0.75 1.52 0.84 0.85 1.42 0.84 1.87 1.98 0.60 1.90 2.05 0.84 0.70 0.53 3.30 6.30 4.11 2.70 1.50 2.70 5.05 3.93 1.50 5.10 5.10 2.40 2.70 0.60 5.61 2.40 5.05 3.30 5.61 5.70 9.49 3.00 6.00 3.30 3.37 5.61 3.30 7.38 7.86 2.40 7.50 8.10 3.30 2.80 2.10 Nectarines Okra Olives Oranges Pasture Peaches Peanuts Pears Pears, Dry Peas, Green Pecans Peppers, Bell Peppers, Sweet Pistachios Plums Potatoes Pumpkins Raspberries Rice Sorghum Soybeans Squash Strawberries Sugar Beets Sunflower Sweet Corn, Fresh Sweet Potatoes Tobacco Tomatoes, Fresh Tomatoes, Processed Walnuts Watermelons Wheat, Spring Wheat, Winter Woodland 2.88 1.44 4.02 2.58 0.68 1.99 0.60 1.34 0.75 1.13 1.98 1.28 0.99 2.72 2.88 1.13 2.84 2.12 0.84 0.84 0.68 1.06 1.98 0.99 0.31 2.78 1.21 1.42 1.40 0.91 1.44 0.38 0.46 0.60 0.31 11.40 5.70 15.90 10.20 2.70 7.89 2.40 5.27 3.00 4.50 7.86 5.05 3.90 10.80 11.40 4.49 11.22 8.40 3.30 3.30 2.70 4.20 7.86 3.90 2.10 11.04 4.80 5.61 5.52 3.60 5.70 1.50 1.80 2.40 2.10 1 Only the highest RQs ­­ i. e. those corresponding to 15 g mammals which have a daily food consumption equal to 95% of their body weight and based on short grass EECs ­­ are included in this table. When RQs are calculated using maximum reported application rates, the acute risk LOC is exceeded for 41 of the 42 uses (RQs: 0.60 ­ 11.36). The restricted use, endangered species, and chronic (RQs: 1.5 ­ 45) risk LOCs are exceeded for all 42 uses (Table 10b). ­160­ Table 10b Mammalian (herbivores) highest acute and chronic risk quotients 1 for nongranular carbaryl based on a rat LD50 of 301 mg/ kg ppm and, a developmental rat NOAEC of 80 ppm, and maximum reported use rates (Doane data) for 42 uses Use site [appl. rate (lb ai/ A), No. appl] Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Use Site [appl. rate (lb ai/ A) No. appl] Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Alfalfa (1. 5, 1) Almonds (4, 1) Apples (3. 2, 1) Apricots (4, 1) Asparagus (4, 1) Beans, Lima (1. 3, 1) Beans, snap (1. 6, 1) Cabbage (2, 1) Canola (0. 5, 1) Cantaloupe (1. 2, 1) Carrots (0. 8, 1) Cauliflower (1, 1) Celery (2, 1) Cherries (5, 1) Corn, Field (1. 5, 2, 14) Cucumbers (1, 1) Grapefruit (12.8, 1) Grapes (2. 5, 1) Lemons (8, 1) Lettuce (1, 1) Oranges (15, 1) 1.13 3.03 2.43 3.03 3.03 0.99 1.21 1.52 0.38 0.91 0.60 0.75 1.53 3.78 2.00 0.75 9.70 1.90 6.06 0.75 11.36 4.5 12.0 9.62 12.0 12.0 3.9 4.8 6.0 1.5 3.6 2.4 3.0 6.0 15.0 7.9 3.0 38.4 7.5 24.0 3.0 45.0 Peaches (5, 1) Peanuts (2, 1) Pears (2, 1) Pecans (3, 2, 7) Peppers (2, 1) Pistachios (5, 1) Plums (4, 1) Potatoes (1. 5, 1) Pumpkins (1. 5, 1) Rice (1. 3, 1) Sorghum (0. 5, 1) Squash (1. 2, 1) Sugar Beets (1. 2, 1) Sunflower (1, 1) Strawberries (2, 1) Sweet Corn (1. 5, 2, 3) Tobacco (2, 1) Tomatoes (2, 1) Walnuts (4, 1) Watermelons (2, 1) Wheat (1,1) 3.78 1.52 1.52 4.25 1.52 3.78 3.03 1.13 1.13 0.99 0.38 0.91 0.91 0.75 1.52 2.20 1.52 1.52 3.03 1.52 0.75 15.0 6.0 6.0 16.8 6.0 15.0 12.0 4.5 4.5 3.9 1.5 3.6 3.6 3.0 6.0 8.7 6.0 6.0 12.0 6.0 3.0 1 Only the highest RQs ­­ i. e. those corresponding to 15 g mammals which have a daily food consumption equal to 95% of their body weight and based on short grass EECs ­­ are included in this table. Risk to Granular Products Mammals also may be exposed to granular/ bait pesticides through ingestion and by other routes, such as by walking on exposed granules or by drinking water contaminated with granules. The number of lethal doses (LD50) that are available within one square foot immediately after application (LD50/ ft2) is used as the risk quotient for granular/ bait products. Risk quotients are calculated for small mammals in three weight classes: 15 g, 35 g, and 1000 g. The acute level of concern is exceeded for mammals in the 15 g and 35 g categories for all 40 registered granular uses (Table 11). For 1000 g mammals, the restricted use and endangered species LOCs are exceeded for applications to trees and ornamentals, turfgrass, and tick control. ­161­ Table 11. Mammalian acute risk quotients for granular carbaryl (broadcast, unincorporated) based on a rat LD50 of 301 mg/ kg Uses Rate in lb ai/ A Body Weight (g) Acute RQ 1 (LD50/ ft 2 ) Asparagus, Brassica crops (broccoli, cabbage, cauliflower, collards, etc.), corn (field, sweet), sorghum, solanaceous crops (tomato, pepper, eggplant), leafy vegetables (celery, lettuce, parsley, spinach, etc.), roots & tubers (beets, carrots, radishes, potatoes, etc.), strawberries 2 15 35 1000 4.61 1.98 0.07 Cucurbits (cucumber, melon, pumpkin, squash) 1 15 35 1000 2.30 0.99 0.03 Legumes ( beans, peas, lentils, cowpeas, southern peas), Wheat, millet, Sugar beets 1.5 15 35 1000 3.45 1.48 0.05 Trees and ornamentals, turfgrass, tick control 9. 15 15 35 1000 21.10 9.04 0.32 1 RQ = Appl. rate (lb ai/ a) * (453,590 mg/ lb/ 43,560 ft 2 /a) LD50 mg/ kg * weight of animal (kg) Insects Currently EFED does not assess risk to nontarget insects. However, data from acceptable studies are used to recommend appropriate label precautions. Carbaryl, is highly toxic to domestic and wild bees and should be applied only under the conditions specified by the latest pollinator protection label language. Carbaryl has also been shown to be from moderately to highly toxic to predaceous and parasitic arthropods, including lace bugs, big eyed bugs, lady beetles, carabid ground beetles, hymenopterous parasitoids, predaceous mites, and spiders. Terrestrial Plants There in no data to assess risk to terrestrial plants. However, based on precautionary label language about potential injury to several crop plants, the registrant needs to submit tier I and, if necessary, tier II Seed Germination and Seedling Emergence and Vegetative Vigor studies. Exposure and Risk to Nontarget Aquatic Animals EFED calculates estimated environmental concentrations (EECs) using the PRZM/ EXAMS model. The EECs are used for assessing acute and chronic risks to aquatic organisms. Acute risk assessments are performed using peak EEC values for single and multiple applications. Chronic risk assessments are performed using the 21­ day EECs for invertebrates and 56­ day EECs for fish. The PRZM/ EXAMS program uses basic environmental fate data and pesticide label application information to estimate the expected EECs following treatment of 10 hectares. The ­162­ model calculates the concentration (EEC) of a pesticide in a one hectare, two meter deep pond, taking into account the following: (1) adsorption to soil or sediment, (2) soil incorporation, (3) degradation in soil before washoff to a water body, and (4) degradation within the water body. The model also accounts for direct deposition of spray drift into the water body (assumed to be 1% and 5% of the application rate for ground and aerial applications, respectively). The environmental fate parameters used in the model for this pesticide are: soil KOC 211, solubility: 32 mg/ L, aerobic soil metabolism half­ life of 4 days, hydrolysis: stable at pH 5, 12 days at pH 7, 5 hrs at Ph9, water photolysis21days, aerobicaquaticmetabolismhalf­ life:4.9, anaerobicaquaticmetabolismhalf­ life: 4.9 days. EECs are tabulated in Table 12. Table12.Tier IIsurfacewaterestimated environmentalconcentration(EEC)values derivedfromPRZM/EXAMS modeling for use in ecorisk assessment (Calculated using standard pond.) Use Site, Application Method Number of Applications Per Year Application Rate (Pounds A. I. per Application) Surface Water Acute (ppb) (1 in 10 year peak single day concentration) 21 day (ppb) (1 in 10 year) 60 day (ppb) (1 in 10 year) Sweet Corn (OH), air/ ground Maximum "Average" Maximum Reported 8 2 3 2 3.4 1 46 16 14 26 10 8 21 5 4 Field Corn (OH), air/ ground Maximum "Average" Maximum Reported 4 2 2 2 1 1.5 28 12 18 16 6 9.5 10 3 5 Apples (OR), air/ ground Maximum "Average" Maximum Reported 5 2 2 2 1.2 1.6 8.6 4.5 6.0 4.9 2.5 3 4 1 2 Sugar Beets (MN), air/ ground Maximum "Average" Maximum Reported 2 1 1 1.5 1.5 1.2 19 14 11 11 7 5 5 3 2 Citrus (FL), air/ ground Maximum "Average" Maximum Reported 4 2 3 5 3.4 4.3 274 145 232 137 67 112 79 33 55 Freshwater Fish Acuteand chronicriskquotientsfor freshwaterfish,basedon maximumlabel,QUAaverage, and maximum reported (Doane data) use rates are tabulated in Table 13. The acute risk LOC is exceeded only for the citrus scenario, for all three use rates modeled, whereas the endangered species LOC is met or exceeded for four scenarios, for all three use rates. The chronic risk LOC is is not exceeded for any use scenario, for any use rates. ­163­ Table 13. Risk quotients for freshwater fish based on an Atlantic salmon LC50 of 250 ppb and a fathead minnow NOAEC of 210 ppb, at maximum label use rates, QUA average use rates, and maximum reported use rates Site/ Appl. Method Use Rates LC50 (ppb) NOAEC (ppb) EEC Initial/ Peak (ppb) EEC 60­ Day Ave. (ppb) Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Sweet Corn (OH), air/ ground Maximum "Average" Max Rep 250 210 46 16 14 21 5 4 0.18 0.06 0.06 0.10 0.02 0.02 Field Corn (OH) air/ ground Maximum "Average" Max Rep 250 210 28 12 18 10 3 5 0.11 0.05 0.07 0.05 0.01 0.02 Apples (OR) air/ ground Maximum "Average" Max Rep 250 210 8.6 4.5 6.0 4 1 2 0.03 0.02 0.02 0.02 0.00 0.01 Sugar Beets (MN) air/ ground Maximum "Average" Max Rep 250 210 19 14 11 5 3 2 0.08 0.06 0.04 0.02 0.01 0.01 Citrus (FL) air/ ground Maximum "Average" Max Rep 250 210 274 145 232 79 33 55 1.10 0.58 0.93 0.38 0.16 0.26 The risk quotients for freshwater invertebrates exceed both the acute and chronic LOCs for all five use scenarios modeled, at maximum label use rates, QUA average rates, and maximum reported (Doane data) use rates (Table 14). Table 14. Risk quotients for freshwater invertebrates based on a stonefly EC50 of 1.7 ppb and a water flea NOAEC of 1.5 ppb , at maximum label use rates, QUA average use rates, and maximum reported use rates Site/ Appl. Method Use Rates EC50 (ppb) NOAEC (ppb) EEC Initial/ Peak (ppb) EEC 21­ Day Ave. (ppb) Acute RQ (EEC/ EC50) Chronic RQ (EEC/ NOAEC) Sweet Corn (OH) Maximum "Average" Max Rep 1.7 1.5 46 16 14 26 10 8 27.06 9.40 8.20 17.33 6.67 5.33 Field Corn (OH) Maximum "Average" Max Rep 1.7 1.5 28 12 18 16 6 9.5 16.47 7.06 10.59 10.67 4.00 6.33 Apples (OR) Maximum "Average" Max Rep 1.7 1.5 8. 6 4.5 6.0 4.9 2.5 3 5.06 2.65 3.30 3.27 1.67 2.00 Sugar Beets (MN) Maximum "Average" Max rep 1.7 1.5 19 14 11 11 7 5 11.18 8.24 6.47 7.33 4.67 3.33 Citrus (FL) Maximum "Average" Max Rep 1.7 1.5 274 145 232 137 67 112 161.18 85.29 136.47 91.33 44.67 74.67 ­164­ Estuarine and Marine Animals The acute risk LOC is not exceeded for any of the five use scenarios modeled using maximum label use rates, QUA average rates, and maximum reported rates (Table 15). The acute endangered species LOC is exceeded at maximum label rates for the citrus scenario. Due to the unavailability of core chronic toxicity data, it is not possible to evaluate chronic risk to estuarine/ marine fish at this time. Table 15. Acute risk quotients for estuarine/ marine fish based on a sheepshead minnow LC50 of 2.6 ppm and label maximum and QUA average use rates, at maximum label use rates, QUA average use rates, and maximum reported use rates Site/ Appl. Method Use Rates LC50 (ppb) EEC Initial/ Peak (ppb) (Max Rates) Acute RQ (EEC/ EC50) Sweet Corn (OH) Maximum "Average" Max Rep 2600 46 16 14 0.02 0.01 0.00 Field Corn (OH) Maximum "Average" Max Rep 2600 28 12 18 0.01 0.00 0.01 Apples (OR) Maximum "Average" Max Rep 2600 8.6 4.5 6.0 0.00 0.00 0.00 Sugar Beets (MN) Maximum "Average" Max rep 2600 19 14 11 0.00 0.00 0.00 Citrus (FL) Maximum "Average" Max Rep 2600 274 145 232 0.10 0.06 0.09 The acute risk LOC is exceeded for all five carbaryl use scenarios modeled at maximum label use rates, QUA average rates, and maximum reported (Doane data) rates (Table 16). Due to the unavailability of core chronic toxicity data, it is not possible to evaluate chronic risk to estuarine/ marine fish or invertebrates at this time. ­165­ Table 16. Acute risk quotients for estuarine/ marine invertebrates based on a mysid LC50 of 5.7 ppb and three sets of use rates, at maximum label use rates, QUA average use rates, and maximum reported use rates Site/ Appl. Method Use Rates LC50 (ppb) EEC Initial/ Peak (ppb) (Max Rates) Acute RQ (EEC/ EC50) (Max Rates) Sweet Corn (OH) Maximum "Average" Max Rep 5.7 46 16 14 8.07 2.81 2.46 Field Corn (OH) Maximum "Average" Max Rep 5.7 28 12 18 4.91 2.10 3.16 Apples (OR) Maximum "Average" Max Rep 5.7 8. 6 4.5 6.0 1.51 0.79 1.05 Sugar Beets (MN) Maximum "Average" Max rep 5.7 19 14 11 3.33 2.46 1.93 Citrus (FL) Maximum "Average" Max Rep 5.7 274 145 232 48.07 25.44 40.70 Aquatic Plants Exposure to nontarget aquatic plants may occur through runoff or spray drift from adjacent treated sites or directly from such uses as aquatic weed or mosquito larvae control. An aquatic plant risk assessment for acute risk is usually made for aquatic vascular plants from the surrogate duckweed Lemna gibba. Non­ vascular acute risk assessments are performed using either algae or a diatom, whichever is the most sensitive species. An aquatic plant risk assessment for acuteendangered species is usually made for aquatic vascular plants from the surrogate duckweed Lemna gibba. To date, there are no known non­ vascular plant species on the endangered species list. Runoff and drift exposure is computed from GENEEC. The risk quotient is determined by dividing the pesticide's initial or peak concentration in water by the plant EC50 value. Based on a single core aquatic plant toxicity study available, neither the acute risk nor the endangered species LOC is exceeded for any of the five use scenarios modeled, at maximum label, QUA average, and maximum reported use rates (Table 17). However, to fully assess carbaryl risk to aquatic plants, it is recommended that toxicity studies with Lemna gibba, Anabaena flos­ aquae, Skeletonema costatum, and a freshwater diatom be submitted. ­166­ Table 17. Risk quotients for aquatic plants based on a green alga EC50 of 1,1 ppm and a NOAEC of 0.37 ppm, at maximum label use rates, QUA average use rates, and maximum reported use rates Site/ Appl. Method Use Rates EC50 (ppb) NOAEC (ppb) EEC Initial/ Peak (ppb) Acute RQ (EEC/ EC50) Acute Endangered Species RQ (EEC/ NOAEC) Sweet Corn (OH) Maximum "Average" Max Rep 1100 370 46 16 14 0.04 0.01 0.01 0.12 0.04 0.04 Field Corn (OH) Maximum "Average" Max Rep 1100 370 28 12 18 0.02 0.01 0.02 0.08 0.03 0.05 Apples (OR) Maximum "Average" Max Rep 1100 370 8.6 4.5 6.0 0.01 0.00 0.00 0.02 0.01 0.02 Sugar Beets (MN) Maximum "Average" Max rep 1100 370 19 14 11 0.02 0.01 0.01 0.05 0.04 0.03 Citrus (FL) Maximum "Average" Max Rep 1100 370 274 145 232 0.25 0.13 0.21 0.74 0.39 0.63 Endangered Species The endangered species LOC for birds is met or exceeded for 72 of 74 nongranular carbaryl uses at maximum label use rates, for 18 of 70 carbaryl uses at QUA average use rates, and for 25 of 42 maximum reported use rates. The acute endangered species LOC for mammals is met or exceeded for all (74) uses at maximum label rates, it is exceeded for all (70) uses at QUA average rates, and it is exceeded for all (42) uses at maximum reported use rates. Based on five use scenarios modeled (sweet corn, field corn, apples, sugar beets, and citrus) for assessing risk to aquatic organisms, the freshwater fish endangered species LOC is met or exceeded for four use scenarios, at maximumlabel, QUA average, and maximumreported use rates. The estuarine/ marine fish endangered species LOC is exceeded for one scenario (citrus), at all three use rates modeled. The endangered species LOC for both freshwater and estuarine/ marine aquatic invertebrates is exceeded for all five scenarios and all three use rates modeled. These data indicate that over half of carbaryl uses pose an acute risk to endangered species of birds, while all uses represent an acute risk to endangered species of mammals. With regard to aquatic species, most carbaryl uses are likely to present an acute risk to endangered species of freshwater fish and aquatic invertebrates, both freshwater and marine/ estuarine species. Only the highest use rates (citrus) are likely to pose an acute risk to endangered species of marine/ estuarine fish. ­167­ Appendix C: Toxicity Assessment Toxicity Assessment Toxicity testing reported in this section is not representative of the wide diversity of terrestrial and aquatic organisms in the United States. Two surrogate bird species, the bobwhite quail and the mallard duck, are used to represent the 680+ species of birds found in this country. For mammals, acute studies are usually limited to the Norway rat or the house mouse. Reptiles are not tested, as these are assumed to be subject to similar toxicological effects as birds. Of approximately 100,000 species of insects, spiders, and other terrestrial arthropods, toxicity tests are usually required only for the honey bee. Only two surrogate fish species (rainbow trout and bluegill sunfish) are used to represent the over 2,000 species of freshwater fish found in this country. Amphibians are not tested, as these are assumed to be subject to similar toxicological effects as fish. One crustacean, the water flea, is used to represent all freshwater invertebrates. Estuarine/ marine animal acute toxicity testing is usually limited to a crustacean, a mollusk, and a fish. Toxicity to Terrestrial Animals Birds, Acute and Subacute Toxicity Based on a rock dove lower 95% confidence interval LD50 of 1,000 mg/ kg and a mallard LD50 greater than 2,000 mg/ kg, technical carbaryl can be classified as slightly to practically nontoxic to birds on an acute basis (Table 1). LD50 values for carbaryl as low as 16.2 mg/ kg and 56.2 mg/ kg have been reported for the starling and the red­ winged blackbird, respectively (Schafer et al., 1983). Although these data are based on simple screening tests, and are therefore not reliable for risk assessment purposes, they do suggest that passerine birds may be significantly more sensitive to carbaryl exposure than non­ passerine birds. The registrant is strongly encouraged to submit acute oral toxicity tests with passerine avian species. The guideline 71­ 1 is fulfilled (MRID 00160000). ­168­ Table 1. Summary of avian acute oral toxicity for technical grade carbaryl Species % ai LD50 (mg/ kg) Toxicity Category MRID No. Author/ Year Study Classification 1 Mallard Duck (Anas platyrhynchos) 85 > 2,564 Practically non­ toxic 00160000 Hudson et al. (1984) Core Canada Goose Branta canadensis 50 1,790 Slightly toxic 00160000 Hudson et al. (1984) Supplemental Ring­ necked Pheasant male (Phasianus colchicus) 95 > 2,000 Practically non­ toxic 00160000 Hudson et al. (1984) Supplemental Ring­ necked Pheasant female (Phasianus colchicus) 480g/ L 707 Moderately toxic 00160000 Hudson et al. (1984) Supplemental Sharp­ tailed grouse Tympanuchus phasianellus 85 < 1000 Slightly toxic 00160000 Hudson et al. (1984) Supplemental California quail Lophortyx californicus 480 g/ L > 2000 Practically non­ toxic 00160000 Hudson et al. (1984) Supplemental Rock Dove (Columba livia) 85 1,000 ­ 3000 2 Slightly toxic to Practically non­ toxic 00160000 Hudson et al. (1984) Supplemental 1 Core study satisfies guideline requirements. Supplemental study is scientifically sound, but does not satisfy guidelines. 2 95% confidence interval Two subacute dietary studies using the TGAI are required to establish the toxicity of carbaryl to birds. The preferred test species are mallard duck and bobwhite quail. Results of these tests are summarized in Table 2. The LC50 is higher than 5000 ppm for both species. Therefore, carbaryl is categorized as practically nontoxic to avian species on a subacute dietary basis. An LC50 greater than 10,000 ppm has been reported by Hill and Camardese (1986), confirming that carbaryl's low toxicity to birds on a subacture, dietary basis. The guideline 71­ 2 is fulfilled (MRID 00028757, 00022923). Table 2 : Summary of avian subacute dietary toxicity for technical grade carbaryl Species % ai 5­ Day LC50 (ppm) Toxicity Category MRID No. Author/ Year Study Classification Ring­ necked Pheasant (Phasianus calchicus) 99.8 > 5,000 practically non­ toxic 00028757 Hill et al. (1975) Core Northern bobwhite Quail (Colinus virginianus) 99.8 > 5,000 Practically non­ toxic 00028757 Hill et al. (1975) Core Japanese Quail (Coturnix japonica) 99.8. > 5,000 Practically non­ toxic 00022923 Hill et al. (1975) Supplemental Mallard Duck (Anas platyrhynchos) 99.8 > 5000 Practically non­ toxic 00022923 Hill et al. (1975) Core According to the Ecological Incident Information System (EIIS) database summarizing 6( a) 2 incident reports, bird kills attributed to carbaryl and involving blackbirds, ducks, starlings, grackles ­169­ turkey, and cardinals have been reported in Pennsylvania, Virginia, New Jersey, North Carolina and Michigan (# 1002048­ 001, #1000802­ 001, #1007720­ 020, ## 1000799­ 003, #1004375­ 004) . Birds, Chronic Toxicity Exposure to carbaryl at levels equal to or greater than 1000 ppm in the mallard duck results in adverse reproductive effects, such as decreased number of eggs produced, increased number of cracked eggs, and decreased fertility (Table 3). Guideline 71­ 4 is fulfilled (ACC263701; MRID 00160044). Table 3. Summary of avian reproduction toxicity for technical grade carbaryl Species % ai NOAEC (ppm) LOAC Endpoints MRID. No. Author/ Year Study Classification Northern bobwhite Quail (Colinus virginianus) 99.9 > 3,000 N/ A 00160044 Fletcher (1986) Core Mallard Duck (Anas platyrhynchos) 99.9 300 Number of eggs produced ACC263701 Fletcher (1986) Core Mammals, Acute and Chronic As shown in Table 4, carbaryl is categorized as moderately toxic to small mammals on an acute oral basis (LD50 = 301 mg/ kg). Although at this time two­ generation rat reproduction study data are not available, a LOAEC of 600 ppm and a NOAEC of 80 ppm, based on decreased fetal body weights and increased incomplete ossification of multiple bones (from a rat prenatal development study, MRID# 44732901), suggest that carbaryl has the potential for chronic effects in mammals. Table 4. Summary of mammalian toxicity for technical grade carbaryl Species % ai Test Type Toxicity Value Affected Endpoints MRID No. Laboratory Rat (Rattus norvegicus) 99.0% Acute oral LD50 = 301.0 mg/ kg Morbidity 00148500 Laboratory Rat (Rattus norvegicus) 99.0% Prenatal Development NOAEC/ LOAEC 80 / 600 ppm Decreased fetal body weights and incomplete ossification of multiple bones 44732901 Domestic Dog (Canis familiaris) 99.0% Chronic NOAEC/ LOAEC 45 / 125 ppm Decreased plasma cholinesterase 40166701 42022801 Incidents involving small mammal kills (squirrels, ground squirrel, mole, rabbit) have been recorded in South Carolina and Virginia (# 1000504­ 039, #1000504­ 039). ­170­ Insect Toxicity Technical carbaryl is categorized as highly toxic to bees on an acute contact basis (Table 5). Guideline 141­ 1 is fulfilled (MRID 00036935, 05001991, 05004151). Table 5. Summary of honey bee acute contact toxicity for technical grade carbaryl Species % ai Contact LD50 (µg/ bee) Oral LC50 (µg/ bee) Toxicity Category MRID No. Author/ Year Study Classification Honey Bee (Apis mellifera) tech. 1. 3 0.14 Highly toxic 05001991 Stevenson (1978) Core Honey Bee (Apis mellifera) tech 2.0 ­­­ Highly toxic 00036935 Atkins et al. (1975) Core Honey Bee (Apis mellifera) tech 1.1 0. 11 Highly toxic 05004151 Stevenson (1968) Core The topical LD50 for alfalfa leaf­ cutter bee (Megachile pacifica = M. rotundata) = 262.4 µg/ g (05015678) ( Lee & Brindley 1974). However, exposing leaf­ cutter bees (Megachilidae), alkali bees (Halictidae), and honey bees (Apidae) to 24 hr residues from 80% WP carbaryl applied at the rate of 1 lb/ acre resulted, respectively, in a 85%, 78%, and 69% mortality rate (Johansen 1972) (ID #05000837). Some carbaryl formulations can be highly toxic to bees exposed to direct application, i. e. when bees are actively visiting blooming crops or weeds. Residual toxicity varies with the crops and weather conditions. Carbaryl can also be from moderately to highly toxic to predaceous arthropods. These include lace bugs (Nabidae) (MRID #05010807), big eyed bugs (Geocoridae: Geocoris) (MRID #05010807, ), lady beetles (Coccinellidae: Coccinella, Cryptolaemus, Hippodamia, Lindorus, Rhodolia, Stethorus) (MRID #05013372, 05003978, 05005640), ground beetles (Carabidae: Scarites, Pterostichus, Bembidion, Harpalus) (MRID #05008149), hymenopterous parasitoids (Aphytis, Metaphycus, Spalangia, Leptomastix) (MRID #05003978, 05005640), predaceous mites (Amblyseius, Typhlodromus) (MRID #05004148, 05013359, 05009346), and spiders (MRID #05010807). Bee kill incidents have been reported for North Carolina, California, and Washington (# 1003826­ 016, #1003226­ 021, #1005855­ 001, #1001611­ 002). Toxicity to Freshwater Aquatic Animals Freshwater Fish, Acute Results of toxicity tests with freshwater fish are tabulated in Table 6. Since the LC50 values for the species tested are in the 0.25 ­ 20.0 ppm range, carbaryl can therefore range from highly to slightly toxic to freshwater fish on an acute basis. Guidelines 72­ 1( a) and 72­ 1( c) are fulfilled (MRID 40098001, 00043115). ­171­ Table 6. Summary of freshwater fish acute toxicity for technical grade carbaryl Species % ai 96­ hour LC50 (ppm) (nominal) Toxicity Category MRID No. Author/ Year Study Classification Rainbow Trout (Oncorhynchus mykiss) 99.5 1. 2 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core Chinook Salmon (Oncorhynchus tshawytacha) 99.5 2. 4 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Supplemental Bluegill Sunfish (Lepomis macrochirus) 99.9 14.0 Slightly Toxic 00043115 McCann et al (1969) Core Bluegill Sunfish (Lepomis macrochirus) 99.9 5. 04 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core Channel Catfish (Ictalurus punctatus) 99.9 7. 79 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core Fathead Minnow (Pimephales promelas) 99.5 7. 7 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core Black Crappie (Pomoxis nigromaculatus) 99.5 2. 6 Moderately Toxic 40094602 Johnson & Finley (1986) Core Atlantic Salmon (Salmo salar) 99.5 0. 25 Highly Toxic 40098001 Mayer & Ellersieck (1986) Core Brown Trout (Salmo trutta) 99.5 6. 3 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core Brook Trout (Salvelinus fontinalis) 99.5 3. 0 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core Lake Trout (Salvelinus namaycush) 99.5 0. 69 Highly Toxic 40098001 Mayer & Ellersieck (1986) Core Coho Salmon (Oncorhynchus kisutch) 99.5 2. 4 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core Yellow Pearch (Percs flavescens) 99.5 0. 35 Highly Toxic 40098001 Mayer & Ellersieck (1986) Core Cutthroat Trout (Oncorhynchus clarki) 99.5 0. 97 Highly Toxic 40098001 Mayer & Ellersieck (1986) Core Largemouth Bass (Micropterus salmoides) 99.5 6. 4 Moderately Toxic 40094602 Johnson & Finley (1980) Core Green Sunfish (Lepomis cyanellus) 99.5 9. 5 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core Black Bullhead (Ictalurus melas) 99.5 20.0 Slightly Toxic 40098001 Mayer & Ellersieck (1986) Core Longnose Killifish (Fundulus similis) 99.7 1. 6 Moderately Toxic 40228401 Mayer (1986) Supplemental Carp (Cyprinus carpio) 99.5 5. 3 Moderately Toxic 40098001 Mayer & Ellersieck (1986) Core ­172­ Toxicity was determined for the typical end­ use product as well, with all LC50 values, except one, ranging from 1.4 to 49 ppm, which indicates that carbaryl can be classified as slightly to moderately toxic to freshwater fish (Table 7). Guidelines (b) and 72­ 1( d) are fulfilled (MRID #s 00059202, 00042381, 00151519, 00151417, 42397901, 00124383, 00124391). Table 7. Summary of freshwater fish acute toxicity for carbaryl (typical end­ use product) Species % ai 96­ hr LC50 (ppm) Toxicity Category MRID No. Author/ Year Study Classification Rainbow Trout (Oncorhynchus mykiss) 44 1.4 Moderately Toxic 00151417 Sousa (1985) Core Rainbow Trout (Oncorhynchus mykiss) 81.5 3. 3 Moderately Toxic 42397901 Lintott (1992) Core Rainbow Trout (Oncorhynchus mykiss) 50 3.45 Moderately Toxic 00124383 McCann (1971) Core Rainbow Trout (Oncorhynchus mykiss) 50 4.5 Moderately Toxic 00124383 McCann (1971) Core Bluegill Sunfish (Lepomis macrochirus) 30 49.0 Slightly Toxic 00059202 Mc Caan (1970) Core Bluegill Sunfish (Lepomis macrochirus) 5 290.0 Practically Nontoxic 00042381 McCann (1968) Core Bluegill Sunfish (Lepomis macrochirus) 44 9.8 Moderately Toxic 00151519 Sousa (1985) Core Bluegill Sunfish (Lepomis macrochirus) 50 22.0 Slightly Toxic 00124391 McCann (1971) Core Freshwater Fish, Chronic Results of the required early life­ stage with fish are summarized in Table 8, show that carbaryl has high potential for chronic toxicity to freshwater fish. Exposure to 680 ppb can result in growth effects to young. The guideline requirement 72­ 4( a) for freshwater fish is fulfilled (TOUCARO5). Table 8. Summary of freshwater fish life­ cycle toxicity under flow­ through conditions for technical grade carbaryl Species % ai NOAEC/ LOAC (ppm) Endpoints Affected MRID No. Author/ Year Study Classification Fathead Minnow (Pimephales promelas) 99 0.21/ 0.68 Reproduction TOUCARO5 Carlson (1972) Core Amphibians ­173­ According to a supplemental study with an end­ use product containing 50% carbaryl (MRID 00160000), the LD50 for, the bullfrog (Rana catesbeiana) is greater than 4,000 mg/ kg, or practically nontoxic. Freshwater Invertebrates, Acute Since the EC50 falls in the range of 1.7 ­ 26 ppb, carbaryl is categorized as very highly toxic to aquatic invertebrates on an acute basis (Table 9). Toxicity studies with the typical end­ use product show that carbaryl is very highly toxic to daphnids, with an EC50 in the 4.29 ­ 13.0 ppb range (Table 10). Guideline 72­ 2 is fulfilled (MRID #s 40098001, 42397902, 42397903). Table 9. Summary of freshwater invertebrate acute toxicity for technical grade carbaryl Species/ Static or Flowthrough % ai 48­ hour EC50 (ppb) (nominal) Toxicity Category MRID No. Author/ Year Study Classification Water flea (Daphnia magna) 99.5 5. 6 Very Highly Toxic 40098001 Mayer & Ellersieck (1986) Core Stonefly (Classenia sabulosa) 99.5 96hr LC50= 5.6 Very Highly Toxic 40098001 Mayer & Ellersieck (1986) Supplemental Stonefly (Isogenus sp.) 99.5 96hr LC50= 3.6 Very Highly Toxic 40098001 Mayer & Ellersieck (1986) Supplemental Stonefly (Pteronarcella badia) 99.5 96hr LC50= 1.7 Very Highly Toxic 40098001 Mayer & Ellersieck (1986) Supplemental Scud (Gammarus fasciatus) 99.5 96hr EC50= 26 Very Highly Toxic 40098001 Mayer & Ellersieck (1986) Core Table 10. Acute toxicity to invertebrates (TEP) Species % ai 48­ hour EC50 (ppb) Toxicity category MRID No. Author/ Year Study Classification Water flea (Daphnia magna) 49.0% 7.1 Very highly toxic 00150538 Nicholson and Surprenant (1985) Supplemental Water flea (Daphnia magna) 43.9% 13.0 Very highly toxic 00150540 Nicholson and Surprenant (1985) Supplemental Water flea (Daphnia magna) 47.3% 4.29 Very highly toxic 42432401 Lintott (1992) Supplemental Water flea (Daphnia magna) 43.7% 6.66 Very highly toxic 42397902 Lintott (1992) Core ­174­ Water flea (Daphnia magna) 81.5% 7.2 Very highly toxic 42397903 Lintott (1992) Core Freshwater Invertebrate, Chronic A 21­ day toxicity study preformed with the water flea estimated a NOAEC and a LOAEC of 1.5 ppb and 3.3 ppb, respectively, based on affected reproduction (Table 11). Guideline 72­ 4( b) for freshwater invertebrates is fulfilled (MRID 00150901). Table 11. Summary of freshwater aquatic invertebrate life­ cycle toxicity for technical grade carbaryl Species % ai 21­ day NOAEC/ LOAEC (ppb) Endpoints Affected MRID No. Author/ Year Study Classification Water flea (Daphnia magna) 99.0% 1.5/ 3.3 Reproduction 00150901 Surprenant (1985) Core Toxicity to Estuarine and Marine Animals Estuarine/ Marine Fish, Acute Since the minnow LC50 is 2.6 ppm (Table 12), carbaryl is categorized as moderately toxic to estuarine/ marine fish on an acute basis. The guideline 72­ 3( a) is fulfilled (MRID 42372801). Table 12. Summary of estuarine/ marine fish acute toxicity for technical grade carbaryl Species/ Static % ai 96­ hour LC50 (ppm) (nominal) Toxicity Category MRID No. Author/ Year Study Classification Sheepshead Minnow (Cyprinodon variegatus) 99 2.2 Moderately Toxic 00150539 Sousa and Surprenant (1985) Supplemental Sheepshead Minnow (Cyprinodon variegatus) 99.7% 2.6 Moderately Toxicc 42372801 Lintott (1992) Core Estuarine and Marine Fish, Chronic An estuarine/ marine fish early life­ stage toxicity test using the TGAI is required for carbaryl because the end­ use product is expected to be transported to this environment from the intended use site. Carbaryl is registered for ghost and mud shrimp control in oyster beds in Washington and has the potential to affect nontarget fish and invertebrates outside the application sites. In addition, the pesticide uses are such that its presence in water is likely to be continuous (multiple applications), ­175­ and chronic concerns have been noted for freshwater fish and marine and freshwater. At this point, the guideline 72­ 4( a) for estuarine/ marine fish is not fulfilled. Estuarine and Marine Invertebrates, Acute As shown in Table 13, the 96­ hour mysid shrimp LC50 for technical carbaryl falls is 5.7 ppb (MRID 42343401). Thus, this chemical is categorized as very highly toxic to estuarine/ marine shrimp species on an acute basis. By contrast, carbaryl is moderately toxicity to the oyster (LC50 = 2.7 ppm, MRID 00148221). Guidelines 72­ 3( b) and 72­ 3( c) are fulfilled. Table 13. Summary of estuarine/ marine invertebrate acute toxicity for technical grade carbaryl Species % ai. 48­ hour LC50 (ppb) Toxicity Category MRID No. Author/ Year Study Classification Brown Shrimp (Penaeus aztecus) 99.7 1. 5 Very Highly Toxic 40228401 Mayer (1986) Supplemental Mysid (Mysidopsis bahia) 99 96 hr LC50 = 6.7 Very Highly Toxic 00150544 Hoberg and Surprenant (1985) Supplemental Mysid (Mysidopsis bahia) 99.7 96 hr LC50 = 5.7 Very Highly Toxic 42343401 Lintott (1992) Core Glass Shrimp (Palaemonetes kadiakensis) 99.5 5. 6 Very Highly Toxic 40098001 Mayer & Ellersieck (1986) Supplemental Grass Shrimp (Palaemonetes pugio) 99.7 28 Very Highly Toxic 40228401 Mayer (1986) Supplemental Pink Shrimp (Penaeus duorarum) 99.7 32 Very Highly Toxic 40228401 Mayer (1986) Supplemental Eastern Oyster (Crassostrea virginica) 99.7 96 hr LC50> 2 Very Highly Toxic 40228401 Mayer (1986) Core Eastern Oyster (Crassostrea virginica) 99 2700 Moderately Toxic 00148221 Surprenant, et al. (1985) Core Blue Crab (Callinectes sapidus) 99.7 320 Highly Toxic 40228401 Mayer (1986) Supplemental Fairy Shrimp 95.3% 170 Highly toxic 40094602 Mayer (1986) Supplemental Eastern Oyster (Crassostria virginica) 95.0% >1,000 Moderately toxic 40228401 Mayer (1986) Supplemental Results of toxicity testing using the typical end­ use product are summarized in Table 14. Carbaryl TEPs are highly toxic to mysids, LC50 values ranging from 9.3 to 20.2 ppb (MRID #s 42397904, 42565601, and 42343402), and slightly toxic to oysters (LC50 = 23.6 ppm, MRID 42597301). Guidelines 72­ 3( e) and 72­ 3( f) are fulfilled. ­176­ Table 14. Summary of estuarine/ marine invertebrate acute toxicity for TEP Species % ai. 48­ hour LC50 (ppb) Toxicity Category MRID No. Author/ Year Study Classification Mysid (Mysidopsis bahia) 81.5 9. 6 Very Highly Toxic 42397904 Lintott (1992) Core Mysid (Mysidopsis bahia) 81.5 9. 3 Very Highly Toxic 42565601 McElwee and Lintott (1992) Core Mysid (Mysidopsis bahia) 43.7% 96 hr LC50 = 20.2 Very Highly Toxic 42343402 Lintott (1992) Core Eastern Oyster (Crassostrea virginica) 43.3% 96 hr LC50 = 23,600 Slightly Toxic 42597301 Lintott (1992) Supplemental Estuarine and Marine Invertebrate, Chronic There are no available chronic toxicity data for estuarine/ marine invertebrates. The guideline 72­ 4( b) for estuarine/ marine invertebrates is no fulfilled. 1­ Naphthol Toxicity to Aquatic Organisms The major metabolite of carbaryl degradation by abiotic and microbially mediated processes is 1­ naphthol. As summarized in Table 15, 1­ naphthol is categorized as moderately to highly toxic to aquatic organisms on an acute basis, LC50 values ranging from 0.75 to 1.6 ppm for freshwater fish, from 1.2 to 1.8 ppm for estuarine/ marine fish, from 0.70 to 0.73 ppm for freshwater invertebrates, and from 0.21 to 2.5 ppm for estuarine/ marine invertebrates. Terrestrial Plants Toxicity testing of terrestrial plants is required for non­ herbicide pesticides when the label warns that nontarget plants could be adversely affected. Carbaryl can be used as a fruit thinning agent on apples and pears. However, the label cautions that the product may result in fruit deformity under certain environmental conditions. The label also cautions that application to wet foliage or during periods of high humidity may cause injury to tender foliage. Label language indicates that carbaryl should not be used on Boston ivy, Virginia creeper, and maidenhair fern due to potential injury. Incidents have also been recorded for vegetable crops (tomatoes, potatoes, cabbage, broccoli, pumpkin, squash, cucumbers) in New York and Pennsylvania (# 1009262­ 128; #1009305­ 001). Guideline 122­ 1 is not fulfilled. ­177­ Table 15 Summary of aquatic organisms acute toxicity for carbaryl degradate alpha naphthol Species 96­ hour LC50 (ppm) (nominal) Toxicity Category MRID No. Author/ Year Study Classification Rainbow Trout (Oncorhynchus mykiss) 1.4 Moderately Toxic 40955204 Surprenant (1988) Core Rainbow Trout (Oncorhynchus mykiss) 1.6 Moderately Toxic 00164307 Surprenant (1986) Supplemental Bluegill Sunfish (Lepomis macrochirus) 0.76 Highly Toxic 40955203 Surprenant (1988) Core Bluegill Sunfish (Lepomis macrochirus) 0.75 Highly Toxic 00164305 Surprenant (1986) Supplemental Sheepshead Minnow (Cyprinodon variegatus) 1.2 Moderately Toxic 40955201 Surprenant (1988) Core Sheepshead Minnow (Cyprinodon variegatus) 1.8 Moderately Toxic 00164306 Surprenant (1986) Supplemental Waterflea (Daphnia magna) 48 hr LC50 = 0.73 Highly Toxic 40955205 Surprenant (1988) Core Waterflea (Daphnia magna) 48 hr LC50 = 0.70 Highly Toxic 00164310 Surprenant (1986) Supplemental Mysid (Mysidopsis bahia) 0.21 Highly Toxic 40955202 Surprenant (1988) Core Mysid (Mysidopsis bahia) 0.20 Highly Toxic 00164309 Surprenant (1986) Supplemental Eastern Oyster (Crassostrea virginica) 48 hr LC50 = 2.1 Moderately Toxic 00164308 Surprenant (1986) Core Aquatic Plants Aquatic plant testing is recommended for all pesticides having outdoor uses (Keehner. July 1999). The tests are performed on species from a cross­ section of the nontarget aquatic plant population. The preferred test species are duckweed (Lemna gibba), marine diatom (Skeletonema costatum), freshwater blue­ green algae (Anabaena flos­ aquae), freshwater green alga (Selenastrum capricornutum), and a freshwater diatom. Toxicity testing for aquatic plant species is required for carbaryl because of its registered forestry uses. Data based on a single available core toxicity study with the green alga Pseudokirchneria subcapitata (formerly Selenastrum capricornutum) indicates that the LC50 and NOAEC are, respectively, 1.1 ppm and 0.37 ppm (MRID #42372802). Guideline 122­ 2 is not fulfilled. ­178­ Appendix D: ELL­ FATE ­ Description and example worksheet ELL­ Fate Version 1.2 Developed by Laurence Libelo. February, 1999 This spreadsheet based model calculates the decay of a chemical applied to foliar surfaces for single or multiple applications. I t uses the same principle as the batch code models FATE and TERREEC for calculating terrestrial estimates exposure (TEEC) concentrations on plant surfaces following application. A first order decay assumption is used to determine the concentration at each day after initial application based on the concentration resulting from the initial and additional applications. The decay is calculated by from the first order rate equation: CT = Cie ­kT or in integrated form: ln (CT/ Ci) = kT Where CT = concentration at time T Ci = initial concentration k = reaction rate constant T = time The program calculates concentration on each type of surface on a daily interval for one year. The maximum concentration during the year and the average concentration during the first 56 days are calculated. The inputs used to calculate the amount of the chemical present are in highlighted in yellow on the spread sheet. Outputs are in blue. The inputs required are: Application Rate: Half­ life: Frequency of Application: Maximum # Application per year: The calculated concentrations are used to calculate Avian and Mammalian RQ values. The maximum calculated concentration is divided by user input values of Chronic No Observable Adverse Effects Level and acute LC50 to give RQs for each type of plant surface. The rat LC 50 is calculated by dividing the mammalian LD 50 by 0.05 (to correct for actual food consumption) For 15g, 35g and 1000 g mammals the RQ values are calculated by dividing the maximum concentration for each surface by the LD 50 or NOAEL corrected for consumption (0.95, 0.66 and .15 body wt. for herbivores and ) insectivores and 0.21, 0.15 and 0.3 body wt. for granivore) The number of days that the input value of Chronic No Observable Adverse Effects Level and acute LC50 are exceeded in the first 56 days is calculated by comparing the input value to the calculated concentration. A graph of concentration on each plant surface vs time is plotted and a "level of concern" line can be added at a user specified level. The maximum single application which can be applied and not exceed the toxicity input values if calculated by dividing the input value by the Kenaga maximum concentration for Short Grass (240). ­179­ Carbaryl Chemical Name: Citrus Use Formulation Inputs lbs a. i./ acre 5 Application Rate days 35 Half­ life days 14 Frequency of Application 4 Maximum # Apps./ Year Outputs 56 day Average Maximum Concentration Concentration (PPM) (PPM) 2079.15 3320.98 Short Grass # days 952.94 1522.12 Tall Grass Exceeded 1169.52 1868.05 Broadleaf plants/ Insects on short grass 129.95 207.56 Seeds (in first 56) 0 5000 Acute LC 50 (ppm) Avian Max Single Application 56 300 Chronic NOAEC (ppm) which does NOT exceed 20.833 Avian Acute Chronic RQ Acute RQ (lb a. i.) 1.250 Avian Chronic (Max. res. mult. apps.) 11.07 0.66 Short Grass 8.36 Mammalian Acute # days 5.07 0.30 Tall Grass 0.33 Mammalian Chronic Exceeded 6.23 0.37 Broadleaf plants/ Insects on short grass 0.69 0.04 Seeds (in first 56) 6020 Rat Calculated LC 50 (ppm) 56 301 Acute LD 50 (mg/ kg) Mammalian 56 80 Chronic NOAEL (mg/ kg) 1000 g mammal 35 g mammal 15 g mammal Rat Chronic Rat Acute Dietary Dietary Acute RQ Acute RQ Acute RQ RQ RQ (mult. apps) (mult. apps) (mult. apps) 41.51 0.55 1.65 7.28 10.48 Short Grass 19.03 0.25 0.76 3.34 4.80 Broadleaf plants/ insects 23.35 0.31 0.93 4.10 5.90 Large Insects 2.59 0.03 0.02 0.10 0.14 Seeds (granivore) ­180­ Appendix E: Examples of PRZM Standard Pond Input Files *** PRZM3 Input File for INDEX RESERVOIR, IROHCORN1. inp converted 3/ 30/ 2000 *** *** Modeler: S. Abel *** *** Modified for CARBARYL by Laurence Libelo, 6/ 20/ 00 (standard pond on 7/ 14/ 2000) *** Manning's N values for cornstalk residue, fallow surface, 1 ton/ acre *** *** Cardington silt loam is not one of the benchmark soils *** *** Benchmark soils include: blount; crosby; pewamo; miami; brookston; glynwood *** *** miamian; morley; bennington; and fincastle *** *** IR Spray Drift: Aerial: 0.16; Orchard air blast: 0.063; Ground spray: 0.064 *** *** Standard Pond Spray Drift: Aerial = 0.05; Ground spray = 0.01 *** Application efficiency: aerial = 0.95; ground spray = 0.99 *** *** PCA for corn = 0.46 *** CARBARYL Location: OH Crop: corn MLRA 111 *** ­ RECORD 3 *** 0.72 0.30 0 15.00 1 3 *** ­ RECORED 4 *** 4 *** ­ RECORD 7 *** 0.37 0.43 0.50 10.0 5.80 3 6.00 354.0 *** ­ RECORD 8 *** 1 *** ­ RECORD 9 *** 1 0.25 90.00 100.00 3 91 85 88 0.00 100.00 *** ­ RECORD 9A *** 1 3 *** ­ RECORD 9B, C, D 0101 1605 1110 0.50 0.25 0.30 0.02 0.02 0.02 *** ­ RECORD 10 *** 36 *** ­ RECORD 11 * 160548 260948 111048 1 160549 260949 111049 1 160550 260950 111050 1 160551 260951 111051 1 160552 260952 111052 1 160553 260953 111053 1 160554 260954 111054 1 160555 260955 111055 1 160556 260956 111056 1 160557 260957 111057 1 160558 260958 111058 1 160559 260959 111059 1 160560 260960 111060 1 160561 260961 111061 1 160562 260962 111062 1 160563 260963 111063 1 160564 260964 111064 1 160565 260965 111065 1 160566 260966 111066 1 160567 260967 111067 1 160568 260968 111068 1 160569 260969 111069 1 160570 260970 111070 1 160571 260971 111071 1 160572 260972 111072 1 160573 260973 111073 1 160574 260974 111074 1 160575 260975 111075 1 160576 260976 111076 1 160577 260977 111077 1 160578 260978 111078 1 160579 260979 111079 1 160580 260980 111080 1 160581 260981 111081 1 160582 260982 111082 1 160583 260983 111083 1 *** ­ RECORD 12 *** "average" Application: ground spray ­ 2 apps @ 3.4 lb a. i./ acre *** Application by ground spray ­ 8 apps @ 2 lb a. i./ acre *** ­ RECORD 13 *** 108 1 0 0 *** ­ RECORD ­ 15 *** ­181­ Carbaryl Chemical Kd: 3.0 (Silt Loam Soil); ASM T1/ 2 = 12 days; AnSM T1/ 2 = 24 days *** ­ RECORD 16 *** 300448 0 2 0.00 1.12 0.95 0.05 140548 0 2 0.00 1.12 0.95 0.05 280548 0 2 0.00 1.12 0.95 0.05 300449 0 2 0.00 1.12 0.95 0.05 140549 0 2 0.00 1.12 0.95 0.05 280549 0 2 0.00 1.12 0.95 0.05 300450 0 2 0.00 1.12 0.95 0.05 140550 0 2 0.00 1.12 0.95 0.05 280550 0 2 0.00 1.12 0.95 0.05 300451 0 2 0.00 1.12 0.95 0.05 140551 0 2 0.00 1.12 0.95 0.05 280551 0 2 0.00 1.12 0.95 0.05 300452 0 2 0.00 1.12 0.95 0.05 140552 0 2 0.00 1.12 0.95 0.05 280552 0 2 0.00 1.12 0.95 0.05 300453 0 2 0.00 1.12 0.95 0.05 140553 0 2 0.00 1.12 0.95 0.05 280553 0 2 0.00 1.12 0.95 0.05 300454 0 2 0.00 1.12 0.95 0.05 140554 0 2 0.00 1.12 0.95 0.05 280554 0 2 0.00 1.12 0.95 0.05 300455 0 2 0.00 1.12 0.95 0.05 140555 0 2 0.00 1.12 0.95 0.05 280555 0 2 0.00 1.12 0.95 0.05 300456 0 2 0.00 1.12 0.95 0.05 140556 0 2 0.00 1.12 0.95 0.05 280556 0 2 0.00 1.12 0.95 0.05 300457 0 2 0.00 1.12 0.95 0.05 140557 0 2 0.00 1.12 0.95 0.05 280557 0 2 0.00 1.12 0.95 0.05 300458 0 2 0.00 1.12 0.95 0.05 140558 0 2 0.00 1.12 0.95 0.05 280558 0 2 0.00 1.12 0.95 0.05 300459 0 2 0.00 1.12 0.95 0.05 140559 0 2 0.00 1.12 0.95 0.05 280559 0 2 0.00 1.12 0.95 0.05 300460 0 2 0.00 1.12 0.95 0.05 140560 0 2 0.00 1.12 0.95 0.05 280560 0 2 0.00 1.12 0.95 0.05 300461 0 2 0.00 1.12 0.95 0.05 140561 0 2 0.00 1.12 0.95 0.05 280561 0 2 0.00 1.12 0.95 0.05 300462 0 2 0.00 1.12 0.95 0.05 140562 0 2 0.00 1.12 0.95 0.05 280562 0 2 0.00 1.12 0.95 0.05 300463 0 2 0.00 1.12 0.95 0.05 140563 0 2 0.00 1.12 0.95 0.05 280563 0 2 0.00 1.12 0.95 0.05 300464 0 2 0.00 1.12 0.95 0.05 140564 0 2 0.00 1.12 0.95 0.05 280564 0 2 0.00 1.12 0.95 0.05 300465 0 2 0.00 1.12 0.95 0.05 140565 0 2 0.00 1.12 0.95 0.05 280565 0 2 0.00 1.12 0.95 0.05 300466 0 2 0.00 1.12 0.95 0.05 140566 0 2 0.00 1.12 0.95 0.05 280566 0 2 0.00 1.12 0.95 0.05 300467 0 2 0.00 1.12 0.95 0.05 140567 0 2 0.00 1.12 0.95 0.05 280567 0 2 0.00 1.12 0.95 0.05 300468 0 2 0.00 1.12 0.95 0.05 140568 0 2 0.00 1.12 0.95 0.05 280568 0 2 0.00 1.12 0.95 0.05 300469 0 2 0.00 1.12 0.95 0.05 140569 0 2 0.00 1.12 0.95 0.05 280569 0 2 0.00 1.12 0.95 0.05 300470 0 2 0.00 1.12 0.95 0.05 140570 0 2 0.00 1.12 0.95 0.05 280570 0 2 0.00 1.12 0.95 0.05 300471 0 2 0.00 1.12 0.95 0.05 140571 0 2 0.00 1.12 0.95 0.05 280571 0 2 0.00 1.12 0.95 0.05 300472 0 2 0.00 1.12 0.95 0.05 140572 0 2 0.00 1.12 0.95 0.05 280572 0 2 0.00 1.12 0.95 0.05 300473 0 2 0.00 1.12 0.95 0.05 140573 0 2 0.00 1.12 0.95 0.05 280573 0 2 0.00 1.12 0.95 0.05 ­182­ 300474 0 2 0.00 1.12 0.95 0.05 140574 0 2 0.00 1.12 0.95 0.05 280574 0 2 0.00 1.12 0.95 0.05 300475 0 2 0.00 1.12 0.95 0.05 140575 0 2 0.00 1.12 0.95 0.05 280575 0 2 0.00 1.12 0.95 0.05 300476 0 2 0.00 1.12 0.95 0.05 140576 0 2 0.00 1.12 0.95 0.05 280576 0 2 0.00 1.12 0.95 0.05 300477 0 2 0.00 1.12 0.95 0.05 140577 0 2 0.00 1.12 0.95 0.05 280577 0 2 0.00 1.12 0.95 0.05 300478 0 2 0.00 1.12 0.95 0.05 140578 0 2 0.00 1.12 0.95 0.05 280578 0 2 0.00 1.12 0.95 0.05 300479 0 2 0.00 1.12 0.95 0.05 140579 0 2 0.00 1.12 0.95 0.05 280579 0 2 0.00 1.12 0.95 0.05 300480 0 2 0.00 1.12 0.95 0.05 140580 0 2 0.00 1.12 0.95 0.05 280580 0 2 0.00 1.12 0.95 0.05 300481 0 2 0.00 1.12 0.95 0.05 140581 0 2 0.00 1.12 0.95 0.05 280581 0 2 0.00 1.12 0.95 0.05 300482 0 2 0.00 1.12 0.95 0.05 140582 0 2 0.00 1.12 0.95 0.05 280582 0 2 0.00 1.12 0.95 0.05 300483 0 2 0.00 1.12 0.95 0.05 140583 0 2 0.00 1.12 0.95 0.05 280583 0 2 0.00 1.12 0.95 0.05 *** ­ Record 17 *** 0.0 3 0 *** ­ RECORD 18 *** 0.0 0.0 0.00 *** ­ RECORD 19 *** Soil Series: Cardington silt loam; Hydrogic Group C *** ­ RECORD 20 *** 100.00 0 0 0 0 0 0 0 0 0 *** ­ RECORD 26 *** 0.00 0.00 00.00 *** ­ RECORD 33 *** 2 *** RECORD 34,36,37 1 22.000 1.600 0.294 0.000 0.000 0.000 0.058 0.058 0.000 0.200 0.294 0.086 1.160 3.0 2 78.000 1.650 0.147 0.000 0.000 0.000 0.029 0.029 0.000 1.000 0.147 0.087 0.174 3.0 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­ 7 YEAR PRCP TSER 0 0 RUNF TSER 0 0 INFL TSER 1 1 ESLS TSER 0 0 1. E3 RFLX TSER 0 0 1. E5 EFLX TSER 0 0 1. E5 RZFX TSER 0 0 1. E5 *** PRZM3 Input File for INDEX RESERVOIR, IROHCORN1. inp converted 3/ 30/ 2000 *** *** Modeler: S. Abel *** *** Modified for CARBARYL by Laurence Libelo, 6/ 20/ 00 (standard pond on 7/ 14/ 2000) *** *** Use rate changed to QUA (July 21, 1998 QUA Report) AVERAGE VALUES on 2/ 23/ 01 *** *** Manning's N values for cornstalk residue, fallow surface, 1 ton/ acre *** *** Cardington silt loam is not one of the benchmark soils *** *** Benchmark soils include: blount; crosby; pewamo; miami; brookston; glynwood *** *** miamian; morley; bennington; and fincastle *** *** IR Spray Drift: Aerial: 0.16; Orchard air blast: 0.063; Ground spray: 0.064 *** *** Standard Pond Spray Drift: Aerial = 0.05; Ground spray = 0.01 *** Application efficiency: aerial = 0.95; ground spray = 0.99 *** *** PCA for corn = 0.46 *** CARBARYL Location: OH Crop: corn MLRA 111 *** ­ RECORD 3 *** 0.72 0.30 0 15.00 1 3 *** ­ RECORED 4 *** ­183­ 4 *** ­ RECORD 7 *** 0.37 0.43 0.50 10.0 5.80 3 6.00 354.0 *** ­ RECORD 8 *** 1 *** ­ RECORD 9 *** 1 0.25 90.00 100.00 3 91 85 88 0.00 100.00 *** ­ RECORD 9A *** 1 3 *** ­ RECORD 9B, C, D 0101 1605 1110 0.50 0.25 0.30 0.02 0.02 0.02 *** ­ RECORD 10 *** 36 *** ­ RECORD 11 * 160548 260948 111048 1 160549 260949 111049 1 160550 260950 111050 1 160551 260951 111051 1 160552 260952 111052 1 160553 260953 111053 1 160554 260954 111054 1 160555 260955 111055 1 160556 260956 111056 1 160557 260957 111057 1 160558 260958 111058 1 160559 260959 111059 1 160560 260960 111060 1 160561 260961 111061 1 160562 260962 111062 1 160563 260963 111063 1 160564 260964 111064 1 160565 260965 111065 1 160566 260966 111066 1 160567 260967 111067 1 160568 260968 111068 1 160569 260969 111069 1 160570 260970 111070 1 160571 260971 111071 1 160572 260972 111072 1 160573 260973 111073 1 160574 260974 111074 1 160575 260975 111075 1 160576 260976 111076 1 160577 260977 111077 1 160578 260978 111078 1 160579 260979 111079 1 160580 260980 111080 1 160581 260981 111081 1 160582 260982 111082 1 160583 260983 111083 1 *** ­ RECORD 12 *** Application by ground spray Rate = "average" from QUA memo (July 21, 1998) ­ 2 apps @ 1 lb a. i./ acre *** Application by ground spray ­ 8 apps @ 2 lb a. i./ acre *** ­ RECORD 13 *** 72 1 0 0 *** ­ RECORD ­ 15 *** Carbaryl Chemical Kd: 3.0 (Silt Loam Soil); ASM T1/ 2 = 12 days; AnSM T1/ 2 = 24 days *** ­ RECORD 16 *** 300448 0 2 0.00 1.68 0.95 0.05 140548 0 2 0.00 1.68 0.95 0.05 300449 0 2 0.00 1.68 0.95 0.05 140549 0 2 0.00 1.68 0.95 0.05 300450 0 2 0.00 1.68 0.95 0.05 140550 0 2 0.00 1.68 0.95 0.05 300451 0 2 0.00 1.68 0.95 0.05 140551 0 2 0.00 1.68 0.95 0.05 300452 0 2 0.00 1.68 0.95 0.05 140552 0 2 0.00 1.68 0.95 0.05 300453 0 2 0.00 1.68 0.95 0.05 140553 0 2 0.00 1.68 0.95 0.05 300454 0 2 0.00 1.68 0.95 0.05 140554 0 2 0.00 1.68 0.95 0.05 300455 0 2 0.00 1.68 0.95 0.05 140555 0 2 0.00 1.68 0.95 0.05 ­184­ 300456 0 2 0.00 1.68 0.95 0.05 140556 0 2 0.00 1.68 0.95 0.05 300457 0 2 0.00 1.68 0.95 0.05 140557 0 2 0.00 1.68 0.95 0.05 300458 0 2 0.00 1.68 0.95 0.05 140558 0 2 0.00 1.68 0.95 0.05 300459 0 2 0.00 1.68 0.95 0.05 140559 0 2 0.00 1.68 0.95 0.05 300460 0 2 0.00 1.68 0.95 0.05 140560 0 2 0.00 1.68 0.95 0.05 300461 0 2 0.00 1.68 0.95 0.05 140561 0 2 0.00 1.68 0.95 0.05 300462 0 2 0.00 1.68 0.95 0.05 140562 0 2 0.00 1.68 0.95 0.05 300463 0 2 0.00 1.68 0.95 0.05 140563 0 2 0.00 1.68 0.95 0.05 300464 0 2 0.00 1.68 0.95 0.05 140564 0 2 0.00 1.68 0.95 0.05 300465 0 2 0.00 1.68 0.95 0.05 140565 0 2 0.00 1.68 0.95 0.05 300466 0 2 0.00 1.68 0.95 0.05 140566 0 2 0.00 1.68 0.95 0.05 300467 0 2 0.00 1.68 0.95 0.05 140567 0 2 0.00 1.68 0.95 0.05 300468 0 2 0.00 1.68 0.95 0.05 140568 0 2 0.00 1.68 0.95 0.05 300469 0 2 0.00 1.68 0.95 0.05 140569 0 2 0.00 1.68 0.95 0.05 300470 0 2 0.00 1.68 0.95 0.05 140570 0 2 0.00 1.68 0.95 0.05 300471 0 2 0.00 1.68 0.95 0.05 140571 0 2 0.00 1.68 0.95 0.05 300472 0 2 0.00 1.68 0.95 0.05 140572 0 2 0.00 1.68 0.95 0.05 300473 0 2 0.00 1.68 0.95 0.05 140573 0 2 0.00 1.68 0.95 0.05 300474 0 2 0.00 1.68 0.95 0.05 140574 0 2 0.00 1.68 0.95 0.05 300475 0 2 0.00 1.68 0.95 0.05 140575 0 2 0.00 1.68 0.95 0.05 300476 0 2 0.00 1.68 0.95 0.05 140576 0 2 0.00 1.68 0.95 0.05 300477 0 2 0.00 1.68 0.95 0.05 140577 0 2 0.00 1.68 0.95 0.05 300478 0 2 0.00 1.68 0.95 0.05 140578 0 2 0.00 1.68 0.95 0.05 300479 0 2 0.00 1.68 0.95 0.05 140579 0 2 0.00 1.68 0.95 0.05 300480 0 2 0.00 1.68 0.95 0.05 140580 0 2 0.00 1.68 0.95 0.05 300481 0 2 0.00 1.68 0.95 0.05 140581 0 2 0.00 1.68 0.95 0.05 300482 0 2 0.00 1.68 0.95 0.05 140582 0 2 0.00 1.68 0.95 0.05 300483 0 2 0.00 1.68 0.95 0.05 140583 0 2 0.00 1.68 0.95 0.05 *** ­ Record 17 *** 0.0 3 0 *** ­ RECORD 18 *** 0.0 0.0 0.00 *** ­ RECORD 19 *** Soil Series: Cardington silt loam; Hydrogic Group C *** ­ RECORD 20 *** 100.00 0 0 0 0 0 0 0 0 0 *** ­ RECORD 26 *** 0.00 0.00 00.00 *** ­ RECORD 33 *** 2 *** RECORD 34,36,37 1 22.000 1.600 0.294 0.000 0.000 0.000 0.058 0.058 0.000 0.200 0.294 0.086 1.160 3.0 2 78.000 1.650 0.147 0.000 0.000 0.000 0.029 0.029 0.000 1.000 0.147 0.087 0.174 3.0 ­185­ 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­ 7 YEAR PRCP TSER 0 0 RUNF TSER 0 0 INFL TSER 1 1 ESLS TSER 0 0 1. E3 RFLX TSER 0 0 1. E5 EFLX TSER 0 0 1. E5 RZFX TSER 0 0 1. E5 ­186­ *** PRZM 3.1 Input Data File; ORAPPLEX. INP; Modified April 5, 1998 *** *** Modified for Carbaryl by Laurence Libelo, 6/ 21/ 00 *** *** Use rate changed to QUA (July 21, 1998 QUA Report) AVERAGE VALUES on 2/ 23/ 01 *** *** Crops simulated: Apples, Crabapples, and Quince *** *** Location Washington County, Oregon; Meadow/ Orchard Scenario; MLRA: A2 *** *** Manning's N: Assume sparse grass under mature trees (ca. 20 feet) *** *** Temperature data read *** *** This file is for scenario standardization; Reference chemical is Atrazine *** *** See ORAPPLEX. wpd for scenario details *** Carbaryl Cornelius silt loam, 15% slope, Hydrologic Group: C 0.740 0.150 2 17.000 1 3 9.2 10.3 11.8 13.6 15.30 15.3 14.2 12.5 10.9 9.4 8.6 9.1 4 0.43 3.30 1.0 10.0 5.4 2 15.00 354.0 1 1 0.25 17.0 100.000 3 91 71 71 0.0 600 1 3 0103 0105 0112 0.01 0.01 0.01 0.015 0.015 0.015 36 010448 150548 151248 1 010449 150549 151249 1 010450 150550 151250 1 010451 150551 151251 1 010452 150552 151252 1 010453 150553 151253 1 010454 150554 151254 1 010455 150555 151255 1 010456 150556 151256 1 010457 150557 151257 1 010458 150558 151258 1 010459 150559 151259 1 010460 150560 151260 1 010461 150561 151261 1 010462 150562 151262 1 010463 150563 151263 1 010464 150564 151264 1 010465 150565 151265 1 010466 150566 151266 1 010467 150567 151267 1 010468 150568 151268 1 010469 150569 151269 1 010470 150570 151270 1 010471 150571 151271 1 010472 150572 151272 1 010473 150573 151273 1 010474 150574 151274 1 010475 150575 151275 1 010476 150576 151276 1 010477 150577 151277 1 010478 150578 151278 1 010479 150579 151279 1 010480 150580 151280 1 010481 150581 151281 1 010482 150582 151282 1 010483 150583 151283 1 The label max used (5 apps of 2 lb a. i./ acre (3.3 kg/ ha)) *** Aerial Application: , Aerial @ 95% eff. w/ 5% drift 180 1 0 0 Chemical Kd: 3.0 (silt Loam soil); AeSM: T1/ 2: 12 days; AnSM: T1/ 2 = 24 days *** Record 16: Application information; set specific to carbaryl *** 300448 0 2 0.00 2.24 0.95 0.05 140548 0 2 0.00 2.24 0.95 0.05 280548 0 2 0.00 2.24 0.95 0.05 110648 0 2 0.00 2.24 0.95 0.05 250648 0 2 0.00 2.24 0.95 0.05 300449 0 2 0.00 2.24 0.95 0.05 140549 0 2 0.00 2.24 0.95 0.05 280549 0 2 0.00 2.24 0.95 0.05 110649 0 2 0.00 2.24 0.95 0.05 250649 0 2 0.00 2.24 0.95 0.05 300450 0 2 0.00 2.24 0.95 0.05 140550 0 2 0.00 2.24 0.95 0.05 ­187­ 280550 0 2 0.00 2.24 0.95 0.05 110650 0 2 0.00 2.24 0.95 0.05 250650 0 2 0.00 2.24 0.95 0.05 300451 0 2 0.00 2.24 0.95 0.05 140551 0 2 0.00 2.24 0.95 0.05 280551 0 2 0.00 2.24 0.95 0.05 110651 0 2 0.00 2.24 0.95 0.05 250651 0 2 0.00 2.24 0.95 0.05 300452 0 2 0.00 2.24 0.95 0.05 140552 0 2 0.00 2.24 0.95 0.05 280552 0 2 0.00 2.24 0.95 0.05 110652 0 2 0.00 2.24 0.95 0.05 250652 0 2 0.00 2.24 0.95 0.05 300453 0 2 0.00 2.24 0.95 0.05 140553 0 2 0.00 2.24 0.95 0.05 280553 0 2 0.00 2.24 0.95 0.05 110653 0 2 0.00 2.24 0.95 0.05 250653 0 2 0.00 2.24 0.95 0.05 300454 0 2 0.00 2.24 0.95 0.05 140554 0 2 0.00 2.24 0.95 0.05 280554 0 2 0.00 2.24 0.95 0.05 110654 0 2 0.00 2.24 0.95 0.05 250654 0 2 0.00 2.24 0.95 0.05 300455 0 2 0.00 2.24 0.95 0.05 140555 0 2 0.00 2.24 0.95 0.05 280555 0 2 0.00 2.24 0.95 0.05 110655 0 2 0.00 2.24 0.95 0.05 250655 0 2 0.00 2.24 0.95 0.05 300456 0 2 0.00 2.24 0.95 0.05 140556 0 2 0.00 2.24 0.95 0.05 280556 0 2 0.00 2.24 0.95 0.05 110656 0 2 0.00 2.24 0.95 0.05 250656 0 2 0.00 2.24 0.95 0.05 300457 0 2 0.00 2.24 0.95 0.05 140557 0 2 0.00 2.24 0.95 0.05 280557 0 2 0.00 2.24 0.95 0.05 110657 0 2 0.00 2.24 0.95 0.05 250657 0 2 0.00 2.24 0.95 0.05 300458 0 2 0.00 2.24 0.95 0.05 140558 0 2 0.00 2.24 0.95 0.05 280558 0 2 0.00 2.24 0.95 0.05 110658 0 2 0.00 2.24 0.95 0.05 250658 0 2 0.00 2.24 0.95 0.05 300459 0 2 0.00 2.24 0.95 0.05 140559 0 2 0.00 2.24 0.95 0.05 280559 0 2 0.00 2.24 0.95 0.05 110659 0 2 0.00 2.24 0.95 0.05 250659 0 2 0.00 2.24 0.95 0.05 300460 0 2 0.00 2.24 0.95 0.05 140560 0 2 0.00 2.24 0.95 0.05 280560 0 2 0.00 2.24 0.95 0.05 110660 0 2 0.00 2.24 0.95 0.05 250660 0 2 0.00 2.24 0.95 0.05 300461 0 2 0.00 2.24 0.95 0.05 140561 0 2 0.00 2.24 0.95 0.05 280561 0 2 0.00 2.24 0.95 0.05 110661 0 2 0.00 2.24 0.95 0.05 250661 0 2 0.00 2.24 0.95 0.05 300462 0 2 0.00 2.24 0.95 0.05 140562 0 2 0.00 2.24 0.95 0.05 280562 0 2 0.00 2.24 0.95 0.05 110662 0 2 0.00 2.24 0.95 0.05 250662 0 2 0.00 2.24 0.95 0.05 300463 0 2 0.00 2.24 0.95 0.05 140563 0 2 0.00 2.24 0.95 0.05 280563 0 2 0.00 2.24 0.95 0.05 110663 0 2 0.00 2.24 0.95 0.05 250663 0 2 0.00 2.24 0.95 0.05 300464 0 2 0.00 2.24 0.95 0.05 140564 0 2 0.00 2.24 0.95 0.05 280564 0 2 0.00 2.24 0.95 0.05 110664 0 2 0.00 2.24 0.95 0.05 250664 0 2 0.00 2.24 0.95 0.05 300465 0 2 0.00 2.24 0.95 0.05 140565 0 2 0.00 2.24 0.95 0.05 280565 0 2 0.00 2.24 0.95 0.05 ­188­ 110665 0 2 0.00 2.24 0.95 0.05 250665 0 2 0.00 2.24 0.95 0.05 300466 0 2 0.00 2.24 0.95 0.05 140566 0 2 0.00 2.24 0.95 0.05 280566 0 2 0.00 2.24 0.95 0.05 110666 0 2 0.00 2.24 0.95 0.05 250666 0 2 0.00 2.24 0.95 0.05 300467 0 2 0.00 2.24 0.95 0.05 140567 0 2 0.00 2.24 0.95 0.05 280567 0 2 0.00 2.24 0.95 0.05 110667 0 2 0.00 2.24 0.95 0.05 250667 0 2 0.00 2.24 0.95 0.05 300468 0 2 0.00 2.24 0.95 0.05 140568 0 2 0.00 2.24 0.95 0.05 280568 0 2 0.00 2.24 0.95 0.05 110668 0 2 0.00 2.24 0.95 0.05 250668 0 2 0.00 2.24 0.95 0.05 300469 0 2 0.00 2.24 0.95 0.05 140569 0 2 0.00 2.24 0.95 0.05 280569 0 2 0.00 2.24 0.95 0.05 110669 0 2 0.00 2.24 0.95 0.05 250669 0 2 0.00 2.24 0.95 0.05 300470 0 2 0.00 2.24 0.95 0.05 140570 0 2 0.00 2.24 0.95 0.05 280570 0 2 0.00 2.24 0.95 0.05 110670 0 2 0.00 2.24 0.95 0.05 250670 0 2 0.00 2.24 0.95 0.05 300471 0 2 0.00 2.24 0.95 0.05 140571 0 2 0.00 2.24 0.95 0.05 280571 0 2 0.00 2.24 0.95 0.05 110671 0 2 0.00 2.24 0.95 0.05 250671 0 2 0.00 2.24 0.95 0.05 300472 0 2 0.00 2.24 0.95 0.05 140572 0 2 0.00 2.24 0.95 0.05 280572 0 2 0.00 2.24 0.95 0.05 110672 0 2 0.00 2.24 0.95 0.05 250672 0 2 0.00 2.24 0.95 0.05 300473 0 2 0.00 2.24 0.95 0.05 140573 0 2 0.00 2.24 0.95 0.05 280573 0 2 0.00 2.24 0.95 0.05 110673 0 2 0.00 2.24 0.95 0.05 250673 0 2 0.00 2.24 0.95 0.05 300474 0 2 0.00 2.24 0.95 0.05 140574 0 2 0.00 2.24 0.95 0.05 280574 0 2 0.00 2.24 0.95 0.05 110674 0 2 0.00 2.24 0.95 0.05 250674 0 2 0.00 2.24 0.95 0.05 300475 0 2 0.00 2.24 0.95 0.05 140575 0 2 0.00 2.24 0.95 0.05 280575 0 2 0.00 2.24 0.95 0.05 110675 0 2 0.00 2.24 0.95 0.05 250675 0 2 0.00 2.24 0.95 0.05 300476 0 2 0.00 2.24 0.95 0.05 140576 0 2 0.00 2.24 0.95 0.05 280576 0 2 0.00 2.24 0.95 0.05 110676 0 2 0.00 2.24 0.95 0.05 250676 0 2 0.00 2.24 0.95 0.05 300477 0 2 0.00 2.24 0.95 0.05 140577 0 2 0.00 2.24 0.95 0.05 280577 0 2 0.00 2.24 0.95 0.05 110677 0 2 0.00 2.24 0.95 0.05 250677 0 2 0.00 2.24 0.95 0.05 300478 0 2 0.00 2.24 0.95 0.05 140578 0 2 0.00 2.24 0.95 0.05 280578 0 2 0.00 2.24 0.95 0.05 110678 0 2 0.00 2.24 0.95 0.05 250678 0 2 0.00 2.24 0.95 0.05 300479 0 2 0.00 2.24 0.95 0.05 140579 0 2 0.00 2.24 0.95 0.05 280579 0 2 0.00 2.24 0.95 0.05 110679 0 2 0.00 2.24 0.95 0.05 250679 0 2 0.00 2.24 0.95 0.05 300480 0 2 0.00 2.24 0.95 0.05 140580 0 2 0.00 2.24 0.95 0.05 280580 0 2 0.00 2.24 0.95 0.05 110680 0 2 0.00 2.24 0.95 0.05 250680 0 2 0.00 2.24 0.95 0.05 300481 0 2 0.00 2.24 0.95 0.05 ­189­ 140581 0 2 0.00 2.24 0.95 0.05 280581 0 2 0.00 2.24 0.95 0.05 110681 0 2 0.00 2.24 0.95 0.05 250681 0 2 0.00 2.24 0.95 0.05 300482 0 2 0.00 2.24 0.95 0.05 140582 0 2 0.00 2.24 0.95 0.05 280582 0 2 0.00 2.24 0.95 0.05 110682 0 2 0.00 2.24 0.95 0.05 250682 0 2 0.00 2.24 0.95 0.05 300483 0 2 0.00 2.24 0.95 0.05 140583 0 2 0.00 2.24 0.95 0.05 280583 0 2 0.00 2.24 0.95 0.05 110683 0 2 0.00 2.24 0.95 0.05 250683 0 2 0.00 2.24 0.95 0.05 *** Record 17: Filtra., disposit. foliar pest. after harvest, and plant uptake *** 0.0 3 0.0 *** Record 18: Foliar dissipation parameters *** 0.0 0.0 0.50 Cornelius silt loam, 15% slope, Hydrologic Group: C 148.0 0 0 0 0 0 0 0 0 0 *** Record 26: Soil volatilization constants *** 0.0 0.0 0.0 *** Record 33 *** 5 *** Record 34 *** 1 15.0 1.30 0.329 0.0 0.0 0.0 *** Record 36: Soil half­ life rate constants; repeat for each horizon *** 0.058 0.058 0.0 *** Record 37: *** 0.1 0.329 0.099 2.30 3.0 *** Record 39: Omitted; parent/ daughter transformation rates *** 2 13.0 1.38 0.338 0.0 0.0 0.0 0.029 0.029 0.0 1.0 0.338 0.108 1.11 3.0 3 15.0 1.58 0.340 0.0 0.0 0.0 0.029 0.029 0.0 1.0 0.340 0.110 0.21 3.0 4 55.0 1.52 0.358 0.0 0.0 0.0 0.029 0.029 0.0 5.0 0.358 0.148 0.145 3.0 5 50.0 1.46 0.202 0.0 0.0 0.0 0.029 0.029 0.0 5.0 0.202 0.142 0.07 3.0 0 YEAR 5 YEAR 5 YEAR 5 1 1 1 ­­­­ 6 YEAR PRCP TSER 0 0 RUNF TSER 0 0 ESLS TSER 0 0 1.0E3 RFLX TSER 0 0 1.0E5 EFLX TSER 0 0 1.0E5 RZFX TSER 0 0 1.0E5 ­190­ *** PRZM2 Version 3.12 Input Data File *** *** MNSUGAR1. inp Index Reservoir Scenario created on 12/ 13/ 99 *** *** Modified for CABRBARYL 6/ 21/ 00 by Laurence Libelo *** *** Bearden soil is a Benchmark soil with ca. 800K mapped acres in MLRA 56 *** *** Sugar beets, conventional tillage *** *** Highest acreage sugarbeet state is MN; highest county in MN is Polk *** *** Manning's N value set to 0.02 for residues applied to fallow surfaces *** *** Application timing information provided by Russ Severson (?), *** University of Minnesota Agricultural Extension Service, Polk County, MN, *** (218) 281­ 8696 *** PCA for sugarbeets not available, use default PCA of 0.87 *** Chemical: Carbaryl Bearden Silty Clay Loam; HYGP: C; MLRA F­ 56, Polk County, Minnesota 0.760 0.500 0 12.00 1 3 4 0.28 0.12 0.50 10 3 3.00 354.0 1 1 0.10 20.00 80.00 3 91 82 91 0.00 100.00 1 3 0101 1605 1110 0.43 0.18 0.43 0.02 0.02 0.02 36 160548 061048 161048 1 160549 061049 161049 1 160550 061050 161050 1 160551 061051 161051 1 160552 061052 161052 1 160553 061053 161053 1 160554 061054 161054 1 160555 061055 161055 1 160556 061056 161056 1 160557 061057 161057 1 160558 061058 161058 1 160559 061059 161059 1 160560 061060 161060 1 160561 061061 161061 1 160562 061062 161062 1 160563 061063 161063 1 160564 061064 161064 1 160565 061065 161065 1 160566 061066 161066 1 160567 061067 161067 1 160568 061068 161068 1 160569 061069 161069 1 160570 061070 161070 1 160571 061071 161071 1 160572 061072 161072 1 160573 061073 161073 1 160574 061074 161074 1 160575 061075 161075 1 160576 061076 161076 1 160577 061077 161077 1 160578 061078 161078 1 160579 061079 161079 1 160580 061080 161080 1 160581 061081 161081 1 160582 061082 161082 1 160583 061083 161083 1 Application Schedule: 2 aerial app @ 1.5 lb a. i./ acre (1.68 kg/ ha, 95% app. eff, 16% spray drift 72 1 0 0 Carbaryl: Kd: 3.0; AeSM: T1/ 2 = 12 days; AnSM: T1/ 2 = 24 days 300448 0 2 0.00 1.68 0.95 0.16 140548 0 2 0.00 1.68 0.95 0.16 300449 0 2 0.00 1.68 0.95 0.16 140549 0 2 0.00 1.68 0.95 0.16 300450 0 2 0.00 1.68 0.95 0.16 140550 0 2 0.00 1.68 0.95 0.16 300451 0 2 0.00 1.68 0.95 0.16 140551 0 2 0.00 1.68 0.95 0.16 300452 0 2 0.00 1.68 0.95 0.16 140552 0 2 0.00 1.68 0.95 0.16 300453 0 2 0.00 1.68 0.95 0.16 140553 0 2 0.00 1.68 0.95 0.16 300454 0 2 0.00 1.68 0.95 0.16 140554 0 2 0.00 1.68 0.95 0.16 ­191­ 300455 0 2 0.00 1.68 0.95 0.16 140555 0 2 0.00 1.68 0.95 0.16 300456 0 2 0.00 1.68 0.95 0.16 140556 0 2 0.00 1.68 0.95 0.16 300457 0 2 0.00 1.68 0.95 0.16 140557 0 2 0.00 1.68 0.95 0.16 300458 0 2 0.00 1.68 0.95 0.16 140558 0 2 0.00 1.68 0.95 0.16 300459 0 2 0.00 1.68 0.95 0.16 140559 0 2 0.00 1.68 0.95 0.16 300460 0 2 0.00 1.68 0.95 0.16 140560 0 2 0.00 1.68 0.95 0.16 300461 0 2 0.00 1.68 0.95 0.16 140561 0 2 0.00 1.68 0.95 0.16 300462 0 2 0.00 1.68 0.95 0.16 140562 0 2 0.00 1.68 0.95 0.16 300463 0 2 0.00 1.68 0.95 0.16 140563 0 2 0.00 1.68 0.95 0.16 300464 0 2 0.00 1.68 0.95 0.16 140564 0 2 0.00 1.68 0.95 0.16 300465 0 2 0.00 1.68 0.95 0.16 140565 0 2 0.00 1.68 0.95 0.16 300466 0 2 0.00 1.68 0.95 0.16 140566 0 2 0.00 1.68 0.95 0.16 300467 0 2 0.00 1.68 0.95 0.16 140567 0 2 0.00 1.68 0.95 0.16 300468 0 2 0.00 1.68 0.95 0.16 140568 0 2 0.00 1.68 0.95 0.16 300469 0 2 0.00 1.68 0.95 0.16 140569 0 2 0.00 1.68 0.95 0.16 300470 0 2 0.00 1.68 0.95 0.16 140570 0 2 0.00 1.68 0.95 0.16 300471 0 2 0.00 1.68 0.95 0.16 140571 0 2 0.00 1.68 0.95 0.16 300472 0 2 0.00 1.68 0.95 0.16 140572 0 2 0.00 1.68 0.95 0.16 300473 0 2 0.00 1.68 0.95 0.16 140573 0 2 0.00 1.68 0.95 0.16 300474 0 2 0.00 1.68 0.95 0.16 140574 0 2 0.00 1.68 0.95 0.16 300475 0 2 0.00 1.68 0.95 0.16 140575 0 2 0.00 1.68 0.95 0.16 300476 0 2 0.00 1.68 0.95 0.16 140576 0 2 0.00 1.68 0.95 0.16 300477 0 2 0.00 1.68 0.95 0.16 140577 0 2 0.00 1.68 0.95 0.16 300478 0 2 0.00 1.68 0.95 0.16 140578 0 2 0.00 1.68 0.95 0.16 300479 0 2 0.00 1.68 0.95 0.16 140579 0 2 0.00 1.68 0.95 0.16 300480 0 2 0.00 1.68 0.95 0.16 140580 0 2 0.00 1.68 0.95 0.16 300481 0 2 0.00 1.68 0.95 0.16 140581 0 2 0.00 1.68 0.95 0.16 300482 0 2 0.00 1.68 0.95 0.16 140582 0 2 0.00 1.68 0.95 0.16 300483 0 2 0.00 1.68 0.95 0.16 140583 0 2 0.00 1.68 0.95 0.16 0.0 3 0.00 0.0 0.00 0.50 Bearden Silty Clay Loam; Hydrologic Group C; 100.00 0 0 0 0 0 0 0 0 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 4 1 10.00 1.400 0.377 0.000 0.000 0.58 0.58 0.00 0.10 0.377 0.207 1.160 3.0 2 8.00 1.400 0.377 0.000 0.000 0.029 0.029 0.00 1.00 0.377 0.207 1.160 3.0 3 54.00 1.500 0.292 0.000 0.000 0.029 0.029 0.00 2.00 0.292 0.132 1.160 3.0 4 28.00 1.800 0.285 0.000 0.000 0.029 0.029 0.00 2.0 0.285 0.125 0.174 3.0 ­192­ 0 YEAR 5 YEAR 5 YEAR 5 1 1 1 ­­­­ 1 YEAR *** PRCP TSER 0 0*** RUNF TCUM 0 0 *** ESLS TSER 0 0 1.0E3*** *** RFLX TSER 0 0 1.0E5*** *** EFLX TSER 0 0 1.0E5*** *** RZFX TSER 0 0 1.0E5*** ­193­ PRZM3 Input File, flcit. inp (Jan 28 2000) *** original file source unknown *** *** Source of crop and soil data unknown *** *** modified for carbaryl by Laurence Libelo, 6/ 21/ 00 *** *** modifified for Standard Pond 7/ 17/ 2000 *** *** Use rate changed to QUA (July 21, 1998 QUA Report) AVERAGE VALUES on 2/ 23/ 01 *** Location: Osceola County, FL.; Crop: citrus; MLRA 156A 0.77 0.15 0 25.00 1 1 4 0.10 0.13 1.00 10.0 3 1.00 354.0 1 1 0.10 100.00 80.00 3 94 84 89 0.00 100.00 1 3 0101 21 9 2209 0.10 0.10 0.10 .023 .023 .023 36 110548 170748 10848 1 110549 170749 10849 1 110550 170750 10850 1 110551 170751 10851 1 110552 170752 10852 1 110553 170753 10853 1 110554 170754 10854 1 110555 170755 10855 1 110556 170756 10856 1 110557 170757 10857 1 110558 170758 10858 1 110559 170759 10859 1 110560 170760 10860 1 110561 170761 10861 1 110562 170762 10862 1 110563 170763 10863 1 110564 170764 10864 1 110565 170765 10865 1 110566 170766 10866 1 110567 170767 10867 1 110568 170768 10868 1 110569 170769 10869 1 110570 170770 10870 1 110571 170771 10871 1 110572 170772 10872 1 110573 170773 10873 1 110574 170774 10874 1 110575 170775 10875 1 110576 170776 10876 1 110577 170777 10877 1 110578 170778 10878 1 110579 170779 10879 1 110580 170780 10880 1 110581 170781 10881 1 110582 170782 10882 1 110583 170783 10883 1 Application at "average" value from QUA (July 21, 1998 QUA Report) 2 apps / 3.4 lb a. i. per app *** Application: 4 aerial appls @ 5 lb a. i./ ac/ year (5.6 kg/ ha) @95% eff, w/ 5% drift 72 1 0 0 CARBARYL on FL Cirtus 300448 0 2 0.00 3.81 0.95 0.05 140548 0 2 0.00 3.81 0.95 0.05 300449 0 2 0.00 3.81 0.95 0.05 140549 0 2 0.00 3.81 0.95 0.05 300450 0 2 0.00 3.81 0.95 0.05 140550 0 2 0.00 3.81 0.95 0.05 300451 0 2 0.00 3.81 0.95 0.05 140551 0 2 0.00 3.81 0.95 0.05 300452 0 2 0.00 3.81 0.95 0.05 140552 0 2 0.00 3.81 0.95 0.05 300453 0 2 0.00 3.81 0.95 0.05 140553 0 2 0.00 3.81 0.95 0.05 300454 0 2 0.00 3.81 0.95 0.05 140554 0 2 0.00 3.81 0.95 0.05 300455 0 2 0.00 3.81 0.95 0.05 140555 0 2 0.00 3.81 0.95 0.05 300456 0 2 0.00 3.81 0.95 0.05 140556 0 2 0.00 3.81 0.95 0.05 300457 0 2 0.00 3.81 0.95 0.05 ­194­ 140557 0 2 0.00 3.81 0.95 0.05 300458 0 2 0.00 3.81 0.95 0.05 140558 0 2 0.00 3.81 0.95 0.05 300459 0 2 0.00 3.81 0.95 0.05 140559 0 2 0.00 3.81 0.95 0.05 300460 0 2 0.00 3.81 0.95 0.05 140560 0 2 0.00 3.81 0.95 0.05 300461 0 2 0.00 3.81 0.95 0.05 140561 0 2 0.00 3.81 0.95 0.05 300462 0 2 0.00 3.81 0.95 0.05 140562 0 2 0.00 3.81 0.95 0.05 300463 0 2 0.00 3.81 0.95 0.05 140563 0 2 0.00 3.81 0.95 0.05 300464 0 2 0.00 3.81 0.95 0.05 140564 0 2 0.00 3.81 0.95 0.05 300465 0 2 0.00 3.81 0.95 0.05 140565 0 2 0.00 3.81 0.95 0.05 300466 0 2 0.00 3.81 0.95 0.05 140566 0 2 0.00 3.81 0.95 0.05 300467 0 2 0.00 3.81 0.95 0.05 140567 0 2 0.00 3.81 0.95 0.05 300468 0 2 0.00 3.81 0.95 0.05 140568 0 2 0.00 3.81 0.95 0.05 300469 0 2 0.00 3.81 0.95 0.05 140569 0 2 0.00 3.81 0.95 0.05 300470 0 2 0.00 3.81 0.95 0.05 140570 0 2 0.00 3.81 0.95 0.05 300471 0 2 0.00 3.81 0.95 0.05 140571 0 2 0.00 3.81 0.95 0.05 300472 0 2 0.00 3.81 0.95 0.05 140572 0 2 0.00 3.81 0.95 0.05 300473 0 2 0.00 3.81 0.95 0.05 140573 0 2 0.00 3.81 0.95 0.05 300474 0 2 0.00 3.81 0.95 0.05 140574 0 2 0.00 3.81 0.95 0.05 300475 0 2 0.00 3.81 0.95 0.05 140575 0 2 0.00 3.81 0.95 0.05 300476 0 2 0.00 3.81 0.95 0.05 140576 0 2 0.00 3.81 0.95 0.05 300477 0 2 0.00 3.81 0.95 0.05 140577 0 2 0.00 3.81 0.95 0.05 300478 0 2 0.00 3.81 0.95 0.05 140578 0 2 0.00 3.81 0.95 0.05 300479 0 2 0.00 3.81 0.95 0.05 140579 0 2 0.00 3.81 0.95 0.05 300480 0 2 0.00 3.81 0.95 0.05 140580 0 2 0.00 3.81 0.95 0.05 300481 0 2 0.00 3.81 0.95 0.05 140581 0 2 0.00 3.81 0.95 0.05 300482 0 2 0.00 3.81 0.95 0.05 140582 0 2 0.00 3.81 0.95 0.05 300483 0 2 0.00 3.81 0.95 0.05 140583 0 2 0.00 3.81 0.95 0.05 0. 1 0.00 0.000 0.50 Soil Series: Adamsville sand; Hydrogic Group C *** Kd for sandy loam = 1.7 100.00 0 0 0 0 0 0 0 0 0 00.0 0.00 00.00 3 1 10.000 1.440 0.086 0.000 0.000 0.000 .058 .058 0.000 0.100 0.086 0.036 0.580 1.7 2 10.000 1.440 0.086 0.000 0.000 0.000 .029 .029 0.000 1.000 0.086 0.036 0.580 1.7 3 80.000 1.580 0.030 0.000 0.000 0.000 .029 .029 0.000 5.000 0.030 0.023 0.116 1.7 0 WATR YEAR 10 PEST YEAR 10 CONC YEAR 10 1 6 11 ­­­­ 1 DAY RUNF TSER 0 0 1. E0 ­195­

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EPA-HQ-OPP-2002-0138-0013

Supporting & Related Material

Page 1 of 8 U. S. ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM PC Code No. 129106 DP Barcode: D279109 SUBJECT: EFED Review of Documents Relative to Section 24c Special Local Needs Registration of Carbaryl for Use on Oyster Beds. TO: Anthony Britten, Chemical Review Manager Betty Shackleford, Product Manager Special Review and Reregistration Division FROM: Thomas M. Steeger, Ph. D., Senior Biologist Environmental Risk Branch IV/ EFED (7507C) Through: Betsy Behl, Branch Chief Environmental Risk Branch IV/ EFED (7507C) The Environmental Fate and Effects Division (EFED) has completed its review of the materials submitted relative to the Section 24c Special Local Needs registration of carbaryl for use on oyster beds in Willapa Bay and Grays Harbor, Washington, to control ghost shrimp (Callianassa californiensis) and mud shrimp (Upogebia pugettensis). The documents included 1) a report on concentrations of carbaryl and its degradate (1­ naphthol) in marine sediments from sites treated with or adjacent areas treated with Sevin (Stonic 1999); 2) a fact sheet on chemicals of special concern in Washington State; 3) a memo from the State of Washington's Department of Ecology's review of data relevant to the environmental effects of applying Sevin ™ to control burrowing shrimp in Willapa Bay and Grays Harbor oyster beds; 4) a copy of the memorandum of agreement between the Washington State Department of Ecology, the Willapa/ Grays Harbor Oyster Growers' Association and other state government and private organizations; and 5) a Washington State Department of Ecology publication entitled Carbaryl Concentrations in Willapa Bay and Recommendations for Water Quality Guidelines (Johnson 2001). Except for more recent studies conducted by Washington State University and the Washington Department of Ecology, much of the older (pre­ 1996) data had procedural problems that limited the utility of the data. The more recent data indicate that carbaryl residues in the water column were generally at or below an effect threshold of 0.1 ug/ L Although large carbaryl applications can affect water quality in areas distant from spray sites, the Washington Department of Ecology concluded that "no widespread effects from carbaryl would be expected in Wallapa Bay after the end of the [carbaryl] application period." Carbaryl has been used on approximately 600 acres of Willapa Bay and 200 acres of Grays Harbor at a rate of 7.5 to 10 lbs/ acre/ year since the 1960's. Carbaryl is applied as a wettable powder Page 2 of 8 to tidelands at low low [Spring] tide primarily by helicopter; however, hand spraying is used in some instances. The label restricts aerial applications within 200 feet of a channel or slough; hand spraying is prohibited within 50 feet of a channel or slough. The data collected and/ or reviewed by the Washington Department of Ecology indicate that carbaryl residues drop below the level of quantitation (< 0.004 ug/ L) approximately 6 weeks after application. While concentrations in nontarget areas immediately following the carbaryl application period are likely to inflict mortality to aquatic organisms, no data are provided to demonstrate that threatened and/ or endangered species (e. g. salmonids) are adversely affected by the treatments to oyster beds. While these documents provide additional information on the environmental fate and effects of carbaryl in estuarine/ marine environments, EFED's review of Washington's Section 24c petition was based on the required guideline fate and effects data provided by the registrant in support of the reregistration of carbaryl. Although the EFED reregistration eligibility document (RED) for carbaryl does not estimate environmental concentrations for applications directly to tidelands for control of burrowing shrimp in oyster culture, it does discuss the use. Data submitted in support of reregistration (MRID 419826­ 06) indicate that estuarine/ marine invertebrates will likely be impacted by this route of exposure and that certain species, e. g., Dungenese crab (Cancer magister), may experience 100% mortality in the application area. However, the assessment goes on to note that effects on aquatic invertebrates will likely be temporary as most populations show signs of recovery within 2 months. Additionally, the chapter suggests that carbaryl applications that reduce the potential for drift to nontarget sites, such as direct injection of carbaryl into the sediment, may help mitigate nontarget effects. Review of Submitted Literature 1) Screening Survey of Carbaryl (Sevin) and 1­ naphthol Concentrations in Willapa Bay Sediments The study was undertaken to determine the long­ term persistence of carbaryl and 1­ naphthol; more specifically, the study objectives were to: ° Determine if there are residues of carbaryl and its degradate 1­ naphthol in the marine sediments at historically sprayed sites and unsprayed adjacent sites ° Monitor the depletion of these compounds in sediments following applications of Seven ™ . ° Measure concentrations of carbaryl in centrifuged sediment pore water. ° Determine drift potential. The study was divided into two phases, pre­ spray and post­ spray. Sampling was conducted in Willapa Bay in areas deemed to be conducive to carbaryl persistence. Thus, areas with muddy and/ or fine sediments were selected since they were believed to be more likely to retain both carbaryl and 1­ naphthol. Sandy sediments were not believed to provide sufficient clay or organic material with which carbaryl and/ or its degradate could sorb. Page 3 of 8 0 500 1000 1500 2000 2500 3000 3500 010 2030 40 50 60 Days after Treatment Carbaryl (ppb) Figure 1 Average carbaryl concentrations in sediment collected from Willapa Bay at 2, 30 and 60 days after treatment. Pre­ spray samples were collected from areas that had been sprayed in previous years or were adjacent to areas that had been sprayed in previously. A reference site, Nemah Oyster Reserve, was sampled as an area that had never been sprayed. Post­ spray samples were collected immediately following carbaryl treatment and also included areas adjacent to spray sites. Treated sites included areas that had been sprayed in years past in addition to the recent treatment. Sampling was typically conducted 2, 30 and 60 days after treatment (DAT). Sediment samples were collected using a stainless steel 17­ cm diameter device that allowed sediment samples to be stratified into 0 ­ 2 cm, 2 ­ 7.5 cm, and 7.5 ­ 15 cm depths. Total organic carbon (TOC) and sediment size were also analyzed. Carbaryl and 1­ naphthol residues were measured both in whole sediment and in centrifuged pore water. Quality assurance spiked sediment samples suggest considerable amount of variability in recovery of standards. The results may be negatively biased. Based on the pre­ spray study results, all of the historically sprayed sites, adjacent unsprayed sites and the reference site showed no carbaryl or 1­ naphthol residues above the detection limit range of 21 to 58 ppb. One sample representing the shallowest area adjacent to historically sprayed beds had trace (29 ppb) residues of carbaryl. Post­ spray study results indicate that carbaryl concentrations at sprayed sites ranged from 2,000 to 3,400 ppb by 2 DAT, 180 to 220 ppb by 30 DAT, and 86 ­ 120 ppb by 60 DAT (Figure 1). Although, adjacent sites contained as much as 2,000 ppb 2 DAT, residues in sediment at all adjacent sites at 60 DAT were close to detection limits and ranged from 27 to 32 ppb. Residues for the 1­ naphthol ranged from detection limits to as high as 170 ppb at 2 DAT and by 30 DAT all samples had dropped to detection limits (22 to 33 ppb); one sample at 60 DAT contained naphthol at 34 ppb. The report concluded that once carbaryl degrades to 1­ naphthol, the degradate appears to readily leave the sediment. It did not however, allow for the fact that the degradate could have been present in deeper reaches of the sediment. At adjacent sites, 1 naphthol ranged as high as 120 ppb 2 DAT and then dropped to below detection limits for the remaining sample periods. Carbaryl residues in pore water were only detected 60 DAT and ranged from 0.57 to 1.15 ppb. It is difficult to understand though how the limit of detection for pore water was so much lower than that for sediment. Carbaryl was only detected in one sediment pore water sample collected from an adjacent site; the residue was close to the limit of detection at 0.05 ppb. Page 4 of 8 Analyses of sediment grain size and total organic carbon revealed that the clay­ silt fraction of the post spray sites ranged from 25% to 73% while TOC ranged from 0.58% to 2.07%. Grain size and TOC were strongly correlated (Pearson R 2 range 0.89 ­ 0.96); however, there was no correlation between carbaryl residues and TOC. The study concludes that carbaryl is clearly persistent in treatment areas with residues being detected up to 60 DAT. Additionally, residues in sites adjacent to treated areas indicate that drift does occur. Drift to nontarget sites was attributed to wind, depth of water sampled, and both surface and bottom water currents. Additionally, sediment pore water concentrations exceeded the National Academy of Sciences and Engineering water quality recommendation for carbaryl of 0.06 ppb. Additionally, historic sampling revealed that water column concentrations prior to application ranged as high as 9.2 ppb. The report notes that QA/ QC standards suggested that actual pore water concentrations may be higher than those reported. It is uncertain how much naphthol was present in the water column; however, given that naphthol is more toxic than the parent, the potential affect of the residues on aquatic animals is a legitimate concern. Finally the report compares the sediment residue data to available toxicity data on carbaryl and concludes that Dungeness crab larvae exposed to carbaryl at concentrations ranging from 0.1 to 10 ppb for 25­ days exhibited both molting effects and mortality. Although no formal data were provided on the numbers of organisms affected; the author reports that marine fish and invertebrate mortality was observed 2 DAT. The author proposes that the incidental kills could serve as forage for other fish and foraging birds that would then bioaccumulate carbaryl in their tissues. The report further suggests that indirect effects, such as endocrine disruption and mutagenicity, are not sufficiently characterized and that coupled with direct effects and the potential for bioaccumulation in the food chain, carbaryl and 1­ naphthol have the potential to impact threatend and/ or endangered salmon stocks. The study would have been more thorough had water column concentrations of carbaryl been measured. Given that the compound was applied using both aerial and hand­ held sprayers, it is difficult to assess the affect of drift relative to application method. It would have also been helpful to know how representative the areas sampled were of the total areas treated in terms of TOC and grain size. Additionally, the limit of detection (25 ­ 35 ppb) was not sufficiently low to document residues in sediment and pore water that may have been sufficiently high to effect benthic invertebrates. 2) Chemicals of Special Concern in Washington State Report published by the Washington Department of Ecology provides a brief overview of the environmental fate and effects of carbaryl. Although the overview has footnote numbers, no references were provided; therefore, data supporting carbaryl's characterization could not be verified. The report implies that carbaryl is relatively persistent and that recoveries of aquatic systems exposed to carbaryl have taken as long as 3 years. According to the overview, carbaryl is teratogenic, immunosuppressive, and degrades to carcinogenic compounds. Page 5 of 8 3) Washington Department of Ecology Review of Data Relevant to the Envrionmental Effects of Applying Carbaryl to Control Burrowing Shrimp in Willapa Bay and Grays Harbor Oyster Beds (1987). The object of the Washington Department of Ecology review was to answer the following questions: ° How long do carbaryl and its primary hydrolysis product 1­ naphthol persist in the water column? ° What concentrations of carbaryl and 1­ naphthol in water are toxic to marine organisms? ° How long do carbaryl and 1­ naphthol persist in the sediments? ° What concentrations of carbaryl and 1­ naphthol in sediment are toxic to marine organisms? ° What are the effects on abundance and diversity of infauna? ° What are the effects on abundance and diversity of epifauna? ° What mortality is experienced by Dungenees crab and how does this affect the fishery? ° What mortality is experienced by fish? ° Are birds adversely affected? ° What are the potential ecological impacts of Sevin applications? While the environmental fate studies on water column and sediment concentrations during and after application of carbaryl showed a decline in carbaryl and 1­ naphthol concentrations, much of the data were discounted due to poor detection limits and procedural deficiencies. Open literature reviews of ecological effects revealed that carbaryl is more toxic to crustaceans than to molluscs or fish; however, the degradate 1­ naphthol is less toxic to crustaceans than carbaryl but more toxic than the parent to molluscs and fish. Subacute effects of carbaryl were reported at concentrations below the detection limit (1 mg/ L) of most of the monitoring studies reported; the report states that circumstantial evidence suggests the potential for toxic effects at or below 0.1 mg/ L in sediment. Sublethal effects included reduced development of oysters and delayed molting of crab larvae, malformations in fish eggs and adults. Toxicity of carbaryl is reported to increase with temperature. Although the report fails to conclusively resolve whether carbaryl and its 1­ naphthol degradate are sufficiently persistent to effect aquatic life, it notes that the target population of burrowing shrimp take a number of years to recover. However, failure of a treated area to recover may be due to a number of factors and may not result exclusively on the toxicity of carbaryl or its degradate. Page 6 of 8 0 100 200 300 400 500 600 1976 1978 1980 1982 1984 1986 1988 Year Acres Treated Figure 2. Number of acres treated with carbaryl in Willapa Bay over years. 0 10000 20000 30000 40000 50000 60000 0 100 200 300 400 500 600 Number of AcresTreated Number of Crabs Killed Figure 3. Number of crabs killed versus number of acres treated with carbaryl in Willapa Bay. Fisheries data collected on Willapa Bay from 1977 to 1986 show (Figure 2) that the number of acres treated with carbaryl increased each year. And that the number of crabs killed by carbaryl treatment also increased (Figure 3) as the number of acres treated increased. The number of crabs killed was significantly correlated (Pearson Correlation coefficient = 0.72; p > rho = 0.0187) with the number of acres treated. Over the observation period an average of 53 crabs (standard error = 13) were killed per acre. Follow70000 up studies by the University of Washington that [Dungeness] crab in treated areas are impacted but that further studies are required to establish population­ level effects in Willapa Bay. Mortalities to fish were limited to small specimens which were entrapped in shallow pools by the outgoing tide and directly exposed to carbaryl during treatment; however, the reviewed literature did not address the potential for indirect mortality. Althoughno studieswereconducted,the reportconcludedthatlikelihood ofacuteorchronic effects of carbaryl on birds was remote. Whether there are broad ecological impacts associated with the use of carbaryl to control burrowing shrimp in Willapa Bay remains an uncertainty. The Environmental Impact Statement concluded that the use of carbaryl by the commercial oyster industry was not expected to cause significant impacts on the estuarine ecosystem when applied at current levels. It based this conclusion on the fact that: ° Carbaryl is not accumulated by any food chain component or transmitted to higher levels in the food chain. ° No chemically active radical group remains to contaminate the estuarine environment. ° Only a small percentage of the total intertidal lands are treated annually; 0.8% in Willapa Bay and 0.3% in Grays Harbor. Page 7 of 8 The report recommends though that further work be conducted to evaluate the persistence of carbaryl and 1­ naphthol in sediment and to better document the effects of nontarget mortality. 4) Burrowing Shrimp Integrated Pest Management Memorandum of Agreement The memorandum of agreement (MOA) was established between the Washington State Department of Ecology, Washington State Department of Agriculture, the Washington State Commission on Pesticide Registration, the Washington Department of Fish and Wildlife, the Willapa/ Grays Harbor Oyster Growers Association, the Pacific Coast Shellfish Growers Association and the Pacific Shellfish Institute. The agreement acknowledges that while carbaryl and its 1­ naphthol degradate affect nontarget species, are likely transported several hundred yards offsite by tidal action, and may persist for several weeks in the water column and sediments within Willapa Bay/ Grays Harbor, treatment for burrowing shrimp is necessary if economic losses due to diminished oyster harvests are to be avoided. The agreement acknowledges that additional data on the environmental fate and effects of carbaryl are necessary and that alternative methods of control should be explored to mitigate adverse effects especially on threatened/ endangered salmonids. The MOA establishes a process and time for the development of a "sustainable site­ specific, environmentally sound and ecologically based [integrated] pest management plan for the control of burrowing." The MOA outlines criteria to be met, i. e., demonstration that burrowing shrimp populations have reached a size sufficient to inflict economic losses, before which carbaryl can be applied. 5) Carbaryl Concentrations in Willapa Bay and Recommendations for Water Quality Guidelines. In the summer of 2000, the Washington State Department of Ecology initiated a study of Willapa Bay. The study was a follow­ up on the Stonic (1999) study from 1996 to 1997 and concern that carbaryl persisted at a level of 0.7 ug/ L. The objectives of the study were to: ° determine if there is a carbaryl background that persists in Willapa Bay water outside the July to August spray period; ° analyzie carbaryl in other potential sources to Willapa Bay; ° achieve quantitation limits for carbaryl sufficiently low to evaluate the potential for causing toxicity to sensitive marine organisms; ° review the literature on carbaryl's effects on marine organisms and evaluate appropriate water quality guidelines for carbaryl in Willapa Bay. Results from the study show that carbaryl was frequently detected in Willapa Bay up to 4 days after application to oyster beds and that carbaryl was transported several miles from the site of application. However, the study showed no evidence of carbaryl background in the Willapa Bay water column. Additionally, tributaries and cranberry bog drainages were not significant carbaryl sources. Carbaryl had dropped to levels below quantitation (0.004 ug/ L) approximately 1 month after application Page 8 of 8 Based on a review of toxicity data on 35 marine species, the report recommended 0.06 ug/ L as a probable safe level for marine organisms and a range of 0.1 to 0.7 ug/ L as a potential effects threshold. The value of 0.06 ug/ L was based on a National Academy of Science approach using an EC50 of 6 ug/ L for inhibiting molting in Dungeness crab larvae divided by a 100X safety factor. The data collected from open literature suggests that carbaryl is more toxic to crustaceans and echinoderms than to fish, molluscs, or polychaetes. The study notes that while similar information was not collected on the 1 naphthol degradate, one study has shown it to be roughly twice as toxic to fish as the parent compound but less toxic to crustaceans. Carbaryl was detected at concentrations within the proposed potential effects threshold several miles from treatment areas up to several days following application. The report recommended that future water quality monitoring focus on the period during or immediately after carbaryl applications and that data are collected on carbaryl's 1­ naphthol transformation product. Additionally, the report recommends that future effects testing include more sensitive test species and indigenous aquatic species that serve as prey for endangered/ threatened species References Stonic, Cynthia. 1999. Screening Survey of Carbaryl (Sevin ™ ) and 1­ naphthol Concentrations in Willapa Bay Sediments. Washington State Department of Ecology. Publication No. 99­ 323. Johnson, Art. 2001. Carbaryl Concentrations in Willapa Bay and Recommendations for Water Quality Guidelines. Washington State Department of Ecology. Environmental Assessment Program. Publication No. 01­ 03­ 005.

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EPA-HQ-OPP-2002-0138-0014

Supporting & Related Material

Page 1 of 5 U. S. ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM PC Code No. 129106 DP Barcode: D283014 SUBJECT: EFED Review of Relyea Paper Entitled "Predator­ induced stress makes the pesticide carbaryl more deadly to gray treefrog tadpoles (Hyla versicolor) " TO: Anthony Britten, Chemical Review Manager Betty Shackleford, Product Manager Special Review and Reregistration Division FROM: Thomas M. Steeger, Ph. D., Senior Biologist Environmental Risk Branch IV/ EFED (7507C) Through: Betsy Behl, Branch Chief Environmental Risk Branch IV/ EFED (7507C) The Environmental Fate and Effects Division (EFED) has completed its review of the research article entitled "Predator­ induced stress makes the pesticide carbaryl more deadly to gray treefrog tadpoles (Hyla versicolor)" published in the February 2001 issue of the Proceedings of the National Academy of Science. The paper, authored by Rick Relyea and Nathan Mills (Department of Biology, University of Pittsburg) provides data demonstrating that prolonged sub­ acute exposure of gray treefrog tadpoles to carbaryl at 3 to 4% of the reported LC50 (2.5 ­ 20.6 mg/ L) killed 10 to 60% of the tadpoles. Furthermore, the paper claims that in the presence of "predatory cues" carbaryl was 2 to 4 times more lethal to tadpoles. The authors conclude that "under more realistic conditions of increased exposure times and predatory stress [simulated in their study], current application rates for carbaryl can potentially devastate gray treefrog populations" and that given the common mechanism of action, i. e., acetylcholinesterase inhibition, of carbaryl with other widely used pesticides (carbamates and organophosphates), the "negative impacts may be widespread in nature." While EFED concurs that biotic and abiotic effects do impact the toxicity of chemicals, we do not concur with the author's contention that their protocol is indicative of "more realistic ecological conditions" than EFED's current battery of acute and chronic toxicity tests; all of these studies are conducted under rigidly controlled laboratory conditions and are not intended to be representative of all of the variables that may affect the toxicity of a compound in the field. Furthermore, the EFED environmental fate and ecological risk assessment chapter on carbaryl submitted in support of the re­ registration eligibility decision does attempt to account for carbaryl's risk to amphibians and is to some extent protective to amphibians at the concentrations discussed Page 2 of 5 in the Relyea and Mills paper. However, while the authors are correct that a cumulative assessment of the effects of all chemicals acting through a similar mode of action may be more realistic, the logistics of conducting such an evaluation would require additional resources than are currently available in EFED. The EFED environmental fate and ecological risk assessment chapter on carbaryl contains both acute and chronic amphibian toxicity data (see Attachment 1 for excerpt on amphibians from chapter). Although bullfrogs (Rana catesbeiana) are relatively inured (LD50 > 4,000 mg/ Kg) to carbaryl on an acute oral exposure basis, leopard frog tadpoles (Rana blairi) exhibited a 90% reduction in swimming activity at carbaryl concentrations in the 3.5 ­ 7.2 mg/ L range. The chapter notes that such an impairment would likely render the tadpoles [prey] vulnerable to predation provided the predators were not similarly impaired. Furthermore, the chapter notes that chronic exposure of southern leopard frogs (Rana sphenocephala) to carbaryl led to developmental and growth effects and that the long­ term effects of short­ term carbaryl exposures to amphibians during critical life stages was uncertain and could potentially lead to population­ level effects. Therefore, the EFED risk assessment does discuss qualitatively the potential susceptibility of amphibians following both acute and chronic exposure to carbaryl. EFED does not typically evaluate risk to aquatic animals on a species­ by­ species or class­ byclass basis but rather relies on surrogate species as representatives of broad ranges of aquatic organisms. As with most screening­ level risk assessments conducted by EFED, the carbaryl chapter used fish toxicity data as a surrogate for amphibians. Toxicity values for freshwater fish ranged from 0.25 to 20 mg/ L; the most sensitive species, i. e., Atlantic salmon (Salmo salar) with a 96­ hour LC50 value of 0.25 mg/ L, was selected for calculating risk quotient (RQ) values used in EFED's assessment of ecological risk to freshwater vertebrates. The salmon LC50 value represents roughly 10% of the lower LC50 range (2.5 to 20.6 mg/ L) for amphibians reported in Relyea and Mills paper. Given that EFED's levels of concern (LOC), i. e., the ratio of expected environmental concentrations (EEC) to the LC50 value, for endangered is 0.05, if the EEC was greater than 0.01 mg/ L, it would exceed EFED's LOC. Therefore, the ecological risk assessment for aquatic vertebrates is protective for species with 96­ hour LC50 values greater than 0.01 mg/ L. (0.04% of the range reported by Relyea and Mills). EFED concurs with the study authors that biotic and abiotic effects can impact the toxicity of pesticides and that it is difficult to account for these effects on the basis of the limited laboratory tests that are typically available for evaluating the effects of pesticides. EFED also concurs with the authors that chemicals with similar modes of action may have additive toxicities and that cummulative assessments may better account for toxicity; however, the practicality of implementing such evaluations is limited for screening­ level assessments. EFED is uncertain regarding how representative the Relyea and Mills article is of field effects though or of the direct effects of carbaryl and predatory cues. The experimental design included 10 tadpoles in 10­ liter polyethylene tubs containing filtered tapwater. In a 10­ day static renewal study, they changed water on days 3 and 7. In 16­ day static­ renewal exposures, they changed water every 4 days. Water quality parameters (dissolved oxygen, temperature, pH and Page 3 of 5 ammonia) were measured midway through the 16­ day exposure studies. Predator treatments consisted of a larval salamander (Ambystoma maculatum) housed within a 250­ ml plastic cup, covered with a fiberglass window screening, in each of the exposure tanks; controls consisted of the plastic cup alone. Nominal carbaryl concentrations ranged from 0.045 to 0.54 mg/ L; both negative and solvent (acetone) controls were run concurrently. The results demonstrate that increased ammonia concentrations were associated (P< 0.0001, range of means = 0.21 ­ 0.99 mg/ L) with carbaryl concentration, an effect attributed to the presence of dead tadpoles and excess unconsumed food. A regression analysis of survival against ammonia was significant (P < 0.001, but not particularly predictive (R 2 = 0.395). Predators had no effect on ammonia (P > 0.1) and only had small effects on oxygen and pH (9% decrease in oxygen, P < 0.0001; 5% decrease in pH, P = 0.019). Given that water quality parameters were only measured midway through the study and that both tadpoles and thus feeding rates were likely increasing throughout the study, ammonia levels may have been considerably higher toward the end of the studies. Thus it is unclear whether ammonia, pH and dissolved oxygen had an effect on the toxicity of carbaryl to tadpoles. It is noteworthy that the Relyea and Mills data showed precipitous declines in tadpole survival after 5 days of exposure. Although it is difficult to design a study that can accurately reflect field conditions and particularly predator­ prey relationships, EFED is not convinced that the Relyea and Mills study could be interpreted as more representative of field conditions. Typically, prey demonstrate predator avoidance behavior in the presence of a perceived threat. In this study, tadpoles were unable to escape their perceived threat; predatory cues, i. e., seeing a predator (visual cues) may have protracted their response well beyond the chemical cues released following the salamander's consumption of tadpoles. It is questionable whether tadpoles would have remained in view of a potential predator under more realistic conditions. In refined ecological assessments, EFED oftentimes has mesocosm study data available to assess the risk of pesticides under "field conditions". These studies, while considerably more expensive that the Relyea and Mills protocol, may represent the most accurate reflection of controlled field studies. It is interesting to note though that while mesocosm studies may yield LC50 values similar to laboratory studies, they rarely provide LC50 values showing enhanced toxicity. Test species within these studies are better able to rely on compensatory mechanism to shield themselves from the toxic effects of chemicals. In addition, the environmental fate of pesticides is often different under field conditions. Under alkaline conditions, i. e., pH > 7, carbaryl undergoes hydrolysis with half­ lives ranging from 0.15 to 12 days. While Relyea and Mills accurately note carbaryl's susceptibility to hydrolysis, they fail to mention that under aearobic conditions, carbaryl is also microbially degraded in the aquatic environment with a half life of approximately 5 days. It is likely that gray treefrogs in the Relyea and Mills study were exposed to carbaryl concentrations considerably lower than nominal after 3 to 4 days. Thus the actual exposure regime may have been more representative of pulsed exposures to declining concentrations of carbaryl and increasing concentrations of ammonia. While it is clear that predators had an effect on the response of tadpoles to the exposure regime, EFED does not concur that the test results are representative of the effects of predation on carbaryl toxicity alone. Page 4 of 5 EFED concurs with Relyea and Mills that both biotic and abiotic factors impact the toxicity of pesticides and that current screening methods do not account for the full range of these effects nor do screening level assessments take into account aggregate effects from exposure to chemicals with similar modes of action. Screening­ level assessments attempt to identify where EFED's LOCs are exceeded and where EFED has uncertainties regarding risk. With respect to amphibians, the chapter discusses the likelihood of acute and chronic effects from current uses of carbaryl. Page 5 of 5 Attachment 1. Excerpt on Amphibians from the Environmental Fate and Ecological Risk Assessment for the Reregistration of Carbaryl Chapter According to an available supplemental study with a 50% carbaryl formulation, the LD50 for the bullfrog (Rana catesbeiana) is greater than 4,000 mg/ kg, or practically nontoxic (MRID 00160000). A single acute exposure of plains leopard frog tadpoles (Rana blairi) to carbaryl concentrations in the 3.5 ­ 7.2 mg/ L range led to a 90% reduction in swimming activity, including sprint speed and sprint distance, activity ceasing completely at 7.2 mg/ L (Bridges 1997). This reduction in activity and swimming performance may result in increased predation rates and, because activity is closely associated with feeding, may result in slowed growth that could lead to failure to complete metamorphosis. Acute exposure to low carbaryl levels may not only affect immediate survival of tadpoles but also impact critical life history functions. On a chronic basis, carbaryl has been shown to have the potential to adversely affect amphibians. In a recent study, nearly 18% of southern leopard frog (Rana sphenocephala) tadpoles exposed to carbaryl during development exhibited some type of developmental deformity, including both visceral and limb malformations, compared to a single deformed (< 1%) control tadpole demonstrating that carbaryl exposure can result in amphibian deformities (Bridges, 2000). Although the length of the larval period was the same for all experimental groups, tadpoles exposed throughout the egg stage were smaller than their corresponding controls. Because exposure to nonpersistent chemicals may last for only a short period of time, it is important to examine the long­ term effects that short­ term exposure has on larval amphibians and the existence of any sensitive life stage. Any delay in metamorphosis or decrease in size at metamorphosis can impact demographic processes of the population, potentially leading to declines or local extinction.

epa

2024-06-07T20:31:42.419674

regulations

EPA-HQ-OPP-2002-0138-0015

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES CERTIFIED MAIL June 29, 2001 Danielle LaRochelle Registration Product Manager Aventis CropScience USA P. O. Box 12014 2 T. W. Alexander Drive Research Triangle Park, NC 27709 Re: Preliminary Risk Assessments for Human Health and for Environmental Fate and Ecological Effects for the Reregistration Eligibility Decision on Carbaryl Dear Ms. LaRochelle: Enclosed are the preliminary risk assessments for human health and for environmental fate and ecological effects for the reregistration eligibility decision for carbaryl. This advance opportunity to review EPA's pesticide risk assessments for errors is an integral part of a wider effort to involve the public in implementation of the Food Quality Protection Act of 1996, as described in section VIII of the Federal Register notice published on March 15, 2000 (65 FR 14200). Within the next 30 days, please identify and comment on any errors in the enclosed preliminary risk assessments. During this phase of the reregistration process, you should only address typographic, mathematical, or computational type of errors. Upon receipt of your "error correction" submission, the Agency will evaluate your comments and will revise the preliminary risk assessments as necessary. At this phase, EPA will not address comments that concern matters of policy, interpretation, or applicability of data. There will be future opportunities to address these type of comments as part of the public participation process. In addition, we would like you to review the risk assessment documents for confidential business information (CBI). Please inform the Agency in writing of any claims of CBI contained in these documents. If we do not receive notice in writing of any such claims, within 30 days from the receipt of this letter, we will assume the document is free of CBI. Also, please inform EPA of any pertinent completed, pending, or planned studies, and 2 any other sources of information you intend to submit on carbaryl. Providing EPA with a timetable for completing and submitting such information will enable us to better plan for refining the risk assessments and completing the reregistration and tolerance reassessments. In September 2001, EPA expects to release to the public your comments to both preliminary risk assessments, the Agency's response to your comments, and the revised human health and environmental risk assessments. These documents will be placed in the Public Docket and/ or posted on EPA's website (www. epa. gov/ pesticides/ reregistration/ status. htm). EPA will announce the availability of these documents via a Notice of Availability in the Federal Register and through an electronic listserver message. Please send your response in both printed and electronic form, within 30 days of receipt of this letter, including claims of CBI, and other requested information to me at the following address: Anthony Britten US EPA (7508C) 1200 Pennsylvania Avenue, N. W. Washington, D. C. 20460 Email Address: britten. anthony@ epa. gov If you have any questions, please feel free to contact me at (703) 308­ 8179 or by email. Sincerely, Anthony Britten, Chemical Review Manager Reregistration Branch 3 Special Review and Reregistration Division 2 Enclosures

epa

2024-06-07T20:31:42.423865

regulations

EPA-HQ-OPP-2002-0138-0016

Supporting & Related Material

August 8, 2001 Mr. Anthony Britten Special Review and Reregistration Division Office of Pesticide Programs (7508C) U. S. Environmental Protection Agency Room 266A, Crystal Mall 2 1921 Jefferson Davis Highway Arlington, Virginia 22202 Corr. # daL075­ 01 Dear Mr. Britten, Re: Carbaryl; Chemical number 56801; EPA Reg. No. 264­ 324 Review of the Preliminary Risk Assessments for Human Health and for Environmental Fate and Ecological Effects for the Reregistration Eligibility Decision on Carbaryl We have completed our review of the preliminary human health and environmental fate and ecological effects risk assessments for the Reregistration Eligibility Decision of carbaryl. Our comments on the Agency's assessments are enclosed in the following documents: Review of the Draft Human Health Risk Assessment Review of the Draft Environmental Fate and Ecological Risk Assessment for the Reregistration of Carbaryl Hard copies of the above documents will be sent by express mail within the next week. Key issues discussed in these documents are as follow: DRAFT HUMAN HEALTH RISK ASSESSMENT FQPA Considerations A 2­ Generation reproduction study was recently completed and submitted to the Agency. The No Observable Effect Levels (NOELs) for carbaryl administered in the diet, in CD® (SD) rats under the conditions of this study, were: ° For parental systemic toxicity: 75 ppm ° For parental reproductive toxicity: 1500 ppm ° For offspring toxicity: 75 ppm In addition, Aventis has submitted to the EPA a revised Developmental Neurotoxicity Study (DNT) which demonstrated that no alterations in brain morphometric measurements were observed in the offspring, thus no increased sensitivity was observed in the pups. Aventis firmly believes that with the submission of these two studies, the data gap for the 2­ generation reproduction study is fulfilled and the issue with the developmental neurotoxicity study is resolved. Thus, the Agency has the required data to justify removing the extra 10X FQPA Safety Factor from the risk calculations throughout the Human Health Risk Assessment for carbaryl. Mr. Anthony Britten August 8, 2001 Page 2 Additional Uncertainty Factors For the chronic study in dogs, Aventis does not agree with the additional 3X for a lack of a NOEL in the study. According to the policy issued in August 2000 concerning the endpoint for selection for cholinesterase inhibiting compounds, the Agency stated that the red blood cell (RBC) inhibition should be used instead of the plasma. The NOEL for RBC cholinesterase inhibition was 125 ppm (3.1 mg/ kg/ day). Additionally, Aventis believes that the brain cholinesterase inhibition observed at the 125 ppm level was slightly above background level and was not of toxicological concerns due to the lack of clinical signs observed at this dose level. Furthermore, Aventis performed a five­ week study in dogs, which agreed with the results of the chronic study. Therefore, it is our opinion that all calculations based on the chronic dog in the document should be adjusted to reflect the removal of the 3X­ safety factor. Cancellation of Certain Uses of Carbaryl Use on Barley, Oats, Rye, and Cotton: Changes should be made throughout the Human Health Risk Assessment and associated supporting documents to reflect the cancellation of the use on barley, oats, rye, and cotton. It should be noted that Aventis CropScience labels for the technical materials and the end­ use products containing carbaryl were amended to delete these uses. The Agency has already approved the labeling changes. Use on Poultry: Aventis CropScience will no longer support the use of carbaryl for direct application to poultry, as well as the poultry quarters treatment. We will submit a request for cancellation of these uses in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). The cancellation of this use causes a significant improvement in the risk assessment since poultry are the major contributor to the risk estimate. We believe that only the dietary analyses conducted without poultry should be included in the HED Chapter. Analyses including poultry would be unrealistic and misleading. Dietary Exposure Assessment An industry­ sponsored Carbamate Market Basket Survey (CMBS) was conducted and submitted to the Agency for use in the dietary exposure and risk assessment for carbaryl. The Carbamate Market Basket Survey Task Force met with EPA/ HED before the start of the study to review the purpose and design of the study. The EPA assured the task force that the study data would be used in risk assessments, taking precedence over all other monitoring or field trial data available for those crops. A surrogation plan according to HED SOP 99.3 was also assured. These data provide more realistic measures of residues to which consumers are exposed and they should be included in the dietary analyses as agreed upon by the CMBS Task Force and the EPA. Water Exposure Assessment EPA has based its assumptions about concentrations of carbaryl in drinking water upon model simulations. Aventis CropScience conducted a drinking water monitoring program that provides the best estimate of concentrations of carbaryl in drinking water. The study uses the sampling design for acute endpoints recommended in industry/ EPA meetings during 1999 (weekly sampling during times of peak concentrations over a three­ year period). Twenty sites, representative of the most vulnerable community water systems in the highest use areas of carbaryl, were selected. These included 16 sites in agricultural areas and 4 locations in urban areas. Samples were collected from the inlet and outlet water at each sampling interval. Outlet samples were only analyzed when residues were present in the inlet samples. The analytical method has a limit of quantification of 0.030 ppb and a limit of detection of 0.002 ppb. The study provides information on concentrations of carbaryl in community water systems most likely to contain the highest concentrations of carbaryl. Residues of carbaryl in other areas would be expected to be Mr. Anthony Britten August 8, 2001 Page 3 lower. The study should be used in the carbaryl exposure calculations as it provides the drinking water concentrations needed for FQPA dietary assessments. Occupational and Residential Exposure Assessment Aventis CropScience has conducted, or is in the process of conducting, studies relevant to the refinement of the occupational and residential risk assessment. These studies are as follows: Study Anticipated Completion Date 4­ Week Repeated­ Dose Dermal Toxicity Study with SEVIN ® XLR Plus in Rats. September 2001 4­ Week Repeated­ Dose Dermal Toxicity Study with SEVIN ® 80S in Rats. September 2001 4­ Week Repeated­ Dose Dermal Toxicity Study with Carbaryl Technical in Rats. September 2001 Measurement of Pesticide Exposure of Suburban Residents Associated with the Residential Use of Carbaryl. March 2002 Biological monitoring of citrus orchard application and post­ application apple thinning and cherry harvesting job functions March 2002 DRAFT ENVIRONMENTAL FATE AND ECOLOGICAL RISK ASSESSMENT Carbaryl Studies to Fulfill Requirements Aventis CropScience is in the process of conducting, or has scheduled, studies relevant to the refinement of the environmental risk assessments for carbaryl and the major degradate 1­ naphthol. These studies are as follows: Rate and Route of Aerobic Degradation in Soils. These studies have been initiated with parent carbaryl applied to four diverse U. S. soils. The data are intended to provide additional half­ life determinations for parent carbaryl and the major degradate 1­ naphthol. Expected completion date: March 2002 Aerobic Aquatic Metabolism in Two Water/ Sediment Systems. These studies have been initiated with parent carbaryl applied to two distinct U. S. water/ sediment systems. The data are intended to provide additional half­ life determinations for parent carbaryl and the major degradate 1­ naphthol. In addition, further identification of additional degradation products is anticipated. Expected completion date: March 2002 Mr. Anthony Britten August 8, 2001 Page 4 Adsorption and Desorption of 1­ Napthol to five soils. This study has been scheduled to evaluate the adsorption and desorption of the major carbaryl degradate to five soils/ sediment. The data are intended to provide information necessary to evaluate the environmental risks from 1­ naphthol in standard models. Expected completion date: March 2002 For the reregistration process in the EU, Aventis CropScience is in the process of conducting, or has scheduled, studies relevant to the refinement of the ecotoxicological risk assessments for carbaryl and the major degradate 1­ naphthol. These studies are as follows: Studies with Carbaryl: Acute oral LD50 in mallard ducks Dynamic acute LC50 in bluegill sunfish Acute toxicity in Daphnia Acute toxicity in Chironomus riparius Toxicity in Selenastrum capricornutum Acute oral and contact toxicity in honeybees 14­ d toxicity in earthworms Effects on soil microorganisms (nitrification/ carbon cycle) Effect on sewage treatment Studies with 1­ naphthol Early life­ stage study in fathead minnows Acute toxicity in Daphnia Acute toxicity in Daphnia in presence of sediment Chronic toxicity in Daphnia 14­ d toxicity in earthworms Formulated Product Vegetative Vigor Toxicity in Selenastrum capricornutum Acute oral and contact toxicity in honeybees Effect on non­ target arthropods 14­ d toxicity in earthworms Effects on soil microorganisms (nitrification/ carbon cycle) Ecotoxicological Risk Assessments Aventis has pointed out several errors in the PRZM input parameters (see comments made to Tables 5 and 6 of the draft RED). Overly conservative estimates of foliar dissipation half­ lives and changes in ecotoxicology study endpoints would dictate a re­ calculation of the EECs and risk quotients is warranted in a number of instances. Mr. Anthony Britten August 8, 2001 Page 5 Endocrine Disruption Reports in the open literature on the reproductive effects of carbaryl in wild mammals are at best ambivalent. The recently submitted 2­ generation study in rats demonstrates the absence of reproductive effects. As EPA pointed out, findings reported in the literature were made at concentrations well above the highest peak concentration modeled. Therefore these findings are irrelevant for a risk assessment and at the current stage of discussion about endocrine disruption. If the concern about the endocrine potential of carbaryl persists, the issue should be revisited once the Agency's endocrine disrupter screening and testing program as well as a policy on how to incorporate positive findings into an ecological risk assessment have been fully developed. Mobility The classification of carbaryl as mobile to very mobile is inconsistent with measured Koc values of 177 to 249 (MRID 43259301). According to the widely used classification scheme of McCall, et al. (1980) wherein Koc values between 150 and 500 denote medium mobility in soil, carbaryl would be classified as having medium mobility in most soils. This classification of medium mobility is further supported by the acceptable column leaching study (MRID 43320701) in which aged carbaryl residues were only slightly mobile in a number of soils. The mobility of carbaryl would be expected to be higher in sandy soils or in soils of low organic matter. 1­ Napthol Fate and Transport The Agency is requiring additional information on the persistence and mobility of 1­ naphthol, a major environmental degradate of carbaryl. However, a half­ life for 1­ naphthol of less than 1 day can be calculated from the carbaryl aerobic soil metabolism study (MRID 42785101). The data from this study demonstrate that under aerobic soil conditions the formation and decline of 1­ naphthol, starting from parent carbaryl, is complete in less than 14 days. This half­ life can be used for preliminary environmental fate modeling to estimate EECs for 1­ naphthol. The EPA suggested that 1­ naphthol is not strongly sorbed to soil. Additional information available in the literature demonstrates that the sorption of 1­ naphthol to soil is stronger than that seen for carbaryl itself. Hassett et al. (1981) has demonstrated that the sorption of 1­ naphthol was the result of sorption to organic carbon resulting in Koc values between 431 and 15,618. These data indicate that 1­ naphthol is less mobile and less susceptible to leaching than carbaryl itself, and they demonstrate that at least a portion of the 1­ naphthol residue is tightly sorbed to soil constituents. To meet the requirement for information on the adsorption and desorption of 1­ naphthol by the Agency, the registrant is conducting an adsorption/ desorption study to meet the 163­ 1 guideline. Study results should be available for submission to the Agency in the first quarter of the calendar year 2002. Ground Water EPA summarized information on the detection of carbaryl in groundwater from the EPA Pesticides in Groundwater Database, the EPA STORET database and the NAWQA database. Each of the databases shows a pattern of very low levels of carbaryl detection in few groundwater resources. These analyses confirm several statements made by the Agency that carbaryl have limited potential to impact groundwater resources. However, on page 2 of the Memorandum issued June 28, 2001, in conjunction with the EFED RED chapter for carbaryl, EPA is requiring additional information on "Surface and groundwater monitoring in urban and suburban use areas (non­ guideline)." Based on the characteristics of carbaryl and the available data demonstrating limited impact of carbaryl on ground water resources, additional studies to evaluate the potential for carbaryl to contaminate groundwater are unnecessary and unwarranted. Mr. Anthony Britten August 8, 2001 Page 6 Please let me know if you need any additional information. My phone number is (919) 549­ 2718. Sincerely, Danielle A. Larochelle Danielle A. Larochelle Registration Manager 1 CARBARYL Chemical ID No. 056801; Case 0080 Review of the Draft Human Health Risk Assessment August 8, 2001 Aventis CropScience P. O. Box 12014, 2 T. W. Alexander Drive Research Triangle Park, NC 27709 2 TABLE OF CONTENTS GENERAL COMMENTS ........................................................................................................ 3 FQPA Considerations ......................................................................... 3 Additional UncertaintyFactors ........................................................... 3 Cancellation of Certain Uses of Carbaryl ........................................... 3 Dietary Exposure Assessment ............................................................ 4 Water Exposure Assessment .............................................................. 4 Occupational and Residential Exposure Assessment ......................... 4 PART I ­ TOXICOLOGY DATA BASE ................................................................................... 6 Line­ by­ Line Review of the Toxicology Data Base Evaluation from the Human Health Risk Assessment Document for Carbaryl (June 19, 2001) ........................................................................ 6 PART I ­ TOXICOLOGY DATA BASE .................................................................................. 20 SUPPORTING DISCUSSIONS ....................................................... 20 PART II ­ DIETARY AND WATER EXPOSURE/ RISK ASSESSMENT ...................................... 32 Line­ by­ Line Review of the Dietary and Water Exposure Assessment of the Human Health Risk Assessment Document for Carbaryl (June 19, 2001) ...................................................................... 32 Line­ by­ Line Review of the Supporting Document "Revised Dietary Exposure Analysis for the HED Revised Human Health Risk Assessment (Felicia A. Fort; April 26, 2001)" ...................... 40 PART II ­ DIETARY AND WATER EXPOSURE/ RISK ASSESSMENT ...................................... 44 SUPPORTING DISCUSSIONS ....................................................... 44 PART III ­ RESIDUE CHEMISTRY CONSIDERATIONS .......................................................... 51 Line­ by­ Line Review of the Residue Chemistry Information Included in the Human Health Risk Assessment Document for Carbaryl (June 19, 2001) ...................................................................... 51 Line­ by­ Line Review of the Supporting Document "Product and Residue Chemistry Chapters for the Reregistration Eligibility Decision (Felecia Fort; November 14, 2000)" ...................... 53 Line­ by­ Line Review of the Supporting Document "Carbaryl: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document (Jeffrey L. aDawson; June 28, 2001)" .................. 59 PART IV ­ OCCUPATIONAL AND RESIDENTIAL EXPOSURE/ RISK ASSESSMENT ............... 64 SUPPORTING DISCUSSION ......................................................... 64 APPENDIX I ................................................................................................................... 66 3 General Comments FQPA Considerations A 2­ Generation reproduction study was recently completed and submitted to the Agency. The No Observable Effect Levels (NOELs) for carbaryl administered in the diet, in CD® (SD) rats under the conditions of this study, were: ° For parental systemic toxicity: 75 ppm ° For parental reproductive toxicity: 1500 ppm ° For offspring toxicity: 75 ppm In addition, Aventis has submitted to the EPA a revised Developmental Neurotoxicity Study (DNT) which demonstrated that no alterations in brain morphometric measurements were observed in the offspring, thus no increased sensitivity was observed in the pups. Aventis firmly believes that with the submission of these two studies, the data gap for the 2­ generation reproduction study is fulfilled and the issue with the developmental neurotoxicity study is resolved. Thus, the Agency has the required data to justify removing the extra 10X FQPA Safety Factor from the risk calculations throughout the Human Health Risk Assessment for carbaryl. Additional UncertaintyFactors For the chronic study in dogs, Aventis does not agree with the additional 3X for a lack of a NOEL in the study. According to the policy issued in August 2000 concerning the endpoint for selection for cholinesterase inhibiting compound, the Agency stated that the red blood cell (RBC) should be used instead of the plasma. The NOEL for RBC cholinesterase inhibition was 125 ppm (3.1 mg/ kg/ day). Additionally, Aventis believes that the brain cholinesterase inhibition observed at the 125 ppm level was slightly above background level and was not of toxicological concerns due to the lack of clinical signs observed at this dose level. Furthermore, Aventis performed a five­ week study in dogs, which agreed with the results of the chronic study. Therefore, it is our opinion that all calculations based on the chronic dog in the document should be adjusted to reflect the removal of the 3X­ safety factor. Cancellation of Certain Uses of Carbaryl Use on Barley, Oats, Rye, and Cotton Changes should be made throughout the Human Health Risk Assessment and associated supporting documents to reflect the cancellation of the use on barley, oats, rye, and cotton. It should be noted that Aventis CropScience labels for the technical materials and the end­ use products containing carbaryl were amended to delete these uses. The Agency has already approved the labeling changes. Please refer to Part III of this document (Residue Chemistry Considerations) for current labeling information. Corrections on label acceptance dates are also provided in Part III. 4 Use on Poultry Aventis CropScience will no longer support the use of carbaryl for direct application to poultry, as well as the poultry quarters treatment. We will submit a request for cancellation of these uses in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). The cancellation of this use causes a significant improvement in the risk assessment since poultry are the major contributor to the risk estimate. We believe that only the dietary analyses conducted without poultry should be included in the HED Chapter. Analyses including poultry would be unrealistic and misleading. Dietary Exposure Assessment An industry­ sponsored Carbamate Market Basket Survey (CMBS) was conducted and submitted to the Agency for use in the dietary exposure and risk assessment for carbaryl. The Carbamate Market Basket Survey Task Force met with EPA/ HED before the start of the study to review the purpose and design of the study. The EPA assured the task force that the study data would be used in risk assessments, taking precedence over all other monitoring or field trial data available for those crops. A surrogation plan according to HED SOP 99.3 was also assured. These data provide more realistic measures of residues to which consumers are exposed and they should be included in the dietary analyses as agreed upon by the CMBS Task Force and the EPA. Water Exposure Assessment EPA has based its assumptions about concentrations of carbaryl in drinking water upon model simulations. Aventis CropScience conducted a drinking water monitoring program that provides the best estimate of concentrations of carbaryl in drinking water. The study uses the sampling design for acute endpoints recommended in industry/ EPA meetings during 1999 (weekly sampling during times of peak concentrations over a three­ year period). Twenty sites, representative of the most vulnerable community water systems in the highest use areas of carbaryl, were selected. These included 16 sites in agricultural areas and 4 locations in urban areas. Samples were collected from the inlet and outlet water at each sampling interval. Outlet samples were only analyzed when residues were present in the inlet samples. The analytical method has a limit of quantification of 0.030 ppb and a limit of detection of 0.002 ppb. The study provides information on concentrations of carbaryl in community water systems most likely to contain the highest concentrations of carbaryl. Residues of carbaryl in other areas would be expected to be lower. The study should be used in the carbaryl exposure calculations as it provides the drinking water concentrations needed for FQPA dietary assessments. Occupational and Residential Exposure Assessment Aventis CropScience has conducted, or is in the process of conducting, studies relevant to the refinement of the occupational and residential risk assessment. These studies are as follows: 5 Study Anticipated Completion Date 4­ Week Repeated­ Dose Dermal Toxicity Study with Sevin XLR Plus in Rats. September 2001 4­ Week Repeated­ Dose Dermal Toxicity Study with Sevin 80S in Rats. September 2001 4­ Week Repeated­ Dose Dermal Toxicity Study with Carbaryl Technical in Rats. September 2001 Measurement of Pesticide Exposure of Suburban Residents Associated with the Residential Use of Carbaryl. March 2002 Biological monitoring of citrus orchard application and postapplication apple thinning and cherry harvesting job functions March 2002 6 Part I ­ Toxicology Data Base Line­ by­ Line Review of the Toxicology Data Base Evaluation from the Human Health Risk Assessment Document for Carbaryl (June 19, 2001) 1.0 Executive Summary Section Number 1.0 Page: 3 Paragraph: 4 Line: 3 EPA comment: In the developmental neurotoxicity study in the rat, alterations in brain morphometric measurements were observed in offspring. Aventis' response: Aventis has submitted to EPA a revised DNT, which demonstrated no alterations in brain morphometric measurements taken in the offspring, thus no increased sensitivity was observed in the pups. The details of this study will be discussed below in the supporting `Discussion Section'. Page: 3 Paragraph: 5 Line: 3 EPA comment: No acceptable two­ generation reproduction study is available. Aventis' response: Aventis has submitted to EPA a new 2­ Generation Reproduction Study with carbaryl, which neither demonstrated that carbaryl is a reproductive toxicant nor demonstrated that the pups were more sensitive than the dams. The NOELs for carbaryl administered in the diet, in CD® (SD) rats under the conditions of this study were: ° For parental systemic toxicity: 75 ppm ° For parental reproductive toxicity: 1500 ppm ° For offspring toxicity: 75 ppm The details of this study will be discussed below in the supporting `Discussion Section'. Page: 3 continued on page 4 Paragraph: 5 Lines: 4 ­7 EPA comment: In the developmental neurotoxicity study, maternal toxicity was observed at the same dose as changes in brain morphometric measurements in offspring; however, these brain measurements were not performed at the next lower dose and consequently, there is some uncertainty about the NOAEL for this effect. 7 Aventis' response: As stated above, Aventis has submitted to EPA a revised DNT, which demonstrated no alterations in brain morphometric measurements taken in the offspring, thus no increased sensitivity was observed in the pups. The details of this study will be discussed below in the supporting `Discussion Section'. Page: 4 Paragraph: 5 ­ continuation from page 3 Lines: 2 ­9 EPA comment: The 10x Food Quality Protection Act (FQPA) Safety Factor has been retained because: 1) the toxicology data base is incomplete; there is a data gap for the multi­ generation reproduction study in rats; 2) an assessment of susceptibility following pre­/ post­ natal exposure to carbaryl could not be made due to the data gap for the reproduction study; 3) there is concern for the results of the developmental neurotoxicity study (uncertainty about NOAEL). Based on these considerations, the 10x safety factor was applied to all population subgroups in assessing risks from acute and chronic dietary exposures and residential exposures of all durations. Aventis' response: As stated above, Aventis has submitted to EPA a revised DNT and a new 2­ Generation Reproduction Study that has a direct impact on the FQPA Safety Factor. Aventis firmly believes that with the submission of these two studies, the data gap for the 2­ generation reproduction study will be fulfilled and the NOEL question for the DNT will be resolved. Thus, the Agency has the required data to reduce the FQPA Safety Factor from 10X to 1X. Page: 4 Paragraph: 1 Lines 1­ 6: EPA comment: Carbaryl has been classified as a Group C possible human carcinogen based on an increased incidence of hemangiosarcomas and combined hemangiomas/ hemangiosarcomas in CD­ 1 mice at 1000 ppm (146 mg/ kg/ day) and above. Mechanistic metabolism studies and a study in heterozygous p53­ deficient mice were considered inadequate to demonstrate a mode of action for the vascular tumors. The default linear low dose extrapolation was used for risk assessment; the Q1* is 1.19 x 10 ­2 (mg/ kg/ day) ­1 based on the mouse vascular tumors. Aventis' response: Aventis strongly believes that the use of carbaryl products presents no imminent carcinogenic risk to users based on the following points: Current data support a hypothesis that high doses of carbaryl in life­ time studies produce tumors via a non­ genotoxic mechanism, possibly related to altered metabolism at these high doses. 8 At doses less than the MTD, there was an increased incidence of tumors only in 1 site of 1 sex of 1 species. The increased incidence of vascular tumors in the male mice after two years of administration is of questionable biological significance. In the p53 knockout mouse model, which was demonstrated, to be sensitive to the induction of vascular tumors by a genotoxic reference compounds, carbaryl was found to be negative. The weight­ of­ the evidence indicates that carbaryl shows no potential for genotoxicity Epidemiological data on carbaryl production workers show no increase in tumor incidence. In the two­ year bioassay conducted in the CD1 mouse, a statistically significantly higher incidence of vascular tumors was noted in males at 1,000 and 8,000 ppm. In females, no statistically significant change in the incidence of vascular tumors was observed. The overall incidence of vascular tumors was 2, 6, 10 and 10 in males and 3, 3, 4 and 9 in females at 0, 100, 1,000 and 8,000 ppm, respectively. In order to address the biological significance of the vascular tumors, the p53 knockout mouse model was used as a tool to study chemical carcinogenesis (Donehower, 1996). The p53 mouse is a genetically manipulated mouse in which one allele of the p53 tumor suppresser gene has been inactivated. One of the assumptions with the knockout model is that a mutation at the intact p53 allele is necessary for the development of the carcinogenic process. In principle nongenotoxic compounds, which induce tumors by other mechanisms should not induce tumors in this system. The p53 knockout mouse model was validated by testing two compounds: urethane, a genotoxic compound known to produce vascular tumors in standard carcinogenicity bioassays, and d­ limonene, which is neither genotoxic nor carcinogenic in mice but which is known to be carcinogenic in the male rat by a well described non­ genotoxic mechanism. In the validation study, the p53 model proved to be very efficient for the induction of vascular tumors by genotoxic compounds (Bigot, 1999; Carmichael et al. 1999). Therefore, this model will produce an unambiguous response to specifically identify genotoxic compounds. Therefore, carbaryl was tested in the p53 mouse. The objectives of the studies were to evaluate if carbaryl would induce vascular tumors in this model and to set a NOEL in this sensitive and specific model. Additionally, this model provides evidence that the tumors observed in the standard carcinogenicity bioassays resulted from an indirect genotoxic effect. 9 Carbaryl was administered continuously via the diet to groups of 20 male heterozygous p53 knockout mice at concentrations of 0, 10, 30 100, 300, 1,000 and 4,000 ppm for at least 180 days. At the end of the study, all animals were necropsied, selected organs weighed and a range of tissues were taken, fixed and examined microscopically. Carbaryl did not induce mortalities or clinical signs related to the treatment. Only a slight decrease in food consumption during the first eight weeks was observed at 4,000 ppm. This observation was correlated with a lower body weight evolution in comparison with the control animals. No tumors were found in the 4,000 ppm group. In the other treated groups, a few sporadic tumors were found, but they were clearly unrelated to treatment and representative of the spontaneous tumor types present in mice of this age and strain. In particular, it should be noted that no tumors were found in the liver, kidney or vascular system, which were seen in the original mouse oncogenicity study with carbaryl. The only treatment­ related non­ proliferative change observed was the presence of globular deposits in the umbrella cell layer of the urinary bladder at 100 ppm or more. In conclusion, the data from the p53 studies, the following conclusion can be made: 1). The p53 model was validated with urethane one of the few compound known to induce specifically vascular tumors. 2). Carbaryl was negative, and also did not accelerate the formation of any other tumor types. 3). There is a clear NOEL at 4000 ppm (approximately 716 mg/ kg b. w./ day) in the p53 mouse study for carcinogenicity. 4). Carbaryl is not a genotoxic carcinogen. Thus the weight­ of­ the evidence indicates that carbaryl is not a genotoxic agent in humans. In addition, epidemiological data on carbaryl production workers show no increase in tumor incidence. The two epidemiology studies of Aventis CropScience (formerly Rhône­ Poulenc and Union Carbide) factory workers representing a sub­ population of the general public with the highest exposure (i. e., exposure on a daily basis over many years). Thus, the data from these studies represent a potential "worst­ case" for chronic carbaryl exposure to humans. The results from these studies show that the overall mortality experience of the cohort is significantly less than expected when compared to both United States and West Virginia male death rates. In general, these studies support conclusion that there were no excess cases of cancer in this working population. A further discussion of this study and the entire carcinogenicity issue will be discussed below in the supporting `Discussion Section'. 10 Page: 4 Paragraph: 2 Lines 5­ 12: EPA comment: The toxicity endpoints selected for risk assessment are based on neurotoxic effects of ChEI. The dose levels used for the acute and chronic dietary risk assessment, i. e. 10 mg/ kg and 3.1 mg/ kg/ day, were both from studies (acute neurotoxicity study in the rat and chronic toxicity study in the dog, respectively) in which a NOAEL was not determined. Therefore, an additional uncertainty factor of 3x was added to the customary 100x uncertainty factor [10x for extrapolation from animal studies to humans and 10x for intraspecies (human) variation]. The acute and chronic reference doses were 0.03 mg/ kg and 0.01 mg/ kg/ day, respectively. Aventis' response: Concerning the acute neurotoxicity study in rats, Aventis does not disagree with the Agency's assessment for this endpoint. However, for the chronic study in dogs, Aventis does not agree with the additional 3X for a lack of a NOEL in the study. According to the policy issued in August 2000 concerning the endpoint for selection for cholinesterase inhibiting compound, the Agency stated that the red blood cell (RBC) should be used instead of the plasma. The NOEL for RBC cholinesterase inhibition was 125 ppm (3.1 mg/ kg/ day). Additionally, Aventis believes that the brain cholinesterase inhibition observed at the 125 ppm level are slightly above background level and were not of toxicological concerns due to the lack of clinical signs observed at this dose level. Furthermore, Aventis performed a five­ week study in dogs, which agreed with the results of the chronic study. Therefore, it is our opinion that all calculations based on the chronic dog in the document should be adjusted to reflect the removal of the 3X safety factor. Page: 4 Paragraph: 2 Lines 1­ 6: EPA comment: No dermal or inhalation studies were available. Aventis' response: As part of the 60­ day public comment period, Aventis will be submitting three 21­ day dermal studies, which cover the technical material and the formulated products SEVIN® XLR, and SEVIN® 80S. The study results will not be available in time to provide the information to the Agency as part of the 30­ day comment period. Similarly, Aventis will be submitting comments for the inhalation requirement as part of the 60­ day public comment period. However, it should be noted that in the document titled, "Carbaryl: Toxicology Chapter For RED" the inhalation study was not listed as a data gap on page 25 of that document. 11 Page: 8 Paragraph: 3 Lines 1­ 10: EPA comment: HED calculated the risks of carbaryl exposure in tobacco. Based on a pyrolysis study submitted by the registrant, residues of carbaryl total approximately 44.58 ppm in tobacco smoke (side­ stream and main­ stream combined). Since this is a composited sample of main­ stream and side­ stream smoke, it greatly exaggerates the actual exposure to the smoker, whose primary route of exposure is via mainstream smoke. HED further assumed that 100% inhaled is absorbed (i. e., that none of the residue is exhaled along with the smoke). These assumptions result in an extreme overestimate of actual likely exposure. Comparing exposure to the short­ term inhalation Lowest­ Observable­ Adverse­ Effects­ Level (LOAEL) of 10 mg/ kg/ day, the short­ term MOE for carbaryl exposure from the use of tobacco is estimated to be 1000 for males and 900 for females. The MOEs are less than the residential short­ term inhalation target MOE of 3000 and therefore, the risks exceed HED's level of concern for the general population. Aventis' response: The relative risk of carbaryl, which is not a genotoxic agent, as compared to the many direct acting genotoxic agents contained in main­ and side­ stream smoke is insignificant and is not calculable. The calculation presented by the Agency is crude at best and does not have any impact on the relative risk of smoking cigarettes. Page: 10 Paragraph: 2 Lines 1­ 18: EPA comment: HED evaluated reports of human carbaryl poisonings and adverse reactions associated with its use from the following sources: OPP Incident Data System (IDS); Poison Control Centers' Toxic Exposure Surveillance System; California Department of Pesticide Regulation; the National Pesticide Telecommunications Network (NPTN); open literature; and an unpublished study submitted by the registrant. The data from IDS indicated that a majority of cases from carbaryl exposure involved dermal reactions. A number of other cases involved asthmatics and people who experienced hives and other allergic type reactions. It is noted that the dermal sensitization study in the guinea pig was negative. Reports of allergic­ type reactions in humans could be evidence of a difference in species sensitivity or could be attributable to inert ingredients in the marketed formulations. According to California data, about half have the cases involved skin and eye effects in handlers. About a quarter of the skin reactions were due to workers that were exposed to residues on crops. Reports from the literature are very limited but tend to support the finding that carbaryl has irritant properties. The Poison Control Center cases involving non­ occupational adults and older children showed an increased risk in five of the six measures used for comparing carbaryl incidents to all other pesticides. The carbaryl cases were almost twice as likely to require serious health care (hospitalization or treatment in a critical care unit) and were two and a half times more likely to experience major medical 12 outcome (life­ threatening effects or significant residual disability) than other pesticides. This pattern of increased risk was not seen among occupational reports or in young children. This may mean that careless handling by nonprofessionals is a particular hazard. Aventis' response: As stated by the Agency, reports from the literature are very limited. To draw such conclusions that carbaryl cases were almost twice as likely to require serious health care (hospitalization or treatment in a critical care unit) and were two and a half times more likely to experience major medical outcome (life­ threatening effects or significant residual disability) than other pesticides is speculative and goes too far in assigning increased frequency values based on limited and often unconfirmed information. The reports cited by the Agency from poison control centers are difficult to interpret because the relative causative agent is frequently not identified. If the agent is identified by officials, the majority of the time it is stated by the officials that the causative agent is merely speculation on their part and that the real agent is not readily known with great certainty. According to test conducted by Aventis on both technical grade and formulation products, carbaryl is not a skin sensitizer. Furthermore, epidemiological data on carbaryl production workers showed no pattern of skin reaction. This would indicate that if the product is used according to the label, the relative risks of skin reactions to carbaryl are very low. Page: 10 Paragraph: 3 Lines 1­ 5: EPA comment: Five case report studies suggested that carbaryl might be a cause of chronic neurological or psychological problems. Some of these effects appear to be consistent with those reported from organophosphate poisoning. However, unlike organophosphates, no controlled studies have been undertaken. If such effects occur as a result of over­ exposure to carbaryl, they appear to be relatively rare. The effects reported among the five case reports are too inconsistent to draw any conclusions, but do suggest the need for further study. Aventis' response: Aventis agrees with the Agency that the five case studies cited are weak at best and that the Agency should not be drawing any conclusions based on such inconsistent data. The discussion of such data will lead the reader to draw inappropriate conclusions. Furthermore, epidemiological data on carbaryl production workers showed no such pattern and would indicate that if the product is used according to the label, the relative risks of carbaryl are very low. Page: 11 Paragraph: 1 Lines 1­ 3: EPA comment: The epidemiologic study submitted by the registrant compared mortality rates in plant workers exposed to carbaryl to the general population. HED concluded that 13 the sample of workers was too small and the period of follow­ up too short to permit definitive conclusions. Aventis' response: Aventis disagrees with the Agency that the mortality rates in plant workers exposed to carbaryl cannot be translated to the general population. The study was statistically designed to specifically address this concern and to examine other non­ mortality endpoints. The two epidemiology studies of Aventis CropScience (formerly Rhône­ Poulenc) factory workers representing a sub­ population of the general public with the highest exposure (i. e., exposure on a daily basis over many years). Thus, the data from these studies represent a potential "worst­ case" for chronic carbaryl exposure to humans. The results from these studies show that the overall mortality experience of the cohort is significantly less than expected when compared to both United States and West Virginia male death rates. In general, these studies support conclusion that there were no excess cases of cancer in this working population. Page: 11 Paragraph: 4 Lines 2­ 4: EPA comment: However, certain key information, which would help refine the risk assessment, is missing. Toxicology data gaps include a reproduction study, a 21­ day dermal study in the rat, a 90­ day inhalation study in the rat and a micronucleus study. Aventis' response: The Agency has previously granted a wavier for the in vivo cytogenicity/ micronucleus. Furthermore, Aventis has fulfilled the data requirement for the in vivo mouse micronucleus study. Aventis believes that repeating the in vivo mouse micronucleus study is not appropriate based on the fact that the top dose in the currently submitted mouse micronucleus was 200 mg/ kg/ day and was similar to the mid­ dose of 250 mg/ kg/ day tested in an acute gavage study in mice. At the 250 mg/ kg dose level tested in the acute study plasma, RBC, and brain cholinesterase inhibition was seen. The percent cholinesterase inhibition observed was 45.7, 45.7, and 57.8, respectively. At the highest dose tested (500 mg/ kg) in the acute study, percent cholinesterase inhibition for plasma, RBC, and brain was 59.8, 57.1, and 66.6, respectively. Additionally, the clinical signs observed at both the 250 and 500 mg/ kg dose levels were very similar in both findings and incidences. Repeating the mouse micronucleus study at a slightly higher dose level would not result in an increase in significant clinical signs. Therefore, the base results of the study concerning clastogenic or aneugenic effects would not change. Carbaryl is not mutagenic for these endpoints. As previously indicated in this document, Aventis will be submitting three 21­ day dermal studies which cover the technical material and for the formulated products SEVIN XLR and SEVIN 80S. Similarly, Aventis will be submitting comments for the inhalation requirement as part of the 60­ day public comment period. 14 However, it should be noted that in the document titled, "Carbaryl: Toxiccology Chapter For RED" the inhalation study was not listed as a data gap on page 25 of that document. Section Number 3.0 Hazard Profile Page: 14­ 15 Paragraph: 1 Lines: 1­ 10 EPA comment: The Toxicology Chapter of the RED was prepared by Dr. Virginia Dobozy (D240992 dated December 13, 1999). The toxicology database is of good quality; however, it is incomplete. The following studies are required: two­ generation reproduction study, 21­ day dermal toxicity study with cholinesterase measurements, 90­ day inhalation study with cholinesterase measurements and micronucleus study. The lack of a reproduction study and some uncertainty about the findings in offspring in the developmental neurotoxicity study are obstacles to assessing special sensitivity of infants and children and as such, the 10x FQPA Safety Factor was retained. However, the database provides sufficient information for selecting toxicity endpoints for risk assessment and therefore, supports a reregistration eligibility decision for the currently registered uses. Aventis' response: As stated previously, Aventis has submitted to EPA a revised DNT and a new 2­ Generation Reproduction Study, which have a direct impact on the FQPA Safety Factor. Aventis firmly believes that with the submission of these two studies, the data gap for the 2­ generation reproduction study is fulfilled and the DNT NOEL question will be resolved. Thus, the Agency has the required data to reduce the FQPA Safety Factor from 10X to 1X. As for the 21­ day dermal, 90­ day inhalation and mouse micronucleus studies, the need for these studies is addressed in the previous comments made by Aventis. Page: 17 Paragraph: 1 Lines: 1­ 6 EPA comment: In the developmental neurotoxicity study, clinical signs of toxicity and plasma and brain ChEI were seen in maternal animals at the same dose (10 mg/ kg/ day) as changes in brain morphometric measurements (decreases in cerebellar measurements in females on Day 11 post­ partum) were observed in offspring; however, brain measurements were not conducted at the next lower dose. The lowest NOAEL after a single dose administration in adult animals was for maternal animals in the developmental neurotoxicity study, i. e., 1 mg/ kg/ day. Aventis' response: Aventis has submitted to EPA a revised DNT Study, which demonstrated that no alterations in brain morphometric measurements were observed in the offspring, thus no increased sensitivity was observed in the pups. The details of this study 15 will be discussed below in the supporting `Discussion Section'. Page: 17 Paragraph: 2 Lines: 1­ 3 EPA comment: No subchronic studies in the rat or dog are available, except for the subchronic neurotoxicity study in rats. The chronic toxicity data showed that, in dogs, decreases in plasma, RBC and brain ChE were observed at 10 mg/ kg/ day; clinical signs of toxicity were also observed in both sexes. Aventis' response: For the chronic study in dogs, Aventis does not agree with the additional 3X for a lack of a NOEL in the study. According to the policy issued in August 2000 concerning the endpoint for selection for cholinesterase inhibiting compound, the Agency stated that the RBC should be used instead of the plasma. The NOEL for RBC cholinesterase inhibition was 125 ppm (3.1 mg/ kg/ day). Additionally, Aventis believes that the brain cholinesterase inhibition observed at the 125 ppm level is slightly above background level and was not of toxicological concerns due to the lack of clinical signs observed at this dose level. Furthermore, Aventis performed a five­ week study in dogs, which agreed with the results of the chronic study. Therefore, it is our opinion that all calculations based on the chronic dog in the document should be adjusted to reflect the removal of the 3X safety factor. Page: 17 Paragraph: 3 Lines: 1­ 21 EPA comment: The Health Effects Division's (HED) Cancer Peer Review Committee (CPRC)( 12/ 8/ 93) classified carbaryl as a Group C ­ possible human carcinogen based on an increased incidence of hemangiosarcomas and combined hemangiomas/ hemangiosarcomas in male mice. Both the low dose extrapolation (Q1*) and margin of exposure (MOE) approaches were proposed for risk assessment. In addition, an RfD approach would be provided to assess the most sensitive non­ cancer health endpoint for comparison to the linear and MOE approaches. The CPRC requested additional metabolism studies, which could 1) direct the selection of the more appropriate quantitative approach; and 2) provide insight into the significance of the tumors seen only at excessively toxic doses. Additional metabolism studies, including mechanistic studies, were submitted subsequent to the 1993 meeting. A subgroup of the Cancer Assessment Review Committee (CARC) met on September 3, 1998, to review the metabolism studies and concluded that the data from all available metabolism studies were not adequate to support a nonlinear mode of action, as described in the 1996 EPA Proposed Guidelines for Carcinogen Risk Assessment, and therefore recommended that the default linear approach should be used for the cancer risk assessment. The revised Q1*, based on the CD­ 1 mouse dietary study with ¾ Interspecies Scaling Factor, is 1.19 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents. Subsequently, the registrant submitted a special study in genetically modified mice. Carbaryl was administered to heterozygous p53­ deficient (knockout) male mice in the diet at concentrations of up to 4000 ppm (716.6 mg/ kg/ day) for six 16 months. There was no evidence of neoplastic or preneoplastic changes in the vascular tissues of any organ. A model validation study demonstrated that vascular tumors occur in heterozygous p53 deficient mice within six months of administration of a known genotoxic carcinogen (urethane). Aventis' response: Aventis strongly believes that the use of carbaryl products presents no imminent carcinogenic risk to users based on the following points: Current data support a hypothesis that high doses of carbaryl in life­ time studies produce tumors via a non­ genotoxic mechanism, possibly related to altered metabolism at these high doses. At doses less than the MTD, there was an increased incidence of tumors only in 1 site of 1 sex of 1 species. The increased incidence of vascular tumors in the male mice after two years of administration is of questionable biological significance. In the p53 knockout mouse model, which was demonstrated, to be sensitive to the induction of vascular tumors by a genotoxic reference compounds, carbaryl was found to be negative. The weight­ of­ the evidence indicates that carbaryl shows no potential for genotoxicity Epidemiological data on carbaryl production workers show no increase in tumor incidence. As background, in the two­ year bioassay conducted in the CD1 mouse, a statistically significantly higher incidence of vascular tumors was noted in males at 1,000 and 8,000 ppm. In females, no statistically significant change in the incidence of vascular tumors was observed. The overall incidence of vascular tumors was 2, 6, 10 and 10 in males and 3, 3, 4 and 9 in females at 0, 100, 1,000 and 8,000 ppm respectively. In order to address the biological significance of the vascular tumors, the p53 knockout mouse model was used as potential tool to study chemical carcinogenesis (Donehower, 1996). The p53 mouse is a genetically manipulated mouse in which one allele of the p53 tumor suppresser gene has been inactivated. One of the assumptions with the knockout model is that a mutation at the intact p53 allele is necessary for the development of the carcinogenic process. In principle non­ genotoxic compounds, which induce tumors by other mechanisms should not induce tumors in this system. The p53 knockout mouse model was validated by testing two compounds: urethane, a genotoxic compound known to produce vascular tumors in standard carcinogenicity bioassays, and d­ limonene, 17 which is neither genotoxic nor carcinogenic in mice but which is known to be carcinogenic in the male rat by a well described non­ genotoxic mechanism. In the validation study, the p53 model proved to be very efficient for the induction of vascular tumors by genotoxic compounds (Bigot, 1999; Carmichael et al. 1999). Therefore, this model will produce an unambiguous response to specifically identify genotoxic compounds. Therefore, carbaryl was tested in the p53 mouse. The objectives of the studies were to evaluate if carbaryl would induce vascular tumors in this model and to set a NOEL in this sensitive and specific model. Additionally, this model provides evidence that the tumors observed in the standard carcinogenicity bioassays resulted from an indirect geneotoxic effect Carbaryl was administered continuously via the diet to groups of 20 male heterozygous p53 knockout mice at concentrations of 0, 10, 30 100, 300, 1,000 and 4,000 ppm for at least 180 days. At the end of the study, all animals were necropsied, selected organs weighed and a range of tissues were taken, fixed and examined microscopically. Carbaryl did not induce mortalities or clinical signs related to the treatment. Only a slight decrease in food consumption during the first eight weeks was observed at 4,000 ppm. This observation was correlated with a lower body weight evolution in comparison with the control animals. No tumors were found in the 4,000 ppm group. In the other treated groups, a few sporadic tumors were found, but they were clearly unrelated to treatment and representative of the spontaneous tumor types present in mice of this age and strain. In particular, it should be noted that no tumors were found in the liver, kidney or vascular system, which were seen in the original mouse oncogenicity study with carbaryl. The only treatment­ related non­ proliferative change observed was the presence of globular deposits in the umbrella cell layer of the urinary bladder at 100 ppm or more. In conclusion, the data from the p53 studies, the following conclusion can be made: 1). The p53 model was validated with urethane one of the few compound known to induce specifically vascular tumors. 2). Carbaryl was negative, and also did not accelerate the formation of any other tumor types. 3). There is a clear NOEL at 4000 ppm in the p53 mouse study for carcinogenicity. 4). Carbaryl is not a genotoxic carcinogen. Thus the weight­ of­ the evidence indicates that carbaryl is not a genotoxic agent in humans. In addition, epidemiological data on carbaryl production workers show no increase in tumor incidence. The two epidemiology studies of Aventis CropScience (formerly Rhône­ Poulenc) factory workers representing a sub­ 18 population of the general public with the highest exposure (i. e., exposure on a daily basis over many years). Thus, the data from these studies represent a potential "worst­ case" for chronic carbaryl exposure to humans. The results from these studies show that the overall mortality experience of the cohort is significantly less than expected when compared to both United States and West Virginia male death rates. In general, these studies support conclusion that there were no excess cases of cancer in this working population. Page: 18 Paragraph: 1 Lines: 1­ 8 EPA comment: Carbaryl was not mutagenic in the Salmonella typhimurium assay or genotoxic in the Unscheduled DNA Synthesis assay. In a chromosomal aberration test using Chinese Hamster Ovary (CHO) cells, carbaryl was clastogenic in the presence of S9 activation. The CPRC (1993 meeting) required an in vivo cytogenetics study in rodents to provide insight into the structural and/ or numerical aberrations in the study. The mouse micronucleus study submitted to satisfy this requirement was deemed unacceptable. HED concluded that, based on a Weight of the Evidence assessment, the database does not support that carbaryl acts as a DNA­ reactive mutagen. However, this alone is not sufficient to demonstrate a mode of action for establishing a threshold cancer risk assessment. Aventis' response: The Agency has previously granted a wavier for the in vivo cytogenicity/ micronucleus. Furthermore, Aventis has fulfilled the data requirement for the in vivo mouse micronucleus study. Aventis believes that repeating the in vivo mouse micronucleus study is not appropriate based the fact that the top dose in the currently submitted mouse micronucleus was 200 mg/ kg/ day and was similar to the mid­ dose of 250 mg/ kg/ day tested in an acute gavage study in mice. At the 250 mg/ kg/ day dose level tested in the acute study plasma, RBC, and brain cholinesterase inhibition was seen. The percent cholinesterase inhibition observed was 45.7, 45.7, and 57.8, respectively. At the highest dose tested (500 mg/ kg) in the acute study, percent cholinesterase inhibition for plasma, RBC, and brain were 59.8, 57.1, and 66.6, respectively. Additionally, the clinical signs observed at both the 250 and 500 mg/ kg were very similar in both findings and incidences. Repeating the mouse micronucleus study at a slightly higher dose level would not result in an increase in significant clinical signs. Therefore, the base results of the study concerning clastogenic or aneugenic effects would not change. Carbaryl is not mutagenic for these endpoints. Page: 18 Paragraph: 6 Lines: 1­ 8 EPA comment: The FQPA Safety Committee concluded at meetings on November 29, 1999 and April 16, 2001, that the 10x safety factor should be retained because: 1) the toxicology data base is incomplete; there is a data gap for the multi­ generation reproduction study in rats; 2) an assessment of susceptibility following pre­/ post­ 19 natal exposure to carbaryl could not be made due to the data gap for the reproduction study; 3) there is concern for the results of the developmental neurotoxicity study (uncertainty about NOAEL/ LOAEL for brain morphometric alterations). The Committee concluded the 10x safety factor should be applied to all population subgroups when assessing acute and chronic dietary exposures and residential exposures of all durations. Aventis' response: As stated above, Aventis has submitted to EPA a revised DNT Study and a new 2­ Generation Reproduction Study which will have a direct impact on the FQPA Safety Factor. Aventis firmly believes that with the submission of these two studies, the data gap for the 2­ generation reproduction study will be fulfilled and clarification of the DNT NOEL issue will be provided. Thus the Agency has the required data to reduce the FQPA Safety Factor from 10X to 1X. 20 Part I ­ Toxicology Data Base SUPPORTING DISCUSSIONS Supplemental Developmental Neurotoxicity Study Findings The document submitted to EPA describes the supplemental histomorphometric evaluation performed on the cerebellum of rat pups and adults from the carbaryl developmental neurotoxicity study (Robinson and Broxup 2001). This additional work was conducted in response to the EPA review of the study final report. In that review, EPA indicated that the bilateral decrease in the length of the cerebellum accompanied by a non­ statistically significant 5% decrease in cerebellar weights in the day 11 females and the bilateral increase in the width of the cerebellum in the day 70 female animals at the highest tested dose (10 mg/ kg/ day) may possibly be treatment related. Further, some forebrain measurements may have also been affected. In order to clarify the treatment relationship of these findings, the Agency recommended that additional morphometric measurements be performed to support the NOEL and that the thickness of the cellular layers in the cerebellum be more fully described. The submitted report addresses the EPA comments by presenting additional evaluations of the high dose animals, only. The evaluations clearly demonstrate that there are no treatment­ related morphometric findings in the cerebellum of male and female pups and adults. These findings are in agreement with the results from the high dose group animals in the study final report that found no treatment­ related changes in: 1) Brain weights in male and female pups; 2) Cerebellar weights in male and female pups; 3) Terminal body weights in male and female pups; 4) Brain weights in male and female adults; 5) Terminal body weights in male and female adults; 6) FOB measurements and motor activity in male and female pups; 7) Motor activity, auditory startle response, passive avoidance, and water maze measurements in male and female adults. The evaluations clearly demonstrate there are no treatment related morphometric alterations of the cerebellum in male and female pups or adults treated with carbaryl at a dose of 10 mg/ kg/ day, from Day 6 of gestation to Day 10 post­ partum, inclusively. In addition, in the forebrain no measurable bilateral differences are detected between control and carbaryl exposed pups and adults. In conclusion, carbaryl did not induce any morphologic or morphometric changes in either the cerebellum or the forebrain in animals receiving a high dose of 10 mg/ kg/ day. As described, the new morphometric results revealed no changes at the high dose, are in agreement with the lack of treatment­ related effects on terminal body, brain, and cerebellar weights, as well as behavioral and motor activity tests in male and female pups and adults. 21 2­ Generation Reproduction Study Findings A 2­ Generation reproduction study with carbaryl technical was completed at Research Triangle Institute located in North Carolina, USA, in order to provide information on the influence of carbaryl technical on the reproductive performance in rats (Tyl et al. 2001). The purpose of this study was to evaluate the potential of carbaryl, administered in the feed to CD rats, to produce alterations in parental fertility, maternal pregnancy and lactation, and growth and development of the offspring for two generations, one litter per generation. This study was performed in compliance with U. S. EPA FIFRA GLP Standards (U. S. EPA, 1989), the U. S. EPA OPPTS Testing Guidelines (U. S. EPA, 1998), and the OECD testing guidelines for a two­ generation reproductive toxicity study (OECD, 1983). Male and female CD® (Sprague­ Dawley) rats (the FO generation) were administered carbaryl (1­ naphthyl methylcarbamate; CAS No. 63­ 25­ 2) in the feed at 0, 75, 300, and 1500 ppm, available ad libitum, 30 animals/ sex/ dose, for ten weeks. Body weights and feed consumption were recorded weekly, and clinical signs were recorded at least once daily. Vaginal cytology was evaluated for the last three weeks of the prebreed period. Animals were then randomly mated within treatment groups for a two­ week mating period to produce the Fl generation, with exposure continuing. FO males were necropsied after the delivery period, with histological evaluation of reproductive and other organs and andrological assessments (reproductive organ weights, epididymal sperm number, motility and morphology, testicular homogenization­ resistant spermatid head counts, daily sperm production, and efficiency of daily sperm production). Fl litters were culled to ten pups on postnatal day (pnd) 4 and weaned on pnd 21. At weaning, up to three weanlings/ sex/ litter were necropsied, and 30/ sex/ dose were selected as Fl parents of the F2 generation. FO females were then necropsied with organ weights, stage of estrus at necropsy, enumeration of ovarian primordial follicles, and histopathology of reproductive and other selected organs. Selected Fl weanlings, 30/ sex/ dose, were administered carbaryl in the diet for a ten­ week prebreed exposure period, with acquisition of vaginal patency in females and preputial separation in males assessed, and vaginal cytology for estrous cyclicity in Fl selected females evaluated during the last three weeks of the prebreed exposure period. They were mated for a two­ week period, as described above. At weaning of F2 litters, up to three weanlings/ sex/ litter were necropsied. Fl males were necropsied after the delivery period, with histopathology and andrological assessments (as described above). At weaning of the F2 litters, parental Fl females were then necropsied with histopathology, as described above, and F2 weanlings, up to three/ sex/ litter, were necropsied. Dietary exposure to carbaryl for two generations, one litter per generation, at 0, 75, 300, and 1500 ppm, resulted in: decreased body weights and decreased weight gains in P0 and P1 parental males and females, accompanied by decreased feed consumption at 1500 ppm, and slightly reduced body weights and feed consumption at 300 ppm; Fl and P2 offspring toxicity (reduced body weights during lactation beginning on post­ natal day (pnd) 4 through lactation and continuing in selected P1 offspring through acquisition of puberty) at 1500 ppm; increases in P1 pup mortality at 1500 ppm and in P2 pup mortality 22 at 300 ppm and 1500 ppm during lactation, especially early (pnd 0­ 4), accompanied by reduced maternal body weights in FO and P1 dams at 1500 ppm and 300 ppm, and delayed vaginal opening and preputial separation in selected Fl offspring at 1500 ppm considered an indirect effect related to body weight decreases. In conclusion, the NOELs for carbaryl administered in the diet, in CD® (SD) rats under the conditions of this study, were: ° parental systemic toxicity: 75 ppm ° parental reproductive toxicity: 1500 ppm ° offspring toxicity: 75 ppm EPIDEMIOLOGIC DATA ­ Epidemiological data on carbaryl: standardized mortality ratio analysis of employees exposed to carbaryl at the Rhône­ Poulenc Institute, West Virginia plant. The National Institute of Occupational Safety and Health (NIOSH) and the Union Carbide Corporation (UCC) on chemical production plants in the Kanawha Valley (KV) of West Virginia originally initiated an epidemiological study. One of the plants included in this extensive epidemiology study was the facility at which carbaryl is produced in Institute, West Virginia. The plant was acquired by Rhône­ Poulenc (now Aventis CropScience) from UCC in December 1986. The study (Pastides 1993) reported here investigated the total and cause­ specific mortality experience of employees exposed to carbaryl at the production plant. No additional information other than what was available in the original database was collected about the health or mortality experience of individuals employed at this plant for this study. The central results of this report were presented in terms of Standardized Mortality Ratios (SMR's) and 95% confidence intervals (95% CI's). Carbaryl technical is manufactured, packaged, and shipped from the Aventis CropScience plant in Institute, West Virginia. Besides carbaryl, the plant also produces other agricultural products. In the past, numerous other chemical compounds were produced there, including butanol, styrene, acetaldehyde, toluene, fluorocarbons and others. Carbaryl is produced in crystalline form, as well as in an oil­ based solution (41% carbaryl). Final processing includes crystallizing, drying, bin storage, and packing. Exposure to carbaryl would occur among three basic categories of employees: those in the manufacturing unit, those in maintenance, and those in packaging and distribution. For employees of the carbaryl unit, UCC tracked through 1988 the vital status, and cause of death information, of all individuals who were first hired between the start­ up of the carbaryl unit in 1960 through 1978. Employees hired after 1978 were not part of the NIOSH/ UCC KV study. 23 Using the KV database, UCC conducted SMR analyses of the employees from the entire Institute plant in the past. However, no separate examination of data from employees specifically exposed to carbaryl was made. In the overall Institute study, no excess risk in total mortality, total cancer mortality, or site­ specific cancer mortality, was observed. In the carbaryl specific study, a total of 522 employees were identified within the UCC database as belonging to one of the three­ carbaryl exposure groups; (158­ Carbaryl Production, 229­ Packing and Distribution, 327­ Maintenance) Because of some overlap between the groups and because some individuals did not meet the NIOSH/ UCC cohort entry criteria, the final number of employees available for the SMR analysis was 488. These 488 employees contributed 7,531.5 person­ years to the mortality analysis. This number represents the combined number of years in which these employees were followed through 1988. As of the end of 1988, twenty­ five deaths were identified from this cohort of employees. Elevated SMR's, reflecting an observed number of deaths greater than the number expected were seen for cancer of the pancreas, cancer unspecified, and cancer of the brain and other parts of the nervous system. In the former two categories, the excess was slight and based on only a single death; furthermore the wide confidence intervals suggest a relatively imprecise SMR estimate and one that is well within the range of chance variation. In the case of brain and nervous system cancer, the higher SMR suggested a possibility of some association with work in the carbaryl unit, yet the very wide confidence interval indicates that the SMR estimate has low precision. In other words, the estimate is unstable, is within the range of chance variation, and reflects the small sample size on which it is based. Furthermore, review of the death certificates of these two individuals revealed that these tumors were of different histologic origin; one was reported as an astrocytoma, the other as a glioblastoma multiforme. This information reduces the plausibility that both malignancies were caused by the same exposure. The next phase of the carbaryl plant worker epidemiology study has been completed (Pastides and Zorn, 1997), and the results are based on vital status of employees through 1994. The new cohort consisted of 817 employees (488 from the previous analysis and 329 who were hired after 1978). Taking into account restriction criteria, as described in the report, the restricted cohort that reflects the number of employees who worked across departments is 599. As previously shown, the overall mortality experience of the cohort is significantly less than expected when compared to both United States and West Virginia male death rates. In general, the follow­ up study supported the results from the initial study that there were no excess cases of cancer in this working population. 24 Carcinogenicity Issue – Historical Perspective and as presented to JMPR and submitted to EPA in 2000 A. Combined Oncogenicity/ Chronic Toxicity Studies 1) Carbaryl produced tumors primarily at the highest dose tested. The dietary concentrations in the rat study were 0, 250, 1500, and 7500 ppm (approximately 13, 75, and 375 mg/ kg b. w.); for the mouse study the concentrations of technical carbaryl were 0, 100, 1000, and 8000 ppm (approximately 12, 143, and 1143 mg/ kg). The highest doses were chosen to satisfy the U. S. EPA requirement for an MTD, while the lower doses were selected for determining the NOEL and to produce moderate toxicity in tissues and on cholinesterase. Considering an approximate acute oral LD 50 in rats and mice of 250 mg/ kg, these doses would therefore be equivalent to 0.06, 0.6 and 4.6 times the acute oral LD 50 for mice and 0.05, 0.3 and 1.5 times the acute oral LD 50 for rats. (The high doses for the mouse and rat, respectively, also would be equivalent on a body weight basis to a 70­ kg person consuming approximately 80 grams and 26 grams of technical carbaryl per day for a lifetime.) These MTD levels caused a significant reduction in body weight and body weight gain in both species, especially early in the study. Several other parameters, such as cholinesterase, were also significantly affected throughout the studies at the top doses. The U. S. EPA in their review of the studies agreed that the highest doses in the mouse and rat study exceeded the MTD. As a result, these MTD levels were deemed inappropriate for chronic testing. Therefore, the only relevant findings for establishing a carcinogenic classification are the vascular system tumors in male mice. 2) The data supporting the oncogenic potential of carbaryl is equivocal since tumors occurred only at one site of one sex of one species when irrelevant data at doses exceeding the MTD are excluded from consideration. Rat Study In the rat carcinogenicity study, carbaryl produced tumors in both sexes (thyroid and bladder in males; liver and bladder in females) but only at the MTD (375 mg/ kg). At the low and intermediate doses (13 and 75 mg/ kg, respectively) there was no indication of an increased incidence of tumors at any of the sites for which increases occurred at the top dose. Thus, at levels less than the MTD, carbaryl has not produced tumors in rats, whether considering the current study or a previous study in which another rat strain was tested. 25 Mouse Study In the mouse carcinogenicity study, carbaryl produced tumors (liver and vascular) in females only at the highest dose tested (1143 mg/ kg). At the low and intermediate doses (12 and 143 mg/ kg, respectively) there was no indication of an increased incidence of tumors at any of the sites for which increases occurred at the top dose. Thus, at doses less than the MTD, carbaryl did not produce tumors in female mice in the current study or in an older study. In male mice, carbaryl produced tumors in the vascular system and kidney at the highest dose tested (1143 mg/ kg b. w.). At the low and intermediate doses (12 and 143 mg/ kg) there was no indication of an increased incidence in kidney tumors. At the low and intermediate doses there was an apparent increase in the incidence of vascular tumors as follows: Dose Male Mouse Vascular Tumors (mg/ kg) Benign Malignant Total 0 122 12 1 6 7 143 1 9 10 1143 3 7 10 However, despite a nearly 10­ fold increase in dose increments, the total tumors observed at the intermediate and high doses were the same. The number of malignant tumors actually was slightly lower at the high dose than at the intermediate dose. Thus, these results show there is no clear linear dose­ response relationship from the intermediate dose to the high dose, despite a nearly 10­ fold difference in dose increment. With regard to statistical significance, the performing laboratory indicated that statistical significance was just achieved at the p< 0.05 levels for the top dose, while the intermediate dose results were just above this level of statistical significance (this result was due to the actuarial­ type statistical analysis used for tumor incidence and onset). However, the U. S. EPA and U. K. authorities have performed separate statistical analyses and the tumor incidence at the intermediate dose also was found to fall within statistical significance. Based on the results from the original study report, a NOEL could be established based on the lowest dose tested at approximately 12 mg/ kg b. w. However, arguments are made in succeeding sections that 18­ month historical control data from the performing laboratory are inadequate to determine if the incidence of tumors at any of these doses is biologically significant. As previously stated, vascular tumors were produced in the female mice but only at the top dose and with a very similar incidence (N = 9) as observed in the males at the top dose. In most other aspects of the study, e. g., body weight effects, clinical signs, clinical 26 pathology, etc., the females reacted very similar to males. However, there was no indication of an increased incidence of vascular tumors in females at the low or intermediate doses as was observed in the male mice. Thus, these facts raise questions regarding the biological significance of the vascular tumors, which occurred in the male mice. 3) Adequate historical control data were not available from the laboratory conducting the chronic toxicity and oncogenicity studies. Historical data from the laboratory at which the mouse oncogenicity study was conducted was only available for studies conducted up to 18 months. Aventis CropScience was not certain if these data accurately reflected the incidence of vascular tumors in 24­ month CD­ 1 mice. Additional information was obtained from other sources and summarized (Klonne, 1995) to compare historical control data from several sources and at several study intervals to that of the data for the carbaryl study. The following key observations were made: An increase in the spontaneous vascular tumor incidence appears to occur from 18 to 24 months of age in mice. An increase in the spontaneous vascular tumor incidence over the last 10 years may be occurring in CD­ 1 mice. The carbaryl study (a 2­ year study) should be compared to historical control data from 2­ year old mice generated during the last 10 years. In general, considering the most relevant historical control data outside of the performing laboratory, the incidences of vascular tumors in major organs (spleen/ liver) in male mice at the low and middle doses fall within the historical control ranges. 4) The lack of significant histopathological findings at the one­ year interim sacrifice of both the mouse and rat studies did not correlate with the detection of tumors in certain tissues at the end of the study. To further investigate the mechanism by which carbaryl induced multiple tumors in the rat and the mouse after two years of exposure, a decision was made to re­ evaluate the histological slides of target organs from the interim sacrifice after one year of treatment. The purpose of this work was to identify if subtle changes present at one year could explain the appearance of tumors seen at two years. Histopathological examinations were conducted on the target organs (liver, kidney, thyroid gland, urinary bladder) from the control and high dose groups in rats and/ or mice. The review was conducted independently by two of Aventis CropScience's pathologists (Debruyne and Irisarri, 1996). In the rat, at the end of a 52­ week exposure period to carbaryl technical by the dietary 27 route, the re­ evaluation of the histological slides revealed the presence of microscopic changes not previously reported in the bladder (transitional epithelial hyperplasia in both male and females), kidney (pelvic urothelial hyperplasia in males), and thyroid (thyroid follicular hypertrophy in males) and liver (hepatocellular hypertrophy in males and females). In the mouse, no microscopic changes were detected at the end of the 52­ week exposure period. These new findings prompted the Aventis CropScience to conduct further studies to confirm cell proliferation in the various tissues (associated with positive tumor formation) and to re­ examine the histological slides from the chronic toxicity and oncogenicity studies. 5) Oncogenicity and chronic toxicity slide review Aventis CropScience then commissioned independent pathologists to re­ examine the histological slides at the 1­ year and 2­ year sacrifices from the chronic toxicity and oncogenicity studies to determine what other (if any) discrepancies exist outside of those determined by the Aventis CropScience's internal review. This peer review study was conducted according to US. EPA Peer Review policy guidelines. The results of this review showed no differences from the original study pathologists review. B. Carcinogenic Mechanism 1) Subsequent to the two­ year studies, Aventis CropScience proactively performed in vivo genotoxicity studies. In response to the results of the mouse oncogenicity study, Aventis CropScience proactively conducted an in vivo DNA adduct study in mice at a concentration similar to the top dose used in the two­ year carcinogenicity study (i. e., 8000 ppm) to determine if carbaryl caused any genotoxic effects (Sagelsdorff, P. 1994). Results indicated that carbaryl did not interact with the DNA in mice, even at the excessive dose used in the study. Additionally, an in vivo rat bone marrow chromosomal aberration study was conducted and showed that carbaryl did not produce chromosomal aberrations at doses up to approximately 50% of the acute oral LD 50 (McEnaney, 1993). Although there was no indication of genotoxic effects in the rat chromosomal aberration and mouse DNA adduct studies, Aventis CropScience recently conducted an in vivo micronucleus study in mice to determine if carbaryl produced aneuploidy in this species. Results from the mouse micronucleus assay again showed no genotoxic effects (Marshall, 1996). Thus, results from these in vivo studies indicate that the mechanism of action of carbaryl in the production of tumors in the two­ year oncogenicity studies does not occur via a direct genotoxic effect. 28 2) The weight­ of­ the­ evidence approach indicates that carbaryl shows little potential as a genotoxin. There have been nearly 50 literature and Aventis CropScience reports on the genotoxicity of carbaryl. The number of test systems and endpoints is extensive. In neither bacterial nor mammalian cell cultures has carbaryl demonstrated any significant mutagenic potential. In various in vitro DNA damage and repair assays there is no convincing evidence to suggest that carbaryl produces DNA damage. While carbaryl has shown some clastogenic potential in vitro, these changes occur at or near cytotoxic levels. In addition, studies performed in vivo, the mouse DNA adduct and rat chromosomal aberration (previously discussed), a mouse dominant lethal study, and an evaluation for mouse micronucleated polychromatic erythrocytes all have been negative. The absence of tumor induction in a 6­ month carcinogenicity study conducted in the p53 knockout mouse demonstrated that the tumors observed in the standard two­ year bioassays in rats and mice are not linked to an indirect genotoxic mechanism. 3) It is possible that altered metabolism from unrealistically high doses of carbaryl plays a significant role in the formation of these tumors. The results from the metabolism study indicated that the carbaryl was almost completely absorbed and metabolized (approximately 90%) and that there was essentially no difference in the metabolism between the sexes or in the low versus the high dose. Likewise, there was no difference in the metabolism between the single versus multiple doses. The data also indicated that the low dose was almost completely eliminated in 12 hours and the high dose was almost completely eliminated in 24 hours. Two metabolites, 5,6­ dihydro­ 5, 6­ dihydroxy carbaryl and 3,4­ dihydro­ 3, 4­ dihydroxy carbaryl were identified to be approximately 8% and 1%, respectively, of the total dose and were found to be primarily conjugated to glucuronide. These metabolites are very likely result from the metabolism of epoxide intermediates. Other metabolites, which were likely formed from the epoxide intermediates, were identified as 5­ hydroxycarbaryl (13%) and 4­ hydroxycarbaryl (6%) and conjugated carbaryl (3%). Epoxide intermediates have been proposed to be the proximate carcinogen for several classes of carcinogens. Depending on such factors as the stability of the epoxide intermediate, the ability of the cell to detoxify the epoxide (related to such factors as the available glutathione stores, epoxide hydrase activity, etc.), the excretion pattern of the compound, etc., these reactive intermediates may be routinely handled by the body just like other endogenous epoxides or could be available to react with cellular components. Thus, it is possible that excessively high doses of carbaryl could alter the normal metabolism, distribution, and/ or excretion pattern in many different ways, e. g., saturate the normal metabolic pathways with a shift of carbaryl metabolism through the epoxide 29 intermediates, deplete the available glutathione stores available for conjugation, increase the half­ life of the epoxide intermediates, increase tissue concentrations of carbaryl and its metabolites due to diminished ability for excretion, etc. Additionally, saturation of many enzyme systems with large carbaryl substrate concentrations could allow accumulation of endogenous chemicals and by­ products of normal metabolism that would otherwise be detoxified and excreted. 4) Vascular tumors. In the two­ year bioassay conducted in the CD1 mouse, a statistically significantly higher incidence of vascular tumors was noted in males at 1,000 and 8,000 ppm. In females, no statistically significant change in the incidence of vascular tumors was observed. A search of the literature indicated there is very few chemical agents known to induce vascular tumors in humans, among them utherane and vinyl chloride were identified (Creech, J. L. Jr et Johnson, M. N. 1974). Angiosarcoma of liver in the manufacture of polyvinyl chloride. (J. Occup. Med. 16: 150­ 151; Marion, M. J., De Vivo, I., Smith, S., Luo, J. C. and Brandt­ Rauf, P. W. 1996). The molecular epidemiology of occupational carcinogenesis in vinyl chloride exposed workers (Int. Arch. Occup. Environ. Health, 68: 394­ 398) and the mechanism underlying the formation of vascular tumors is through the formation of etheno­ adducts, formed maybe by reactive oxygen species (Barbin, A. 2000. Etheno­ adduct­ forming chemicals: from mutagenicity testing to tumor mutation spectra. Mutation Res. 462: 55­ 69: Nair, J., Barbin, A., Velic, I. and Bartsch, H. 1998). Etheno DNA­ base adducts from endogenous reactive species (Mutation Res. 424: 59­ 69). All those compounds would have been found to induce vascular tumors in the p53 model. Thus, the study using the genetically modified heterozygous p53 knockout mouse was designed to address the potential role of an indirect genotoxic mechanism in the induction of vascular tumors in mice. Carbaryl was administered continuously via the diet to groups of 20 male heterozygous p53 knockout mice at concentrations of 0, 10, 30 100, 300, 1,000 and 4,000 ppm for at least 180 days. No treatment related tumors were found even in the highest dose ppm group. In particular, it should be noted that no tumors were found in the liver, kidney or vascular system. Under the conditions of this study, the NOEL is 4,000 ppm (approximately 716 mg/ kg b. w./ day) for neoplastic changes. C. Epidemiological/ Worker Exposure Information Epidemiological evaluations of carbaryl production workers, the population of exposed persons with the highest and most consistent carbaryl exposure, show no indication of effects on tumor incidence. The two epidemiology studies of Aventis CropScience factory workers representing a sub­ population of the general public with the highest exposure (i. e., exposure on a daily basis over many years). Thus, the data from these studies represent a potential worstcase for chronic carbaryl exposure to humans. The results from these studies show that 30 the overall mortality experience of the cohort is significantly less than expected when compared to both United States and West Virginia male death rates. In general, these studies support conclusion that there were no excess cases of cancer in this working population. SUMMARY Aventis CropScience strongly believes that the use of carbaryl products present no imminent carcinogenic risk to users based on the following points: Current data support a hypothesis that high doses of carbaryl in life­ time studies produce tumors via a non­ genotoxic mechanism, possibly related to altered metabolism at these high doses At doses less than the MTD, there was an increased incidence of tumors only in 1 site of 1 sex of 1 species. The increased incidence of vascular tumors in the male mice after two years of administration is of questionable biological significance In the p53 knockout mouse model, which was demonstrated, to be sensitive to the induction of vascular tumors by a genotoxic reference compound, carbaryl was found to be negative The weight­ of­ the evidence indicates that carbaryl shows little potential for genotoxicity Epidemiological data on carbaryl production workers show no increase in tumor incidence 31 REFERENCES 1. Bigot, D. 1999. Validation on Transgenic Mice – p53 Knockout Mice – to Predict Rodent Carcinogenicity. Non­ Guideline Study. Rhône­ Poulenc Agro. Study No. SA 97040. November 10, 1999. 460pp. MRID 45281802. 2. Carmichael NGC, Debruyne ELM and Bigot­ Lasserre D. 2000 The p53 heterozygous knockout mouse as a model for chemical carcinogenesis in vascular tissue. Envi. Health Perspective. 108: 61­ 65. 3. Debruyne, E. and Irisarrri, E. (1996). Carbaryl technical ­ chronic toxicity study in the rat (HWA Study No. 656­ 139) and the mouse (HWA Study No. 656­ 138): evaluation of histological slides. Rhône­ Poulenc agrochimie report No. R& D/ CRSA/ TOX­ HPA­ 4. Unpublished report. MRID 45365503. 4. Donehower LA: The p53­ deficient mouse: a model for basic and applied cancer studies. Semin. Cancer Biol., 7, 269­ 278 (1996). 5. Klonne, D. R. 1995. Carbaryl­ mouse historical control data ­ position paper, November 1995. Rhône­ Poulenc. 74 pp. MRID 45365501. 6. Marshall, R. 1996. Carbaryl: induction of micronuclei in the bone marrow of treated mice. CH Study No. 198/ 89­ 1052. Corning Hazelton. Unpublished report. MRID 44069301. 7. McEnaney, S. 1993. Study to evaluate the chromosome damaging potential of carbaryl technical by its effects on the bone marrow cells of treated rats. Hazelton Microtest. Hazleton U. K. Study No. 198/ 64. Unpublished report. MRID 43039301. 8. Pastides, H. 1993. Standardized mortality ratio analysis of employees exposed to carbaryl at the Rhône­ Poulenc Institute, West Virginia Plant. Unpublished report. MRID 42901501. 9. Pastides, H., and M. Zorn. 1997. An evaluation of the mortality experience of carbaryl unit employees at the Rhône­ Poulenc Institute, West Virginia Plant. Unpublished report. MRID 44349901 10. Sagelsdorff, P. 1994. Investigation of the potential of protein­ and DNA­ binding of carbaryl. CIBA­ GEIGY Limited Toxicology Services/ Cell biology. Study No. CB93/ 52, unpublished report. MRID 43282201. 11. Robinson, K. and Broxup, B. 2001 A Developmental Neurotoxicity Study of Orally Administered Carbaryl, Technical Grade, in the Rat. Lab. I. D. Number 97391. Performed by ClinTrials BioResearch Ltd. 34 pages. Submitted to EPA in July 2001. 12. Tyl, R. W., Myers, C. B., and Marr, M. C. 2001 Two­ Generation Reproductive Toxicity Evaluation of Carbaryl (RPA007744) Administered in the Feed to CD (Sprague­ Dawley) Rats. RTI I. D. Number 65C­ 07407­ 400. Performed by Research Triangle Institute. 906 pages. Submitted to EPA in June 2001. 32 Part II ­ Dietary and Water Exposure/ Risk Assessment Line­ by­ Line Review of the Dietary and Water Exposure Assessment of the Human Health Risk Assessment Document for Carbaryl (June 19, 2001) 1.0 Executive Summary Page: 3 Paragraph: 5 Line: 3 EPA Comment: No acceptable two­ year reproduction study is available. Aventis Response: A study has been completed and submitted. The data gap to remove the 10X FQPA safety factor has been filled. Page: 6 Paragraph: 2 Line: 1 EPA Comment: Monitoring data for carbaryl residues in ground and surface water are available but they are of limited utility in developing estimated environmental concentrations for the aggregate dietary (food and water) risk assessment. Aventis Response: Monitoring data submitted by Aventis is directly applicable to drinking water residue use in the aggregate (food and water) assessment. Worst­ case community water supply systems, targeted for maximum carbaryl use, were monitored for three years on a weekly basis during peak carbaryl use times. 4.0 Exposure Assessment and Characterization 4.2.1 Residue Profile Page: 25 Paragraph: 2 Line: 1 EPA Comment: HED conducts dietary risk assessments using the DEEM™ which incorporated consumption data generated in USDA's Continuing Surveys of Food Intakes by Individuals (CSFII), 1989­ 1992. Aventis Response: The CSFII data for the years 1994­ 1996 have been available for several years now. These data should be used as it reflects the most recent eating patterns and habits of the U. S. population that is currently available. 33 Page: 26 Paragraph: 3 Lines: 1­ 5 EPA Comment: Most of the processing factors were obtained from processing studies submitted by the registrant and compiled in a memo entitled "Carbaryl Anticipated Residues for Carcinogenic Dietary Risk Assessment." S. Hummel, 12/ 3/ 93. Aventis Response: The studies in this memo are older processing studies submitted in the 1980's or even earlier. New residue processing studies were done in the early­ to midnineties in conjunction with the Residue Chemistry DCI. These studies are listed with MRID numbers in EPA's Product and Residue Chemistry documents. The factors are listed in the `Discussion Section' below. These factors should be used in the dietary risk assessment as they represent newer, GLP data. Page: 27 Paragraph: 1 Line: 5 EPA Comment: As discussed in section 3.2, the 10X safety factor is retained for carbaryl. Aventis Response: The data gaps and concerns for the FQPA safety factor have been addressed by Aventis with the submission of the 2­ generation rat reproduction study and the additional data generated for the developmental neurotoxicity study. Based upon the outcome of the studies provided, the 10X safety factor is no longer justified and should be removed. There are no populations of concern in this assessment when the corrected RfD is used in the risk calculation (excluding poultry and using the CMBS data). 4.2.2 Acute Dietary Exposure Assessment Page: 29 Table 6: EPA Comment: The top heading of the table is labeled "Acute­ All Commodities at the 99.9 th percentile of exposure (Market Basket Survey Data Used in Place of PDP/ FDA data.) Aventis Response: This top table heading should be labeled: "Acute­ All Commodities at the 99.9 th Percentile of Exposure (Market Basket Survey Data Not Included). 4.2.5 Characterization/ Uncertainties of the Risk Estimates 34 Page: 31 Paragraph: 1 Line: 1 EPA Comment: Cooking factors were available for potatoes only. Aventis Response: A survey of the literature data revealed numerous cooking and washing studies for carbaryl. See `Discussion Section' for a list of these studies and a table of processing/ washing/ cooking factors that can be derived for carbaryl from these literature studies. 4.3 Water Exposure/ Risk Pathway Page: 31 Paragraph: 5 Line: 4 EPA comment: Some non­ targeted monitoring data are available but they are of limited utility in developing estimated environmental concentrations (EECs) for ecological and human health risk assessment. Aventis' response: Aventis believes that the highest estimated EECs of relevance for ecological risk assessment are not relevant for estimating human health risks due to the lack of proximity of drinking water sources to likely areas of highest ecological risk. The drinking water monitoring program conducted by the registrant provides a real world assessment of the potential for human exposure to carbaryl in drinking water derived from surface water. Drinking water concentrations derived from PRZM/ EXAMS greatly overestimate the potential exposure to carbaryl in drinking water, generally by several orders of magnitude. Monitoring Data Page: 32 Paragraph: 4 Line: 2 (and elsewhere) EPA comment: USGS NAQWA (sic) program Aventis' response: The correct abbreviation for the USGS water monitoring program is NAWQA. Page: 32 Paragraph: 5 Line: 2 EPA comment: Because of limitation in the analytical methods used there is some question as to the accuracy of carbaryl analysis. 35 Aventis' response: This generalized statement needs to be qualified or deleted. Whereas the authors of reports written as part of the NAWQA program have been clear about the potential limitations of the quantitative nature of the carbaryl data in the database, they have also been clear about the validity of the qualitative nature of the data. The use of the multi­ residue method in the NAWQA program does have some limitations as a result of the large numbers of diverse pesticides and degradation products that they are monitoring. However, the QC/ QA data generated as part of the NAWQA program (described in the discussion section on surface water at the end of the EFED response) demonstrates the validity of the detections of carbaryl in the studies. The monitoring study conducted by the registrant, and reported in this section, does not have the same potential limitations in the analytical method since the method is looking specifically for only carbaryl. Therefore, the analytical method used by the registrant does not raise questions about the accuracy of the carbaryl analysis. Page: 32 Paragraph: 5 Line: 3 EPA comment: Poor analytical methods probably have resulted in lower detection rates and lower concentrations than actually present. Aventis' response: This generalized statement should be deleted for reasons provided above and in the discussion section of the EFED response. Page: 33 Paragraph: 2 Line: 6 EPA comment: The data do not give a good indication of the effectiveness of treatment because samples existing and entering the treatment plant were different. In several cases, finished water had higher concentrations than raw water and finished water had detectable carbaryl when the raw did not. Aventis' response: Obtaining matched samples is not possible because of varying residence time through the treatment system, as well as mixing that occurs. The minimal amount of carbaryl residues found also made observations regarding treatment less definitive. However, an examination of the data does indicate that carbaryl concentrations were generally lower in finished water than in raw water samples collected at the same time. These data do include several instances where carbaryl was detected over a few weeks in the raw water so the effect of sample time is less important. The statement regarding several cases of finished water having higher concentrations than raw water is misleading and certainly does not consider the analytical uncertainty for concentrations below the level of quantification and near the level of detection. There were only two cases when finished water was greater than raw water when the concentrations in finished water were greater than 0.01 ppb (only one­ third of the quantification limit). One 36 case was when the raw water was 0.009 ppb and the finished water was 0.011 ppb. These two analyses are essentially equivalent, especially considering that they are only about a third of the quantification limit. The other case was at the Deerfield community water system. This drinking water facility uses a small river without a reservoir as a source for a small Community Water System. Farms are located immediately upstream of the facility. The intake is also not continuous (shut down over weekends). Therefore, getting a matching sample is quite difficult, especially for a short duration spike as a result of spray drift, summer thunderstorm, or perhaps a spill that almost immediately enters the river as a runoff event. The rarity of this event is demonstrated by the absence of residues of this magnitude the next year (2000). Samples collected through this time of the year in 2001 also do not indicate a similar event. Although the data from this site cannot be used to determine the peak concentration, the data provide a distribution of residues through the three­ year period which will define up to the 99 th percentile concentration of the distribution. The Deerfield, Michigan community water system is one of the systems in which the greatest variability of residues would be expected. Most of the other community water systems are located on larger rivers, lakes, or reservoirs. Because the design of study called for analysis of finished water only when there were residues in the raw water, there was only one finished sample analyzed when the raw water contained no residues. This sample was collected at the Deerfield community water system at the sampling interval after the finding of 0.16 ppb in the Deerfield system. The residue level in this sample was 0.004 ppb. The difference between 0.004 ppb and non­ detect is insignificant, and if real can probably be attributed to water at much higher concentrations remaining in the system from the previous week. Page: 33 Paragraph: 2 Line: 10 EPA comment: This illustrates that carbaryl contamination is transient, and that it is unlikely that any sampling would catch the actual peak concentration Aventis' response: The role of a peak concentration is in dietary exposure assessment is undergoing re­ examination within EPA. The current policy of EPA appears to define a certain percentile as an appropriate value for use in screening assessments, but the exact percentile to be used is being defined by EPA management. For more comprehensive assessments, a distribution of values is preferred. The peak concentration in this study was measured at a community water system on a small river. The registrant agrees that the sampling schedule was not adequate to determine the true peak in such systems. Most of the other community water systems are located on larger rivers, lakes, or reservoirs. Therefore, the peak values are not likely to be an order of magnitude greater than 37 the amounts detected in this monitoring program. Page: 33 Paragraph: 2 Line: 13 EPA comment: Non­ targeted monitoring, such as the NAWQA program has shown that much higher concentrations occur. Aventis' response: The main reason why the drinking water monitoring study did not show residues as high as in the NAWQA program is the location of the sampling points. Drinking water supplies tend to be located on larger surface water bodies than NAWQA sampling points (or in other words, the intakes for community water systems tend to be downstream of NAWQA sampling points). This additional time allows for additional degradation and dilution to occur. Finding the highest concentration at the Deerfield, Michigan system is not surprising since this intake is on one of the smallest surface water bodies included in the monitoring study. Page: 33 Paragraph: 2 Line: 14 EPA comment: This study, while useful, does not provide sufficient information to allow estimation of actual peak and mean concentrations that actually occur in all areas or the effect of treatment. Aventis' response: Because most of the samples did not contain carbaryl residues, accurate estimates of the actual peak and mean concentrations can not be obtained. However, the distributions obtained from all sites can be used to define up to the 99 th percentile concentration. The average cannot be accurately determined; however, the timeweighted average is only slightly above the limit of detection (and certainly less than 0.01 ppb) at all 20 sites. The study provides information on concentrations of carbaryl in community water systems most likely to contain the highest concentrations of carbaryl. Residues of carbaryl in other areas would be expected to be lower. The study does not provide information on concentrations in smaller surface water bodies or in areas where surface water is not used for drinking water. Because drinking water concentrations are what is needed for FQPA dietary calculations, this information is suitable for use in dietary exposure assessments. Page: 34 Table 8 EPA comment: Carbaryl EEC Values Aventis' response: Aventis has provided a more detailed response to this same table that is presented as Table 6 in the draft EFED chapter. An electronic copy of the EPA Memorandum on "Refined Estimated Environmental Concentrations for 38 Carbaryl" (DP Bar Code D267276, authored by E. Laurence Libelo, July 23, 2001, and sent to Anthony E. Britten and Virginia Dobozy) was provided to Aventis and contains the PRZM model inputs that were used to generate the EECs shown in this table. An abbreviated version of our response to the information from EFED is included below. It would be useful to add another column to Table 8 to specify which method of application was used to generate the EECs. It would also be of benefit for the Agency to state which of the carbaryl labels were used to develop the "maximum" label application rate scenarios. The model parameters listed in the Memorandum show that the "average" scenarios for citrus and apples were conducted using aerial applications. Few applications to these crops are made aerially. Therefore, the model results overestimate the contributions from spray drift since the "average" applications to these crops are made using ground airblast equipment with lower spray drift inputs. The "maximum label rate" application scenario for apples that is allowed by the Sevin brand XLR PLUS label (E. P. A. Reg. No 264­ 333), the Sevin brand 80WSP and CHIPCO Sevin brand 80WSP labels (E. P. A. Reg. No 264­ 526) and the CHIPCO Sevin brand SL label (E. P. A. Reg. No 264­ 335) is 5 applications at 3­ lb. ai/ A/ application made every 14 days. The scenario used in the model applies less than the maximum amount of product allowed by the labels. In addition, application timing was used in the modeling for the Index Reservoir scenario (applications made by air every 4 days) that would be a violation of the Aventis labels that restrict applications to a minimum of every 14 days. The "average" scenario for sweet corn in Ohio should be 3 applications at 1.1 lb ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not the 2 applications at 3.4 lb ai/ A/ application as listed in the table. The PRZM input file shows the correct inputs of 3 applications at 1.1­ lb ai/ A/ application. Likewise, the "average" scenario for sugar beets in Minnesota should be 1 application at 1.3­ lb ai/ A/ application. The "Citrus" scenario would be more appropriately labeled Oranges. For the average scenario, the 3.4 lb. ai/ A/ application rate listed in Table 8 is for oranges which is the highest "average" application rate for any type of citrus. Therefore, this "average" scenario for oranges is at the high end for all citrus and overestimates the EECs for use in the other citrus crops. 4.3.1 DWLOCs for Acute Dietary Exposure. 39 Page: 35 Paragraph: 1 Line: 7 EPA Comment: Therefore, there is no allowable contribution for water to the risk cup. Aventis Response: Based on a corrected acute reference dose for carbaryl (no 10X FQPA safety factor) and the exposure assessment that uses the Carbamate Market Basket Data, DWLOCs can be calculated. (see `Discussion Section' for calculations.) 4.3.2 DWLOCs for Chronic Dietary Exposure Page 36 Table 9 EPA Comment: DWLOC( chronic) calculations in Table. Aventis Response: Based on a corrected chronic reference dose for carbaryl (no 10X FQPA safety factor) the DWLOCs should be calculated as shown in the `Discussion Section'. Based on the corrected values, there are no population subgroups of concern. 8.0 Data Needs/ Label Requirements Product Chemistry Data Gaps Page: 97 Paragraph: 2 Line 1 EPA Comment: Additional data are required depicting carbaryl residue in/ on cotton gin byproducts. Aventis Response: Aventis is not supporting the cotton use and has removed this crop from the labels. Aventis CropScience requested cancellation of this use in a letter to Mr. George Tompkins, RD, on January 22, 1999. A Federal Register Notice dated April 14, 1999 announced receipt by the Agency of an application from RhonePoulenc Ag Company (now Aventis CropScience) to cancel the use of carbaryl products on cotton 40 Line­ by­ Line Review of the Supporting Document "Revised Dietary Exposure Analysis for the HED Revised Human Health Risk Assessment (Felicia A. Fort; April 26, 2001)" Conclusions/ Summary Page: 2 Paragraph: 1 Line: 8 EPA comment: At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has not been completely approved for use in dietary risk assessments. Aventis Response: The CMBS protocols were presented to EPA for comment before the studies were started. These studies were specifically conducted to obtain more realistic residues for consumer's "at the plate" to be used in dietary assessments. As agreed with EPA before this study was started, the CMBS data should take precedence over others for use in dietary assessment (after their quality review has been completed). Chronic Page: 2 Paragraph: 2 Line: 8 EPA comment: When poultry is not considered in the risk estimate, the dietary exposure is < 6% of the cPAD for all population subgroups. Aventis Response: When a corrected cRfD is used (no FQPA 10X) and poultry is not included in the risk estimate, the dietary exposure is < 0.6% of the cRfD for all population subgroups. Acute Page: 3 Continuation from Paragraph: 4 of Page 2 Line: 3 EPA Comment: Subsequent dietary analyses and all additional sensitivity analyses were conducted without poultry; the risk estimates were still of concern for all population subgroups with the all infants population subgroup consuming 260% of the aPAD when CMBS data were used. Aventis Response: When a corrected aRfD is used (no FQPA 10X) , there are no concerns for all population subgroups. The all infants population subgroup consumes 26% of the aRfD when CMBS data are used. 41 Residue Data Page: 5; Paragraph: 2; Line: 4 EPA comment: FDA monitoring data were used for … cherries, raspberry, blueberry, raspberry, asparagus, … Aventis response: Second listing of "raspberry" can be deleted. Page: 5; Paragraph: 2; Line: 9 EPA comment: Field trial data were used for the commodities, garden beets, turnips, mustards, dried beans, almonds, pecans, walnuts, field corn grain, rice, flax seed, okra, olive, peanuts, pistachio, and sunflower. Aventis response: According to Table 6a, the following commodities should be added to this list: sugar beets and dried peas Page: 5; Paragraph: 2; Line: 11 EPA comment: For oysters, the tolerance of 2 ppm was used in the assessment. Aventis response: According to Table 6a, the tolerance of 0.2 ppm was also used for Dill (fresh) in the assessment. Processing Factors Page 6 Paragraph: 1 Table 2 EPA comment: Most of the carbaryl processing factors were obtained from processing studies submitted by the registrant and compiled in a memo entitled "Carbaryl Anticipated Residues for Carcinogenic Dietary Risk Assessment", S. Hummel, 12/ 3/ 93. Aventis Response: As previously state, the studies in this memo were older processing studies submitted in the 1980's or even earlier. New residue processing studies were done in the early­ to mid­ nineties in conjunction with the Residue Chemistry DCI. These studies are listed with MRID numbers in EPA's Product and Residue Chemistry documents. The factors are listed in the Discussion section. These factors should be used in the dietary risk assessment as they represent newer, GLP data. 42 Consumption data Page: 7 Paragraph: 1 Line: 1 EPA Comment: HED conducts dietary risk assessments using the DEEM™ which incorporated consumption data generated in USDA's Continuing Surveys of Food Intakes by Individuals (CSFII), 1989­ 1992. Aventis response: As previously stated the CSFII data for the years 1994­ 1996 have been available for several years now. These data should be used as it reflects the most recent eating patterns and habits of the U. S. population that is currently available. Results Page: 7 Paragraph: 2 Line 2 EPA comment: Additional cooking and processing studies would allow further refinement. Aventis response: A literature search resulted in many literature references to cooking, washing and peeling studies for carbaryl treated commodities. Average cooking, washing factors can be derived from these literature studies. See the `Discussion Section' for a list of the references and the average calculated factors. Characterization/ Uncertainties of the Risk Estimates. Page: 9 Paragraph: 2 Line: 1 EPA comment: Additional cooking factors could further reduce the risk estimates. Aventis response: Numerous literature studies have been conducted on other commodities, see the `Discussion Section'. Attachment 1: Anticipated Residues Summary and Residue Distribution Files Table 6a: Summary of Anticipated Residues for Carbaryl (Market Basket Data not included) and Table 6b: Summary of Market Basket Survey Data. Aventis Comments: EPA/ BEAD reports a maximum of 84% crop treated for cranberries and an average of 39% crop treated for cranberries. Three years of data were obtained from the Cranberry Institute (memo from Gary Deziel, Manager of Research and Communication, Cranberry Institute.) These data show maximum acres treated 43 for 1992, 39%; 1996, 37%; and 1998, 36%. Based on these data and private conversations, the maximum percent crop treated for cranberries is 39% with an average of 37%. Barley, oats, rye and cotton/ cottonseed are not supported by Aventis and should not be included in the risk assessment. A letter date May 7, 1999 to Ms. Kathryn Boyle confirmed Rhône­ Poulenc's (now Aventis CropScience) decision not to support the registration of carbaryl products on the commodities barley, oats, and rye. These uses have been deleted from our technical and end­ use product labels. Residue Data Sources: The following data sources are more appropriate to use for the crops listed in the table, according to priority rules for use of residue data (Market Basket (MBS)> PDP> FDA> Field Trial (FT)> tolerance) and the Translation of Monitoring Data HED SOP 99.3 (March 26, 1999). Food EPA Used More Appropriate Source Brussels Sprouts Cabbage FDA Lettuce MBS Cabbage Cabbage FDA Lettuce MBS Collards Mustard FT Spinach PDP Eggplant Pepper FDA Tomato MBS Endive Leaf lettuce FDA Spinach PDP Kale Mustard FT Spinach PDP Kohlrabi Cabbage FDA Broccoli MBS Mustard Greens Mustard FT Spinach PDP Paprika H. Pepper FDA Tomato MBS Chili Pepper H. Pepper FDA Tomato MBS Other Pepper H. Pepper FDA Tomato MBS Sweet Pepper S. Pepper FDA Tomato MBS Pimentos H. Pepper FDA Tomato MBS Strawberries Strawberry FDA Strawberry PDP Strawb. Juice Strawberry FDA Strawberry PDP Swiss Chard Celery PDP Spinach PDP Page 41 Residue Distribution Files RDF# 68 Almonds and RDF# 69 Chestnuts appear to have used the almond hull field trial data rather than the almond nutmeat field trial (mostly NDs) data for the residue values. Page 44 Residue Distribution Files RDF# 86 to RDF# 92. Meat and milk. There is no clear indication or discussion anywhere in the document regarding the source of these residue data or how the values were derived (e. g., derived from theoretical animal diets or monitoring data). (see Discussion below). 44 Part II ­ Dietary and Water Exposure/ Risk Assessment SUPPORTING DISCUSSIONS Surface Water Concentrations In section 5.0, page 33 (Table 6), EPA has based its assumptions about concentrations of carbaryl in drinking water upon model simulations. The data from the registrant drinking water monitoring program provide the best estimate of concentrations of carbaryl in drinking water. This study uses the sampling design for acute endpoints recommended in industry/ EPA meetings during 1999 (weekly sampling during times of peak concentrations over a three­ year period). Twenty sites representing the highest carbaryl use areas were selected based on the information provided in Appendix I. Included are 16 sites in agricultural areas and 4 locations in urban areas. Samples were collected from the inlet and outlet water at each sampling interval. Outlet samples were only analyzed when residues were present in the inlet samples. The analytical method had a limit of quantification of 0.030 ppb and a limit of detection of 0.002 ppb. Error! Reference source not found. summarizes the results of the monitoring at each of the 20 community water systems. The maximum concentration observed was 0.16 ppb (average of four samples, the highest was 0.18 ppb) in a finished water sample from the Deerfield community water system located on the River Raisin in Lenawee County, Michigan. There were only five other samples above the limit of quantification of 0.030 ppb. One was a raw water sample containing 0.31 ppb from the Little Potato Slough Mutual community water system near Lodi in San Joaquin County, California (the source is the Little Potato Slough). The corresponding finished water sample was 0.007 ppb. A second one was a raw water sample in Brockton, MA which contained 0.031 ppb. No detectable residues were found in the corresponding finish water sample. The last three samples were from the Shades Mountain plant of the Birmingham community water system on the Cahaba River in Jefferson County, Alabama . Two were raw and finished samples of 0.038 and 0.032 ppb at the same sampling interval in 2001. The other sample was 0.035 ppb in the raw water in a 2000 sample (the corresponding finished sample did not contain carbaryl residues. All residues were transient so the time weighted average concentration of carbaryl in each of the years was 0.005 ppb or less at all 20 community water systems. 45 Table 1.Summary of results from the carbaryl drinking water monitoring study. Site Major Uses Maximum Concentration (ppt) TWA Conc. (ppt)* in Outlet Water Inlet Water Outlet Water 1999 2000 2001** 1999 2000 2001** 1999 2000 Manatee, FL citrus 9 3 ND 11 ND NA 1 1 West Sacramento, CA orchards, nuts 3 24 ND 3 10 NA 1 1 Lodi, CA orchards, nuts 12 31 ND 4 7 NA 1 1 Riverside, CA grapes, tree crops 8ND ND ND NANA 1 1 Lake Elsinore, CA citrus ND 3 6 NA NA Analysis Pending 1 1 Corona, CA citrus ND ND ND NA NA NA 1 1 Beaumont, TX various agricultural ND ND ND NA NA NA 1 1 Point Comfort, TX rice, tree crops 18 5ND ND NDNA 1 1 Penn Yan, NY grapes, apples ND 23 ND NA ND NA 1 1 Westfield, NY grapes, apples 21 5 ND ND 9 NA 1 1 Jefferson, OR vegetables, strawberries ND 10 ND NA ND NA 1 1 Coweta, OK pecans 4 ND *** ND NA *** 1 1 Pasco, WA apples, potatoes 2 3 ND ND ND NA 1 1 Manson, WA apples ND ND ND NA NA NA 1 1 Deerfield, MI vegetables 10 4 ND 160 ND NA 5 1 Brockton, MA cranberries 31 27 ND ND 3 NA 1 1 East Point, GA home and garden 18 18 4 3 8 ND 1 1 Midlothian, TX home and garden 14 ND 14 ND NA ND 1 1 Cary, NC home and garden 4ND ND ND NANA 1 1 Birmingham, AL home and garden 23 35 38 ND ND 32 1 1 * Annual Time Weighted Concentration, outlet values substituted for inlet values when available; values below the detection limit were considered to be half the detection limit. ** Results represent one to six months of sampling into the third year program. *** No results available for the third year of sampling. 46 ND Not detected. NA No outlet samples analyzed due to carbaryl residues not being detected in inlet samples. Appropriateness of the Carbamate Market Basket Survey Data The Agency questions the appropriateness of the use of these data in several discussions of the dietary risk assessment. The CMBS Task Force met with EPA/ HED before the start of the study to review the purpose of the study and protocols for the study. The EPA assured the task force that the study data would be used in risk assessments, taking precedence over all other monitoring or field trial data available for those crops. A surrogation plan according to HED SOP 99.3 was also assured. The specific target of this study was to measure more realistic residues that consumer's are exposed to "at the plate". The study protocol was designed to mimic the typical consumer shopping at his/ her local grocery store and the preparation he would do at home before consuming or further cooking/ preparing the food. The PDP data is taken from distribution centers before the grocery stores are reached and some typical preparation is done. The CMBS data would therefore be expected to have somewhat lower and more realistic measures of residues consumers are exposed to. There is likely to be even further reduction of residues before the food is "put on the plate" by storing, cooking, slicing, peeling or other preparation. It would be very difficult to justify within the industry, further generation of these much needed data for other crops/ compounds if EPA decided at this late date that the data could not be used. Secondary Residues Although residue distribution files are presented by the Agency in Attachment 1 of the Dietary Assessment Support Document for meat and milk commodities, there is no place in the document where these residue numbers and residue distribution files are discussed. Aventis neither can determine the source of the residue data was (monitoring or theoretical animal diets) nor how the data were translated or calculated. We request that a more detailed description of this process be provided to us. Processing Factors EPA uses processing factors listed in a 1993 memo by S. Hummel. Examination of this document shows that the source of these processing factors is studies that were conducted in the 1980s or even earlier. As part of the Residue Chemistry DCI for carbaryl in the early 1990s, numerous residue­ processing studies were conducted along with residue (RAC) field trials. These studies are referenced in the Product and Residue Chemistry Support Document prepared by the EPA. These processing studies and the derived factors, which were conducted under GLP conditions to more recent specifications, are the factors that should be used in the current dietary risk assessment. A table of these factors is listed here. 47 Food Process Average PF Citrus Dried Pulp 1.46 Juice 0. 06 Oil 13.92 Molasses 0.47 Field Corn Small grits 0.25 Meal 0.25 Flour 0.25 Starch 0.25 Crude Oil 3. 38 Refined Oil 0. 25 Grapes Pasteurized Juice 0. 24 Wet Pomace 1.37 Dry Pomace 3.85 Processed Raisins 1. 37 Unprocessed Raisins 2. 17 Raisin Waste 4. 88 Olives Olive oil 0. 81 Peanuts Meal 0.29 Refined Oil 0. 29 Pome Juice 0. 40 Wet Pomace 1.26 Dry Pomace 3.70 Potatoes Wet Peel 1.00 Dry Peel 0.75 Flakes 0.75 Chips 0. 75 Rice Polished Rice 0.03 Hulls 2.37 Bran 0.36 Soybeans Hulls 0.35 Meal 0.22 Crude Oil 2. 71 Refined Oil 0. 005 Sunflowers Hulls 0.35 Meal 0.03 Crude Oil 0. 18 Refined Oil 0. 03 Tomatoes Juice 0. 52 Wet Pomace 1.74 Dry Pomace 2.89 Puree 1. 26 Paste 2. 01 Wheat Middlings 0.42 Shorts 0.83 Asp Grain Fractions 11.79 LG Flour 0.08 Patent Flour 0.10 Wheat Germ 0.65 Wheat Bran 1.03 48 Cooking Washing Factors EPA states several times that cooking/ washing studies would further reduce the anticipated residues used in the assessment and reduce the risk estimates. Aventis conducted a general literature search for studies such as this. A table of factors is listed followed by the references found in the general literature. Average cooking, washing and canning factors could be derived from these references and applied to the risk assessment as supported by these literature studies. Food Process Reduction Reference Broccoli Cooking/ washing 55% 8 Cabbage Heads Cooking 90% 2 Cabbage Heads Washing 75% 2 Cauliflower Cooking/ washing 94% 4 Grapes Washing 49%; 85% 7 Green Beans Canning 100% 11 Green Beans Cooking/ blanching 81% 11 Green Beans Washing 52% 11 Okra Cooking 42%; 25% 1,14 Okra Cooking/ steaming 82% 1,14 Okra Washing 80%; 66%; 70% 1,14 Onions Washing 89%; 98%; 100% 9 Orchard Fruit Washing 50% 12 Peas Cooking/ boiling 85% 3 Peas Washing 70% 3 Spinach Canning 99.5% 10 Spinach Washing 70% 10 Tomatoes Peeling/ washing 99% 5,6 Tomatoes Puree/ catsup 98% 5,6 Tomatoes Washing 66%; 68%, 84% 5,6 1. Indian Journal of Plant Protection. 1996, 24, 86­ 89. 2. Pest Management and Econ. Zoology. 1994, 2, 131­ 134. 3. Plant Protection Bulletin. 1988, 40, 12­ 13. 4. Beitrage zur Trop. Land. Veter. 1982, 20, 89­ 95. 5. Indian Journal of Entomology. 1978, 40, 187­ 190. 6. Indian Journal of Entomology. 1973, 34, 31­ 34. 7. Indian Journal of Ag Sciences. 1978, 48, 179­ 183. 8. J. Ag. Food Chem. 1969, 15, 215­ 216. 9. J. Food Science Technology. 1978, 15, 215­ 216. 10. J. Ag. Food Chem. 1968, 16, 967­ 973. 11. J. Ag. Food Chem. 1968, 16, 962­ 966. 12. J. Assoc. Off. Anal. Che,. 1989, 72, 533­ 535. 13. Env. Health Criteria 1994, 153, 358pp. 49 14. Indian Journal of Ag Sciences. 1976, 45, 139­ 144. 15. Indian Journal of Env. Health Acute DWLOC EPA indicates there is no room in the risk cup for water and DWLOCs cannot be calculated. If a corrected acute RfD is used (no FQPA 10X), acute DWLOCs can be calculated as follows: US Population: Acute RfD= 0.03 mg/ kg Exposure= 0.005937 mg/ kg (from EPA assessment without poultry and with CMBS data) 70 kg. Man, 2­ liter consumption Acute DWLOC is 842ppb Children 1­ 6: Acute RfD= 0.03 mg/ kg Exposure= 0.008363 mg/ kg (from EPA assessment without poultry and with CMBS data) 10kg child, 1 liter consumption Acute DWLOC is 216ppb Aventis monitoring programs of raw surface drinking water have shown 0.16 ppb as the maximum encountered. NAWQA data shows 5 ppb as the maximum encountered in ground or surface water. These monitoring numbers would indicate there is no concern for dietary and drinking water exposure in an aggregate situation. Chronic DWLOCs EPA indicates there is some concern for subpopulations for drinking water in the chronic scenarios. If a corrected chronic RfD is used (no FQPA 10X) chronic DWLOCs can be calculated as follows: US Population: Chronic RfD= 0.01 mg/ kg Exposure = 0.000037 mg/ kg (from EPA assessment without poultry) 70kg man, 2 liter consumption Chronic DWLOC is 349 ppb Children 1­ 6: Chronic RfD= 0.01 mg/ kg Exposure= 0.000062 mg/ kg (from EPA assessment without poultry) 10kg child, 1 liter consumption Chronic DWLOC is 99 ppb 50 Aventis and NAWQA monitoring data averages are significantly less than the maximum values of 0.16 ppb and 5 ppb numbers cited above. There are no populations of concern for aggregate exposure to food and water for carbaryl. 51 Part III ­ Residue Chemistry Considerations Line­ by­ Line Review of the Residue Chemistry Information Included in the Human Health Risk Assessment Document for Carbaryl (June 19, 2001) 1.08 Data Needs/ Label Requirements Product Chemistry Data Gaps Page 95 Paragraph 3 Line 1­ 3 EPA comment: A review of the labels and supporting residue data indicate that several label amendments are required. Details are provided in the Product and Residue Chemistry Chapters (DP Barcode: D238151) dated October 17, 2000. Aventis response: Most of these label amendments have already been made and approved by the EPA. See detailed information in the review of the Residue Chemistry Chapter below. Page 96 Paragraph 7 Lines 1­ 2 EPA comment: Adequate residue data are available on olives provided that use directions for olives are amended to remove the statement allowing the use of summer oil as an adjuvant. Aventis response: The statement allowing the use of summer oil as an adjuvant has already been deleted from the use directions for olives. Page: 97 Paragraph: 2 Line 1 EPA comment: Additional data are required depicting carbaryl residue in/ on cotton gin byproducts. Aventis response: Aventis is not supporting the cotton use and has removed this crop from the labels. Aventis CropScience requested cancellation of this use in a letter to Mr. George Tompkins, RD, on January 22, 1999. A Federal Register Notice dated April 14, 1999 announced receipt by the Agency of an application from RhonePoulenc Ag Company (now Aventis CropScience) to cancel the use of carbaryl products on cotton. 52 Page: 97 Paragraph: 3 Lines 1­ 4 EPA comment: The registrant does not intend to support carbaryl on avocados, barley, maple sap, oats, rye, and sweet sorghum; however, IR­ 4 has indicated (correspondence from K. Dorschner, IR­ 4 Project, 9/ 15/ 94) that they may fulfill the residue data requirements for some of these commodities. These data have not been submitted. Aventis response: IR­ 4 has not generated the residue data necessary to support these uses. Aventis CropScience will not support these uses. Page: 97 Paragraph: 4 Lines 1­ 2 EPA comment: The reregistration requirements for magnitude of the residue in livestock commodities are not fulfilled. Additional data are required to support dermal and poultry house uses. Aventis response: Aventis CropScience will neither support dermal nor poultry house uses of carbaryl. A request for cancellation of these uses in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) will be submitted shortly to the Agency. 53 Line­ by­ Line Review of the Supporting Document "Product and Residue Chemistry Chapters for the Reregistration Eligibility Decision (Felecia Fort; November 14, 2000)" Cover Memo Residue Chemistry Page 2 Paragraph 3 1 st Bullet Pont EPA comment: A review of the labels and supporting residue data indicate that several label amendments are required. Aventis response: Most of these label amendments have already been made and approved by the EPA. Page 3 6 th Bullet Point Lines 1­ 2 EPA comment: Adequate residue data are available on olives provided that use directions for olives are amended to remove the statement allowing the use of summer oil as an adjuvant. Aventis response: The statement allowing the use of summer oil as an adjuvant has already been deleted from the use directions for olives. Page: 4 1 st Bullet Point Line 1 EPA comment: Additional data are required depicting carbaryl residue in/ on cotton gin byproducts. Aventis response: Aventis is not supporting the cotton use and has removed this crop from the labels. Aventis CropScience requested cancellation of this use in a letter to Mr. George Tompkins, RD, on January 22, 1999. A Federal Register Notice dated April 14, 1999 announced receipt by the Agency of an application from RhonePoulenc Ag Company (now Aventis CropScience) to cancel the use of carbaryl products on cotton. Page: 4 2 nd Bullet Point Lines 1­ 4 EPA comment: The registrant does not intend to support carbaryl on avocados, barley, maple sap, oats, rye, and sweet sorghum; however, IR­ 4 has indicated (Correspondence from K. Dorschner, IR­ 4 Project, 9/ 15/ 94) that they may fulfill the residue data requirements for some of these commodities. These data have not been submitted. 54 Aventis response: IR­ 4 has not generated the residue data necessary to support these uses. Aventis CropScience will not support these uses. Page: 4 3 rd Bullet Point Lines 1­ 2 EPA comment: The reregistration requirements for magnitude of the residue in livestock commodities are not fulfilled. Additional data are required to support dermal and poultry house uses. Aventis response: Aventis CropScience will neither support dermal nor poultry house uses of carbaryl. A request for cancellation of these uses in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) will be submitted shortly to the Agency. Residue Chemistry Chapter of the Reregistration Eligibility Decision (RED) Document Residue Chemistry Considerations Summary of Science Findings Page 3 Table A1. Carbaryl EPs with Food/ Feed Uses Registered to Aventis Ag Company EPA comment: Label acceptance dates for Carbaryl EPs are listed Aventis response: Label acceptance dates listed for certain products are incorrect. Acceptance dates of the most recently EPA approved labels for SEVIN® 80S, SEVIN® 5% Bait, SEVIN® XLR PLUS, SEVIN® RP2, SEVIN® RP4, SEVIN® 4F, and SEVIN® 80WSP are listed below. EPA Reg. No. Corrected Label Acceptance Date Product Name 264­ 316 1/ 13/ 2000 Notification 7/ 26/ 2001 SEVIN® brand 80S Carbaryl Insecticide 264­ 320 6/ 11/ 1999 SEVIN® brand 5% Bait Carbaryl Insecticide 264­ 333 2/ 8/ 2001 SEVIN® brand XLR Carbaryl Insecticide (Alternate brand name: SEVIN® brand XLR PLUS Carbaryl Insecticide) 264­ 334 Notification 10/ 29/ 1999 SEVIN® brand RP2 Carbaryl Insecticide 264­ 335 10/ 18/ 2000 SEVIN® brand RP4 Carbaryl Insecticide 264­ 349 1/ 13/ 2000 SEVIN® brand 4F Carbaryl Insecticide 55 264­ 526 4/ 12/ 2000 SEVIN® brand 80 WSP Carbaryl Insecticide The following SLN Nos are no longer active: SEVIN® brand 50W: CA830007, NC820007 SEVIN® brand 80S: CA8300007, WA900013 SEVIN® brand XLR: NC960003, OH960003, OR950006, PA960002, VA950001, WA940021 SEVIN® brand 4F: FL890037 Page 3 Paragraph 2 Lines 1­ 2 EPA comment: Use directions for sugar beets on all labels should be amended to specify a maximum of two applications at a maximum single application rate of 1.5­ lb ai/ A and a 28­ day PHI. Aventis response: This change has been made on all Aventis CropScience product labels. Page 3 Paragraph 3 Lines 1­ 2 EPA comment: Use directions for sweet corn on the G formulations should be amended to specify a 48­ day PHI for stover. Aventis response: This change has been made. Page 3 Paragraph 4 Lines 1­ 2 EPA comment: As the registrant is no longer supporting uses on avocado, the SLN labeling (CA83007) for use of carbary (sic) on avocados in CA should be revoked. Aventis response: This SLN label has been canceled. Page 3 Paragraph 5 Line 1 EPA comment: Use directions for cotton on all labels should be amended to remove the 14­ day PHI for forage. Aventis response: The use of carbaryl products on cotton has been canceled. 56 Page 4 Paragraph 1 Lines 1­ 3 EPA comment: Based on acceptable residue data on okra from IR­ 4, the registrant should amend use directions on FIC and WP labels to specify a maximum or four applications per season at 1.5 lb ai/ A/ application at a minimum re­ treatment interval (RTI) of 6 days and a minimum PHI of 3 days. Aventis response: The current labels allow the application of 1 to 1.5 lb. ai/ A on a 6­ to 8­ day interval. A maximum of 6­ lb ai/ A may be applied per season with a PHI of 3 days. Page 4 Paragraph 2 Lines 1­ 2 EPA comment: Use directions for olives on all labels should be amended to remove the statement allowing the use of a tank mix with summer oil. Aventis response: This change has been made on all Aventis CropScience product labels. Page 4 Paragraph 3 Lines 1­ 3 EPA comment: Based on acceptable residue data on prickly pear cactus from IR­ 4, the registrant should amend use directions on FIC and WP labels to specify a maximum of three applications per season at 2 lb ai/ A/ application at a minimum RTI of 7 days and a minimum PHI of 3 days. Aventis response: The current labels allow the application of 2 lb ai/ A on a 7 to 10 day interval. A maximum of 6 lb ai/ A may be applied per season with a PHI of 3 days. GLN 860.1300: Nature of the Residue ­ Livestock Page 5 Paragraph 4 Lines 2­ 6 EPA comment: The registrant has stated its intention to support dermal uses on poultry and carbaryl uses in poultry houses and, according to REFS, these uses are on carbaryl labels. If the registrant intends to support these uses of carbaryl on poultry, tolerances, supported by adequate metabolism and magnitude of the residue data, will be required, at levels appropriate for these uses. Aventis response: Aventis CropScience will no longer support the use of carbaryl for direct application to poultry, as well as the poultry quarters treatment. We will submit a request for cancellation of these uses in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). 57 GLN 860.1500: Crop Field Trials Page 9 Paragraph 2 Lines 1­ 3 EPA comment: Adequate data are available to reassess the tolerances for residues of carbaryl in/ on sugar beet roots and tops provided that use directions on five currently approved labels are modified to allow a maximum of two applications per season at 1.5 lb ai/ A/ application and a PHI of 28 days Aventis response: The labels were amended to conform to these requirements. Page 10 Paragraph 3 Lines 1­ 2 EPA comment: Adequate data are available on olives provided that use directions for olives are amended to remove the statement allowing the use of summer oil as an adjuvant. Aventis response: The labels were amended to conform to this requirement. Page: 10 Paragraph 5 Lines 2­ 3 EPA comment: Additional data are required depicting carbaryl residue in/ on cotton gin byproducts. Aventis response: Aventis is not supporting the cotton use and has removed this crop from the labels. Page: 10 Paragraph 6 Lines 1­ 4 EPA comment: The registrant does not intend to support carbaryl on avocados, barley, maple sap, oats, rye, and sweet sorghum; however, IR­ 4 has indicated (correspondence from K. Dorschner, IR­ 4 Project, 9/ 15/ 94) that they may fulfill the residue data requirements for some of these commodities. These data have not been submitted. Aventis response: IR­ 4 has not generated the residue data necessary to support these uses. Aventis CropScience will not support these uses. Table A2. Food/ Feed Use Patterns on EP Labels Subject to Reregistration for Carbaryl (Case 0080) Page: 16 EPA comment: 58 Maximum Single Application Rate, ai: 3.0 lb/ A & 4.0 lb/ A (CA only). Aventis response: Maximum Single Application Rate, ai: 3.0 lb/ A & 4.0 lb/ A (CA only). An additional application at the dormant or delayed dormant timing may be made at a maximum rate of 5 lb/ A. Page: 21 Site: Beet, Sugar EPA comment: The maximum seasonal rate for sugar beets is 4.0­ lb ai/ A. Aventis response: The rate for the 80 WSP is 4.0­ lb ai/ A. however, the maximum seasonal rate for flowable formulations to sugar beets is 3.0 lb ai/ A. Page: 23 Site: Broccoli, Brussels sprouts, etc. EPA comment: The preharvest interval for broccoli, Brussel sprouts, cabbage, cauliflower, Chinese cabbage, collards, kale, kohlrabi, and mustard greens is 3 days. Aventis response: The preharvest interval for broccoli, Brussel sprouts, cabbage, cauliflower, and kohlrabi is 3 days. The preharvest interval for Chinese cabbage, collards, kale, and mustard greens is 14 days. Page: 26 Site: Citrus fruits EPA comment: The maximum seasonal rate to Citrus Fruits in CA is 20.0 lbs/ A Aventis response: The maximum seasonal rate to Citrus Fruits in CA is 16.0 lbs/ A 59 Part IV ­ Occupational and Residential Exposure/ Risk Assessment Line­ by­ Line Review of the Supporting Document "Carbaryl: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document (Jeffrey L. aDawson; June 28, 2001)" 1.0 Occupational and Residential Exposure/ Risk Assessment 1.3 Summary of Hazard Concerns Page: 12 Table 1: EPA comment: UF column for short­ term dermal, inhalation & non­ dietary ingestion reads "3000 for residential and 300 for occupational" Aventis response: This box should read, "3000 for residential and 300 for occupational,+ dermal absorption factor" for consistency purposes. However, for the reasons previously stated the extra 10X and 3X MOS factors should be removed due to the recently submitted toxicological studies. EPA comment: UF column for intermediate­ term dermal, inhalation & non­ dietary ingestion reads "1000 for residential and 100 for occupational" and the Type of Exposure column refers only to dermal exposure. Aventis response: The UF box should read, "1000 for residential and 100 for occupational,+ dermal absorption factor" for consistency purposes. The 1000X MOS factor should be reduced as the extra 10X MOS is no longer necessary. In addition, the Type of Exposure box should read "Intermediate­ term dermal, inhalation, & non­ dietary ingestion" for accuracy. 2.0 Occupational Exposures and Risk 2.1.2 Data and Assumptions for Handler Exposure Scenarios Occupational Handler Exposure Studies Page: 34 Paragraph: 3 Note to Chemical Review Managers: EPA comment: " There are no data compensation issues associated with the use of …the propoxur trigger sprayer study has a signed PHED data waiver but just has not been included into PHED at this time. 60 Aventis response: Although Bayer has submitted a data compensation waiver for the inclusion of the propoxur study in PHED, the data compensation waiver is applicable only to the data cited once in PHED. Specifically, the first paragraph of the data compensation waiver form states, `The following pertains only to those data taken from company studies and incorporated into the generic exposure monitoring database'. In addition, the 29 December 1986 memorandum from Douglas Campt, Director of OPP to pesticide registrants regarding the formation of PHED, specifically states on page 2, bullet point 1 Those companies who submit data for inclusion in the data base will waive their compensation rights under FIFRA to the data when referenced generically as part of the data base. However, existing compensation rights will apply when a company's data is cited specifically. Aventis concludes that the specific referencing of the Bayer propoxur exposure study rather than a PHED generic study number does not eliminate the data compensation rights of Bayer. Aventis believes that the Health Effects Division should seek specific guidance from the Office of General Counsel regarding the data compensation status of the propoxur study for use in the carbaryl RED. 2.0 Occupational Exposures and Risk 2.1.2 Data and Assumptions for Handler Exposure Scenarios Page: 32 Paragraph: First bullet Line 2: EPA comment: If additional information such as average or typical rates are available, these values are used as well in order to allow risk managers to make a more informed risk management decision. Average application rates were available from the SMART meeting and BEAD's QUA. These data indicate that in most cases, average application rates differ from maximum application rates on average by a factor of two. For example, when interpreting the results of the cancer assessment, the small differences generally seen in the available rates should be considered along with the overall magnitude of the cancer risk results. Aventis response: Aventis believes that the average or typical application rates provided in the document should be used in the determination of intermediate­ term, chronic, and cancer risk assessments. The use of the label maximum application rates for each application becomes extremely unlikely for intermediate term grower exposure assessments of 10 applications, commercial intermediate­ term assessments of 30 applications, and chronic or cancer risk assessments. Although the Agency may believe it is obligated to look at the maximum application rates for exposure durations longer than the short­ term assessments, it should as it states provide 61 estimates of risk based on average application rates for the intermediate­ term and longer risk assessments. Appendix C provides and utilizes only label maximum application rates for the estimation of intermediate­ term and chronic MOEs in Tables 3, 4, 5, 6, 8, 9, 10, and 11. The risk assessment must provide MOEs based on average application rates to allow risk managers to make a more informed risk management decision. 2.0 Occupational Exposures and Risk 2.1.2 Data and Assumptions for Handler Exposure Scenarios Page: 42 Table 9: EPA comment: LCO Turfgun exposure estimates obtained from ORETF study OMA002 are based on the wettable powder formulation data. The dermal exposure estimates are 0.99 mg/ lb a. i., 0.72 mg/ lb a. i., and 0.38 mg/ lb a. i. for single layer no gloves, single layer gloves, and double layer gloves clothing scenarios, respectively. Inhalation exposure is 0.062 mg/ lb a. i. The Table 9 footnote states WP formulation used for turfgun assessment as the unit exposures for this scenario were slightly higher than for the other formulations (i. e., well within a factor of 2). Aventis response: Sevin is sold to the professional lawn care market as either an 80S in water soluble packaging or as the SL liquid formulation. Therefore, the use of the wettable powder formulation is not appropriate. Therefore, the dermal exposure for the single layer of clothing and glove scenario should be 0.66 mg/ lb a. i. based on all formulations and the inhalation exposure should be 0.007 mg/ lb a. i. based on the higher water­ soluble packaging estimate compared to the flowable liquid inhalation exposure estimate of 0.002 mg/ lb a. i. 2.3 Occupational Risk Characterization 2.3.1 Handler Characterization Page: 103 Paragraph: 2 Line: 19 EPA comment: Where available, average use rates were also used to provide for a more informed risk management decision Aventis response: While Aventis agrees that average use rates should be used for intermediate­ term and longer repeated exposure risk assessments, the use of average application rates in the exposure assessments does not appear evident. The MOEs presented for intermediate­ term and longer risk are based on label maximum application rates. The position of Aventis is that handler MOEs for intermediate­ term and 62 longer risk assessments should be based on average application rates and not label maximum rates as presented in the assessment. 3.0 Residential and Other Non­ Occupational Exposures and Risks 3.1.1 Handler Exposure Scenarios Page: 116 Table 27: EPA comment: Table 27 states that Hose­ end sprayer data for mix your own (not the locking/ no contact package) considered. Aventis response: The dermal and inhalation exposure estimates of 2.61 mg/ lb a. i. and 0.010 mg/ lb a. i., respectively, for the ready­ to­ use (RTU) hose end sprayer need to be included in the handler exposure scenario estimations of homeowner exposure during application to lawns. The use of the product in this packaging results in exposure estimates that are different than the dial type sprayer (DTS). Because the RTU sprayer is a significant method of lawn application, the consideration of the potential exposure and risk for lawn applications with the RTU sprayer need to be presented and discussed in the risk assessment. The difference in exposure potential between the DTS and RTU hose­ end sprayers may provide important information for risk management decisions that are currently lacking. 3.0 Residential and Other Non­ Occupational Exposures and Risks 3.1.3 Residential Handler Exposure and Non­ Cancer Risk Estimates Page: 122 Table 28: EPA comment: Scenario 3, Fire Ant MOEs are based on the use of 100 gallons or 0.75 lb a. i./ event for the garden vegetable hose­ end spray scenario and 5 gallons or 0.0375 lb a. i./ event for garden low pressure handwand applications. Aventis response: Aventis does not understand why there is a 20­ fold difference in the amount of active ingredient handled between the hose­ end sprayer and hand wand application of carbaryl to control fire ants at the same site, gardens. Aventis believes that the use of 0.0375 lb a. i./ event is reasonable for a vegetable garden and that the use of 100 gallons of spray or 0.75 lb a. i./ A is more representative of a lawn spot application to control fire ants. Scenario 3, Fire ant vegetable garden use should be reduced to 0.075 lb a. i./ event, which is similar to the other scenario 3 vegetable garden uses and consistent with the fire ant control in vegetable gardens using the low pressure hand wand equipment. Any estimation of fire ant 63 control on the lawn should be based on exposure data from the ORETF hose­ end sprayer exposure study (OMA004) and not from the carbaryl vegetable garden exposure study (MRID 44459801). 3.0 Residential and Other Non­ Occupational Exposures and Risks 3.1.4 Residential Handler Exposure and Risk Estimates for Cancer Page: 128 Table 29: EPA comment: Presentation of cancer risks to three significant figures. Aventis response: Aventis does not believe that the expression of cancer risks to three significant figures accurately portrays the lack of precision in the risk assessment. Cancer risks should be presented as either one or two significant figures, consistent with HED policy. The use of three significant figures is leading to the portrayal of cancer risks such as 1.08 x 10 ­6 for fire ants or 1.24 x 10 ­6 for vegetable garden dusts as being in excess of the 1 x 10 ­6 guideline. Both of these risks are more correctly presented as 1 x 10 ­6 to present the lack of precision in the cancer risk assessment. Appendix F: Carbaryl Residential Handler Exposure Data Table 2. Input Parameters for Carbaryl Homeowner Handler Exposure and Risk Calculations EPA comment: Inhalation unit exposures are estimated based on a breathing volume of 29 l/ min. Aventis response: The recommended breathing volume for adult short­ term exposure is 1.0 m 3 /hr or 17 l/ min for light activities (U. S. EPA Exposure Factors Handbook, Volume 1 General Factors, EPA/ 600/ P­ 95/ 002Fa). In discussions between the ORETF and the regulatory advisory board to ORETF, it was agreed that application of home pesticide products constituted light activities and that the 17 l/ min breathing rate will be used. The 29 l/ min rate used by HED is the PHED default and represents agricultural work practices that are more strenuous than home pesticide application. Therefore, all residential inhalation exposure estimates should be based on 17 l/ min breathing volume or 59% of the inhalation exposure estimates presented in the HED assessment. 64 Part IV ­ Occupational and Residential Exposure/ Risk Assessment SUPPORTING DISCUSSION Occupational and Residential Exposure Assessment The assessment of occupational and residential exposure and risk prepared by Mr. Jeff Dawson was a comprehensive assessment of excellent quality. This is reflected by the relatively minimal number of factual error comments provided by Aventis CropScience. Based on the quality of the initial assessment, the major effort regarding the assessment of occupational and residential exposure to carbaryl will involve refinement of the risk assessment. Aventis CropScience has conducted, or is in the process of conducting, studies relevant to the refinement of the occupational and residential risk assessment. These studies are as follows: 4­ Week Repeated­ Dose Dermal Toxicity Study with Sevin XLR Plus in Rats. The study is completed and a draft report is currently in review by Aventis. The results of this study are intended to replace the current dermal exposure toxicity endpoints based on oral toxicity used for short­ term and intermediate­ term occupational and residential handler exposure when handling liquid formulations of carbaryl. Expected completion date: September 2001 4­ Week Repeated­ Dose Dermal Toxicity Study with Sevin 80S in Rats. The study is completed and a draft report is currently in review by Aventis. The results of this study are intended to replace the current dermal exposure toxicity endpoints based on oral toxicity used for short­ term and intermediate­ term occupational and residential handler exposure when handling solid formulations of carbaryl. Expected completion date: September 2001 4­ Week Repeated­ Dose Dermal Toxicity Study with Carbaryl Technical in Rats. The study is completed and a draft report is currently in review by Aventis. The results of this study are intended to replace the current dermal exposure toxicity endpoints based on oral toxicity used for short­ term and intermediate­ term occupational and residential postapplication dermal exposure. Expected completion date: September 2001 Measurement of Pesticide Exposure of Suburban Residents Associated with the Residential Use of Carbaryl. This is an ongoing biological monitoring study of 10 families in California and 10 families in Missouri. The study will monitor the absorbed dose of carbaryl resulting from a lawn broadcast application and subsequent vegetable garden application of carbaryl by an adult family member. Postapplication absorbed dose of all adults and children aged four to seventeen will be followed over a three­ day period. The participants' postapplication activities will be recorded but not controlled to establish a range of absorbed 65 doses. The data will be used along with the residential exposure assessment to improve understanding of residential exposure to carbaryl. Expected completion date: March 2002 University of California ­ Riverside biological monitoring of citrus orchard application and postapplication apple thinning and cherry harvesting job functions is completed in the field. The results from these studies will be used to refine the PHED and ARTF­ based exposure estimates. These are high exposure potential work functions and the biological monitoring data are intended to refine the assessments of these work functions. Expected completion date: March 2002 66 APPENDIX I Business Confidential Surface Water Monitoring for Residues of Carbaryl in High Use Areas of the United States (Stone Environmental, Inc. Report #99­ 1005­ F) (hard copy provided) 1 CARBARYL PC Code No. 056801; Case 0080 Review of the Draft Environmental Fate and Ecological Risk Assessment for the Reregistration of Carbaryl August 6, 2001 Aventis CropScience P. O. Box 12014, 2 T. W. Alexander Drive Research Triangle Park, NC 27709 2 CARBARYL PC Code No. 056801; Case 0080 Review of the Draft Environmental Fate and Ecological Risk Assessment for the Reregistration of Carbaryl TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................... 2 GENERAL COMMENTS .................................................................................................................... 5 TRANSMITTAL DOCUMENT ............................................................................................................ 9 Data Gaps ............................................................................................................................... 9 Environmental Fate and Transport ............................................................................... 9 Water Resources ........................................................................................................... 9 Ecological Effects Data requirement .......................................................................... 10 Label Information ....................................................................................................... 11 DRAFT RED DOCUMENT .............................................................................................................. 13 1.0 Summary and Environmental Risk Conclusions ........................................................... 13 Risk to Terrestrial Organisms ..................................................................................... 13 Fate and Water Assessment ........................................................................................ 13 2.0 Introduction .................................................................................................................... 14 3.0 Integrated Risk Characterization ................................................................................... 15 Introduction ................................................................................................................. 15 Aquatic Organisms ...................................................................................................... 15 Terrestrial Organisms ................................................................................................. 16 Endocrine Disruption Concerns .................................................................................. 18 Uncertainties ............................................................................................................... 19 4.0 Environmental Fate Assessment .................................................................................... 20 Exposure Characterization .......................................................................................... 20 Persistence .................................................................................................... 23 Mobility ........................................................................................................ 24 Field Dissipation ........................................................................................... 25 Foliar Dissipation ......................................................................................... 27 Atmospheric Transport ................................................................................. 28 1­ Naphthol Fate and Transport ..................................................................... 28 Aquatic Exposure Assessment .................................................................................... 30 Surface Water ............................................................................................... 30 Estimated Environmental Concentrations for Terrestrial Ecological Risk Assessment32 5.0 Drinking Water Assessment .......................................................................................... 32 Water Resources Assessment ..................................................................................... 32 Drinking Water Exposure Assessment ......................................................... 33 Water Treatment Effects .............................................................................. 37 Ground Water Resources .............................................................................. 38 3 Surface Water Resources .............................................................................. 39 6.0 Hazard and Risk Assessment for Aquatic Organisms .................................................. 45 Hazard assessment for Aquatic organisms ................................................................. 45 Estuarine/ Marine Fish .................................................................................. 45 Aquatic Plants ............................................................................................... 45 Risk Assessment for Aquatic Organisms .................................................................... 45 Estuarine/ Marine Fish .................................................................................. 46 7.0 Hazard and Risk Assessment for Terrestrial Organisms .............................................. 46 Hazard Assessment for Terrestrial Organisms ........................................................... 46 Mammalian ................................................................................................... 46 Risk Assessment for Terrestrial Organisms ................................................................ 46 Avian Risk .................................................................................................... 46 Mammalian Risk .......................................................................................... 47 Reproduction Effects .................................................................................... 48 9.0 References (non­ MRID) ............................................................................................... 50 Appendix A: Environmental Fate Study Reviews (DERs) ................................................. 50 Appendix B: Refined Water Memo .................................................................................... 50 Appendix C: Ecological Risk Assessment .......................................................................... 51 Toxicity Endpoints Used in the Risk Assessment ...................................................... 51 Avian Acute and Chronic Risk ................................................................................... 51 Risk from Exposure to Non­ granular Products ........................................................... 52 Risk from Exposure to Granular Products .................................................................. 52 Aquatic Plants ............................................................................................................. 52 Appendix D: Toxicity Assessment ...................................................................................... 52 Birds, Chronic Toxicity .............................................................................................. 53 Mammals, Acute and Chronic .................................................................................... 53 Freshwater Fish, Acute ............................................................................................... 54 Freshwater Invertebrates, Acute ................................................................................. 54 Estuarine and Marine Invertebrates, Acute ................................................................. 54 DISCUSSION ............................................................................................................................. 56 1. Surface Water Concentrations ........................................................................................ 56 Summary of Registrant Surface Water/ Drinking Water Monitoring Program ........... 56 Summary of Surface Water Data from the NAWQA Program .................................. 58 Summary of Carbaryl Analytical Methods used in the NAWQA Program ................ 60 Gas Chromatography/ Mass Spectroscopy Method ...................................... 60 High­ Performance Liquid Chromatography/ Photodiode­ Array Method ..... 64 Summary of Surface Water Data from the California DPR Surface Water Database 64 2. Ground Water Concentrations ........................................................................................ 66 Summary of Ground Water Data from the NAWQA Program .................................. 66 REFERENCES ............................................................................................................................ 68 4 TABLE OF CONTENTS (continued) Tables Table 1. Summary Of Results From The Carbaryl Drinking Water Monitoring Study. 57 Table 2. Carbaryl Detections Reported In Pesticides In Streams Update (Larson, 2001) ........................................................................................................... 58 Table 3. Frequency Of Carbaryl Detections By GC/ MS In Different Concentration Ranges Reported In The NAWQA Database As Of July 16, 2001 ............ 59 Table 4. Frequency Of Carbaryl Detections By LC/ PDA In Different Concentration Ranges Reported In The NAWQA Database As Of July 16, 2001 ............ 59 Table 5. Recovery And Precision For Multiple Determinations Of Carbaryl In GC/ MS Method For Carbaryl Spiked In Different Water Samples ............ 61 Table 6. Percent Recoveries Of Carbaryl Detected By The NAWQA GC/ MS Method In Laboratory Control Spikes And Field Matrix Spikes At A Spiking Level Of 0.1 µ g/ L ................................................................................................. 63 Table 7. Recovery And Precision For Multiple Determinations Of Carbaryl In LC/ PDA Method For Carbaryl Spiked In Different Water Samples .......... 64 Table 8. Carbaryl Detections Reported In California DPR Surface Water Monitoring Database ...................................................................................................... 65 Table 9. Limits Of Quantification For Carbaryl Analytical Methods Reported In California DPR Surface Water Monitoring Database ................................. 65 Table 10. Carbaryl Detections Reported In Pesticides In Ground Water Update (Kolpin, 2001) ............................................................................................. 67 Confidential Business Attachments APPENDIX 1 .............................................................................................................................. 70 APPENDIX 2 .............................................................................................................................. 71 The last page of this report is number 70 \# "0" 70. 5 General Comments The EFED draft chapter of the carbaryl RED is very thorough using a wealth of references. The use of published literature over submitted data is significant. The quality of the published literature is at times at least questionable and other times does not fulfill the requirements set by EPA for studies submitted by the registrant (e. g. thorough description of test conditions, clear identification of the test material, analytical verification, GLP etc.). Data of such poor quality should not be used as key information in the risk assessment. For the 30­ day response not all literature references could be verified or the quality ascertained. There is a high level of redundancy in the document making it difficult to read. Reducing repetitions to a minimum would facilitate the reading. We believe it is inappropriate to include DERs in the RED Chapters. A summary of study findings is already presented in the document. DERs should be made available to the public through the regular procedure under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. The use of carbaryl on barley, oats, rye, cotton, and livestock are cancelled . It should be noted that Aventis CropScience labels for the technical materials and the end­ use products containing carbaryl were amended to delete these uses. The Agency has already approved the labeling changes (please refer to HED response document, Section III for details). Aventis CropScience will no longer support the use of carbaryl on poultry (direct application and poultry quarters treatment). We will shortly submit a request for cancellation of these uses in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) (please refer to HED response document, Section III for details). Aventis CropScience is in the process of conducting, or has scheduled, studies relevant to the refinement of the environmental risk assessments for carbaryl and the major degradate 1­ naphthol. These studies are as follows: Rate and Route of Aerobic Degradation in Soils. These studies have been initiated with parent carbaryl applied to four diverse U. S. soils. The data are intended to provide additional half­ life determinations for parent carbaryl and the major degradate 1­ naphthol. Expected completion date: March 2002 Aerobic Aquatic Metabolism in Two Water/ Sediment Systems. These studies have been initiated with parent carbaryl applied to two distinct U. S. water/ sediment systems. The data are intended to provide additional half­ life determinations for parent carbaryl and the major degradate 1­ naphthol. In addition, further identification of additional degradation products is anticipated. Expected completion date: March 2002 Adsorption and Desorption of 1­ Napthol to five soils. This study has been scheduled to evaluate the adsorption and desorption of the major carbaryl degradate to five soils/ sediment. The data are intended to provide information necessary to evaluate the 6 environmental risks from 1­ naphthol in standard models. Expected completion date: March 2002 For the reregistration process in the EU, Aventis CropScience is in the process of conducting, or has scheduled, studies relevant to the refinement of the ecotoxicological risk assessments for carbaryl and the major degradate 1­ naphthol. These studies are as follows: Studies with Carbaryl: Acute oral LD50 in mallard ducks Dynamic acute LC50 in bluegill sunfish Acute toxicity in Daphnia Acute toxicity in Chironomus riparius Toxicity in Selenastrum capricornutum Acute oral and contact toxicity in honeybees 14­ d toxicity in earthworms Effects on soil microorganisms (nitrification/ carbon cycle) Effect on sewage treatment Studies with 1­ naphthol Early life­ stage study in fathead minnow Acute toxicity in Daphnia Acute toxicity in Daphnia in presence of sediment Chronic toxicity in Daphnia 14­ d toxicity in earthworms Formulated Product Vegetative Vigor Toxicity in Selenastrum capricornutum Acute oral and contact toxicity in honeybees Effect on non­ target arthropods 14­ d toxicity in earthworms Effects on soil microorganisms (nitrification/ carbon cycle) Ecotoxicological Risk Assessments Aventis has pointed out several errors in the PRZM input parameters (see comments made to Tables 5 and 6 of the draft RED), overly conservative estimates of foliar dissipation half­ lives and changes in ecotoxicology study endpoints. This indicates that a re­ calculation of the EECs and risk quotients are warranted in a number of instances. Endocrine Disruption Reports in the open literature on the reproductive effects of carbaryl in wild mammals are at best ambivalent. The recently submitted 2­ generation study in rats demonstrates the absence of 7 reproductive effects. As EPA pointed out, findings reported in the literature were made at concentrations well above the highest peak concentration modeled. Therefore these findings are irrelevant for a risk assessment and at the current stage of discussion about endocrine disruption. If the concern about the endocrine potential of carbaryl persists, the issue should be revisited once the Agency's endocrine disrupter screening and testing program as well as a policy on how to incorporate positive findings into an ecological risk assessment have been fully developed. Mobility The classification of carbaryl as mobile to very mobile is inconsistent with measured Koc values of 177 to 249 (MRID 43259301). According to the widely used classification scheme of McCall, et al. (1980) wherein Koc values between 150 and 500 denote medium mobility in soil, carbaryl would be classified as having medium mobility in most soils. This classification of medium mobility is further supported by the acceptable column leaching study (MRID 43320701) in which aged carbaryl residues were only slightly mobile in a number of soils. The mobility of carbaryl would be expected to be higher in sandy soils or in soils of low organic matter. 1­ Napthol Fate and Transport The Agency is requiring additional information on the persistence and mobility of 1­ naphthol, a major environmental degradate of carbaryl. However, a half­ life for 1­ naphthol of less than 1 day can be calculated from the carbaryl aerobic soil metabolism study (MRID 42785101). The data from this study demonstrate that under aerobic soil conditions the formation and decline of 1­ naphthol, starting from parent carbaryl, is complete in less than 14 days. This half­ life can be used for preliminary environmental fate modeling to estimate EECs for 1­ naphthol. The EPA suggested that 1­ naphthol is not strongly sorbed to soil. Additional information available in the literature demonstrates that the sorption of 1­ naphthol to soil is stronger than that seen for carbaryl itself. Hassett et al. (1981) has demonstrated that the sorption of 1­ naphthol was the result of sorption to organic carbon resulting in Koc values between 431 and 15,618. These data indicate that 1­ naphthol is less mobile and less susceptible to leaching than carbaryl itself, and they demonstrate that at least a portion of the 1­ naphthol residue is tightly sorbed to soil constituents. (A copy of this article is being submitted with the response to the draft RED.) To meet the requirement for information on the adsorption and desorption of 1­ naphthol by the Agency, the registrant is conducting an adsorption/ desorption study to meet the 163­ 1 guideline. Study results should be available for submission to the Agency in the first quarter of the calendar year 2002. Surface Water/ Drinking Water Aventis disagrees with EPA that the modeling simulations provide a conservative, though not unreasonable, estimate on possible concentrations in drinking water. Drinking water concentrations derived from PRZM/ EXAMS greatly overestimate the potential exposure to carbaryl in drinking water, generally by several orders of magnitude. Results from the drinking 8 water monitoring program conducted by the registrant provides a `real world' assessment of the potential for human exposure to carbaryl in drinking water derived from surface water. Ground Water EPA summarized information on the detection of carbaryl in groundwater from the EPA Pesticides in Groundwater Database, the EPA STORET database and the NAWQA database. Each of the databases shows a pattern of very low levels of carbaryl detection in few groundwater resources. These analyses confirm several statements made by the Agency that carbaryl have limited potential to impact groundwater resources. However, on page 2 of the Memorandum issued June 28, 2001, in conjunction with the EFED RED chapter for carbaryl, EPA is requiring additional information on "Surface and groundwater monitoring in urban and suburban use areas (non­ guideline)." Based on the characteristics of carbaryl and the available data demonstrating limited impact of carbaryl on ground water resources, additional studies to evaluate the potential for carbaryl to contaminate groundwater are unnecessary and unwarranted. 9 Line­ by­ Line Review of the Carbaryl EFED RED Chapter Transmittal Document Data Gaps Environmental Fate and Transport Page: 2 Paragraph: 1 Line: 1 EPA comment: Fate information on the degradation product 1­ naphthol is required. 1. Mobility – adsorption and desorption studies for the 1­ naphthol degradate (163­ 1) 2. Persistence – aerobic soil metabolism study on 1­ naphthol Aventis' response: Literature data (Hassett et al. 1981) on the adsorption of 1­ naphthol are provided in this response. Aventis is in the process of conducting an additional adsorption/ desorption study on 1­ naphthol and intends to submit study data to EPA by March 2002. The degradation of 1­ naphthol under aerobic soil conditions has been widely reported in the literature. Several citations are included in the EPA draft RED. The half­ life of 1­ naphthol estimated from the acceptable aerobic soil persistence study on carbaryl (MRID 42785101) is less than 1 day. Aventis is conducting additional laboratory aerobic soil degradation studies on carbaryl that will be used to provide additional determinations of the half­ life for the degradate 1­ naphthol and satisfy the Agency's requirement for data on the persistence of 1­ naphthol. Aventis intends to submit these study data to EPA by March 2002. Water Resources Page: 2 Paragraph: 3 and 4 EPA comment: "EFED believes that adequate data are available to support the conclusions reached for carbaryl's impact on surface water and groundwater quality with the exceptions noted below. Additional information is needed to characterize the impact of the degradate 1­ naphthol [in] groundwater and surface water. Surface and groundwater monitoring in urban and suburban use areas (non­ guideline)" are required. 10 Aventis' response: The surface water­ monitoring program conducted by Aventis includes monitoring in urban and suburban use areas. Aventis believes that the need for information on the degradate 1­ naphthol will be satisfied by the aerobic soil and adsorption/ desorption data that will be submitted to the Agency. These data can be used to evaluate the availability of 1­ naphthol using established EPA modeling guidelines. The Agency's proposed requirement for groundwater monitoring is unnecessary and is addressed in Aventis' response to Agency comments in the draft RED. Ecological Effects Data requirement Page: 2 EPA comment: The ecological toxicity database is complete except for: 6. Aquatic Plant Growth Guideline 122­ 2 Aventis' response: The data requirement should be deleted. Aquatic plant growth studies were submitted to the Agency in 1992. An October 04, 2000 OPP Guideline Status Report (Chemical Review Management System) lists the guideline 122­ 2 status as "Acceptable/ Satisfied". The studies are: MRID No. Title Acceptability Code 42372101 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To The Freshwater Blue­ Green Alga, Anabaena flos­ aquae, Under Static Test Conditions: Lab Project Number: J9112004E. Unpublished Study Prepared By Toxikon Environmental Sciences. 53 P. June 25, 1992 Upgradable 42372102 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To Duckweed, Lemna gibba G3, Under Static Test Conditions: Lab Project Number: J9112004G. Unpublished Study Prepared By Toxikon Environmental Sciences. 53 P. January 1, 1992 Upgradable 42372802 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To The Freshwater Green Alga, Selenastrum capricornutum Under Static Conditions: Lab Project Number: J9112004C. Unpublished Study Prepared By Toxikon Environmental Sciences. 53 P. June 9, 1992 Acceptable 42431601 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To The Freshwater Diatom, Navicula pelliculosa, Under Static Test Conditions: Lab Project Number: J9112004F. Unpublished Study Prepared By Toxikon Environmental Sciences. 52 P. August 10, 1992 Acceptable 42431602 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To The Saltwater Diatom, Skeletonema costatum, Under Static Test Conditions: Lab Project Number: J9112004D. Unpublished Study Prepared By Toxikon Environmental Sciences. 49 P. August 10, 1992 Supplemental 11 Page: 2 EPA comment: The ecological toxicity database is complete except for: 7. Submission of a FETOX amphibian toxicity study is required. Aventis' response: The data requirement should be deleted. From the published results it is evident that carbaryl is practically non­ toxic to the bullfrog. Effects in plain leopard frogs are reported at levels well above environmental concentrations. These results were obtained testing U. S. native species. In the proposed FETOX assay, a non­ native species Xenopus laevis is used. This African species is unique in its behavior. Neither the species nor the test methods are suitable for ecotoxicological purposes. As the risk to amphibians can be evaluated from the studies cited, and as the effects are only at levels well above the EEC, this study should not be required. Label Information Page: 3 EPA comment: For terrestrial and residential uses: 1. "Do not apply directly to water, or to areas where surface water is present or to intertidal areas below the mean high water mark. Do not contaminate water when disposing of equipment washwater or rinsate." Aventis' response: Similar language is already present on Aventis' SEVIN® labels. Page: 3 EPA comment: For terrestrial and residential uses: 3. "This product may contaminate water through drift of spray in wind. This product has a high potential for runoff for several days after application after application (sic). Poorly draining soils and soils with shallow water tables are more prone to produce runoff that contains this product. Household labels – Avoid applying this product to ditches, swales, and drainage ways. Runoff of this product will be reduced by avoiding applications when rainfall is forecasted to occur within 48 hours. Agricultural Label – A level, well maintained vegetative buffer strip between areas to which this product is applied and surface water features such as ponds, streams, and springs will reduce the potential for contamination of water from rainfall­ runoff. Runoff of this product will be reduced by 12 avoiding applications when rainfall is forecasted to occur within 48 hours." Aventis' response: Aventis would like to further discuss appropriate label language with the Agency. However, it should be noted that light to moderate rainfall (or irrigation) after application will also help move carbaryl residues deeper into the soil, thus making them less susceptible to runoff. The language in the last sentence should be changed to read, "… when heavy rainfall is….". Page: 3 EPA comment: For terrestrial and residential uses: 4. This pesticide is toxic to fish and aquatic invertebrates. Aventis' response: Aventis' SEVIN labels currently state "This product is extremely toxic to aquatic and estuarine invertebrates." Page: 3 EPA comment: For terrestrial and residential uses: 5. This product is highly toxic to bees exposed to direct treatment or residues on blooming crops or weeds. Do not apply this product or allow it to drift to blooming crops or weeds if bees are visiting the treatment area. Aventis' response: Aventis' SEVIN labels currently contain similar language. 13 Draft RED Document 1.0 Summary and Environmental Risk Conclusions Risk to Terrestrial Organisms Page: 1 Paragraph: 4 Line: 2 EPA comment: As discussed in pp. 44 ­ 45 and in Appendix D. Aventis' response: The mammalian risk quotients are discussed on pages 48 to 50 and in Appendix C, not as described in this text. Fate and Water Assessment Page: 3 Paragraph: 5 Line: 3 EPA comment: …in the U. S. G. S NAQWA program. NAQWA… Aventis' response: The abbreviation for the U. S. G. S. program is NAWQA Page: 5 Paragraph: 1 Line: 7 EPA comment: …estimate of possible concentrations drinking water. Aventis' response: missing word – …concentrations "in" drinking… Page: 5 Paragraph: 4 Line: 4 EPA comment: …hydrolyzes in neutral (half­ life = 12 days) and alkaline environments (pH 9 half­ life = 3.2). Aventis' response: Missing units of after second half­ life. The units are hours, so "= 3.2 hours)". Page: 5 Paragraph: 4 Line: 5 EPA comment: …photolysis in water with a half­ life of 21 days 14 Aventis' response: this is for photolysis in sterile water, not microbially­ active water, so the phrase would be more precise as "… photolysis in sterile water…". Page: 5 Paragraph: 4 Line: last EPA comment: (Kf =1.7 to 3.2). Aventis' response: The upper value Kf for carbaryl should be listed as 3.5 as referenced by EPA elsewhere (e. g. Table 3, page 20) in the document. 2.0 Introduction Page: 6 Paragraph: 2 Line: 1­ 3 EPA comment: Carbaryl (1­ naphthyl N­ methylcarbamate) is a broad­ spectrum carbamate insecticide and acaricide registered for control of over 300 species of insects and mites on over 100 crop and noncrop use sites, including homeowner uses; pet, poultry, and livestock uses;… Aventis' response: Carbaryl is no longer registered for use on livestock. Aventis CropScience will not support the reregistration of the use on poultry (direct application and poultry quarters treatment). We will shortly submit a request for cancellation of this use in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). Page: 6 Paragraph: 3 Line: 2­ 3 EPA comment: Approximately 2.5 million pounds of carbaryl are applied annually in the U. S. A map showing the widespread use of carbaryl in agriculture is shown in figure 1. Aventis' response: Summation of the data in Figure 1 gives a total of approximately 3.3 million pounds of carbaryl. Both the 2.5 and 3.3 million­ pound figures are inconsistent with the value of 4 million pounds cited on page 35. The 2.5 million pounds is an average of usage over 1987 to 1996 developed in a memo by Frank Hernandez, July 21, 1998. The value of 2.5 million pounds in the text should be qualified with the additional information on the fact that it is an average for usage over 1987 to 1996 and is not a value for a single year. Page: 7 Paragraph: 1 Line: 3­ 4 15 EPA comment: Carbaryl is also used extensively for residential and other non­ agricultural uses, being the second most commonly insecticide (sic) used in the home. Aventis' response: Carbaryl is not registered for use inside homes. It is registered for use outdoors in the lawn and garden around homes. In addition, an evaluation of the Vista (Triad) data for the last seasonal year from October 1999 to September 2000 shows retail sales for carbaryl at 18.7 million dollars. Carbaryl is listed as number 7 based on retail sales behind other active ingredients such as chlorpyrifos, diazinon, imidacloprid, hydramethylnon and tralomethrin. Therefore this sentence would be more appropriately worded as: "Carbaryl is also used for residential and other non­ agricultural uses, being the seventh most commonly used insecticide around the home." Page: 7 Figure 1 EPA comment: Figure 2 Aventis' response: This is labeled as Figure 2 when it is Figure 1 3.0 Integrated Risk Characterization Introduction Page: 8 Paragraph: 1 Line: last EPA comment: Carbaryl is mobile to very mobile in the environment (Kf =1.7 to 3.2). Aventis' response: The upper value Kf for carbaryl should be listed as 3.5 as referenced by EPA elsewhere (e. g. Table 3, page 20) in the document. The classification of carbaryl as mobile to very mobile is inconsistent with measured Koc values of 177 to 249. According to the widely used classification scheme of McCall et al. carbaryl would be classified as having medium mobility in soil. This classification of medium mobility is further supported by the acceptable column leaching study (MRID 43320701) in which carbaryl residues were only slightly mobile in a number of soils. Aquatic Organisms Page: 10, Paragraph: 1, Line: 13 EPA comment: Submission of a FETOX amphibian toxicity study is encouraged. Aventis' response: 16 The data requirement should be deleted. From the published results it is evident that carbaryl is practically non­ toxic to the bullfrog. Effects in plain leopard frogs are reported at levels well above environmental concentrations. These results were obtained testing U. S. native species. In the proposed FETOX assay a non­ native species Xenopus laevis is used. This African species is unique in its behavior. Neither the species nor the test methods are suitable for ecotoxicological purposes. As the risk to amphibians can be evaluated from the studies cited, and as the effects are only at levels well above the EEC, this study should not be required. Page: 10, Paragraph: 3, Line: 6/ 7 EPA comment: …resulting in a temporary impairment of burying behavior and increasing exposure to predators. Aventis' response: A reference for this statement should be added. Page: 11, Paragraph: 2, Line: 7 EPA comment: In a mesocosms study, at carbaryl… Aventis' response: Typographical error. Change to "In a mesocosm study, at carbaryl…" Terrestrial Organisms Page: 12 Paragraph: 2 EPA comment: (use of rock dove LD50 ) Aventis' response: The reference cited for this value in Table 1 of Appendix D is currently not available to Aventis. Table 1 of Appendix D gives a range of 1000 – 3000 mg/ kg for the LD50. It should be assured that 1000 is indeed the correct value. Page: 12 Paragraph: 3 Line: 3 ­ 6 EPA comment: On a chronic basis, the NOAEC is 300 ppm for the mallard duck, based on adverse reproduction effects, including reduced egg production, decreased fertility, increase incidence of cracked eggs, increased embryonic mortality, and reduced hatching success. Aventis' response: The sentence should be changed. The embryonic mortality and the hatching success were not different from the control. 17 Page: 13 Paragraph: 1 Line: 1 EPA comment: …( rat LD50 = 307 mg/ kg) Aventis' response: Typographical error, the LD50 is 301 mg/ kg. Page: 13 Paragraph: 1 Line: 2 – 4 EPA comment: …based on decreased fetal body weights and increased incomplete ossification of multiple bones in the laboratory rat (LOAEC = 600 ppm, NOAEC = 80 ppm), has the potential for mammalian chronic effects. Aventis' response: A new chronic reproduction study in rats has been submitted by Aventis. This study is more relevant for an ecological risk assessment than the developmental study cited. The new study resulted in a NOAEC of 75 ppm. Page: 13 Paragraph: 3 Line: 1 EPA comment: Information available in the open literature suggests potential reproduction effects of carbaryl on mammals. Aventis' response: The sentence should be changed or deleted. The literature cited in the paragraph show ambivalent results. While some references seem to support that sentence, other references do not substantiate such a claim. The potential for reproductive effects in mammals is evaluated in the recently submitted 2­ generation study in rats. No reproductive effects were seen in that guideline study. The NOAEC of 75 ppm was based on pup mortality. Page: 13 Paragraph: 4 Line: 5 EPA comment: According to surveys conducted by the American Beekeeping Federation and the Washington State Department of Agriculture, carbaryl is one of the pesticides most frequently mentioned as being associated with bee kills. Aventis' response: A reference should be provided for this statement. 18 Page: 14 Paragraph: 4 Line: 1­ 4 EPA comment: The uses of carbaryl on crops (corn, cotton, soybeans, sorghum, wheat, barley, oats, and rye), forests and pasture/ rangeland were addressed by the US Fish and Wildlife Service (USFWS) in the reinitiation of consultation in September 1989. The Service found jeopardy to a total of 86 species – 6 amphibians, 47 freshwater fish, 27 freshwater mussels, and 5 aquatic crustaceans. Aventis' response: The use of carbaryl on barley, oats, rye, and cotton has been cancelled. It should be noted that all Aventis CropScience labels for the technical materials and the end­ use products containing carbaryl were amended to delete these uses. The Agency has already approved the labeling changes. Findings from the assessment made by the USFWS should be reevaluated considering the cancellation of the use on barley, oats, rye, and cotton. Page: 14 Paragraph: 5 Line: 7 EPA comment: The RPAs and RPMs in the 1989 B. O. may need to be reassessed… Aventis' response: The acronyms used should be explained. Endocrine Disruption Concerns Page: 15 Paragraph: 3 EPA comment: (Report on potential endocrine effects) Aventis' response: The paragraph should be deleted. As EPA pointed out, the findings reported in the literature were made at concentrations well above the highest peak concentration modeled. Therefore these findings are irrelevant for a risk assessment and at the current stage of discussion about endocrine disruption. If the concern about the endocrine potential of carbaryl persists, the issue should be revisited once the Agency's endocrine disrupter screening and testing program, as well as a policy on how to incorporate positive findings into an ecological risk assessment have been fully developed. Page: 15 Paragraph: 4 EPA comment: Furthermore, a number of field and laboratory studies report reproduction effects with mammals, suggesting that the possibility of endocrine disruption effects on wild mammals should be further examined. 19 Aventis' response: The statement should be deleted or modified. As pointed out above, reports on reproductive effects of carbaryl in the open literature are at least ambivalent. The recently submitted 2­ generation study in rats demonstrated the absence of reproductive effects. If the general statement about the potential for endocrine disruption of carbaryl is maintained, references (or a cross­ reference within the document) for the above claim should be provided. Uncertainties Page: 15 Paragraph: Last Line: 4 EPA comment: In the absence of a valid two­ generation rat reproduction study, mammalian chronic RQs were based on a rat prenatal development study NOAEC (MRID# 44732901). Aventis' response: A new two­ generation study in rats was recently submitted. 20 4.0 Environmental Fate Assessment Exposure Characterization Page: 16 Paragraph: 3 Line: 8 EPA comment: Environment (Kf =1.7 to 3.2). Aventis' response: The upper value Kf for carbaryl should be listed as 3.5 as referenced by EPA elsewhere in the document (e. g. Table 3, page 20). Page: 16 Paragraph: 3 Line: last sentence EPA comment: Detailed discussion and reviews (DERs) of the studies that are included in this assessment are attached in Appendix A. Aventis' response: It is inappropriate to include the DERs in the RED. A summary of study findings is already included in the EFED Chapter. DERs should be made available to the public through the regular procedure under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. Page: 16 Paragraph: 4 Line: 4 EPA comment: lower levels (generally less than 0.01 : /L). Aventis' response: value missing units ­ (generally less than 0.01 : g/ L). Page: 16 Paragraph: 5 Line: 4 EPA comment: …monitoring data is of limited utility in developing EECs for ecological and human health risk assessment. Aventis' response: The drinking water monitoring program conducted by the registrant provides a real world assessment of the potential for human exposure to carbaryl in drinking water derived from surface water. Drinking water concentrations derived from PRZM/ EXAMS greatly overestimate the potential exposure to carbaryl in drinking water, generally by several orders of magnitude. 21 Page: 17 Paragraph: 1 Line: 2­ 3 EPA comment: The maximum rate was taken from the carbaryl labels. Aventis' response: It would be of benefit for the Agency to be explicit and list the carbaryl labels that were used to develop the maximum application rates for the model scenarios. The reference cited in the EFED Chapter regarding the use of carbaryl on crops indicate that current labels were not used for the Agency's assessment. Many of these crops have been deleted from Aventis' labels for a few years Application rates, number of applications per season, and PHI's also have changed for several crops on the labels. Page: 17 Paragraph: 2 Line: 2 EPA comment: For the Index Reservoir scenario using maximum label rates, acute EEC values ranged from about 10 : g/ L from sugar beets to about 500 : g/ L from citrus (Table 6). Aventis' response: Table 6 on page 33 shows a concentration of 19 : g/ L for sugar beets treated with the maximum label rate of 2 x 1.5 lb ai, not 10 as stated in this sentence. A low EEC value of 9 : g/ L for sugar beets results from the "maximum reported" application scenario of 1 x 1.2 lb ai/ A. Page: 17 Paragraph: 2 Line: 3 EPA comment: Chronic EECs ranged from about 1 to 28 : g/ L. Aventis' response: Table 6 on page 33 shows that this is correct when considering all of the model scenarios. However, either the same maximum label rate reference should be used as in the preceding sentence (in which case the minimum chronic EEC would be 2), or the basis for the preceding sentence should be changed from the maximum label rate to include all application scenarios to keep the comparisons consistent. Page: 17 Paragraph: 2 Line: 8 EPA comment: The results of the modeling provide an (sic) conservative, though not unreasonable, estimate on (sic) possible concentrations [in] drinking water. Aventis' response: It should be clear that Aventis' surface water monitoring program provides a more reasonable estimate of the potential drinking water exposure to carbaryl than the modeling numbers, which overestimate exposure by several orders of magnitude. 22 Page: 17 Paragraph: 2 Line: last EPA comment: …and model input and output files are attached in appendix B. Aventis' response: The PRZM input files for only the Index Reservoir drinking water modeling were provided as an electronic copy. The PRZM input files for the standard pond scenarios were not provided in the draft RED so Aventis could not assess the data. None of the output files were provided. Page: 18 Figure 2 EPA comment: Figure 1. Generalized carbaryl degradation pathway Aventis' response: This should be labeled Figure 2, not Figure 1. Page: 19 Table 3 EPA comment: Hydrolysis half­ life at pH 9 stated to be 5 hours. Aventis' response: The study results, and the summary of the study presented on page 20, show the correct half­ life at pH 9 to be 3.2 hours. Page: 19 Table 3 EPA comment: Aerobic Aquatic half­ life ­ 4.9. Aventis' response: The Aerobic Aquatic half­ life is 4.9 days Page: 19 Table 3 EPA comment: Soil metabolism T1/ 2, anaerobic, assumed stable 23 Aventis' response: If this guideline is satisfied by the data submitted for guideline 162­ 3, it is not clear why the compound is assumed to be stable rather than having a half­ life in line with the 72 days that resulted from the anaerobic aquatic study. Although this parameter plays a fairly insignificant role in estimating the amount of carbaryl available for runoff in the models, it could play a significant role if one were to use this value in estimating leaching potential in subsurface horizons. Page: 20 Table 3 EPA comment: Batch Equilibrium 1/ n values ranged from 0.86­ 1.02 Aventis' response: These values are for the desorption isotherms only. For the adsorption isotherms that were used to calculate the adsorption Kf and Koc values listed in the table, the correct range of 1/ n values are 0.78 to 0.84 as stated on page 22. Page: 20 Table 3 EPA comment: Foliar Dissipation 30 days Willis and McDowell, 1987 Aventis' response: The foliar dissipation half­ life listed by EFED is incorrect. Table IV of the Willis and McDowell review lists 10 foliar half­ lives for various formulations of carbaryl applied to different crops. Five of these half­ lives are for a study designed to evaluate a new analytical procedure for measuring carbaryl residues on plants. This study was conducted on plants grown in a greenhouse, with some of them receiving an unknown amount of simulated rainfall. These studies on greenhouse­ grown plants should not be used to evaluate foliar persistence in the field. The foliar persistence of pesticides can be considerably different for residues on and in plants grown in greenhouses versus the field. Eliminating the half­ lives for the greenhouse­ grown plants results in the following half­ lives for carbaryl on field plants: Cotton, 1.2, 1.3, 1.5 days; strawberry, 4.1 days; tomato 1.4 days. Therefore, the longest half­ life of 4.1 days should be listed in this table. Aventis intends to conduct a more thorough review of the data on the foliar dissipation of carbaryl and prepare a more detailed response during the 60­ day public comment period. 24 Persistence Microbially­ Mediated Processes Page: 21 Paragraph: 3 Line: 3 EPA comment: with an initial concentration of 11.2 mg/ L, degraded with a half­ life of 4.0 days in sandy Aventis' response: The units for ppm soil concentration should be given as mg/ kg. Page: 21 Paragraph: 3 Line: 4­ 5 EPA comment: The major degradate was 1­ naphthol which further degraded rapidly to non­ detectable levels within 14 days. Aventis' response: The data from this study demonstrate that under aerobic soil conditions the formation and decline of 1­ naphthol, starting from parent carbaryl is complete in less than 14 days. The study data show an average maximum 1­ naphthol level of 34.5% of applied carbaryl by day 1, declining to 2.8% by day 2, 0% by day 4, 0.2% by day 7 and 0% at day 14. These data suggest a preliminary half­ life of less than 1 day for the major degradate 1­ naphthol. Page: 21 Paragraph: 3 Line: 8­ 9 EPA comment: In anaerobic aquatic soil carbaryl with an about 10 mg/ L degraded with a half­ life of 72.2 days. Aventis' response: Several words appear to be missing from this sentence. One suggestion: "Carbaryl degraded with a half­ life of 72.2 days in anaerobic aquatic sediment with an initial carbaryl concentration of about 10 mg/ L." Page: 22 Paragraph carried over from page 21 Line: 4 on pg 22 EPA comment: Chudhry and Wheeler, 1988 Aventis' response: This reference is not included in the reference list 25 Mobility Page: 22 Paragraph: 1 Line: 1 EPA comment: Carbaryl is considered to be mobile to very mobile in soils. Aventis' response: See response directly below. Page: 22 Paragraph: 3 Line: 1­ 2 EPA comment: Based on batch equilibrium experiments (MRID 43259301) carbaryl was determined to be very mobile to mobile in soils. Aventis' response: The classification of carbaryl as mobile to very mobile is inconsistent with measured Koc values of 177 to 249. According to the widely used classification scheme of McCall, et al. (1980) wherein Koc values between 150 and 500 denote medium mobility in soil, carbaryl would be classified as having medium mobility in most soils. This classification of medium mobility is further supported by the acceptable column leaching study (MRID 43320701) in which aged carbaryl residues were only slightly mobile in a number of soils. The mobility of carbaryl would be expected to be higher in sandy soils or in soils of low organic matter. Field Dissipation Page: 22 Paragraph: 5 Line: 3 EPA comment: The submitted field and aquatic dissipation studies were determined to be unacceptable, and did not provide useful information on movement and dissipation of carbaryl or its degradation products. Aventis' response: The field dissipation study (MRID 41982605) submitted in 1991 demonstrated that carbaryl dissipated very rapidly (t1/ 2 < 1 week) with no measurable leaching. The study included two sites, one in North Carolina and one in California. At the North Carolina site, ~ 95% of the Time 0 residues had dissipated by the first sampling period 7 days after application (the planned first sampling at 3 days was not collected due to rain). Similarly, ~ 85% of the Time 0 residues had dissipated by 7 days after application at the California site. Concerning the movement of carbaryl, samples were taken to a depth of 0.9 meters in increments of 0.15 meters. No residues were found below the upper 0.15 meters. 26 Page: 23 Paragraph: 3 Line: 2 EPA comment: Because of inappropriate sampling intervals, poor sample storage stability, lack of degradate monitoring, rainfall and irrigation that were less than evapotranspiration, and irrigation water with high pH, these studies do not provide reliable information on the rate of dissipation of parent carbaryl or formation of degradation products. Aventis' response: The estimated half­ life determined from this study was < 3 days. Sampling at intervals such that several sampling events are taken prior to the half­ life of the product is impractical for rapidly degrading chemicals (e. g., those with half­ lives less than a week). For this rapidly degrading chemical an estimate of the half­ life should be sufficient for risk assessments even if it is not precise. After the report was submitted to California, the freezer storage stability recoveries at six and nine months were measured but not reported. Rainfall plus irrigation approximated an inch a week and was more than enough to maintain a good soil moisture for agricultural purposes. Sulfuric acid is routinely added to irrigation water in the region of California where the field test was conducted to neutralize the water's high pH. Although not stated in the report, the irrigation water in the California trial was treated in the typical commercial fashion. The acid is injected into the irrigation pipe as water is pumped through it. Unfortunately, the pH of the water arriving at the field after treatment was not measured. Aquatic Field Dissipation Page: 24 Paragraph: 2 Line: 3 EPA comment: They (do) not provide useable information on the dissipation of carbaryl and 1­ naphthol in aquatic field conditions. Aventis' response: The soil metabolism study referred to in the report found that the total water soluble metabolites did not exceed 5% of the total radioactive residue, the primary hydrolysis product, 1­ naphthol, was not found, and that the only analyte of concern was the parent insecticide, carbaryl. A soil metabolism study reviewed concurrently by the Agency was issued later (MRID 42785101, classified "acceptable") with similar results. Although the major soil metabolite, 1­ naphthol, was found at significant levels at day 0 and day 1, the levels were less than 0.7% by day 4 and non­ detectable by day 14. Two other metabolites were identified but never exceeded levels of 1.7% of the total residue. Again the only residue of concern was the parent insecticide, carbaryl. If present, 1­ naphthol would have been detected by the residue method used to measure the residues of carbaryl in the soil. 27 The estimated half­ life determined from this study was < 2 days. Sampling at intervals such that several sampling events are taken prior to the half­ life of the product is impractical for rapidly degrading chemicals (e. g. those with half­ lives less than a week). Page: 24 Paragraph: 2 Line: 4 EPA comment: Frozen storage stability data were provided for only 6 months, although the water samples were stored for up to 14 months and the soil samples were stored for up to 17.5 months prior to analysis. The data suggest that carbaryl and 1­ naphthol degraded significantly during storage. In the six months of storage carbaryl degraded an average of 34 % in Texas water and 39% in from Mississippi. 1­ naphthol degraded 50% in water from Texas and 69% from Mississippi. Degradation did not appear linear, and it is not possible to extrapolate out to 14 months. It was therefore not possible to evaluate the actual concentrations of carbaryl and 1­ naphthol in the samples or estimate the dissipation rates. Aventis' response: The existing 6­ month storage stability provides sufficient information to calculate the concentrations of carbaryl in the samples. However, the metabolite 1­ naphthol was shown to degrade significantly under the same freezer conditions. This instability simply confirms that 1­ naphthol's presence in the environment would be very limited and should not be of concern. Foliar Dissipation Page: 24 Paragraph: Last EPA comment: The reported rates of carbaryl dissipation from foliar surfaces varies from 1 days to 30 days. In their review of literature data on pesticide foliar persistence, Willis and McDowell (1987) report that carbaryl dissipation rates varied from 1.2 to 29.5 days… For terrestrial risk assessment modeling EFED used 35 days… Aventis' response: As stated in comments to Table 3, the foliar dissipation half­ life used by EFED for terrestrial risk assessment is too long and should be corrected. Table IV of the Willis and McDowell review lists 10 foliar half­ lives for various formulations of carbaryl applied to different crops. Five of these half­ lives are for a study designed to evaluate a new analytical procedure for measuring carbaryl residues on plants. This study was conducted on plants grown in a greenhouse, with some of them receiving an unknown amount of simulated rainfall. These studies on greenhouse­ grown plants should not be used to evaluate foliar persistence in the field. The foliar persistence of pesticides can be considerably different for residues on and in plants grown in greenhouses versus the field. Eliminating the half­ lives for the greenhouse­ grown plants results in the following 28 half­ lives for carbaryl on field plants: Cotton, 1.2, 1.3, 1.5 days; strawberry, 4.1 days; tomato 1.4 days. Therefore, the longest half­ life of 4.1 days should be used for terrestrial risk assessment modeling. Aventis will conduct a more thorough review of the data on the foliar dissipation of carbaryl and prepare a more detailed response during the 60­ day public comment period. Atmospheric Transport Page: 25 Paragraph: 1 Line: 2 EPA comment: Waite, et al., 1995 Aventis' response: This reference is not included in the reference list Page: 25 Paragraph: 1 Line: 3 EPA comment: Beyer et al., (1995) Aventis' response: This reference is not included in the reference list Page: 25 Paragraph: 3 Line: 5 EPA comment: Schomburg et al. (1991) Aventis' response: This reference is not included in the reference list 1­ Naphthol Fate and Transport Page: 26 Paragraph: 2 Line: 1­ 2 EPA comment: In an aerobic soil metabolism study (MRID 42785101), 1­ naphthol degraded rapidly to non­ detectable levels within 14 days. 29 Aventis' response: The data from this study demonstrate that under aerobic soil conditions the formation and decline of 1­ naphthol, starting from parent carbaryl, is complete in less than 14 days. The study data show an average maximum 1­ naphthol level of 34.5% of applied carbaryl by day 1, declining to 2.8% by day 2, 0% by day 4, 0.2% by day 7 and 0% at day 14. These data suggest a preliminary half­ life of less than 1 day for the major degradate 1­ naphthol. This half­ life can be used for preliminary environmental fate modeling to estimate EECs for 1­ naphthol. Page: 26 Paragraph: 3 Line: 1 EPA comment: No guideline information was submitted on 1­ naphthol sorption. Literature information suggests that it is not strongly sorbed. Aventis' response: The statement suggesting that 1­ naphthol is not strongly sorbed to soil should be deleted. In support of the 1­ naphthol sorption statement the Agency has cited only one paper by Karthikeyan et al. (1999) that was conducted using aluminum hydroxide as the sorbent. Soil is composed of much more than aluminum hydroxide, so this study is more of a mechanistic description of sorption to this one component of soil and not a study of sorption to soil as a whole. This cited study reported that 1­ naphthol does not show significant sorption to aluminum hydroxide when allowed to sorb for 20 hours in the dark in the absence of oxygen. However, there was a significant increase in sorption with increasing equilibration time, and as the Agency stated, the increase is influenced by pH, as would be expected for an acidic phenolic compound. Additional information available in the literature demonstrates that the sorption of 1­ naphthol to soil is stronger than that seen for carbaryl itself. Hassett et al. (1981) have demonstrated that the sorption of 1­ naphthol was the result of sorption to organic carbon resulting in an average Koc of 431 ± 40 for 10 of the 16 soil samples they tested. In the remaining 6 soil samples the Koc was even higher (1,645 to 15,618). Hassett et al. (reference submitted as part of 30­ day response document) hypothesized that the higher Kocs in these 6 soils, in which the organic carbon to clay ratio was very low, the clay surfaces were more accessible and the sorption of 1­ naphthol was apparently controlled by the clay fraction. In Burgos et al. (1999), cited by EPA elsewhere in the RED, it was shown that there is significant sorption of 1­ naphthol to two sandy soils, and that oxidative coupling reactions were responsible for the strongly bound portion. In an earlier paper by Burgos et al. (1996) it was shown that both biologically­ mediated and soil­ catalyzed oxidative coupling lead to significant binding of 1­ naphthol residues to soil. These data indicate that 1­ naphthol is less mobile and less susceptible to leaching than carbaryl itself, and they demonstrate that at least a portion of the 1­ naphthol residue is tightly sorbed to soil constituents. To meet the requirement by the Agency for information on the adsorption and desorption of 1­ naphthol, the registrant is conducting an adsorption/ desorption study to meet the 30 163­ 1 guideline. Study results should be available for submission to the Agency in the first quarter of the calendar year 2002. Aquatic Exposure Assessment Surface Water Page: 26 Paragraph 4 Line 1 EPA comment: Five crop scenarios: apples, field corn, sweet corn, oranges and sweet potatoes scenarios were use in modeling for surface water EEC. Aventis' response: The fifth crop modeled was sugar beets (not sweet potatoes). Page: 27 Table 4 EPA comment: Hydrolysis half­ life at pH 9 stated to be 5 hours. Aventis' response: The study results, and the summary of the study presented on page 20, show the correct half­ life at pH 9 to be 3.2 hours. Page: 27 Table 4 EPA comment: (Koc = 211 for SCIGROW) Aventis' response: This is the mean Koc. According to EPA guidance the median Koc (209) should be used for SCI­ GROW, although this difference would not be expected to affect the model results. Pages: 27­ 28 Table 5 EPA comment: Tier II surface water estimated environmental concentration (EEC) values derived from PRZM/ EXAMS modeling for use in ecorisk assessment (calculated using standard pond.) Aventis' response: The PRZM input tables were not provided for the standard pond scenarios, so the assumption is made that the same application methods were used for the standard pond as for the Index Reservoir scenarios that were provided as an electronic copy of a draft of Appendix B. 31 It would be of benefit for the Agency to state which of the carbaryl labels were used to develop the "maximum" label application rate scenarios. It would be useful to add another column to this table to specify which method of application was used to generate the EECs rather than the generic "air/ ground" in column 1. There are a number of errors in the input parameters (noted below) that would lead to changes in the calculated EECs and therefore the risk quotients for these uses. If the modeling for the "average" scenarios were conducted using aerial applications for citrus and apples (as was the case for the Index Reservoir scenarios), then the model results over­ estimate the contributions from spray drift. Few applications to these crops are made aerially. Therefore, the model results over­ estimate the contributions from spray drift since the "average" applications to these crops are made using ground airblast equipment with a spray drift of 6.3% in the model versus aerial applications with a spray drift of 16%. The "average" scenario for sweet corn in Ohio should be 3 applications at 1.1 lb. ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not the 2 applications at 3.4 lb. ai/ A/ application as listed in the table. It should be noted that the "average" scenario presented in this table, 2 applications per year at 3.4 lb. ai per application, exceed the maximum rate allowed on the label. The maximum label rate application scenario for apples that is allowed by the Sevin brand XLR PLUS label (E. P. A. Reg. No 264­ 333), the Sevin brand 80WSP and CHIPCO Sevin brand 80WSP labels (E. P. A. Reg. No 264­ 526) and the CHIPCO Sevin brand SL label (E. P. A. Reg. No 264­ 335) is 5 applications at 3 lb. ai/ A/ application made every 14 days. The scenario used in the model applies less than the maximum amount of product allowed by the labels. In addition, if the same application timing was used in the modeling for the standard pond scenario as was used in the index reservoir scenario (applications made by air every 4 days) this would be a violation of the Aventis labels which restrict applications to a minimum of every 14 days. The "average" scenario for sugar beets in Minnesota should be 1 application at 1.3 lb. ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not 1 application at 1.5 lb. ai/ A/ application as listed in the table. The "Citrus" scenario would be more appropriately labeled Oranges. For the average scenario, the 3.4 lb. ai/ A/ application rate listed in Table 5 is for oranges (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD"), which is the highest "average" application rate for any type of citrus. Therefore, this "average" scenario for oranges are at the high end for all citrus and overestimates the PRZM/ EXAMS derived EECs for use in the other citrus crops. "Average" application rates for other citrus as listed in the memo are: 32 Lemons – 1.3 applications at 2.7 lb ai/ A/ appl Grapefruit – 1.6 applications at 1.4 lb ai/ A/ appl Citrus, other – 1.8 applications at 1.8 lb ai/ A/ appl The maximum label application rate for citrus is 7.5 lb ai per application, not 5 lb ai, with a maximum of 20 lb ai total allowed per year. In California only, a single application is allowed at the rate of 5 to 16 lb ai per season for control of California red scale and yellow scale. Estimated Environmental Concentrations for Terrestrial Ecological Risk Assessment Page: 29 Paragraph: 2 Line: 2­ 4 EPA comment: In the absence of reliable foliar dissipation data a dissipation half­ life of 35 days is used. Published literature shows that carbaryl dissipation rates vary, and are among the highest observed for any pesticide (Willis and McDowell, 1987). Aventis' response: As stated in more detail above, some of the foliar dissipation half­ lives listed in this reference are high because they were generated in the greenhouse, not in the field, and therefore they should not be used. Eliminating the half­ lives for the greenhouse­ grown plants results in the following half­ lives for carbaryl on field plants: Cotton, 1.2, 1.3, 1.5 days; strawberry, 4.1 days; tomato 1.4 days. Therefore, the longest half­ life of 4.1 days should be used for terrestrial risk assessment modeling. Page: 29 Paragraph: 2 Line: 6 EPA comment: A more thorough description of the model calculations and ELL­ FATE outputs are attached in Appendix B. Aventis' response: No such description or attachments were provided, so Aventis did not have the opportunity to evaluate the model. Page: 29 Paragraph: 2 Line: last EPA comment: …Tables 4,7, 8 and 9, Appendix D. Aventis' response: These tables are in Appendix C. 33 5.0 Drinking Water Assessment Water Resources Assessment Page: 29 Paragraph: 3 Line: 3 EPA comment: Carbaryl tends not to partition to soil, aquifer solids, or sediment. Aventis' response: This sentence is misleading and should be reworded. Carbaryl does partition onto these sorbents, but the sorption coefficients are not high. Suggest rewording this such as: "Carbaryl tends not to bind tightly to soil, aquifer solids, or sediment." Page: 29 Paragraph: 4 EPA comment: Under certain conditions carbaryl can be expected to persist in the environment. Under low pH conditions the compound is stable to hydrolysis. In anaerobic environments metabolism is fairly slow (t½ = 72 days). This suggests that carbaryl may leach to ground water and persist in some aquifers. Aventis' response: This last statement should be removed. In contrast to this hypothesis are the data presented in the NAWQA and EPA databases that demonstrate that carbaryl is not likely to leach to ground water and is not likely to persist in aquifers. The fact that carbaryl has been widely used in agricultural and urban settings for more than 35 years, and yet is found at concentrations greater than 0.1 : g /L in only 0.027% of the agricultural wells, urban wells and aquifers sampled by NAWQA (Kolpin, 2001), indicates that this statement has little merit. Furthermore, the last sentence is in direct contradiction to the statement made at the beginning of the preceding paragraph that carbaryl "… has limited potential to leach to ground water." Page: 30 Paragraph: 1 Lines 1­ 3 EPA comment: Surface water monitoring studies show that carbaryl is the second most widely detected insecticide after diazinon. Carbaryl, at typically low concentrations, is found in greater than 20 % of surface samples at concentrations up to 7 ppb. Aventis' response: These summary statements are based on the NAWQA database, with the exception of the 7 ppb concentration. The highest reported value in the NAWQA database is 5.5 ppb. The value of 7 ppb does not come from the NAWQA database but from the report by Werner et al. (2000). In fact, a maximum carbaryl concentration of 8.4 ppb was reported for surface water samples in the California DPR surface water database (see discussion section). The sources of the information should not be mixed, or the source of the information should be explicitly stated. 34 Drinking Water Exposure Assessment Page: 30 Paragraph: 2 Line: 3­ 4 EPA comment: Carbaryl is the second most commonly detected insecticide in surface water, and can be expected to contaminate drinking water derived from surface water bodies. Aventis' response: The surface water­ monitoring program conducted by Aventis shows an insignificant impact of carbaryl on drinking water. Page: 30 Paragraph: 2 Line: 7 EPA comment: The maximum reported value was 7.0 : g /L. Aventis' response: The maximum value reported in the NAWQA database is 5.5 : g /L. The only carbaryl detection reported in the study by Werner et al. (2000) was 7.0 : g /L. The maximum value reported in the California DPR Surface Water database is 8.4 : g /L. Since all of the statistics made in this paragraph refer to the NAWQA data, the reference to the maximum reported concentration should be 5.5 : g /L. Page: 30 Paragraph: 4 Line: 2 EPA comment: Older studies using GC or GC/ MS generally have poor recovery and quantitation limits. Because of this difficulty in analysis the actual concentration of carbaryl in groundwater and surface waters may be higher than reported. Aventis' response: The basis for making this generalization is not readily apparent and these statements should be removed. Comments regarding the recovery reported for the GC/ MS method used in the NAWQA survey are made below in reference to statements made on page 34 paragraph 5, and are elucidated in the discussion section at the end of this response document. The method detection limit (MDL) reported for the GC/ MS method used for the NAWQA program is 0.003 ppb (Zaugg et al., 1995; Larson et al. , 1999). The limit of detection for the HPLC/ MS/ MS method used in the carbaryl surface water monitoring study being conducted by the registrant (LOD, 0.002 ppb; LOQ 0.030 ppb) is similar to the GC/ MS method used for the NAWQA program. In addition to the GC/ MS method used in the NAWQA program, carbaryl was also analyzed by HPLC/ photodiode­ array detection in a limited number of samples with a MDL of 0.008 (Werner et al., 1996). Therefore, the quantification limits reported for the GC/ MS method used to generate a majority of the carbaryl data in the NAWQA database is very similar to the quantification limits for available HPLC methods. See the discussion section at the end 35 of this response document for a summary of the available NAWQA data obtained by the GC/ MS and HPLC/ PDA methods. Page: 30 Paragraph: 4 Line: 4 EPA comment: More recent studies using HPLC/ MS should provide better data on the true extent and magnitude of water contamination from the use of carbaryl. Aventis' response: Aventis believes that our ongoing targeted surface water­ monitoring program using HPLC/ MS/ MS accurately reflects the extent and magnitude of carbaryl exposure in drinking water derived from surface water. Drinking Water Modeling Page: 31 Paragraph: carried over from page 30 Line: 8 EPA comment: A partial list of input parameters for the PRZM/ EXAMS modeling are given in Table 4. Aventis' response: The partial list of input parameters in Table 4 includes multiple conservative assumptions likely to lead to significant over­ estimation of the potential surface water concentrations of carbaryl. Page: 31 Paragraph: 2 Line: 1 EPA comment: For the Index Reservoir scenario using maximum label rates, acute EEC values ranged from about 10 : g/ L from sugar beets to about 500 : g/ L from citrus (Table 6). Aventis' response: Table 6 on page 33 shows a concentration of 19 : g/ L for sugar beets treated with the maximum label rate of 2 x 1.5 lb ai, not 10 as stated in this sentence. A low EEC value of 9 : g/ L for sugar beets results from the "maximum reported" application scenario of 1 x 1.2 lb ai/ A. Page: 31 Paragraph: 2 Line: 3 EPA comment: Chronic EECs ranged from about 1 to 28 : g/ L. 36 Aventis' response: Table 6 on page 33 shows that this is correct when considering all of the model scenarios. However, either the same maximum label rate reference should be used as in the preceding sentence (in which case the minimum chronic EEC would be 2), or the basis for the preceding sentence should be changed from the maximum label rate to include all application scenarios to keep the comparisons consistent. Page: 31 Paragraph: 2 Line: 6 EPA comment: It is highly unlikely that any but the most extensive targeted monitoring would capture the actual peak concentrations. Aventis' response: The role of a peak concentration in dietary exposure assessment is undergoing reexamination within EPA. The current policy of EPA appears to define a certain percentile as an appropriate value for use in screening assessments, but the exact percentile to be used is being currently set by EPA management. (The most recent documents from EPA cite the 95 th or 99 th percentile.) For more comprehensive assessments, a distribution of values is preferred. Page: 31 Paragraph: 2 Line: 7 EPA comment: The results of the modeling provide a conservative, though not unreasonable, estimate on possible concentrations drinking water.( sic) Aventis' response: The modeling, performed according to EPA procedures, provides an upper bound estimate on potential concentrations in drinking water from surface water. Whether the modeling estimates are reasonable depends on the specific assumptions. For carbaryl, the three­ year monitoring program (conducted according to EPA and ILSI guidance available at the time the study was started) shows that the model calculations are unreasonable. These conservative assumptions include a 3x factor on both the aerobic soil and aerobic aquatic half lives, assuming the maximum drift rate for aerial applications throughout the county (in Florida citrus almost all applications are by air blast with ground equipment), and the application rate over a watershed. The conservative nature of the application assumption alone probably results in an overprediction by at least two orders of magnitude. The modeling calculations assume an application rate of 17.4 lbs/ acre of watershed annually. In Hardee County, the county with the highest usage of carbaryl, the average use rate on a countywide basis is only 0.31 lb/ acre (See Appendix II). In Manatee County, the county with the highest usage containing a watershed used to supply drinking water, the average rate on a countywide basis is 0.027 lb/ acre. 37 Page: 31 Paragraph: 2 Line: 8 EPA comment: A more detailed assessment of the source of water used to provide drinking water and the relationship between the areas where carbaryl is used and surface water sources is required to more accurately evaluate possible human exposures. Aventis' response: As mentioned by EPA in this document, ground water is the source of the majority of Florida drinking water. Many of the counties with the highest use of carbaryl contain no watersheds used to provide drinking water. As discussed more fully in Appendix I, the watershed supplying the Manatee County Water Treatment Plant appears to have the most carbaryl usage of drinking water watersheds in Florida. Water Treatment Effects Page: 31 Paragraph: 3 Line: 8 EPA comment: Since relatively (sic) few water treatment facilities in the U. S. use ozone the limited data available do not indicate that carbaryl is likely to be degraded in the majority of treatment plants. Aventis' response: The monitoring program conducted by the registrant shows that removal occurs in some treatment plants. The effect of treatment seemed to be greater in systems using carbon treatment. Page: 33 Table 6 EPA comment: Drinking Water EECs Aventis' response: Many of the comments for this table are similar to those for the EECs for ecological risk found in Table 5. The PRZM model input parameters for the Index Reservoir scenarios were received as an electronic copy of a draft of Appendix B. These input files are very useful for assessing the scenarios that have been modeled. It would be useful to add another column to Table 6 to specify which method of application was used to generate the EECs (and thus the application efficiency and spray drift values). It would be of benefit for the Agency to state which of the carbaryl labels were used to develop the "maximum" label application rate scenarios. There are a number of errors in the input parameters (noted below) that would lead to changes in the calculated EECs and therefore the risk quotients for these uses. 38 The model parameters listed in the electronic draft of Appendix B show that the "average" scenarios for citrus and apples were conducted using aerial applications. Few applications to these crops are made aerially. Therefore, the model results over­ estimate the contributions from spray drift since the "average" applications to these crops are made using ground airblast equipment with a spray drift of 6.3% versus aerial applications with a spray drift of 16%. The "maximum label rate" application scenario for apples that is allowed by the Sevin brand XLR PLUS label (E. P. A. Reg. No 264­ 333), the Sevin brand 80WSP and CHIPCO Sevin brand 80WSP labels (E. P. A. Reg. No 264­ 526) and the CHIPCO Sevin brand SL label (E. P. A. Reg. No 264­ 335) is 5 applications at 3 lb ai/ A/ application made every 14 days. The scenario used in the model applies less than the maximum amount of product allowed by the labels. In addition, application timing was used in the modeling for the index reservoir scenario (applications made by air every 4 days) that would be a violation of the Aventis labels which restrict applications to a minimum of every 14 days. The "average" scenario for sweet corn in Ohio should be 3 applications at 1.1 lb ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not the 2 applications at 3.4 lb ai/ A/ application as listed in the table. The PRZM input file shows the correct inputs of 3 applications at 1.1 lb ai/ A/ application. The "average" scenario for sugar beets in Minnesota should be 1 application at 1.3 lb ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not 1 application at 1.5 lb ai/ A/ application as listed in the table and the PRZM input file. The "Citrus" scenario would be more appropriately labeled Oranges. For the average scenario, the 3.4 lb ai/ A/ application rate listed in Table 5 is for oranges (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD"), which is the highest "average" application rate for any type of citrus. Therefore, this "average" scenario for oranges is at the high end for all citrus and overestimates the EECs for use in the other citrus crops. "Average" application rates for other citrus as listed in the memo are: Lemons – 1.3 applications at 2.7 lb ai/ A/ appl Grapefruit – 1.6 applications at 1.4 lb ai/ A/ appl Citrus, other – 1.8 applications at 1.8 lb ai/ A/ appl Ground Water Resources Page: 34 Paragraph: carried over from page 33 Line: 3 EPA comment: U. S. EPA. Pesticides in Groundwater Database (Jacoby et al., 1992) 39 Aventis' response: This reference is not provided in the reference list. Page: 34 Paragraph: 3 Line: 3 EPA comment: Detections were from (sic) mainly from three use sites: wheat (5.8 % of well samples from wheat land use), orchards and vineyards (1.7 % of well samples from orchard and vineyard land use), and urban (1.8% of urban groundwater samples). Aventis' response: Updated information (noted below) is not summarized in the same manner as in this statement, so direct comparisons cannot be made easily. However, the updated information indicates a similar pattern of low concentrations of carbaryl detections in a limited number of ground water resources. Page: 34 Paragraph: 3 Line: 6 EPA comment: Limitations in analytical methodology (described elsewhere) apply to groundwater sample analysis also suggesting that there (sic) actual maximum concentrations and extent of contamination may be significantly higher. Aventis' response: This statement is misleading and should be deleted. The validation of the most widely used GC/ MS method for the data contained in NAWQA show recoveries of 86 to 94% at spiking levels of 0.1 to 1.0 : g/ L with an MDL of 0.003 : g/ L. The HPLC method validation reported recoveries of 58 to 64% % at spiking levels of 0.1 to 1.0 : g/ L with an MDL of 0.018 : g/ L. Furthermore, using the GC/ MS method, a mean recovery of 115% was found for field matrix spikes of carbaryl at spiking levels of 0.1 : g/ L. With the GC/ MS method MDL of 0.003 : g/ L and a mean recovery of 115% for the field matrix spikes, this method cannot reasonably be characterized as stated by EPA. Additional details of the method validations and field matrix spikes are provided in the `Discussion Section' at the end of this response. Page: 34 Paragraph: 3 Line: last EPA comment: …and updated information is available at: http:// water. wr. usgs. gov/ pnsp/ ja/ est32/. Aventis' response: This web page was last updated in 1998. A more recent update by Kolpin was posted June 11, 2001 at: http:// water. wr. usgs. gov/ pnsp/ pestgw/ and is the source of the updated information included in the `Discussion Section' at the end of this response. 40 Surface Water Resources Monitoring Data Page: 34 Paragraph: 4 Line: 5­ 6 EPA comment: Because of limitation in the analytical methods used there is some question as to the accuracy of carbaryl analysis. Aventis' response: This generalized statement needs to be qualified or deleted. Whereas the authors of reports written as part of the NAWQA program have been clear about the potential limitations of the quantitative nature of the carbaryl data in the database, they have also been clear about the validity of the qualitative nature of the data. The use of the multiresidue method in the NAWQA program does have some limitations as a result of the large numbers of diverse pesticides and degradation products that they are monitoring. However, the QC/ QA data generated as part of the NAWQA program (described in the discussion section on surface water at the end of this response) demonstrate the validity of the detections of carbaryl in the studies. The monitoring study conducted by the registrant, and reported in this section, does not have the same potential limitations in the analytical method since the method is looking specifically for carbaryl. Therefore, the analytical method used by the registrant does not raise questions about the accuracy of the carbaryl analysis. Page: 34 Paragraph: 4 Line: 5­ 6 EPA comment: Poor analytical methods probably have resulted in lower detection rates and lower concentrations than actually present. Aventis' response: This generalized statement should be deleted for reasons provided above and in the discussion section. NAQWA (sic) 41 Change to NAWQA Page: 34 ­ 35 Paragraph: 5 Lines: 5­ 8 EPA comment: Carbaryl analytical results are fairly poor, with a typical mean percent recovery of 24% ( = 15) in laboratory quality control samples, and a method detection limit (MDL) of 0.003 ug/ L. This suggests that the values reported do not represent the maximum concentrations that exist, and that surface water contamination may be more widespread than the data show. Aventis' response: These statements are misleading and should be updated with further quality control data supplied by NAWQA. A discussion of the analytical method used in the NAWQA program is presented in the USGS Open­ File Report 95­ 181 (see Zaugg et al. (1995) in references). The mean percent recovery of 24% noted above can be found in Table 9 of this report and is by no means "typical". A mean recovery value of 24% was reported for reagent­ grade water fortified at a level of 0.03 µ g/ L with a method detection limit said to be 0.003 µ g/ L. Additional recoveries for fortified water samples (reagent­ grade, ground and surface waters) ranged from 10 to 202% (see discussion section). The carbaryl data in the NAWQA database are amended with an "E" qualifier to indicate the variability found with this method, not because the carbaryl concentrations are underestimated. Additional evaluations of field blank, field matrix spike and lab control spike samples as part of the NAWQA program can be found in a provisional report by Martin (1999). This report demonstrates the lack of detection of carbaryl in 100% of the field blanks, and median recoveries of 94.4% in 306 field matrix spikes and 93.0% in 1000 lab control spikes, each at spiking levels of 0.1 µ g/ L. These data suggest an adequate level of detection of carbaryl in the method used in the NAWQA survey of surface and ground water. See the additional discussion at the end of this document for further information regarding recoveries in spiked surface and ground water. Page: 35 Paragraph: 2 Line: 7 EPA comment: …at about 0.1 percent of the amount used in the basins (Larson et al., 1999) http:// water. wr. usgs. gov/ pnsp/ rep/ wrir984222/ load. html. The estimated carbaryl use on in agricultural applications is about 4 million pounds suggesting that 400,000 pounds are delivered to the nations streams draining agricultural areas. 42 Aventis' response: This estimated use of carbaryl for agricultural applications over­ estimates the use of carbaryl by about 1 million pounds. BEAD and USGS data cited on pages 6 and 7 are consistent with lower total pounds of carbaryl applied. In addition, 0.1 percent of 4 million pounds would be 4,000 pounds, not 400,000 pounds. If the 1987 – 1996 average of 2.5 million pounds carbaryl is used in the calculation, the total load suggested to be delivered to streams draining agricultural areas would be 2,500 pounds. Registrant Monitoring Study Page: 35 Paragraph: 4 Line: 11 EPA comment: Carbaryl was analyzed by HPLC/ MS with a limit of detection… Aventis' response: The analytical method used by the registrant in the surface water monitoring study uses tandem mass spectrometry (MS/ MS) as the detection method. This type of detection involves quantification of "daughter" ions from a selected mass fragment and is more selective than an MS method. Therefore, to accurately reflect these differences, the method should be labeled as HPLC/ MS/ MS. Page: 36 Paragraph: 3 Line: 9 EPA comment: In several cases finished water had higher concentration than raw water, and finished water had detectable carbaryl when the raw did not. The highest concentration measured was in finished water (0.18 ppb). Raw water sampled at the same time had much lower concentration (0.010). 43 Aventis' response: This statement is misleading and certainly does not consider the analytical uncertainty for concentrations below the level of quantification and near the level of detection. There were only two cases when finished water was greater than raw water when the concentrations in finished water were greater than 0.01 ppb (only one­ third of the quantification limit). One case was when the raw water was 0.009 ppb and the finished water was 0.011 ppb. These two analyses are essentially equivalent, especially considering that they are only about a third of the quantification limit. The other case was at the Deerfield community water system. This drinking water facility uses a small river without a reservoir as a source for a small Community Water System. Farms are located immediately upstream of the facility. The intake is also not continuous (shut down over weekends). Therefore, getting a matching sample is quite difficult, especially for a short duration spike as a result of spray drift, summer thunderstorm, or perhaps a spill that almost immediately enters the river a runoff event. The rarity of this event is demonstrated by the absence of residues of this magnitude the next year (2000). Samples collected through this time of the year in 2001 also do not indicate a similar event. Although the data from this site cannot be used to determine the peak concentration, the data provide a distribution of residues through the three year period which will define up to the 99 th percentile concentration of the distribution. The Deerfield, Michigan community water system is one of the systems in which the greatest variability of residues would be expected. Most of the other community water systems are located on larger rivers, lakes, or reservoirs. Because the design of study called for analysis of finished water only when there were residues in the raw water, there was only one finished sample analyzed when the raw water contained no residues. This sample was collected at the Deerfield community water system at the sampling interval after the finding of 0.16 ppb in the Deerfield system. The residue level in this sample was 0.004 ppb. The difference between 0.004 ppb and non­ detect is insignificant, and if real can probably be attributed to water at much higher concentrations remaining in the system from the previous week. Page: 36 Paragraph: 4 Line: 1 EPA comment: Non­ targeted monitoring, such as the NAWQA program, has shown much higher concentrations occur indicating that this study, while useful, can not be used to describe the overall distributions that occur throughout the entire use area. Aventis' response: The targets of the drinking water monitoring conducted by the registrant and the NAWQA program are different. The NAWQA program characterized surface water concentrations within a study area while the Aventis drinking water monitoring measured residues in inlets and outlets of drinking water facilities. Also the drinking water monitoring program considered only use areas with drinking water supplies. However, 44 for FQPA dietary assessments, the appropriate target is drinking water rather than surface water. The main reason why the drinking water monitoring study did not show residues as high as in the NAWQA program is the location of the sampling points. Drinking water supplies tend to be located on larger surface water bodies than NAWQA sampling points (or in other words, the intakes for community water systems tend to be downstream of NAWQA sampling points). This additional time allows for additional degradation and dilution to occur. Finding the highest concentration at the Deerfield, Michigan system is not surprising since this intake is on one of the smallest surface water bodies included in the monitoring study (see response to Page: 36, Paragraph: 3, Line: 9 above for a more detailed explanation). Page: 36 Paragraph: 4 Line: 4 EPA comment: This study does not provide sufficient information to allow estimation of actual peak and mean concentrations that actually occur in all use areas. Aventis' response: Because most of the samples did not contain carbaryl residues, accurate estimates of the actual peak and mean concentrations can not be obtained. However, the distributions obtained from all sites can be used to define up to the 99 th percentile concentration. The average cannot be accurately determined; however, the time­ weighted average is only slightly above the limit of detection (and certainly less than 0.01 ppb) at all 20 sites. The peak concentration in this study was measured at a community water system on a small river. The registrant agrees that the sampling schedule was not adequate to determine the true peak in such systems. Most of the other community water systems are located on larger rivers, lakes, or reservoirs. Therefore, the peak values are not likely to be an order of magnitude greater than the amounts present in the collected samples. The distributions obtained in this study are suitable for use in dietary exposure assessments. When EPA policy establishes what percentile concentration is an appropriate regulatory endpoint, then these percentiles can be determined for each of the community water systems monitoring. These percentiles can then be compared with DWLOC values in screening assessments. Page: 37 Paragraph: 2 Line: 1 EPA comment: Only limited information was submitted on sampling site selection… Aventis' response: The summary in Appendix I of this response provides a description of the sites considered for the monitoring study and the rationale for the selection of the twenty sites. This information demonstrates that the community water systems selected for this study 45 are representative of the systems that are most likely to contain the highest concentrations of carbaryl residues. Page: 37 Paragraph: 3 Line: 3 EPA comment: This should include an explanation of why this study did not observe concentrations as high as those found in other, non­ targeted studies, and how the results of this study can be related to concentrations that occur throughout the country. Aventis' response: The main reason why the drinking water monitoring study did not show residues as high as in the NAWQA program is the location of the sampling points. Drinking water supplies tend to be located on larger surface water bodies than NAWQA sampling points (or in other words, the intakes for community water systems tend to be downstream of NAWQA sampling points). This additional time allows for additional degradation and dilution to occur. Finding the highest concentration at the Deerfield, Michigan system is not surprising since this intake is on one of the smallest surface water bodies included in the monitoring study (see response to Page: 36, Paragraph: 3, Line: 9 above). Since the drinking water study targeted drinking water systems in high­ use watersheds, the data from this study are representative of the drinking water systems most likely to contain carbaryl. Sacramento­ San Joaquin River Delta Page: 37 Paragraph: 4 Line: 4 ­ 5 EPA comment: Carbaryl was found to be the sole causative agent at one of 20 sites… The toxicity seemed to persist for several days… Aventis' response: The statement should be revised. The reference cited (Werner et al., 2000) lists carbaryl as "the primary toxicant" (not as the "sole causative agent"), even though an unknown was also found at the same time. No information about the "unknown" is provided. Both conclusions of "sole causative" and of "primary toxicant" cannot be substantiated without further evidence about the nature and concentration of the unknown. Actually, for another site the authors concluded about the unknown found there "in 3 of 21 samples, toxicity observed could not be entirely explained by the identified primary toxicants." Additionally, it is at least questionable if the analytical method employed would detect all potential toxicants beside the insecticides it was set up for. The toxicity seeming to persist is not explained or substantiated in the reference. The citation of such dubious results should be removed from the RED. 46 6.0 Hazard and Risk Assessment for Aquatic Organisms Hazard assessment for Aquatic organisms Estuarine/ Marine Fish Page: 39 Paragraph: 2 Line: 6 EPA comment: …carbaryl water concentration of 1.2 : g/ ml… Aventis' response: To be consistent with the rest of the document the units should be presented in ppm (" carbaryl water concentration of 1.2 ppm") Aquatic Plants Page: 40 Paragraph: 2 Line: 6 EPA comment: Guideline 122­ 2 is not fulfilled. Aventis' response: The chapter should be revised. As detailed above (comments to Page 2 of the Memorandum), studies were submitted in 1992. The status for this requirement in an October 04, 2000 OPP Guideline Status Report (Chemical Review Management System) lists the guideline 122­ 2 status as "Acceptable/ Satisfied". Risk Assessment for Aquatic Organisms Page: 40 Paragraph: 4 Line: 3 EPA comment: …corresponding levels of concern (LOCs) is presented in Appendix D. Aventis' response: The risk quotients are currently listed in Appendix C. Estuarine/ Marine Fish Page: 42 Paragraph: 1 Line: 17/ 18 EPA comment: Chronic toxicity studies with an estuarine/ marine fish species is required. 47 Aventis' response: This requirement should be waived. Given the relatively short half­ life of carbaryl in the aquatic environment and the low acute risk, it is unlikely that estuarine/ marine fish species would be exposed to a chronic risk. Page: 42 Paragraph: 2 Line: 1 EPA comment: There is one carbaryl use in particular that presents a major acute and chronic risk to estuarine/ marine fish. Aventis' response: This sentence should be rephrased. While there might be an acute risk from the application to oyster beds, given that there is only one application every six years according to the reference cited by EPA, it is improbable that estuarine/ marine fish would be exposed to a chronic risk. 7.0 Hazard and Risk Assessment for Terrestrial Organisms Hazard Assessment for Terrestrial Organisms Mammalian Page: 46 Paragraph: 4 Line: 1 EPA comment: With a rat LD50 of 307 mg/ kg… Aventis' response: Typographical error, the rat LD50 is 301 mg/ kg. Risk Assessment for Terrestrial Organisms Avian Risk Nongranular Formulations Page: 47 Paragraph: 4 Line: 5 EPA comment: …levels of concern (LOCs) is presented in Appendix D. Aventis' response: The risk quotients are currently listed in Appendix C. 48 Page: 48 Paragraph: 1 Line: 3 EPA comment: … for 34 of 43 uses at maximum reported rates, and for 37 of 72 uses at "average" rates. (Appendix D, … Aventis' response: The risk quotients are currently listed in Appendix C. Granular Formulations Page: 48 Paragraph: 2 Line: 5 EPA comment: …for any of the granular carbaryl uses (Appendix D, Table 6). Aventis' response: The risk quotients are currently listed in Appendix C. Mammalian Risk Risk to Herbivores/ Insectivores: Nongranular Formulations Risk Quotients for Herbivores/ Insectivores Based on Less than Maximum Label Use Rates Page: 48 Paragraph: 3 Line: 3 & 4 EPA comment: … (Appendix D, Table 10a) and maximum reported (Doane data) use rates data available for 43 uses (Appendix D, Table 10b) Aventis' response: The risk quotients are currently listed in Appendix C. Risk Quotients for Herbivores/ Insectivores Based on Maximum Label Use Rates Page: 48 Paragraph: 6 Line: 1 EPA comment: Carbaryl is moderately toxic to small mammals on an acute oral basis (rat LD50 = 307 mg/ kg) Aventis' response: Typographical error, the rat LD50 is 301 mg/ kg. By using the lower LD50 all acute mammalian risk quotients will change slightly. 49 Page: 49 Paragraph: 1 Line: 3 EPA comment: …corresponding levels of concern (LOCs) is presented in Appendix D. Aventis' response: The risk quotients are currently listed in Appendix C. Risk to Granivores: Nongranular Uses Chronic risk: Nongranular Uses Page: 50 Paragraph: 2 Line: 8 EPA comment: …summarized in Appendix D, Table 9. Aventis' response: The risk quotients are currently listed in Appendix C. Reproduction Effects Page: 50 & 51 Paragraph: 4 / 1 EPA comment: (Review of alleged reproduction effects of carbaryl). Aventis' response: The paragraphs should be changed. The literature cited in these paragraphs show ambivalent results. While some references seem to support the claim of reproductive effects, other references do not. The potential for reproductive effects in mammals was evaluated in the recently submitted 2­ generation study in rats. No reproductive effects were seen in this guideline study. The NOAEC of 75 ppm was based on pup mortality. Page: 51 Paragraph: 4 EPA comment: Feeding 2 or 20 mg/ kg of carbaryl to pregnant rhesus monkeys (Macacca mulatta) Aventis' response: This paragraph should be deleted. As there are no native monkey species in the U. S., this reference is irrelevant for U. S. wildlife species. Additionally, the reference cited is only a brief abstract article consisting of one 17­ line paragraph. Such information should not be the basis for use in a RED risk assessment. 50 9.0 References (non­ MRID) Some of the references cited in EPA's list are not full scientific articles, but only abstracts from meetings (e. g. DeNorsica, 1973; Doughtery et al. , 1971, Chapin et al. 1997). Such "publications" should not be used as references considered in risk assessments. Without a sufficient description of methods and a presentation of detailed results these studies cannot be evaluated to determine if the findings are or are not scientifically plausible. Similarly, at least three of the references (Gladenko et al. 1970, Krylova et al. 1975, Smirnov et al. 1971) cited as proof for reproductive toxicity are in Russian in Cyrillic writing making an appropriate and timely evaluation difficult. Due to the limited review time during the 30­ day comment period, the registrant could not peruse all references. A more detailed response will be provided during the 60­ day comment period. Page: 59 EPA comment: Carmel, R. F., Imhoff, J. C., Hummel, P. R., Cheplick, J. M. and Donigan, A. S., 1997. Aventis' response: The first name should be Carsel. Page: 59 EPA comment: Nkedi­ Kizza and Brown (1988) Aventis' response: The date should be 1998. Appendix A: Environmental Fate Study Reviews (DERs) Page: 62 ff EPA comment: (Environmental fate DERs are included) Aventis' response: The DERs should not be included in the RED. Publication of DERs together with the RED is unusual and will put Aventis in a competitive disadvantage. Appendix B: Refined Water Memo EPA comment: MEMO TO BE INSERTED WHEN APPROVED 51 Aventis' response: This memo was provided as an electronic copy and needs to be inserted into the document. It included text that repeated several sections of the EFED document and it included PRZM input tables for the drinking water concentrations using the Index Reservoir scenario. It would have been of benefit to have the same PRZM inputs for the "standard pond" scenarios that were used to estimate surface water concentrations used in the aquatic risk assessments. Appendix C: Ecological Risk Assessment Toxicity Endpoints Used in the Risk Assessment Page: 129 (e­ version) EPA comment: Aventis' response: Mammalian acute oral LD50 rat = 307 mg/ kg The correct LD50 is 301 mg/ kg Mammalian chronic (reproduction) NOAEC rat = 80 ppm The result of the recently submitted 2­ generation rat study should be used (75 ppm) Avian Acute and Chronic Risk Page: 130 (e­ version) Paragraph: 1 Line: 1 EPA comment: Since the avian LC50 is greater than 5,000 ppm (Appendix E), Aventis' response: The toxicity data are currently listed in Appendix D. Page: 132 – 135 (e­ version) EPA comment: (Acute Risk Quotients in Tables 4 and 5, as well as throughout the document were a reference is made to these quotients) Aventis' response: As the acute risk quotients are calculated on the basis of an LC50 of > 5000 ppm, the quotients should be given as "< (value)", not just the value. The values should also be changed accordingly throughout the document where a reference is made to these quotients. 52 Risk from Exposure to Non­ granular Products Page: 137 – 147 (e­ version) EPA comment: (Text and tables 7 ­ 10) Aventis' response: Text and tables should be revised. A rat LD50 of 307 mg/ kg was used to calculate the acute risk quotients. The correct value is 301 mg/ kg. For calculation of the chronic risk quotient a NOAEC of 80 ppm was taken from a developmental study. The NOAEC of 75 ppm from a more relevant 2­ generation rat study recently submitted should be used instead. Risk from Exposure to Granular Products Page: 147 & 148 (e­ version) EPA comment: (Text and Table 11) Aventis' response: Text and tables should be revised. A rat LD50 of 307 mg/ kg was used to calculate the acute risk quotients. The correct value is 301 mg/ kg. Aquatic Plants Page: 152 (e­ version) EPA comment: Based on a single core aquatic plant toxicity study available… …recommended that toxicity studies with Lemna gibba, Anabaena flos­ aquae, Skeletonema costatum, and a freshwater diatom be submitted. Aventis' response: The respective studies were submitted to the Agency in 1992 (see comments above to Page 2 of the Memorandum for a complete list and status). Appendix D: Toxicity Assessment Page: 157 (e­ version) EPA comment: Table 1 (spelling of author in MRID No. 00160000) 53 Aventis' response: The author of MRID No. 00160000 should be "Hudson et al. ". Also, it is not obvious why the same reference is one time classified "core" and six times "supplemental". The agency should reconsider if the use of a "supplemental" study (i. e., rock dove) in calculating all acute RQ values is justified. Birds, Chronic Toxicity Page: 158 (e­ version) Paragraph: 3 EPA comment: Bird kills attributed to carbaryl and involving blackbirds, ducks, starlings, grackles turkey, and cardinals have been reported in Pennsylvania, Virginia, New Jersey, North Carolina and Michigan (# 1002048­ 001, #1000802­ 001, #1007720­ 020, ## 1000799­ 003, #1004375­ 004). Aventis' response: The paragraph should be moved to the acute bird section. Also, only individuals familiar with this information will recognize the numbers as the incident numbers from the EIIS database. An appropriate reference should be inserted here and in similar citations. Page: 158 Paragraph: 1 Line: 2 & 3 EPA comment: Exposure to carbaryl at levels equal to or greater than 1000 ppm in the mallard duck results in adverse reproduction effects, such as decrease in number of eggs produced include cracked eggs, fertility, embryonic mortality, and hatching success. Aventis' response: The sentence should be changed. The embryonic mortality and the hatching success were not different from the control. Mammals, Acute and Chronic Page: 158 & 159 (e­ version) EPA comment: (rat LD50 of 307 mg/ kg, NOAEC 80 ppm) Aventis' response: The acute LD50 value for rat should be corrected to 301 mg/ kg, and the chronic NOEAC to 75 ppm from the 2­ generation rat study. 54 Freshwater Fish, Acute Page: 161 (e­ version) EPA comment: Table 6 Aventis' response: The study classification of reference MRID 40098001 (Mayer & Ellersieck, 1986) should be reconsidered (and handled in a consistent fashion). A number of times the reference is classified "core", while in other instances the classification is "supplemental". The reference is an overview article with little description of test methods, analytical procedures, GLP, or study details. The results are generally listed in extensive tables (although summarized in the text for some chemicals). Such a review article cannot be regarded as a "core" study equivalent to the guideline studies that have to be prepared by registrants. Also, such studies with insufficient test method descriptions should not be used in a risk assessment as the primary source of information. A submission based on such data would have certainly been rejected by the Agency Freshwater Invertebrates, Acute Page: 163 (e­ version) EPA comment: Table 9 Aventis' response: The study classification of reference MRID 40098001 (Mayer & Ellersieck, 1986) should be reconsidered (and handled in a consistent fashion). A number of times the reference is classified "core", while in other instances the classification is "supplemental". The reference is a review article with little description of test methods, analytical procedures, GLP, or study details. The results are generally listed in extensive tables (although summarized in the text for some chemicals). Such an overview article cannot be regarded as a "core" study equivalent to the guideline studies that have to be prepared by registrants. Also, such studies with insufficient test method descriptions should not be used in a risk assessment as the primary source of information. Estuarine and Marine Invertebrates, Acute Page: 165 (e­ version) EPA comment: Table 13, reference for glass shrimp: Mayer & Ellerersieck Aventis' response: The reference should be corrected in Mayer & Ellersieck. 55 Page: 167 (e­ version) Table 15 EPA comment: Table 15, reference for MRID No. 00265665 Aventis' response: The reference for MRID No. 00265665 should also contain the citation of an author. 56 DISCUSSION 1. Surface Water Concentrations Summary of Registrant Surface Water/ Drinking Water Monitoring Program In section V, page 31 EPA states that the modeling simulations provide a conservative, though not unreasonable, estimate on possible concentrations in drinking water. The data from the registrant drinking water monitoring program provide the best estimate of concentrations of carbaryl in drinking water. This study uses the sampling design for acute endpoints recommended in industry/ EPA meetings during 1999 (weekly sampling during times of peak concentrations over a three year period). Twenty sites representing the highest carbaryl use areas were selected based on the information provided in Appendix I. These included 16 sites in agricultural areas and 4 locations in urban areas. Samples were collected from the inlet and outlet water at each sampling interval. Outlet samples were only analyzed when residues were present in the inlet samples. The analytical method had a limit of quantification of 0.030 ppb and a limit of detection of 0.002 ppb. Table 1 summarizes the results of the monitoring at each of the 20 community water systems. The maximum concentration observed was 0.16 ppb (average of four samples, the highest was 0.18 ppb) in a finished water sample from the Deerfield community water system located on the River Raisin in Lenawee County, Michigan. There were only five other samples above the limit of quantification of 0.030 ppb. One was a raw water sample containing 0.31 ppb from the Little Potato Slough Mutual community water system near Lodi in San Joaquin County, California (the source is the Little Potato Slough). The corresponding finished water sample was 0.007 ppb. A second one was a raw water sample in Brockton, MA which contained 0.031 ppb. No detectable residues were found in the corresponding finish water sample. The last three samples were from the Shades Mountain plant of the Birmingham community water system on the Cahaba River in Jefferson County, Alabama . Two were raw and finished samples of 0.038 and 0.032 ppb at the same sampling interval in 2001. . The other sample was 0.035 ppb in the raw water in a 2000 sample (the corresponding finished sample did not contain carbaryl residues. e. All residues were transient so the time weighted average concentration of carbaryl in each of the years was 0.005 ppb or less at all 20 community water systems. 57 Table 1. Summary of Results from the Carbaryl Drinking Water Monitoring Study. Site Major Uses Maximum Concentration (ppt) TWA Conc. (ppt)* in Outlet Water Inlet Water Outlet Water 1999 2000 2001* * 1999 2000 2001** 1999 2000 Manatee, FL citrus 9 3 ND 11 ND NA 1 1 West Sacramento, CA orchards, nuts 3 24ND310NA1 1 Lodi, CA orchards, nuts 12 31 ND 4 7 NA 1 1 Riverside, CA grapes, tree crops 8ND ND ND NANA 1 1 Lake Elsinore, CA citrus ND 3 6 NA NA Analysis Pending 1 1 Corona, CA citrus ND ND ND NA NA NA 1 1 Beaumont, TX various agricultural ND ND ND NA NA NA 1 1 Point Comfort, TX rice, tree crops 18 5ND ND NDNA 1 1 Penn Yan, NY grapes, apples ND 23 ND NA ND NA 1 1 Westfield, NY grapes, apples 21 5 ND ND 9 NA 1 1 Jefferson, OR vegetables, strawberries ND 10 ND NA ND NA 1 1 Coweta, OK pecans 4 ND *** ND NA *** 1 1 Pasco, WA apples, potatoes 2 3 ND ND ND NA 1 1 Manson, WA apples ND ND ND NA NA NA 1 1 Deerfield, MI vegetables 10 4 ND 160 ND NA 5 1 Brockton, MA cranberries 31 27 ND ND 3 NA 1 1 East Point, GA home and garden 18 18 4 3 8 ND 1 1 Midlothian, TX home and garden 14 ND 14 ND NA ND 1 1 Cary, NC home and garden 4ND ND ND NANA 1 1 Birmingham, AL home and garden 23 35 38 ND ND 32 1 1 * Annual Time Weighted Concentration, outlet values substituted for inlet values when available; values below the detection limit were considered to be half the detection limit. ** Results represent one to six months of sampling into the third year program. *** No results available for the third year of sampling. 58 ND Not detected. NA No outlet samples analyzed due to carbaryl residues not being detected in inlet samples. Summary of Surface Water Data from the NAWQA Program In Section 1 page 3, Section 4 page 28 and in Section 5 page 34, EPA has summarized the available surface water monitoring data from the NAWQA program as having detections in 46% of the 36 NAWQA study units between 1991 and 1998 with a maximum concentration of 5.5 ppb. The following tables summarize the carbaryl analyses presently available from this database. Table 2 is a summary of the carbaryl detections in the updated database analysis recently reported by Larson (2001). This analysis was conducted only for samples collected during a one­ year period of the most intensive sampling from each of the sampling sites. Numerous samples were excluded from this analysis as described by Larson: "A few sites with sufficient sampling for pesticides were excluded from the analysis, in order to minimize bias caused by over­ representation of a particular land use or agricultural setting. … The sampling requirements for a site to be included in the analysis were a minimum of 8 samples collected in 6 or more months during the 1­ year period. In addition, samples must have been collected during the expected period of elevated pesticide concentrations. At most of the sites used in this analysis, 20 to 30 samples were collected during the selected 1­ year period.… Not all samples collected during the year at each site were used in the calculation of the summary statistics, however. Samples collected as part of a fixed­ frequency sampling schedule were included, along with a much smaller number of samples collected during selected high or low flow conditions. Samples collected over a storm hydrograph, or as part of a study of diurnal variability, were excluded in order to avoid bias resulting from repeated sampling during extreme conditions. " Table 2. Carbaryl Detections Reported in Pesticides in Streams Update (Larson, 2001) Site Type Number of Sites Number of Samples Carbaryl Detection Frequency (%) Maximum Estimated Concentration ( µ g/ L) All >= 0.01 ( µ g/ L) >= 0.05 ( µ g/ L) >= 0.10 ( µ g/ L) Agricultural Streams 62 1560 9.2 5. 7 1.8 0. 9 5.2 Urban Streams 22 611 43 37 19 12 3.2 Integrator A 31 595 15 11 2.7 1. 2 0.43 A Large streams and rivers 59 Results in Table 3 and Table 4 show a breakdown of all the carbaryl analyses reported in the USGS NAWQA database, which was downloaded from their web site July 16, 2001. The data are reported separately for the GC/ MS and HPLC/ PDA analyses. Table 3. Frequency of Carbaryl Detections by GC/ MS in Different Concentration Ranges Reported in the NAWQA Database as of July 16, 2001 Land Use Type Number of Samples <= MDL C >0.003 to 0.01 >0.01 to 0.1 ppb >0.1 to 1 ppb >1 ppb No. % No. % No. % No. % No. % All Samples 10379 8388 80.82 617 5.94 1065 10.26 283 2.73 26 0.25 Agricultural 4349 3888 89.40 188 4.32 225 5.17 46 1.06 2 0. 05 Urban 1763 921 52.24 161 9.13 463 26.26 195 11.06 23 1.30 Mixed A 3648 3022 82.84 247 6.77 345 9.46 33 0.90 1 0. 03 Other B 619 557 89.98 21 3.39 32 5.17 9 1. 45 0 0 A Large streams and rivers. Includes all of the "Integrator" sites listed in Larson, et al. ., 1999 and many more. B Includes forest, rangeland, mining, etc. C The method detection limit (MDL) for carbaryl analyzed by the GC/ MS method is 0.003 µ g/ L, but updated MDLs presented in the database may be higher for some analyses and are included in this category. Table 4. Frequency of Carbaryl Detections by LC/ PDA in Different Concentration Ranges Reported in the NAWQA Database as of July 16, 2001 Land Use Type Number of Samples <= MDL C >0.008 to 0.01 >0.01 to 0.1 ppb >0.1 to 1 ppb >1 ppb No. % No. % No. % No. % No. % All Types 5516 5348 96.9 5 9 0. 16 93 1. 69 54 0. 98 12 0. 22 Agricultural 2528 2509 99.2 5 1 0. 04 13 0. 51 3 0.12 2 0. 08 Urban 1189 1064 89.4 9 4 0. 34 64 5. 38 47 3. 95 10 0. 84 Mixed A 1523 1501 98.5 6 4 0. 26 15 0. 98 3 0.2 0 0 Other B 276 274 99.2 8 0 0 1 0. 3610. 360 0 A Large streams and rivers. Includes all of the "Integrator" sites listed in Larson, et al. ., 1999 and many more. B Includes forest, rangeland, mining, etc. C The method detection limit (MDL) for carbaryl analyzed by the LC/ PDA method is 0.008 µ g/ L, but updated MDLs presented in the database may be higher for some analyses and are included in this category. 60 Summary of Carbaryl Analytical Methods used in the NAWQA Program In a number of instances throughout their review, EPA has made reference to the "poor recovery" for carbaryl noted in a NAWQA summary document (Larson, 1999). In this document, reference is made to mean percent recovery of 24% for carbaryl with a method detection limit (MDL) of 0.003 ppb. The Agency cites this low mean recovery several times as evidence that the concentrations of carbaryl reported in the database widely underestimate the actual concentrations of carbaryl in the water samples. This claim is misleading and should be removed from each location in the draft RED for reasons discussed below. Two analytical methods were developed as part of the NAWQA program and both of them have been used in the analysis of carbaryl. The first method, used for a majority of the NAWQA data reported for carbaryl, is a GC/ MS method with an MDL of 0.003 ppb (Zaugg, et al., 1995). The second method, used for a limited number of samples in which carbaryl was analyzed, is an LC/ Photodiode­ Array (PDA) method with an MDL of 0.008 ppb (Werner et al. ., 1996). In the NAWQA database the quantitative data for carbaryl determined by the GC/ MS method are flagged with an "E", as are data for several other analytes, indicating that the analysts have noted "the potential for variable performance" in the analysis of carbaryl. None of the carbaryl data in the NAWQA database has been corrected for procedural recoveries that were noted in the documents described above. Both of these methods are discussed below in relation to the recoveries found for the methods and the potential impact this could have on the analytical data for carbaryl. Gas Chromatography/ Mass Spectroscopy Method The analytical method most used in the NAWQA program for the analysis of carbaryl in water samples is the GC/ MS method described by Zaugg, et al., 1995. In this multi­ residue method, the analytes are first removed from the water sample by sorption on a C­ 18 solid phase and are subsequently eluted from the solid phase, separated by GC and quantified by mass spectroscopy with selected ion monitoring. The identity of each analyte is confirmed by the appropriate combination of retention time and the ratios of three mass ions that are characteristic for the analyte. The recoveries for carbaryl spiked at different levels into three different types of water and analyzed by the GC/ MS method are shown in Table 5 Mean percent recoveries of 151 and 202% were found for carbaryl fortified at 0.1 and 1.0 µ g/ L in reagent grade water. A preliminary MDL of 0.046 µ g/ L was calculated for the 0.1 µ g/ L spiking level. Mean percent recoveries of 10 and 75% were found for carbaryl fortified at 0.1 and 1.0 µ g/ L in a surface water sample collected from the South Platte River. However, carbaryl was detected at 0.18 µ g/ L in this water, or nearly twice the low spike level, raising questions about the validity of this result. Mean percent recoveries of 94 and 86% were found for carbaryl fortified at 0.1 and 1.0 µ g/ L in a ground water sample collected from a well in Denver. A mean recovery value of 24% was reported for reagent­ grade water fortified at a level of 0.03 µ g/ L with a method detection limit calculated at 0.003 µ g/ L. 61 Table 5. Recovery and Precision for Multiple Determinations of Carbaryl in GC/ MS Method for Carbaryl Spiked in Different Water Samples Water type Spike Concentration ( µ g/ L) Mean Recovery (%) MDL Calculated Reagent Grade 0. 1 151 0.046 Reagent Grade 1. 0 202 Surface A 0.1 10 Surface A 1.0 75 Ground B 0.1 94 Ground B 1.0 86 Reagent Grade 0. 03 24 0. 003 A Surface water was collected from the South Platte River near Henderson, Colorado. This water was found to contain significant concentrations of several pesticides including 0.18 µ g/ L carbaryl. This concentration was subtracted from the values determined to give corrected results. B Ground water was collected from the Denver Federal Center Well 15. Whereas the values reported by Zaugg, et al. (1995) are of interest in validating the analytical method, they are not as useful in evaluating the validity of the data contained in the NAWQA database. Therefore, quoting the mean recovery value of 24% for reagent grade water spiked with carbaryl at 0.03 µ g/ L as evidence that the concentrations reported in the database underestimate the actual concentrations of carbaryl present in the water samples is misleading. A more useful measure of the validity of the values in the database lies with the quality control checks that have been incorporated into the analysis of samples in the NAWQA program. In a preliminary report, Martin (1999) reported the quality control data collected as part of the NAWQA surface and ground water programs by the 1991 NAWQA Study Unit teams or the National Water Quality Laboratory (NWQL) during 1992 to 1996. The data that were compiled includes field blanks, laboratory control spikes and field matrix spikes, which are defined below by Martin. "Field blanks were collected at the field site with pesticide­ grade blank water and are exposed to the field and laboratory environments and equipment similarly to environmental samples. Field blanks measure the frequency and magnitude of contamination (one type of positive bias) in environmental water samples from sources in the field and/ or laboratory. Contamination is the main cause of falsepositive detections (detecting a pesticide in a sample when, in truth, it is absent)." "Laboratory control spikes measure the bias and variability of the analytical method at a particular concentration. One laboratory control spike is measured in each analytical set of environmental samples. The laboratory control spike has 62 the target pesticides spiked into pesticide­ grade blank water at the laboratory and extracted, processed, and analyzed like environmental samples. Laboratory control spikes analyzed by GCMS were spiked at 0.1 : g/ L…" "Field matrix spikes measure the bias and variability of the analytical method PLUS any potential effects caused by (1) degradation of pesticides during shipment to the laboratory, (2) inferences in the determination of pesticides from unusual characteristics of the environmental water sample (" matrix effects"), and (3) other chemical processes that cause bias or variability in the measurements of pesticides in environmental water samples. Field matrix spikes analyzed by GCMS were spiked at 0.1 : g/ L,…" All of the carbaryl analyses in the field blanks, field matrix spikes and lab control spikes were conducted following the same method described by Zaugg et al., 1995 that was used to generate a majority of the carbaryl data contained in the NAWQA database. The data below were excerpted from Tables 1 to 4 of the Martin report. Carbaryl is found in these tables under parameter 82680. Out of 145 samples taken as ground water field blanks, carbaryl was not detected in any of the samples indicating a lack of false positives. Out of 171 samples taken as surface water field blanks, carbaryl was reported in two samples (1.2% false positives) at reported concentrations of 0.009 and 0.012 µ g/ L. A summary of the results for the field matrix spikes and the lab control spikes is presented in Table 6 Mean recovery for the 306 field matrix spikes was 115% of the spiking level of 0.1 µ g/ L with a median recovery of 94.4% and a 90 th percentile recovery of 200%. This indicates the potential for the method to over­ estimate the concentration of carbaryl present in the water samples and is consistent with the initial data reported for the reagent water samples by Zaugg et al. (1995). Mean recovery for the 1000 lab control spikes was 99.6% of the spiking level of 0.1 µ g/ L with a median recovery of 93% and a 90 th percentile recovery of 185%. These data suggest an adequate level of detection of carbaryl in QC samples that were analyzed as part of the same process used in the NAWQA survey of pesticides in surface and ground water. 63 Table 6. Percent Recoveries of Carbaryl Detected by the NAWQA GC/ MS Method in Laboratory Control Spikes and Field Matrix Spikes at a Spiking level of 0.1 µ g/ L Sample Type Number of Samples 10 th Percentile Recovery (%) Median Recovery (%) Mean Recovery (%) 90 th Percentile Recovery (%) Maximum Recovery (%) Field Matrix Spike 306 40 94.4 115.0 199.9 456 Laboratory Control Spike 1000 20 93.0 99.6 185.1 329 The following disclaimer was taken verbatim from the provisional report by Martin (1999) and pertains to the data provided above on the recovery of carbaryl in the field matrix spike samples. "The field matrix­ spike data have not been reviewed thoroughly, are provisional, and are subject to change. Further review of the field­ spike data is expected to identify spikes that have extremely high or low recoveries because the spikes either were improperly collected or incorrectly documented in the NAWQA QC data base. The expected result of further review is a data set of field matrix spikes with fewer extreme values than the provisional data set described in this paper; consequently, the provisional data set provides a conservative estimate of the quality of the NAWQA pesticide data. Interpretations of field matrix spike data in this paper are not expected to change greatly as a result of further review of the data, however, the statistics and confidence limits reported in the text and tables will change on further review (especially for pesticides with low numbers of field spikes [less than 50])." 64 High­ Performance Liquid Chromatography/ Photodiode­ Array Method Another analytical method used in the NAWQA program for the analysis of carbaryl in water samples is the LC/ PDA method described by Werner, et al., 1996. This method was used for the analysis of carbaryl in a limited number of samples as noted above. In this multi­ residue method, the analytes are first removed from the water sample by sorption on a Carbopak­ B solid phase extraction cartridge and are subsequently eluted from the solid phase, separated by HPLC and quantified by light absorption using a photodiode­ array detector. The identity of each analyte is confirmed by the appropriate combination of retention time and light absorption characteristics. The recoveries for carbaryl spiked at different levels into three water samples and analyzed by this method is shown in Table 7 The recoveries ranged from 58% to 84% for the different water and spiking levels. Laboratory control spikes in organic­ free water resulted in a mean recovery of 61% over a two­ year sampling period. These results indicate reasonable levels of carbaryl recovery from each of the different types of water evaluated for the method. Table 7. Recovery and Precision for Multiple Determinations of Carbaryl in LC/ PDA Method for Carbaryl Spiked in Different Water Samples Water type Spike Concentration ( µ g/ L) Mean Recovery (%) MDL Calculated Organic­ Free 0.1 82 0. 008 Organic­ Free 1.0 70 Surface A 0.1 84 0. 016 Surface A 1.0 84 Ground B 0.1 58 0. 018 Ground B 1.0 64 Organic Free 0.5 61 C A Surface water was collected from the South Platte River at Englewood, Colorado. B Ground water was collected from Jefferson County, Colorado (Arvada Well 14). C National Water Quality Laboratory results produced using 5 operators and 7 instruments over 2 years (about 350 data points). Summary of Surface Water Data from the California DPR Surface Water Database In Section 5 pages 34 to 37 EPA has summarized surface water monitoring data from various sources. One source not included in this discussion is the California Surface Water Monitoring Database. The number of analyses and the detections of carbaryl residues reported in the database are summarized in Table 8. Carbaryl was detected at levels above the LOQ in only 5.1% of the 2,690 samples analyzed. The mean concentration of carbaryl in the 140 samples above the LOQ was 0.42 ppb. The highest concentration of carbaryl that was detected was 8.4 ppb. 65 An analysis of the data in the California Department of Pesticide Regulation's surface water database as of July 15, 2000 was conducted for carbaryl. The following summary of the contents of the database is adapted from information provided by the California DPR. The database contains monitoring results for pesticides in samples taken from California rivers, creeks, urban streams, agricultural drains, the Delta, and urban stormwater runoff. As of July 15, 2000, the database contained the results of 30 studies conducted by federal, state, and local agencies, private industry, and an environmental group. A total of 4,660 samples were taken in 16 counties from January 1991 through March 2000. Each record in the database is the result of one analysis for a pesticide active ingredient or breakdown product. The database contains a total of 92,296 analytical records. Only information on the analytical detection of carbaryl in these water samples is summarized in Table 8 below. Table 8. Carbaryl Detections Reported in California DPR Surface Water Monitoring Database Land Use Type Number of Samples <= LOQ >0.003 to 0.01 >0.01 to 0.1 ppb >0.1 to 1 ppb >1 ppb No. % No. % No. % No. % No. % All Samples 2690 2553 94.9 1 13 0.48 55 2.04 55 2.04 14 0.52 Concentrations of analytical results that are reported below the limit of quantification are reported as a zero in the database concentration field. The LOQs for the different methods used to generate the data contained in the database ranged from 0.003 to 0.5 µ g/ L, with a majority of the samples analyzed with an LOQ of 0.05 µ g/ L or less (Table 9) . Table 9. Limits of Quantification for Carbaryl Analytical Methods Reported in California DPR Surface Water Monitoring Database LOQ ( µ g/ L) 0.003 0.041 0.044 0.05 0.07 0.1 0. 5 Number of Samples Analyzed 267 238 168 1353 92 53 146 66 2. Ground Water Concentrations In Section 5 page 34 EPA summarized information on the detection of carbaryl in groundwater from the EPA Pesticides in Groundwater Database, the EPA STORET database and the NAWQA database. Each of the databases shows a pattern of very low levels of carbaryl detection in few groundwater resources. These analyses confirm several statements made by the Agency that carbaryl has limited potential to impact groundwater resources. However, on page 2 of the Memorandum issued June 28, 2001, in conjunction with the EFED RED chapter for carbaryl, EPA is requiring additional information on "Surface and groundwater monitoring in urban and suburban use areas (non­ guideline)." Based on the characteristics of carbaryl and the available data demonstrating limited impact of carbaryl on ground water resources, additional studies to evaluate the potential for carbaryl to contaminate groundwater are unnecessary and unwarranted. Summary of Ground Water Data from the NAWQA Program In Section 5, pages 33 ­ 34, EPA has summarized ground water monitoring data available for carbaryl. The database that contains the most extensive evaluation of the impact of the most recent uses of carbaryl on ground water is the NAWQA database. One deficiency of the NAWQA program is that samples are targeted to agricultural and urban areas but not to areas treated with the specific chemical being analyzed. However, given the use patterns of carbaryl, the use of carbaryl has certainly occurred near a number of these wells. Another deficiency is that when residues are found, that while they may be representative of residues in ground water, they may not be representative of residues in ground water used for drinking water due to the location of the sampled wells relative to potable drinking water wells. EPA cited a 1998 review of the NAWQA database by Kolpin and stated: "Carbaryl was detected at greater than the detection limit (0.003 : g/ L) in 1.1 % of groundwater samples from 1034 sites across the U. S. by U. S. G. S. NAQWA (sic) program. The maximum observed concentration was 0.021 : g/ L." This 1998 analysis has been extended by additional study data collected by the NAWQA program. The additional data continue to show a limited number of low level detections of carbaryl in ground water samples. Table 10 below summarizes a more recent provisional review by Kolpin (2001) of the updated NAWQA database. Not all of the water samples were used to calculate the summary statistics as noted by Kolpin: "To preclude bias in these summary statistics from wells that were sampled more than once, the data set was condensed such that each well had a single pesticide analysis. This generally was the first sample collected. However, subsequent samples were selected if these samples contained more pesticide data (i. e., a larger number of pesticides were analyzed). Wells that were designed to be a part of both a land­ use study and a major aquifer survey were used in each summary. 67 Because of uncertainties in the source of water and contributing land­ use area, springs and drains were excluded from these summaries." Table 10. Carbaryl Detections Reported in Pesticides in Ground Water Update (Kolpin, 2001) Site Type Number of Samples Carbaryl Detection Frequency (%) Maximum Estimated Concentration ( µ g/ L) All >= 0.01 ( µ g/ L) >= 0.05 ( µ g/ L) >= 0.10 ( µ g/ L) Agricultural LandUse Wells 1244 0.40 0.16 0.0 0. 0 0.019 Urban Land­ Use Wells 634 2.1 1. 3 0.0 0. 0 0.031 Major Aquifers 1849 0.59 0.54 0.05 0.05 0.539 68 REFERENCES Burgos, W. D., J. T. Novak and D. F. Berry. 1996. Reversible Sorption and Irreversible Binding of Naphthalene and ­Naphthol to Soil: Elucidation of Processes. Environ. Sci. Technol., 30: 1205­ 1211. Burgos, W. D., D. F. Berry, A. Bhandair, and J. T. Novak. 1999. Impact of Soil­ Chemical Interactions on the Bioavailability of Naphthalene and 1­ Naphthol. Water Research, 33: 3789­ 3795. Hassett, J. J., W. L. Banwart, S. G. Wood, and J. C. Means. 1981. Sorption of ­naphthol: Implications concerning the limits of hydrophobic sorption. Soil Sci. Soc. Am. J 45( 1): 38­ 42. Kolpin, D. W. June 11, 2001. Pesticides in Ground Water, Summary statistics; Results of the National Water Quality Assessment Program (NAWQA), 1992­ 1998. Available for download from http:// water. wr. usgs. gov/ pnsp/ pestgw/. Larson, S. J. June 11, 2001. Pesticides in Streams, Summary statistics; Results of the National Water Quality Assessment Program (NAWQA), 1992­ 1998. Available for download from http:// water. wr. usgs. gov/ pnsp/ pestsw/. Martin, J. D. October 27, 1999 .Quality of Pesticide Data for Environmental Water Samples Collected for the National Water­ Quality Assessment Program, 1992­ 96 and Examples of the Use of Quality­ Control Information in Water­ Quality Assessments. Available for review at: http:// water. wr. usgs. gov/ pnsp/ rep/ qcsummary/ McCall, P., D. Laskowski, R. Swann, and H. Dishburger. 1980. Measurement of Sorption Coefficients of Organic Chemicals and Their Use in Environmental Fate Analysis. In: Test Protocols for Environmental Fate & Movement of Toxicants. Proceedings of a Symposium, Association of Official Analytical Chemists, 94th Annual Meeting, October 21, 22, 1980. pp 89­ 109. Werner, I., L. A. Denovic, V. Conner, V. De Vlaming, H. Bailey and D. E. Hinton. 2000. Insecticide­ Caused Toxicity to Ceriodaphnia dubia (Cladocera) in the Sacramento­ San Joaquin River Delta, California. Environmental Toxicology and Chemistry, 19: 215­ 227. Werner, S. L., M. R. Burkhardt and S. N. DeRusseau. 1996. METHODS OF ANALYSIS BY THE U. S. GEOLOGICAL SURVEY NATIONAL WATER QUALITY LABORATORY— DETERMINATION OF PESTICIDES IN WATER BY CARBOPAK­ B SOLIDPHASE EXTRACTION AND HIGH­ PERFORMANCE LIQUID CHROMATOGRAPHY. U. S. Geological Survey Open­ File Report 96­ 216, 42 pp. Available for download from http:// wwwnwql. cr. usgs. gov/ Public/ pubs/ OFR96­ 216/ OFR96­ 216. html. 69 Zaugg, S. D., M. W. Sandstrom, S. G. Smith and K. M. Fehlberg. 1995. METHODS OF ANALYSIS BY THE U. S. GEOLOGICAL SURVEY NATIONAL WATER QUALITY LABORATORY— DETERMINATION OF PESTICIDES IN WATER BY C­ 18 SOLID­ PHASE EXTRACTION AND CAPILLARY­ COLUMN GAS CHROMATOGRAPHY/ MASS SPECTROMETRY WITH SELECTED­ ION MONITORING. U. S. Geological Survey OpenFile Report 95­ 181, 49 pp. Available for download from http:// wwwnwql. cr. usgs. gov/ Public/ pubs/ OFR95­ 181/ OFR95­ 181. html. 70 Confidential Business Attachment APPENDIX 1 Surface Water Monitoring for Residues of Carbaryl in High Use Areas of the United States (Stone Environmental, Inc. Report #99­ 1005­ F) (hard copy provided). 71 Confidential Business Attachment APPENDIX 2 Calculation of County Average Carbaryl Use Rates (hard copy provided)

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1/ 11/ 01 Concerned Citizen Requests Meeting with SRRD about Washington State SLN Registration of Carbaryl. A concerned citizen from Washington State has requested a meeting with SRRD, tentatively scheduled for January 16th, on the reregistration of carbaryl and its use on oyster beds in Washington State as a FIFRA 24( c) Special Local Need (SLN) registration. The concerned citizen lives on one of the two bays affected by carbaryl spraying and opposes the SLN registration. Concerns include spray drift of carbaryl onto the oyster beds of residents who oppose carbaryl, lethality to nontarget invertebrates such as Dungeness crabs, and the general impact of spraying on the bays' ecosystems. An area tribe, the Shoal Water Tribe, has also expressed concerns about carbaryl use in the bay and in nearby cranberry bogs. The bays' oyster farmers have been spraying carbaryl since 1963 to kill burrowing shrimp, which can loosen sediment on the beds and suffocate oyster larvae or "seed." Estimates by the bays' growers association in 1996 placed the annual value of the local industry at $15 to $30 million. Carbaryl spraying on oyster beds has been controversial within the state and the subject of many studies, including studies of potential impacts on endangered species. The state is now writing a draft NPDES permit for the SLN registration of carbaryl in response to the Talent Decision by the 9th Circuit Court of Appeals. (Tony Britten, 703­ 308­ 8179) 1/ 18/ 01 SRRD Meets with Concerned Citizen about Carbaryl SLN Use on WA State Oyster Beds. Carbaryl (brand name SEVIN) is used on oyster beds in two Washington State bays to kill species of burrowing shrimp that loosen sediment and cause loss of oyster crop. A concerned Washington State citizen who opposes this SLN use met with SRRD and requested information, including: (1) any administrative procedures available for aggrieved citizens to request removal of an SLN registration, (2) an explanation why only oysters have a food tolerance when other seafood products from the bays are exposed to carbaryl, and (3) whether states must send EPA new studies that show adverse effects from SLN use. FEAD also met with the citizen to discuss the Talent court decision and a state NPDES permit being issued for the SLN use. The citizen also stated a desire to meet with Aventis, the manufacturer of SEVIN, to discuss concerns about the SLN use. (Tony Britten, 308­ 8179).

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Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES DP Barcode: D276945 PCCode: 056801 Date: August 17, 2002 MEMORANDUM: SUBJECT: Response to Registrant's 30­ day Error Correction Comments on the EFED Risk Assessment Chapter in Support of the Reregistration Eligibility Decision (RED) on Carbaryl To: Anthony Britten, PM Team Reviewer Betty Shackleford, Product Manager 53 Special Review and Reregistration Division (7508C) FROM: E. Laurence Libelo, Ph. D., Environmental Engineer Thomas Steeger, Ph. D., Senior Biologist Environmental Risk Branch IV Environmental Fate and Effects Division (7507C) Angel Chiri, Ph. D., Biologist Biological and Economic Assessment Division THRU: Betsy Behl, Chief ERB IV/ EFED (7507C) The Environmental Fate and Effects Division (EFED) has reviewed the registrant 30­ day (Phase I) error response from Aventis CropScience entitled "Review of the Draft Environmental Fate and Ecological Risk Assessment of the Reregistration of Carbaryl." EFED has revised its risk assessment for the reregistration eligibility decision (RED) and is attaching the revised document. Revisions to the chapter (identified below) reflect only those instances where an actual error was identified. Comments from the registrant that did not identify an actual error but rather were editorial in nature will be addressed after the public comment period (Phase II) has ended. However, several generic issues were raised by the registrant that EFED would like to comment on. These include endocrine disruption, the use of open literature to supplement core data submissions, status of Aventis' water­ monitoring studies, and the role of new data submissions in characterizing risk in the current version of the RED. Endocrine Disruption The risk assessment chapter is not intended to resolve the endocrine disrupting potential of carbaryl. Rather, the chapter summarizes available ecological effect data; EFED believes there are sufficient data to raise concern regarding the endocrine disrupting potential of carbaryl. EFED is required to identify effects that it believes are consistent with responses to endocrine­ mediated pathways. Those chemicals identified as potential endocrine disruptors such as carbaryl, will likely be subject to more refined testing for such effects once the appropriate testing procedures have been 2 identified. However, at this stage of the process EFED is simply identifying potential endocrine disruptors. Open Literature Open literature studies are not intended to fulfill guideline data requirements but rather they are intended to help reduce uncertainty and support concerns regarding risk. Additionally, EFED relies on open literature from peer­ reviewed journals that require proposed publications to undergo the scrutiny of review prior to release to the general public. The registrant contends that toxicity data obtained from published literature are ". . . at times at least questionable and other times does not fulfill the requirements set by EPA for studies submitted by the registrant. Data of such poor quality should not be used as key information in the risk assessment." EFED has routinely relied on published literature particularly in cases where there are insufficient core data and/ or the existing data introduce considerable uncertainty into the risk assessment process. In general, published literature is drawn from peer reviewed journals; while EFED does not have access to the original data on which these studies are based, it is assumed that the study conclusions have undergone some degree of scientific scrutiny to warrant publication. Status of Aventis' Drinking Water Monitoring Studies The registrant makes repeated reference to the drinking water monitoring study data that were submitted. The study is very limited in scope and it is unclear how sites that were monitored relate to locations where carbaryl has been used nationally. It is extremely unlikely that this study sampled peak concentrations. In addition, the study design did not allow EFED to evaluate the effect of drinking water treatment on carbaryl concentrations. The study is also of only limited usefulness for determining concentrations in surface water for use in ecological exposure assessment. Water bodies represented in the study are generally larger then those of concern for ecological exposure. The limitations on this study have been discussed in the reviews of the study interim reports. Additional Data In several instances, the registrant references recently submitted data as addressing uncertainties characterized in the RED. Since these data were not available when the draft RED was written, they were not captured in the RED. Depending on the quality of the new data, they may be included in the RED after they have been reviewed. However, the 30­ day error response phase is not intended to represent an opportunity to submit additional data. Additionally, if data are provided that demonstrate that certain environmental fate and ecological effects endpoints might be substantially different than those used in the RED, it does not discount the reliability and/ or utility of the original studies. For example, if the newly submitted 2­ generation rat study provides a no­ observe effect concentration which is significantly less sensitive than the endpoint used from the rat developmental study, then it is likely that EFED would continue to use the results of the original developmental study, i. e., the most sensitive endpoint, to evaluate chronic toxicity. In the attached document (Attachment A) each of the registrant's comments is addressed. The attachment is in three sections, i. e., General Comments, Transmittal and RED Document Line­ by­ Line Review of the Carbaryl RED Chapter, and Discussion. In the line­ by­ line review, the registrant cites specific EPA comments and then provides their response to the comment. In all three sections, the EFED response to discussions and/ or comments is entitled "EFED Response". In many cases the registrant has provided constructive comments on the EFED science chapter and has helped to assure the document's accuracy. Overall though, the registrant's comments have not affected the basic 3 concerns and uncertainties identified in environmental fate and ecological effects assessment of carbaryl. 4 Attachment A. EFED Responses to 30­ day Error Correction Comments by Registrant CARBARYL PC Code No. 056801; Case 0080 Review of the Draft Environmental Fate and Ecological Risk Assessment for the Reregistration of Carbaryl August 6, 2001 Aventis CropScience P. O. Box 12014, 2 T. W. Alexander Drive Research Triangle Park, NC 27709 5 General Comments The EFED draft chapter of the carbaryl RED is very thorough using a wealth of references. The use of published literature over submitted data is significant. The quality of the published literature is at times at least questionable and other times does not fulfill the requirements set by EPA for studies submitted by the registrant (e. g. thorough description of test conditions, clear identification of the test material, analytical verification, GLP etc.). Data of such poor quality should not be used as key information in the risk assessment. For the 30­ day response not all literature references could be verified or the quality ascertained. EFED Response: EFED feels that all available relevant information should be used in evaluating risk of pesticides with long registration histories. As in other risk assessments literature data were used to supplement and to help evaluate registrant submitted data. Literature data were also used when required core data were not submitted. Literature data were evaluated by EFED scientists prior to the data's inclusion into the risk assessment and data of questionable validity were not used. There is a high level of redundancy in the document making it difficult to read. Reducing repetitions to a minimum would facilitate the reading. EFED Response: While EFED agrees that the chapter includes some redundancy, this does not represent a factual error in the document. EFED has found utility in repeatedly emphasizing certain themes to underscore concern or uncertainty. We believe it is inappropriate to include DERs [data evaluation records] in the RED Chapters. A summary of study findings is already presented in the document. DERs should be made available to the public through the regular procedure under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. EFED Response: EFED concurs with the registrant's comments that DERs should be made available to the public under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. The use of carbaryl on barley, oats, rye, cotton, and livestock are cancelled . It should be noted that Aventis CropScience labels for the technical materials and the end­ use products containing carbaryl were amended to delete these uses. The Agency has already approved the labeling changes (please refer to HED response document, Section III for details). 6 EFED Response: The cancelled uses have been removed. The document reflects uses that were supported at the time the chapter was written; EFED does not have the resources to revise chapters to remain consistent with current mitigation measures; however the chapter does provide a better understanding of why certain mitigation agreements were reached. Aventis CropScience will no longer support the use of carbaryl on poultry (direct application and poultry quarters treatment). We will shortly submit a request for cancellation of these uses in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) (please refer to HED response document, Section III for details). Aventis CropScience is in the process of conducting, or has scheduled, studies relevant to the refinement of the environmental risk assessments for carbaryl and the major degradate 1­ naphthol. These studies are as follows: C Rate and Route of Aerobic Degradation in Soils. These studies have been initiated with parent carbaryl applied to four diverse U. S. soils. The data are intended to provide additional half­ life determinations for parent carbaryl and the major degradate 1­ naphthol. Expected completion date: March 2002 C Aerobic Aquatic Metabolism in Two Water/ Sediment Systems. These studies have been initiated with parent carbaryl applied to two distinct U. S. water/ sediment systems. The data are intended to provide additional half­ life determinations for parent carbaryl and the major degradate 1­ naphthol. In addition, further identification of additional degradation products is anticipated. Expected completion date: March 2002 C Adsorption and Desorption of 1­ Napthol to five soils. This study has been scheduled to evaluate the adsorption and desorption of the major carbaryl degradate to five soils/ sediment. The data are intended to provide information necessary to evaluate the environmental risks from 1­ naphthol in standard models. Expected completion date: March 2002 EFED Response: These studies will be reviewed and evaluated when they are received and if the studies are determined to be scientifically valid, they will be used in future assessments. For the reregistration process in the EU, Aventis CropScience is in the process of conducting, or has scheduled, studies relevant to the refinement of the ecotoxicological risk assessments for carbaryl and the major degradate 1­ naphthol. These studies are as follows: Studies with Carbaryl: Acute oral LD50 in mallard ducks Dynamic acute LC50 in bluegill sunfish Acute toxicity in Daphnia 7 Acute toxicity in Chironomus riparius Toxicity in Selenastrum capricornutum Acute oral and contact toxicity in honeybees 14­ d toxicity in earthworms Effects on soil microorganisms (nitrification/ carbon cycle) Effect on sewage treatment Studies with 1­ naphthol Early life­ stage study in fathead minnow Acute toxicity in Daphnia Acute toxicity in Daphnia in presence of sediment Chronic toxicity in Daphnia 14­ d toxicity in earthworms Formulated Product Vegetative Vigor Toxicity in Selenastrum capricornutum Acute oral and contact toxicity in honeybees Effect on non­ target arthropods 14­ d toxicity in earthworms Effects on soil microorganisms (nitrification/ carbon cycle) Ecotoxicological Risk Assessments Aventis has pointed out several errors in the PRZM input parameters (see comments made to Tables 5 and 6 of the draft RED), overly conservative estimates of foliar dissipation half­ lives and changes in ecotoxicology study endpoints. This indicates that a re­ calculation of the EECs and risk quotients are warranted in a number of instances. EFED Response: EFED has reviewed the estimated environmental concentrations [EECs] and does not agree with Aventis' perspective on PRZM input parameters. Specific comments are addressed in the appropriate sections below. Endocrine Disruption Reports in the open literature on the reproductive effects of carbaryl in wild mammals are at best ambivalent. The recently submitted 2­ generation study in rats demonstrates the absence of reproductive effects. As EPA pointed out, findings reported in the literature were made at concentrations well above the highest peak concentration modeled. Therefore these findings are irrelevant for a risk assessment and at the current stage of discussion about endocrine disruption. If the concern about the endocrine potential of carbaryl persists, the issue should be revisited once the Agency's endocrine disrupter screening and testing program as well as a policy on how to 8 incorporate positive findings into an ecological risk assessment have been fully developed. EFED Response: The ecological risk assessment does not conclude that carbaryl is an endocrine disrupter. EFED has cited open literature and has noted effects in chronic reproduction studies that are consistent with endocrine­ mediated effects. EFED is uncertain regarding the endocrine disrupting capacity of carbaryl and is therefore requesting additional data when the appropriate testing procedures have been identified. Mobility The classification of carbaryl as mobile to very mobile is inconsistent with measured Koc values of 177 to 249 (MRID 43259301). According to the widely used classification scheme of McCall, et al. (1980) wherein Koc values between 150 and 500 denote medium mobility in soil, carbaryl would be classified as having medium mobility in most soils. This classification of medium mobility is further supported by the acceptable column leaching study (MRID 43320701) in which aged carbaryl residues were only slightly mobile in a number of soils. The mobility of carbaryl would be expected to be higher in sandy soils or in soils of low organic matter. EFED Response: There are a number of classification schemes available and EFED does not agree that Macall et al 1980 is the definitive one. However, EFED has revised the chapter to read that "Carbaryl is considered to be moderately mobile in soils." 1­ Napthol Fate and Transport The Agency is requiring additional information on the persistence and mobility of 1­ naphthol, a major environmental degradate of carbaryl. However, a half­ life for 1­ naphthol of less than 1 day can be calculated from the carbaryl aerobic soil metabolism study (MRID 42785101). The data from this study demonstrate that under aerobic soil conditions the formation and decline of 1­ naphthol, starting from parent carbaryl, is complete in less than 14 days. This half­ life can be used for preliminary environmental fate modeling to estimate EECs for 1­ naphthol. EFED Response: Based on the aerobic soil metabolism study of carbaryl it does appear that 1­ naphthol degrades rapidly. However, there are a number of processes occurring simultaneously in the test system. It is not possible to solve for the multiple degradation and sorption/ desorption rate constants from the limited data provided. The registrant is encouraged to provide additional data to resolve this uncertainty. The EPA suggested that 1­ naphthol is not strongly sorbed to soil. Additional information available in the literature demonstrates that the sorption of 1­ naphthol to soil is stronger than that seen for 9 carbaryl itself. Hassett et al. (1981) has demonstrated that the sorption of 1­ naphthol was the result of sorption to organic carbon resulting in Koc values between 431 and 15,618. These data indicate that 1­ naphthol is less mobile and less susceptible to leaching than carbaryl itself, and they demonstrate that at least a portion of the 1­ naphthol residue is tightly sorbed to soil constituents. (A copy of this article is being submitted with the response to the draft RED.) To meet the requirement for information on the adsorption and desorption of 1­ naphthol by the Agency, the registrant is conducting an adsorption/ desorption study to meet the 163­ 1 guideline. Study results should be available for submission to the Agency in the first quarter of the calendar year 2002. EFED Response: EFED will review the data on the mobility of 1­ naphthol when it is submitted. EFED agrees that literature data indicated that the degradate is less mobile then the parent. Surface Water/ Drinking Water Aventis disagrees with EPA that the modeling simulations provide a conservative, though not unreasonable, estimate on possible concentrations in drinking water. Drinking water concentrations derived from PRZM/ EXAMS greatly overestimate the potential exposure to carbaryl in drinking water, generally by several orders of magnitude. Results from the drinking water monitoring program conducted by the registrant provides a `real world' assessment of the potential for human exposure to carbaryl in drinking water derived from surface water. EFED Response: EFED has reviewed the registrant's drinking water survey, and has discussed its limitations in the RED chapter and elsewhere. The study is very limited in scope and it is unclear how sites that were monitored relate to locations where carbaryl has been used nationally. It is extremely unlikely that this study sampled peak concentrations. Until a detailed description of how the sampling locations were chosen and how those sites relate to the rest of the country has been evaluated, it is not possible to use this small­ scale study in our assessment. This information was submitted as part of the registrant's 30­ day comment period response. It will be reviewed along with other submitted data and included in future risk assessments. Ground Water EPA summarized information on the detection of carbaryl in groundwater from the EPA Pesticides in Groundwater Database, the EPA STORET database and the NAWQA database. Each of the databases shows a pattern of very low levels of carbaryl detection in few groundwater resources. These analyses confirm several statements made by the Agency that carbaryl has limited potential to impact groundwater resources. However, on page 2 of the Memorandum issued June 28, 2001, in conjunction with the EFED RED chapter for carbaryl, EPA is requiring additional information on "surface and groundwater monitoring in urban and suburban use areas (non­ guideline)." Based on the characteristics of carbaryl and the available data demonstrating limited impact of carbaryl on ground water resources, additional studies to evaluate the potential for carbaryl to contaminate 10 groundwater are unnecessary and unwarranted. EFED Response: Carbaryl use in agricultural setting is expected to have only limited impact on groundwater resources. However, because of its widespread use by homeowners, it is likely that groundwater impacts will be greatest in residential settings. EFED does not require additional data for groundwater contamination evaluation (e. g. prospective groundwater studies) for agricultural uses but does for residential use. 11 Line­ by­ Line Review of the Carbaryl EFED RED Chapter Transmittal Document Data Gaps Environmental Fate and Transport Page: 2 Paragraph: 1 Line: 1 EPA comment: Fate information on the degradation product 1­ naphthol is required. 1. Mobility – adsorption and desorption studies for the 1­ naphthol degradate (163­ 1) 2. Persistence – aerobic soil metabolism study on 1­ naphthol Aventis' response: Literature data (Hassett et al. 1981) on the adsorption of 1­ naphthol are provided in this response. Aventis is in the process of conducting an additional adsorption/ desorption study on 1­ naphthol and intends to submit study data to EPA by March 2002. The degradation of 1­ naphthol under aerobic soil conditions has been widely reported in the literature. Several citations are included in the EPA draft RED. The half­ life of 1­ naphthol estimated from the acceptable aerobic soil persistence study on carbaryl (MRID 42785101) is less than 1 day. Aventis is conducting additional laboratory aerobic soil degradation studies on carbaryl that will be used to provide additional determinations of the half­ life for the degradate 1­ naphthol and satisfy the Agency's requirement for data on the persistence of 1­ naphthol. Aventis intends to submit these study data to EPA by March 2002. EFED Response: EPA will review and evaluate the new data when it is submitted and will incorporated it into future risk assessments. From the aerobic soil study it does appear that 1­ naphthol degrades rapidly. However, there are a number of processes occurring simultaneously in the test system, and it is not possible to solve for the multiple degradation and sorption/ desorption rate constants from the limited data provided. Water Resources Page: 2 Paragraph: 3 and 4 EPA comment: "EFED believes that adequate data are available to support the conclusions reached for carbaryl's impact on surface water and groundwater quality with the exceptions noted below. Additional information is needed to characterize the impact of the degradate 1­ naphthol [in] groundwater and surface water. ÿ Surface and groundwater monitoring in urban and suburban use areas (non­ guideline)" are required. 12 Aventis' response: The surface water­ monitoring program conducted by Aventis includes monitoring in urban and suburban use areas. Aventis believes that the need for information on the degradate 1­ naphthol will be satisfied by the aerobic soil and adsorption/ desorption data that will be submitted to the Agency. These data can be used to evaluate the availability of 1­ naphthol using established EPA modeling guidelines. The Agency's proposed requirement for groundwater monitoring is unnecessary and is addressed in Aventis' response to Agency comments in the draft RED. EFED Response: EFED will review all additional data when they are submitted. New data will be included in future risk assessments. EFED has reviewed this small­ scale study and does not agree with the registrant's assessment. The limitations of the study have been described in the RED chapter. Ecological Effects Data requirement Page: 2 EPA comment: The ecological toxicity database is complete except for: 6. Aquatic Plant Growth Guideline 122­ 2 Aventis' response: The data requirement should be deleted. Aquatic plant growth studies were submitted to the Agency in 1992. An October 04, 2000 OPP Guideline Status Report (Chemical Review Management System) lists the guideline 122­ 2 status as "Acceptable/ Satisfied". The studies are: MRID No. Title Acceptability Code 42372101 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To The Freshwater Blue­ Green Alga, Anabaena flos­ aquae, Under Static Test Conditions: Lab Project Number: J9112004E. Unpublished Study Prepared By Toxikon Environmental Sciences. 53 P. June 25, 1992 Upgradable 42372102 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To Duckweed, Lemna gibba G3, Under Static Test Conditions: Lab Project Number: J9112004G. Unpublished Study Prepared By Toxikon Environmental Sciences. 53 P. January 1, 1992 Upgradable 42372802 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To The Freshwater Green Alga, Selenastrum capricornutum Under Static Conditions: Lab Project Number: J9112004C. Unpublished Study Prepared By Toxikon Environmental Sciences. 53 P. June 9, 1992 Acceptable MRID No. Title Acceptability Code 13 42431601 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To The Freshwater Diatom, Navicula pelliculosa, Under Static Test Conditions: Lab Project Number: J9112004F. Unpublished Study Prepared By Toxikon Environmental Sciences. 52 P. August 10, 1992 Acceptable 42431602 Lintott, D. (1992) Carbaryl Technical: Acute Toxicity To The Saltwater Diatom, Skeletonema costatum, Under Static Test Conditions: Lab Project Number: J9112004D. Unpublished Study Prepared By Toxikon Environmental Sciences. 49 P. August 10, 1992 Supplemental EFED Response: EPA requires data on 5 aquatic plant species. Only two of the five species provided data that were classified as acceptable and as having fulfilled guideline test requirements. Therefore, EFED is requesting that aquatic plant studies are repeated following EPA guidelines. Page: 2 EPA comment: The ecological toxicity database is complete except for: 7. Submission of a FETOX amphibian toxicity study is required. Aventis' response: The data requirement should be deleted. From the published results it is evident that carbaryl is practically non­ toxic to the bullfrog. Effects in plain leopard frogs are reported at levels well above environmental concentrations. These results were obtained testing U. S. native species. In the proposed FETOX assay, a non­ native species Xenopus laevis is used. This African species is unique in its behavior. Neither the species nor the test methods are suitable for ecotoxicological purposes. As the risk to amphibians can be evaluated from the studies cited, and as the effects are only at levels well above the EEC, this study should not be required. EFED Response: While EFED is concerned about the documented effects of carbaryl on native frogs, it will not require the FETOX study at this time. However, when appropriate test methods have been developed for demonstrating endocrine disrupting effects, EFED will request that carbaryl undergo these tests to better understand the developmental toxicity of carbaryl. 14 Label Information Page: 3 EPA comment: For terrestrial and residential uses: 1. "Do not apply directly to water, or to areas where surface water is present or to intertidal areas below the mean high water mark. Do not contaminate water when disposing of equipment washwater or rinsate." Aventis' response: Similar language is already present on Aventis' SEVIN ® labels. EFED Response: The label language that EFED is requesting is standard language that is consistent with the risks identified for this chemical. Page: 3 EPA comment: For terrestrial and residential uses: 3. "This product may contaminate water through drift of spray in wind. This product has a high potential for runoff for several days after application after application (sic). Poorly draining soils and soils with shallow water tables are more prone to produce runoff that contains this product. Household labels – Avoid applying this product to ditches, swales, and drainage ways. Runoff of this product will be reduced by avoiding applications when rainfall is forecasted to occur within 48 hours. Agricultural Label – A level, well maintained vegetative buffer strip between areas to which this product is applied and surface water features such as ponds, streams, and springs will reduce the potential for contamination of water from rainfall­ runoff. Runoff of this product will be reduced by avoiding applications when rainfall is forecasted to occur within 48 hours." Aventis' response: Aventis would like to further discuss appropriate label language with the Agency. However, it should be noted that light to moderate rainfall (or irrigation) after application will also help move carbaryl residues deeper into the soil, thus making them less susceptible to runoff. The language in the last sentence should be changed to read, "… when heavy rainfall is….". 15 EFED Response: EFED believes that it is difficult to predict rate at which rain will fall and that the degree of runoff from or penetration into soil relative to the amount of rainfall depends on the consistency of the soil. The recommended label language is standard. This is not an error. Further discussion on this topic is more appropriate in a later phase of the reregistration process. Page: 3 EPA comment: For terrestrial and residential uses: 4. This pesticide is toxic to fish and aquatic invertebrates. Aventis' response: Aventis' SEVIN labels currently state "This product is extremely toxic to aquatic and estuarine invertebrates." EFED Response: EFED has requested label language to mitigate risks to both freshwater and estuarine/ marine fish and invertebrates. Page: 3 EPA comment: For terrestrial and residential uses: 5. This product is highly toxic to bees exposed to direct treatment or residues on blooming crops or weeds. Do not apply this product or allow it to drift to blooming crops or weeds if bees are visiting the treatment area. Aventis' response: Aventis' SEVIN labels currently contain similar language. EFED Response: The label language that EFED has requested is intended to emphasize the risk to bees when plants are blooming. 16 Draft RED Document 1.0 Summary and Environmental Risk Conclusions Risk to Terrestrial Organisms Page: 1 Paragraph: 4 Line: 2 EPA comment: As discussed in pp. 44 ­ 45 and in Appendix D. Aventis' response: The mammalian risk quotients are discussed on pages 48 to 50 and in Appendix C, not as described in this text. EFED Response: EFED concurs with the registrant's comments. The references to specific pages and to the appendix have been deleted. Fate and Water Assessment Page: 3 Paragraph: 5 Line: 3 EPA comment: …in the U. S. G. S NAQWA program. NAQWA… Aventis' response: The abbreviation for the U. S. G. S. program is NAWQA EFED Response: EFED concurs with the registrant's comment and has corrected the references to NAWQA acronym throughout the document. Page: 5 Paragraph: 1 Line: 7 EPA comment: …estimate of possible concentrations drinking water. Aventis' response: missing word – …concentrations "in" drinking… 17 EFED Response: EFED concurs with the registrant's comment and has included the word "in". Page: 5 Paragraph: 4 Line: 4 EPA comment: …hydrolyzes in neutral (half­ life = 12 days) and alkaline environments (pH 9 half­ life = 3.2). Aventis' response: Missing units of after second half­ life. The units are hours, so "= 3.2 hours)". EFED Response: EFED concurs with the registrant's comment and has included the proper units, i. e., hours. Page: 5 Paragraph: 4 Line: 5 EPA comment: …photolysis in water with a half­ life of 21 days Aventis' response: this is for photolysis in sterile water, not microbially­ active water, so the phrase would be more precise as "… photolysis in sterile water…". EFED Response: EFED concurs with the registrant's comment and has changed the wording to read "Carbaryl is degraded by abiotic photolysis . . .." Page: 5 Paragraph: 4 Line: last EPA comment: (Kf =1.7 to 3.2). Aventis' response: The upper value Kf for carbaryl should be listed as 3.5 as referenced by EPA elsewhere (e. g. Table 3, page 20) in the document. EFED Response: EFED concurs with the registrant's comment and has changed the range of Kf to read 1.7 – 3.5. 18 2.0 Introduction Page: 6 Paragraph: 2 Line: 1­ 3 EPA comment: Carbaryl (1­ naphthyl N­ methylcarbamate) is a broad­ spectrum carbamate insecticide and acaricide registered for control of over 300 species of insects and mites on over 100 crop and noncrop use sites, including homeowner uses; pet, poultry, and livestock uses;… Aventis' response: Carbaryl is no longer registered for use on livestock. Aventis CropScience will not support the reregistration of the use on poultry (direct application and poultry quarters treatment). We will shortly submit a request for cancellation of this use in accordance with section 6( f)( 1) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). EFED Response: At this time, carbaryl is registered for use on livestock. When the cancellation is processed the wording will be changed for future risk assessments. Page: 6 Paragraph: 3 Line: 2­ 3 EPA comment: Approximately 2.5 million pounds of carbaryl are applied annually in the U. S. A map showing the widespread use of carbaryl in agriculture is shown in figure 1. Aventis' response: Summation of the data in Figure 1 gives a total of approximately 3.3 million pounds of carbaryl. Both the 2.5 and 3.3 million­ pound figures are inconsistent with the value of 4 million pounds cited on page 35. The 2.5 million pounds is an average of usage over 1987 to 1996 developed in a memo by Frank Hernandez, July 21, 1998. The value of 2.5 million pounds in the text should be qualified with the additional information on the fact that it is an average for usage over 1987 to 1996 and is not a value for a single year. EFED Response: EFED concurs with the registrant's comments and the text has been revised. Page: 7 Paragraph: 1 Line: 3­ 4 EPA comment: Carbaryl is also used extensively for residential and other non­ agricultural uses, being the second most commonly insecticide (sic) used in the home. 19 Aventis' response: Carbaryl is not registered for use inside homes. It is registered for use outdoors in the lawn and garden around homes. In addition, an evaluation of the Vista (Triad) data for the last seasonal year from October 1999 to September 2000 shows retail sales for carbaryl at 18.7 million dollars. Carbaryl is listed as number 7 based on retail sales behind other active ingredients such as chlorpyrifos, diazinon, imidacloprid, hydramethylnon and tralomethrin. Therefore this sentence would be more appropriately worded as: "Carbaryl is also used for residential and other non­ agricultural uses, being the seventh most commonly used insecticide around the home." EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Carbaryl is also used for residential and other non­ agricultural uses, being the seventh most commonly used insecticide around the home." Page: 7 Figure 1 EPA comment: Figure 2 Aventis' response: This is labeled as Figure 2 when it is Figure 1 EFED Response: EFED concurs with the registrant's comments and the figure showing carbaryl use in agriculture has been relabeled as Figure 1. 3.0 Integrated Risk Characterization Introduction Page: 8 Paragraph: 1 Line: last EPA comment: Carbaryl is mobile to very mobile in the environment (Kf =1.7 to 3.2). Aventis' response: The upper value Kf for carbaryl should be listed as 3.5 as referenced by EPA elsewhere (e. g. Table 3, page 20) in the document. The classification of carbaryl as mobile to very mobile is inconsistent with measured Koc values of 177 to 249. According to the widely used classification scheme of McCall et al. carbaryl would be classified as having medium mobility in soil. This classification of medium mobility is further supported by the 20 acceptable column leaching study (MRID 43320701) in which carbaryl residues were only slightly mobile in a number of soils. EFED Response: There are many classification systems available; EPA does not agree that the McCall et al. classification is the definitive classification. For example, ASTM (1996) puts Koc of 177 in the medium mobility class approaching the high class. EFED has however revised the chapter to read that "Carbaryl is considered to be moderately mobile in soils." Aquatic Organisms Page: 10, Paragraph: 1, Line: 13 EPA comment: Submission of a FETOX amphibian toxicity study is encouraged. Aventis' response: The data requirement should be deleted. From the published results it is evident that carbaryl is practically non­ toxic to the bullfrog. Effects in plain leopard frogs are reported at levels well above environmental concentrations. These results were obtained testing U. S. native species. In the proposed FETOX assay a non­ native species Xenopus laevis is used. This African species is unique in its behavior. Neither the species nor the test methods are suitable for ecotoxicological purposes. As the risk to amphibians can be evaluated from the studies cited, and as the effects are only at levels well above the EEC, this study should not be required. EFED Response: EFED concurs that the FETOX assay may not represent the most appropriate test for examining the effects of carbaryl on amphibian behavior and development; therefore, EFED is not requiring the study at this time. EFED is however concerned about the effects of carbaryl on amphibians and particularly the developmental effects. When appropriate test methodologies have been identified for examining endocrine disrupting effects, EFED will request that carbaryl undergo these toxicity tests. Page: 10, Paragraph: 3, Line: 6/ 7 EPA comment: …resulting in a temporary impairment of burying behavior and increasing exposure to predators. Aventis' response: A reference for this statement should be added. 21 EFED Response: EFED concurs with the registrant's comments and the appropriate literature citation, i. e., Pozorycki, 1999, has been added. Page: 11, Paragraph: 2, Line: 7 EPA comment: In a mesocosms study, at carbaryl… Aventis' response: Typographical error. Change to "In a mesocosm study, at carbaryl…" EFED Response: EFED concurs with the registrant's comments and the singular form of the noun has been used. Terrestrial Organisms Page: 12 Paragraph: 2 EPA comment: (use of rock dove LD50 ) Aventis' response: The reference cited for this value in Table 1 of Appendix D is currently not available to Aventis. Table 1 of Appendix D gives a range of 1000 – 3000 mg/ kg for the LD50. It should be assured that 1000 is indeed the correct value. EFED Response: The reference, i. e., Hudson, R. H., R. K, Tucker, and M. A. Haegele. 1984. Handbook of toxicity of pesticides to wildlife. U. S. Department of Interior, Fish and Wildlife Service Resource Publication 153. Washington DC, is routinely cited by EFED. The acute toxicity value (LD50 =1,000 mg/ Kg) cited for rock dove represents the lower 95% confidence interval. The text has been revised to note that this number represents the lower 95% confidence interval. Page: 12 Paragraph: 3 Line: 3 ­ 6 EPA comment: On a chronic basis, the NOAEC is 300 ppm for the mallard duck, based on adverse reproduction effects, including reduced egg production, decreased fertility, increase incidence of cracked eggs, increased embryonic mortality, and reduced hatching success. 22 Aventis' response: The sentence should be changed. The embryonic mortality and the hatching success were not different from the control. EFED Response: Although the data evaluation record for the avian reproduction study lists increased embryonic mortality and reduced hatching success as significant effects, reference to these two effects has been deleted from the text since the original study by Fletcher was not available for secondary review. However, reduced egg production, increased incidence of cracked eggs and decreased fertility are reproductive effects that support EFED's concerns regarding the endocrine disrupting potential of carbaryl. Page: 13 Paragraph: 1 Line: 1 EPA comment: …( rat LD50 = 307 mg/ kg) Aventis' response: Typographical error, the LD50 is 301 mg/ kg. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "( rat LD50 = 301 mg/ L) . . ." Page: 13 Paragraph: 1 Line: 2 – 4 EPA comment: …based on decreased fetal body weights and increased incomplete ossification of multiple bones in the laboratory rat (LOAEC = 600 ppm, NOAEC = 80 ppm), has the potential for mammalian chronic effects. Aventis' response: A new chronic reproduction study in rats has been submitted by Aventis. This study is more relevant for an ecological risk assessment than the developmental study cited. The new study resulted in a NOAEC of 75 ppm. EFED Response: At the time the ecological risk assessment was written, the more recent chronic mammalian toxicity data were not available for EFED to review. The difference in NOAEC would not likely impact the magnitude of the chronic risk quotient though. 23 Page: 13 Paragraph: 3 Line: 1 EPA comment: Information available in the open literature suggests potential reproduction effects of carbaryl on mammals. Aventis' response: The sentence should be changed or deleted. The literature cited in the paragraph show ambivalent results. While some references seem to support that sentence, other references do not substantiate such a claim. The potential for reproductive effects in mammals is evaluated in the recently submitted 2­ generation study in rats. No reproductive effects were seen in that guideline study. The NOAEC of 75 ppm was based on pup mortality. EFED Response: EFED believes that the chronic effects cited, i. e., reduced reproduction, disturbances in spermatogenesis, increased resorption of embryos, increased incidence of infertility in females and underdeveloped testes in males, are serious reproductive effects that support EFED's concerns regarding the endocrine disrupting potential of carbaryl. Page: 13 Paragraph: 4 Line: 5 EPA comment: According to surveys conducted by the American Beekeeping Federation and the Washington State Department of Agriculture, carbaryl is one of the pesticides most frequently mentioned as being associated with bee kills. Aventis' response: A reference should be provided for this statement. EFED Response: EFED concurs with the registrant's comments and two literature citations, i. e., Brandi 1997 and Johansen 1997, have been inserted into the text. Page: 14 Paragraph: 4 Line: 1­ 4 EPA comment: The uses of carbaryl on crops (corn, cotton, soybeans, sorghum, wheat, barley, oats, and rye), forests and pasture/ rangeland were addressed by the US Fish and Wildlife Service (USFWS) in the reinitiation of consultation in September 1989. The Service found jeopardy to a total of 86 species – 6 amphibians, 47 freshwater fish, 27 freshwater mussels, and 5 aquatic crustaceans. 24 Aventis' response: The use of carbaryl on barley, oats, rye, and cotton has been cancelled. It should be noted that all Aventis CropScience labels for the technical materials and the end­ use products containing carbaryl were amended to delete these uses. The Agency has already approved the labeling changes. Findings from the assessment made by the USFWS should be reevaluated considering the cancellation of the use on barley, oats, rye, and cotton. EFED Response: EFED does not have the resources to continually revise ecological effects assessments each time mitigation efforts have been reached; however, the chapter has been revised to read " . . . on field crops (corn, soybeans, sorghum wheat) . . .." Page: 14 Paragraph: 5 Line: 7 EPA comment: The RPAs and RPMs in the 1989 B. O. may need to be reassessed… Aventis' response: The acronyms used should be explained. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Reasonable and Prudent Alternatives (RPA) . . . Reasonable and Prudent Measures (RPM) . . .." The acronym B. O. has been replaced with the term Biological Opinion. Endocrine Disruption Concerns Page: 15 Paragraph: 3 EPA comment: (Report on potential endocrine effects) Aventis' response: The paragraph should be deleted. As EPA pointed out, the findings reported in the literature were made at concentrations well above the highest peak concentration modeled. Therefore these findings are irrelevant for a risk assessment and at the current stage of discussion about endocrine disruption. If the concern about the endocrine potential of carbaryl persists, the issue should be revisited once the Agency's endocrine disrupter screening and testing program, as well as a policy on how to incorporate positive findings into an ecological risk assessment have been fully developed. 25 EFED Response: The ecological risk assessment reports on a broad range of chronic effects in both terrestrial and aquatic animals that support EFED's concerns regarding the endocrine disrupting potential of carbaryl. EFED is aware of the fact that its current chronic toxicity tests may not be sensitive indicators of endocrine disrupting effects, therefore the Agency has to rely on open literature to address this uncertainty. EFED agrees that some effects are reported at concentrations that may not be environmentally relevant; however, the data suggest that carbaryl can elicit effects that are consistent with a chemical acting on endocrine­ mediated pathways. Therefore, EFED is requesting that once appropriate methodologies have been defined for screening endocrine disruption effects, carbaryl should undergo such testing. Page: 15 Paragraph: 4 EPA comment: Furthermore, a number of field and laboratory studies report reproduction effects with mammals, suggesting that the possibility of endocrine disruption effects on wild mammals should be further examined. Aventis' response: The statement should be deleted or modified. As pointed out above, reports on reproductive effects of carbaryl in the open literature are at least ambivalent. The recently submitted 2­ generation study in rats demonstrated the absence of reproductive effects. If the general statement about the potential for endocrine disruption of carbaryl is maintained, references (or a cross­ reference within the document) for the above claim should be provided. EFED Response: As stated previously, chronic reproductive tests have resulted in effects that support EFED's concerns regarding the endocrine disrupting potential of carbaryl. Just because one study failed to show similar effects to another, EFED does not believe that it would be reasonable to discount the validity of the earlier study. If anything, the data strongly suggests that additional data are needed to better understand the likelihood of adverse effects. Furthermore, carbaryl should be subjected to tests specifically designed to address whether the chemical is acting through endocrinemediated pathways. Uncertainties Page: 15 Paragraph: Last Line: 4 EPA comment: In the absence of a valid two­ generation rat reproduction study, mammalian chronic RQs were based on a rat prenatal development study NOAEC (MRID# 44732901). 26 Aventis' response: A new two­ generation study in rats was recently submitted. EFED Response: As mentioned previously, the most recent two­ generation reproduction study of rats was not available for review when the risk assessment was written; however, the proposed difference in the NOAEC, i. e., 75 vs 80, would not significantly impact the magnitude of the chronic mammalian risk quotients nor would it alter the fact that significant effects were noted in the developmental study. However, the text has been revised to read "Additionally, mammalian chronic RQs were based on a rat prenatal development study NOAEC (MRID# 44732901) rather than the more traditional use of a 2­ generation reproduction study." 4.0 Environmental Fate Assessment Exposure Characterization Page: 16 Paragraph: 3 Line: 8 EPA comment: Environment (Kf =1.7 to 3.2). Aventis' response: The upper value Kf for carbaryl should be listed as 3.5 as referenced by EPA elsewhere in the document (e. g. Table 3, page 20). EFED Response: EFED concurs with the registrant's comments and the test has been revised to read "Kf = 1.7 to 3.7". Page: 16 Paragraph: 3 Line: last sentence EPA comment: Detailed discussion and reviews (DERs) of the studies that are included in this assessment are attached in Appendix A. Aventis' response: It is inappropriate to include the DERs in the RED. A summary of study findings is already included in the EFED Chapter. DERs should be made available to the public through the regular procedure under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. 27 EFED Response: EFED concurs with the registrant's comments that DERs should be made available to the public under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. Page: 16 Paragraph: 4 Line: 4 EPA comment: lower levels (generally less than 0.01 µ/ L). Aventis' response: value missing units ­ (generally less than 0.01 µg/ L). EFED Response: EFED concurs with the registrant's comments and has revised the text to read "0.01 µg/ L". Page: 16 Paragraph: 5 Line: 4 EPA comment: …monitoring data is of limited utility in developing EECs for ecological and human health risk assessment. Aventis' response: The drinking water monitoring program conducted by the registrant provides a real world assessment of the potential for human exposure to carbaryl in drinking water derived from surface water. Drinking water concentrations derived from PRZM/ EXAMS greatly overestimate the potential exposure to carbaryl in drinking water, generally by several orders of magnitude. EFED Response: The limitations of the monitoring studies are discussed within the chapter and provide sufficient detail to support EFED's contention that "Because of the limited amount of data available and because of potential problems with extant data . . . monitoring data are of limited utility in developing EECs for ecological and human health risk assessment." Page: 17 Paragraph: 1 Line: 2­ 3 EPA comment: The maximum rate was taken from the carbaryl labels. Aventis' response: It would be of benefit for the Agency to be explicit and list the carbaryl labels that were used to develop the maximum application rates for the model scenarios. The reference cited in the EFED Chapter regarding the use of carbaryl on crops indicates that current labels were not used for the Agency's assessment. Many of these crops have been deleted from Aventis' labels for a few years Application 28 rates, number of applications per season, and PHI's also have changed for several crops on the labels. EFED Response: While EFED agrees that additional details are of interest to some readers, it isn't possible to address all potential interests concurrently and still have a reasonably sized document. As noted in the chapter "Average and maximum reported rates were determined by BEAD [Biological and Economic Assessment Division] based on data collected by Doane surveys and registrant market analysis." Page: 17 Paragraph: 2 Line: 2 EPA comment: For the Index Reservoir scenario using maximum label rates, acute EEC values ranged from about 10 µg/ L from sugar beets to about 500 µg/ L from citrus (Table 6). Aventis' response: Table 6 on page 33 shows a concentration of 19 µg/ L for sugar beets treated with the maximum label rate of 2 x 1.5 lb ai, not 10 as stated in this sentence. A low EEC value of 9 µg/ L for sugar beets results from the "maximum reported" application scenario of 1 x 1.2 lb ai/ A. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read ". . . acute EEC values ranged from about 19 :g/ L from sugar beets to about 500 :g/ L . . .." Page: 17 Paragraph: 2 Line: 3 EPA comment: Chronic EECs ranged from about 1 to 28 µg/ L. Aventis' response: Table 6 on page 33 shows that this is correct when considering all of the model scenarios. However, either the same maximum label rate reference should be used as in the preceding sentence (in which case the minimum chronic EEC would be 2), or the basis for the preceding sentence should be changed from the maximum label rate to include all application scenarios to keep the comparisons consistent. 29 EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Chronic EECs ranged from about 2 to 28 :g/ L." Page: 17 Paragraph: 2 Line: 8 EPA comment: The results of the modeling provide an (sic) conservative, though not unreasonable, estimate on (sic) possible concentrations [in] drinking water. Aventis' response: It should be clear that Aventis' surface water monitoring program provides a more reasonable estimate of the potential drinking water exposure to carbaryl than the modeling numbers, which overestimate exposure by several orders of magnitude. EFED Response: The limitations of this study are discussed in the chapter. Page: 17 Paragraph: 2 Line: last EPA comment: …and model input and output files are attached in appendix B. Aventis' response: The PRZM input files for only the Index Reservoir drinking water modeling were provided as an electronic copy. The PRZM input files for the standard pond scenarios were not provided in the draft RED so Aventis could not assess the data. None of the output files were provided. EFED Response: EFED concurs with the registrant's comments; a more comprehensive set of input files have now been included in the chapter (Appendix F). Page: 18 Figure 2 EPA comment: Figure 1. Generalized carbaryl degradation pathway Aventis' response: This should be labeled Figure 2, not Figure 1. 30 EFED Response: EFED concurs with the registrant's comments and the figure entitled Generalized carbaryl degradation pathway has been renumbered Figure 2 Page: 19 Table 3 EPA comment: Hydrolysis half­ life at pH 9 stated to be 5 hours. Aventis' response: The study results, and the summary of the study presented on page 20, show the correct halflife at pH 9 to be 3.2 hours. EFED Response: EFED concurs with the registrant's comments and the hydrolysis half­ life reported for pH in Table 3 has been revised to read 3.2 hours. Page: 19 Table 3 EPA comment: Aerobic Aquatic half­ life ­ 4.9. Aventis' response: The Aerobic Aquatic half­ life is 4.9 days EFED Response: EFED concurs with the registrant's comments and the aerobic aquatic metabolism half­ life reported in Table 3 has been revised to read 4.9 days. Page: 19 Table 3 EPA comment: Soil metabolism T1/ 2, anaerobic, assumed stable 31 Aventis' response: If this guideline is satisfied by the data submitted for guideline 162­ 3, it is not clear why the compound is assumed to be stable rather than having a half­ life in line with the 72 days that resulted from the anaerobic aquatic study. Although this parameter plays a fairly insignificant role in estimating the amount of carbaryl available for runoff in the models, it could play a significant role if one were to use this value in estimating leaching potential in subsurface horizons. EFED Response: EFED concurs with the registrant's comments and anaerobic soil metabolism half­ life reported in Table 3 has been revised to read 72 days. This does not significantly change the model results. Page: 20 Table 3 EPA comment: Batch Equilibrium 1/ n values ranged from 0.86­ 1.02 Aventis' response: These values are for the desorption isotherms only. For the adsorption isotherms that were used to calculate the adsorption Kf and Koc values listed in the table, the correct range of 1/ n values are 0.78 to 0.84 as stated on page 22. EFED Response: EFED concurs with the registrant's comments and the batch equilibrium 1/ n value range reported in Table 3 has been revised to read 0.78 to 0.84. Page: 20 Table 3 EPA comment: Foliar Dissipation 30 days Willis and McDowell, 1987 Aventis' response: The foliar dissipation half­ life listed by EFED is incorrect. Table IV of the Willis and McDowell review lists 10 foliar half­ lives for various formulations of carbaryl applied to different crops. Five of these half­ lives are for a study designed to evaluate a new analytical procedure for measuring carbaryl residues on plants. This study was conducted on plants grown in a greenhouse, with some of them receiving an unknown amount of simulated rainfall. These studies on greenhouse­ grown plants should not be used to evaluate foliar persistence in the field. The foliar persistence of pesticides can be considerably different for residues on and in plants grown in greenhouses versus the field. Eliminating the half­ lives for the greenhouse­ grown plants results in the following half­ lives for carbaryl on field 32 plants: Cotton, 1.2, 1.3, 1.5 days; strawberry, 4.1 days; tomato 1.4 days. Therefore, the longest half­ life of 4.1 days should be listed in this table. Aventis intends to conduct a more thorough review of the data on the foliar dissipation of carbaryl and prepare a more detailed response during the 60­ day public comment period. EFED Response: EFED has reviewed the Willis paper and agrees that the foliar dissipation rate for carbaryl is not well known and may be significantly shorter then the default value used. However, as defined in EFED policy, the default value is used when scientifically valid, statistically robust data are not available to make a more accurate estimation. EFED encourages development of better data to justify using a different value. Persistence Microbially­ Mediated Processes Page: 21 Paragraph: 3 Line: 3 EPA comment: with an initial concentration of 11.2 mg/ L, degraded with a half­ life of 4.0 days in sandy Aventis' response: The units for ppm soil concentration should be given as mg/ kg. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "11.2 mg/ kg". Page: 21 Paragraph: 3 Line: 4­ 5 EPA comment: The major degradate was 1­ naphthol which further degraded rapidly to non­ detectable levels within 14 days. Aventis' response: The data from this study demonstrate that under aerobic soil conditions the formation and decline of 1­ naphthol, starting from parent carbaryl is complete in less than 14 days. The study data show an average maximum 1­ naphthol level of 34.5% of applied carbaryl by day 1, declining to 2.8% by day 2, 0% by day 4, 0.2% by day 7 and 0% at day 14. These data suggest a preliminary half­ life of less than 1 day for the major degradate 1­ naphthol. 33 EFED Response: EFED agrees that the pattern of formation and decline suggests that 1­ naphthol degrades rapidly. However, from the data it is not possible to calculate a valid half­ life for 1­ naphthol degradation. There are too many processes (formation and degradation, sorption and desorption for example) to permit solving the multiple differential equations for the different rate constants. Page: 21 Paragraph: 3 Line: 8­ 9 EPA comment: In anaerobic aquatic soil carbaryl with an about 10 mg/ L degraded with a half­ life of 72.2 days. Aventis' response: Several words appear to be missing from this sentence. One suggestion: "Carbaryl degraded with a half­ life of 72.2 days in anaerobic aquatic sediment with an initial carbaryl concentration of about 10 mg/ L." EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Carbaryl degraded with a half­ life of 72.2 days in anaerobic aquatic sediment with an initial carbaryl concentration of about 10 mg/ L; 1­ naphthol was the major degradate." Page: 22 Paragraph carried over from page 21 Line: 4 on pg 22 EPA comment: Chudhry and Wheeler, 1988 Aventis' response: This reference is not included in the reference list EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Chaudhry et al., 1988. The references section has been revised to include "Chaudhry, G. R., A. N. Ali, and W. B. Wheeler, 1988. Isolation of a methyl parathion_ degrading Pseudomonas sp. that possesses DNA homologous to the opd gene from a Flavobacterium sp. Appl. Environ. Microbiol., 54: 288_ 293. Mobility Page: 22 Paragraph: 1 Line: 1 EPA comment: Carbaryl is considered to be mobile to very mobile in soils. 34 Aventis' response: See response directly below. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Carbaryl is considered to be moderately mobile in soils." Page: 22 Paragraph: 3 Line: 1­ 2 EPA comment: Based on batch equilibrium experiments (MRID 43259301) carbaryl was determined to be very mobile to mobile in soils. Aventis' response: The classification of carbaryl as mobile to very mobile is inconsistent with measured Koc values of 177 to 249. According to the widely used classification scheme of McCall, et al. (1980) wherein Koc values between 150 and 500 denote medium mobility in soil, carbaryl would be classified as having medium mobility in most soils. This classification of medium mobility is further supported by the acceptable column leaching study (MRID 43320701) in which aged carbaryl residues were only slightly mobile in a number of soils. The mobility of carbaryl would be expected to be higher in sandy soils or in soils of low organic matter. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Based on batch equilibrium experiments (MRID 43259301) carbaryl was determined to be moderately mobile to mobile in soils." Field Dissipation Page: 22 Paragraph: 5 Line: 3 EPA comment: The submitted field and aquatic dissipation studies were determined to be unacceptable, and did not provide useful information on movement and dissipation of carbaryl or its degradation products. Aventis' response: The field dissipation study (MRID 41982605) submitted in 1991 demonstrated that carbaryl dissipated very rapidly (t1/ 2 < 1 week) with no measurable leaching. The study included two sites, one in North Carolina and one in California. At the North Carolina site, ~ 95% of the Time 0 residues had dissipated by the first sampling period 7 days after application (the planned first sampling at 3 days was not collected due to rain). Similarly, ~ 85% of the Time 0 residues had dissipated by 7 days after application at the California site. Concerning the 35 movement of carbaryl, samples were taken to a depth of 0.9 meters in increments of 0.15 meters. No residues were found below the upper 0.15 meters. EFED Response: This field dissipation study (MRID 41982605) was reviewed and determined to be scientifically invalid. As described in the text, these studies do not provide reliable information on the rate of dissipation of parent carbaryl or formation of degradation products because of inappropriate sampling intervals, poor sample storage stability, lack of degradate monitoring, rainfall and irrigation that were less than evapotranspiration, and irrigation water with high pH. The registrant is required to conduct additional studies and submit new data. When the studies have been reviewed and determined to be acceptable, the data will be incorporated into future assessments. Page: 23 Paragraph: 3 Line: 2 EPA comment: Because of inappropriate sampling intervals, poor sample storage stability, lack of degradate monitoring, rainfall and irrigation that were less than evapotranspiration, and irrigation water with high pH, these studies do not provide reliable information on the rate of dissipation of parent carbaryl or formation of degradation products. Aventis' response: The estimated half­ life determined from this study was < 3 days. Sampling at intervals such that several sampling events are taken prior to the half­ life of the product is impractical for rapidly degrading chemicals (e. g., those with half­ lives less than a week). For this rapidly degrading chemical an estimate of the half­ life should be sufficient for risk assessments even if it is not precise. After the report was submitted to California, the freezer storage stability recoveries at six and nine months were measured but not reported. Rainfall plus irrigation approximated an inch a week and was more than enough to maintain a good soil moisture for agricultural purposes. Sulfuric acid is routinely added to irrigation water in the region of California where the field test was conducted to neutralize the water's high pH. Although not stated in the report, the irrigation water in the California trial was treated in the typical commercial fashion. The acid is injected into the irrigation pipe as water is pumped through it. Unfortunately, the pH of the water arriving at the field after treatment was not measured. EFED Response: As discussed in the preceding response, the terrestrial field dissipation study was reviewed and determined to be scientifically invalid. The registrant is required to conduct additional studies and submit new data. When the studies have been completed and reviewed and determined to be acceptable the data will be incorporated into future assessments. 36 Aquatic Field Dissipation Page: 24 Paragraph: 2 Line: 3 EPA comment: They (do) not provide useable information on the dissipation of carbaryl and 1­ naphthol in aquatic field conditions. Aventis' response: The soil metabolism study referred to in the report found that the total water soluble metabolites did not exceed 5% of the total radioactive residue, the primary hydrolysis product, 1­ naphthol, was not found, and that the only analyte of concern was the parent insecticide, carbaryl. A soil metabolism study reviewed concurrently by the Agency was issued later (MRID 42785101, classified "acceptable") with similar results. Although the major soil metabolite, 1­ naphthol, was found at significant levels at day 0 and day 1, the levels were less than 0.7% by day 4 and non­ detectable by day 14. Two other metabolites were identified but never exceeded levels of 1.7% of the total residue. Again the only residue of concern was the parent insecticide, carbaryl. If present, 1­ naphthol would have been detected by the residue method used to measure the residues of carbaryl in the soil. The estimated half­ life determined from this study was < 2 days. Sampling at intervals such that several sampling events are taken prior to the half­ life of the product is impractical for rapidly degrading chemicals (e. g. those with half­ lives less than a week). EFED Response: The aquatic field dissipation study was reviewed and determined to be unacceptable since it did not provide useable information on the dissipation of carbaryl and 1­ naphthol under aquatic field conditions. The registrant is encouraged to conduct additional studies and submit new data. In future studies sampling intervals should be selected that are appropriate for the expected half­ life. When the studies have been reviewed and determined to be acceptable the data will be incorporated into future assessments. 37 Page: 24 Paragraph: 2 Line: 4 EPA comment: Frozen storage stability data were provided for only 6 months, although the water samples were stored for up to 14 months and the soil samples were stored for up to 17.5 months prior to analysis. The data suggest that carbaryl and 1­ naphthol degraded significantly during storage. In the six months of storage carbaryl degraded an average of 34 % in Texas water and 39% in from Mississippi. 1­ naphthol degraded 50% in water from Texas and 69% from Mississippi. Degradation did not appear linear, and it is not possible to extrapolate out to 14 months. It was therefore not possible to evaluate the actual concentrations of carbaryl and 1­ naphthol in the samples or estimate the dissipation rates. Aventis' response: The existing 6­ month storage stability provides sufficient information to calculate the concentrations of carbaryl in the samples. However, the metabolite 1­ naphthol was shown to degrade significantly under the same freezer conditions. This instability simply confirms that 1­ naphthol's presence in the environment would be very limited and should not be of concern. EFED Response: As discussed in the preceding response, the aquatic field dissipation study was classified as unacceptable. Degradation did not appear to be linear, and it is not possible to extrapolate out to 14 months; therefore it is not possible to evaluated the actual concentrations of carbaryl and 1­ naphthol in the samples or estimate the dissipation rates. Foliar Dissipation Page: 24 Paragraph: Last EPA comment: The reported rates of carbaryl dissipation from foliar surfaces varies from 1 days to 30 days. In their review of literature data on pesticide foliar persistence, Willis and McDowell (1987) report that carbaryl dissipation rates varied from 1.2 to 29.5 days… For terrestrial risk assessment modeling EFED used 35 days… Aventis' response: As stated in comments to Table 3, the foliar dissipation half­ life used by EFED for terrestrial risk assessment is too long and should be corrected. Table IV of the Willis and McDowell review lists 10 foliar half­ lives for various formulations of carbaryl applied to different crops. Five of these half­ lives are for a study designed to evaluate a new analytical procedure for measuring carbaryl residues on plants. This study was conducted on plants grown in a greenhouse, with some of them receiving an unknown amount of simulated rainfall. These studies on greenhouse­ grown plants should not be used to evaluate foliar persistence in the field. The foliar persistence of pesticides can be considerably different for 38 residues on and in plants grown in greenhouses versus the field. Eliminating the half­ lives for the greenhouse­ grown plants results in the following half­ lives for carbaryl on field plants: Cotton, 1.2, 1.3, 1.5 days; strawberry, 4.1 days; tomato 1.4 days. Therefore, the longest half­ life of 4.1 days should be used for terrestrial risk assessment modeling. Aventis will conduct a more thorough review of the data on the foliar dissipation of carbaryl and prepare a more detailed response during the 60­ day public comment period. EFED Response: EFED agrees that the dissipation of carbaryl on foliar surfaces is not well understood. The registrant is encouraged to submit additional data on foliar dissipation to help clarify the rate and processes involved. Until scientifically valid, statistically robust data are submitted, EFED policy is to use a default value of 35 days and assume first order degradation kinetics. Atmospheric Transport Page: 25 Paragraph: 1 Line: 2 EPA comment: Waite, et al., 1995 Aventis' response: This reference is not included in the reference list EFED Response: EFED concurs with the registrant's comments. The reference section has been revised to include the following reference: Waite, D. T., R. Grover, N. D. Westcott, D. G. Irvine, L. A. Kerr and H. Sommerstad, 1995. Atmospheric Deposition of Pesticides in a Small Southern Saskatchewan Watershed. Environ. Toxicol. and Chem., 14: 1171­ 1175. Page: 25 Paragraph: 1 Line: 3 EPA comment: Beyer et al., (1995) Aventis' response: This reference is not included in the reference list EFED Response: EFED concurs with the registrant's comments. The reference section has been revised to include the following reference: Beyer, D. W., M. S. Farmer and P. J. Sikoski, 1995. Effects of rangeland aerial application on Sevin­ 4­ Oil ® on fish and aquatic invertebrate drift in the Little Missouri River, North Dakota. Arch. Environ. Contam. Toxicol., 28: 27­ 34. 39 Page: 25 Paragraph: 3 Line: 5 EPA comment: Schomburg et al. (1991) Aventis' response: This reference is not included in the reference list EFED Response: EFED concurs with the registrant's comments. The reference section has been revised to include the following reference: Schomburg, C. J., D. E. Glotfelty, and J. N. Seiber, 1991. Pesticide occurrence and distribution in fog collected near Monetery California. Environ. Sci. Technol. 25: 155­ 160. 1­ Naphthol Fate and Transport Page: 26 Paragraph: 2 Line: 1­ 2 EPA comment: In an aerobic soil metabolism study (MRID 42785101), 1­ naphthol degraded rapidly to nondetectable levels within 14 days. Aventis' response: The data from this study demonstrate that under aerobic soil conditions the formation and decline of 1­ naphthol, starting from parent carbaryl, is complete in less than 14 days. The study data show an average maximum 1­ naphthol level of 34.5% of applied carbaryl by day 1, declining to 2.8% by day 2, 0% by day 4, 0.2% by day 7 and 0% at day 14. These data suggest a preliminary half­ life of less than 1 day for the major degradate 1­ naphthol. This half­ life can be used for preliminary environmental fate modeling to estimate EECs for 1­ naphthol. EFED Response: As stated previously, it is not possible to separate the multiple processes occurring in this study, and it is not possible to calculate rate constant for degradation of 1­ naphthol. Additional data on the degradation of 1­ naphthol are required. 40 Page: 26 Paragraph: 3 Line: 1 EPA comment: No guideline information was submitted on 1­ naphthol sorption. Literature information suggests that it is not strongly sorbed. Aventis' response: The statement suggesting that 1­ naphthol is not strongly sorbed to soil should be deleted. In support of the 1­ naphthol sorption statement the Agency has cited only one paper by Karthikeyan et al. (1999) that was conducted using aluminum hydroxide as the sorbent. Soil is composed of much more than aluminum hydroxide, so this study is more of a mechanistic description of sorption to this one component of soil and not a study of sorption to soil as a whole. This cited study reported that 1­ naphthol does not show significant sorption to aluminum hydroxide when allowed to sorb for 20 hours in the dark in the absence of oxygen. However, there was a significant increase in sorption with increasing equilibration time, and as the Agency stated, the increase is influenced by pH, as would be expected for an acidic phenolic compound. Additional information available in the literature demonstrates that the sorption of 1­ naphthol to soil is stronger than that seen for carbaryl itself. Hassett et al. (1981) have demonstrated that the sorption of 1­ naphthol was the result of sorption to organic carbon resulting in an average Koc of 431 ± 40 for 10 of the 16 soil samples they tested. In the remaining 6 soil samples the Koc was even higher (1,645 to 15,618). Hassett et al. (reference submitted as part of 30­ day response document) hypothesized that the higher Kocs in these 6 soils, in which the organic carbon to clay ratio was very low, the clay surfaces were more accessible and the sorption of 1­ naphthol was apparently controlled by the clay fraction. In Burgos et al. (1999), cited by EPA elsewhere in the RED, it was shown that there is significant sorption of 1­ naphthol to two sandy soils, and that oxidative coupling reactions were responsible for the strongly bound portion. In an earlier paper by Burgos et al. (1996) it was shown that both biologically­ mediated and soil­ catalyzed oxidative coupling lead to significant binding of 1­ naphthol residues to soil. These data indicate that 1­ naphthol is less mobile and less susceptible to leaching than carbaryl itself, and they demonstrate that at least a portion of the 1­ naphthol residue is tightly sorbed to soil constituents. To meet the requirement by the Agency for information on the adsorption and desorption of 1­ naphthol, the registrant is conducting an adsorption/ desorption study to meet the 163­ 1 guideline. Study results should be available for submission to the Agency in the first quarter of the calendar year 2002. EFED Response: Data from the Hassett paper have been included. The text reads "Hassett et al. (1981) reported an average 1­ naphthol Koc of 431 (± 40) for 10 of the 16 soils tested. They also found that in other soils with very low organic carbon to clay ratios clay surfaces controlled sorption. Additional data on 41 1­ naphthol sorption is required to fully characterize mobility." Additional data will be reviewed and incorporated into future risk assessments. Aquatic Exposure Assessment Surface Water Page: 26 Paragraph 4 Line 1 EPA comment: Five crop scenarios: apples, field corn, sweet corn, oranges and sweet potatoes scenarios were use in modeling for surface water EEC. Aventis' response: The fifth crop modeled was sugar beets (not sweet potatoes). EFED Response: EFED concurs with the registrant's comments. The text has been revised to read "Five crop scenarios: apples, field corn, sweet corn, oranges and sugar beets scenarios were used in modeling for surface water EEC." Page: 27 Table 4 EPA comment: Hydrolysis half­ life at pH 9 stated to be 5 hours. Aventis' response: The study results, and the summary of the study presented on page 20, show the correct halflife at pH 9 to be 3.2 hours. EFED Response: EFED concurs with the registrant's comments. The hydrolysis half­ life at pH 9 reported in Table 4 has been revised to read "3.2 hours". Page: 27 Table 4 EPA comment: (Koc = 211 for SCIGROW) Aventis' response: This is the mean Koc. According to EPA guidance the median Koc (209) should be used for SCI­ GROW, although this difference would not be expected to affect the model results. 42 EFED Response: EFED concurs with the registrant's comments. The mean soil partitioning coefficient (Koc) reported in Table 4 now reads "( Koc = 209 for SCIGROW)". Pages: 27­ 28 Table 5 EPA comment: Tier II surface water estimated environmental concentration (EEC) values derived from PRZM/ EXAMS modeling for use in ecorisk assessment (calculated using standard pond.) Aventis' response: The PRZM input tables were not provided for the standard pond scenarios, so the assumption is made that the same application methods were used for the standard pond as for the Index Reservoir scenarios that were provided as an electronic copy of a draft of Appendix B. EFED Response: The registrant's assumption is correct, i. e., the same application methods were used for the standard pond as for the Index Reservoir scenarios. Aventis' comment: It would be of benefit for the Agency to state which of the carbaryl labels were used to develop the "maximum" label application rate scenarios. It would be useful to add another column to this table to specify which method of application was used to generate the EECs rather than the generic "air/ ground" in column 1. There are a number of errors in the input parameters (noted below) that would lead to changes in the calculated EECs and therefore the risk quotients for these uses. EFED Response: EFED has reviewed the application rates used in modeling. The changes suggested by the registrant do not result in significant changes in the risk assessment; therefore, the modeling was not redone. As with most chemicals, the labels are in a constant state of flux. Uses are dropped and rates varied constantly. Also this chemical has a large number of labels making it difficult for EFED to monitor the changing "current" labels. The use of average use rates was to allow evaluation of EECs based on rates other then the maximum allowed. The data that were used to calculate "average" are not highly robust. It is also not always possible to use the values in the Quantitative Use Assessment (QUA) as presented. For example the average number of applications for sugar beets was 1.1 per year. EFED selected rates and timing to try to capture the information in the QUA table. The values should nor be considered hard, exact numbers. 43 If the modeling for the "average" scenarios were conducted using aerial applications for citrus and apples (as was the case for the Index Reservoir scenarios), then the model results over­ estimate the contributions from spray drift. Few applications to these crops are made aerially. Therefore, the model results over­ estimate the contributions from spray drift since the "average" applications to these crops are made using ground airblast equipment with a spray drift of 6.3% in the model versus aerial applications with a spray drift of 16%. The "average" scenario for sweet corn in Ohio should be 3 applications at 1.1 lb. ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not the 2 applications at 3.4 lb. ai/ A/ application as listed in the table. It should be noted that the "average" scenario presented in this table, 2 applications per year at 3.4 lb. ai per application, exceed the maximum rate allowed on the label. The maximum label rate application scenario for apples that is allowed by the Sevin brand XLR PLUS label (E. P. A. Reg. No 264­ 333), the Sevin brand 80WSP and CHIPCO Sevin brand 80WSP labels (E. P. A. Reg. No 264­ 526) and the CHIPCO Sevin brand SL label (E. P. A. Reg. No 264­ 335) is 5 applications at 3 lb. ai/ A/ application made every 14 days. The scenario used in the model applies less than the maximum amount of product allowed by the labels. In addition, if the same application timing was used in the modeling for the standard pond scenario as was used in the index reservoir scenario (applications made by air every 4 days) this would be a violation of the Aventis labels which restrict applications to a minimum of every 14 days. The "average" scenario for sugar beets in Minnesota should be 1 application at 1.3 lb. ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not 1 application at 1.5 lb. ai/ A/ application as listed in the table. EFED Response: The Quantitative Use Assessment lists the "average" lb A. I./ acre at 1.5 and the average number of applications as 1.1. The "Citrus" scenario would be more appropriately labeled Oranges. For the average scenario, the 3.4 lb. ai/ A/ application rate listed in Table 5 is for oranges (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD"), which is the highest "average" application rate for any type of citrus. Therefore, this "average" scenario for oranges are at the high end for all citrus and overestimates the PRZM/ EXAMS derived EECs for use in the other citrus crops. "Average" application rates for other citrus as listed in the memo are: 44 Lemons – 1.3 applications at 2.7 lb ai/ A/ appl Grapefruit – 1.6 applications at 1.4 lb ai/ A/ appl Citrus, other – 1.8 applications at 1.8 lb ai/ A/ appl The maximum label application rate for citrus is 7.5 lb ai per application, not 5 lb ai, with a maximum of 20 lb ai total allowed per year. In California only, a single application is allowed at the rate of 5 to 16 lb ai per season for control of California red scale and yellow scale. EFED Response: Table 5 has been revised to read "oranges" instead of "citrus". Estimated Environmental Concentrations for Terrestrial Ecological Risk Assessment Page: 29 Paragraph: 2 Line: 2­ 4 EPA comment: In the absence of reliable foliar dissipation data a dissipation half­ life of 35 days is used. Published literature shows that carbaryl dissipation rates vary, and are among the highest observed for any pesticide (Willis and McDowell, 1987). Aventis' response: As stated in more detail above, some of the foliar dissipation half­ lives listed in this reference are high because they were generated in the greenhouse, not in the field, and therefore they should not be used. Eliminating the half­ lives for the greenhouse­ grown plants results in the following half­ lives for carbaryl on field plants: Cotton, 1.2, 1.3, 1.5 days; strawberry, 4.1 days; tomato 1.4 days. Therefore, the longest half­ life of 4.1 days should be used for terrestrial risk assessment modeling. EFED Response: As in the response provided above, EFED agrees that the dissipation of carbaryl on foliar surfaces is not well known. Until additional data are provided the default value is used. Page: 29 Paragraph: 2 Line: 6 EPA comment: A more thorough description of the model calculations and ELL­ FATE outputs are attached in Appendix B. Aventis' response: No such description or attachments were provided, so Aventis did not have the opportunity to evaluate the model. 45 EFED Response: EFED concurs with the registrant's comments. A more thorough description of the ELL­ FATE model along with copies of its input and output files are contained in Appendix E. Page: 29 Paragraph: 2 Line: last EPA comment: …Tables 4,7, 8 and 9, Appendix D. Aventis' response: These tables are in Appendix C. EFED Response: EFED concurs with the registrant's comments. The text has been revised to read "EEC values calculated for different crop applications are presented in Tables 4, 7, 8, and 9, Appendix C." 5.0 Drinking Water Assessment Water Resources Assessment Page: 29 Paragraph: 3 Line: 3 EPA comment: Carbaryl tends not to partition to soil, aquifer solids, or sediment. Aventis' response: This sentence is misleading and should be reworded. Carbaryl does partition onto these sorbents, but the sorption coefficients are not high. Suggest rewording this such as: "Carbaryl tends not to bind tightly to soil, aquifer solids, or sediment." EFED Response: EFED concurs with the registrant's comments. The text has been revised to read "Carbaryl tends not to bind tightly to soil, aquifer solids, or sediment." Page: 29 Paragraph: 4 EPA comment: Under certain conditions carbaryl can be expected to persist in the environment. Under low pH conditions the compound is stable to hydrolysis. In anaerobic environments metabolism is fairly slow (t½ = 72 days). This suggests that carbaryl may leach to ground water and persist in some aquifers. 46 Aventis' response: This last statement should be removed. In contrast to this hypothesis are the data presented in the NAWQA and EPA databases that demonstrate that carbaryl is not likely to leach to ground water and is not likely to persist in aquifers. The fact that carbaryl has been widely used in agricultural and urban settings for more than 35 years, and yet is found at concentrations greater than 0.1 µg /L in only 0.027% of the agricultural wells, urban wells and aquifers sampled by NAWQA (Kolpin, 2001), indicates that this statement has little merit. Furthermore, the last sentence is in direct contradiction to the statement made at the beginning of the preceding paragraph that carbaryl "… has limited potential to leach to ground water." EFED Response: EFED concurs with the registrant's comments. The last sentence of the paragraph has been deleted and the text reads "Under certain limited conditions carbaryl may be expected to persist in the environment. Under low pH conditions the compound is stable to hydrolysis. In anaerobic environments metabolism is fairly slow (t½ = 72 days)." Page: 30 Paragraph: 1 Lines 1­ 3 EPA comment: Surface water monitoring studies show that carbaryl is the second most widely detected insecticide after diazinon. Carbaryl, at typically low concentrations, is found in greater than 20 % of surface samples at concentrations up to 7 ppb. Aventis' response: These summary statements are based on the NAWQA database, with the exception of the 7 ppb concentration. The highest reported value in the NAWQA database is 5.5 ppb. The value of 7 ppb does not come from the NAWQA database but from the report by Werner et al. (2000). In fact, a maximum carbaryl concentration of 8.4 ppb was reported for surface water samples in the California DPR surface water database (see discussion section). The sources of the information should not be mixed, or the source of the information should be explicitly stated. EFED Response: EFED concurs with the registrant's comments. The text has been revised to read "Surface water monitoring studies show that carbaryl is the second most widely detected insecticide after diazinon. Carbaryl, at typically low concentrations, is found in greater than 20 % of surface samples in NAWQA studies at concentrations up to 5.5 ppb. Carbaryl is detected more frequently in nonagricultural areas (about 40%) then in agricultural areas (about 5 %). A maximum carbaryl concentration of 8.4 ppb was reported for surface water samples in the California DPR surface water database. Carbaryl is generally not widely detected in groundwater monitoring studies though some studies have found concentrations of up to several hundred ppb. Concentrations as high as 610 : g/ L have been detected in one case but typical groundwater concentrations are much lower. NAWQA 47 studies have found that about 1 % of groundwater samples have measurable levels (> 0.003 : g/ L) of carbaryl, with a maximum concentration of 0.02 : g/ L. Targeted studies designed to measure carbaryl in groundwater are not available." Drinking Water Exposure Assessment Page: 30 Paragraph: 2 Line: 3­ 4 EPA comment: Carbaryl is the second most commonly detected insecticide in surface water, and can be expected to contaminate drinking water derived from surface water bodies. Aventis' response: The surface water­ monitoring program conducted by Aventis shows an insignificant impact of carbaryl on drinking water. EFED Response: EFED's interpretation of the surface water­ monitoring program conducted by Aventis has been discussed previously in this document. Page: 30 Paragraph: 2 Line: 7 EPA comment: The maximum reported value was 7.0 µg /L. Aventis' response: The maximum value reported in the NAWQA database is 5.5 µg /L. The only carbaryl detection reported in the study by Werner et al. (2000) was 7.0 µg /L. The maximum value reported in the California DPR Surface Water database is 8.4 µg/ L. Since all of the statistics made in this paragraph refer to the NAWQA data, the reference to the maximum reported concentration should be 5.5 µg /L. EFED Response: EFED concurs with the registrant's comments. The text has been revised to read "The maximum reported value in surface water was 8.4 µg/ L." Page: 30 Paragraph: 4 Line: 2 EPA comment: Older studies using GC or GC/ MS generally have poor recovery and quantitation limits. Because of this difficulty in analysis the actual concentration of carbaryl in groundwater and surface waters may be higher than reported. 48 Aventis' response: The basis for making this generalization is not readily apparent and these statements should be removed. Comments regarding the recovery reported for the GC/ MS method used in the NAWQA survey are made below in reference to statements made on page 34 paragraph 5, and are elucidated in the discussion section at the end of this response document. The method detection limit (MDL) reported for the GC/ MS method used for the NAWQA program is 0.003 ppb (Zaugg et al., 1995; Larson et al. , 1999). The limit of detection for the HPLC/ MS/ MS method used in the carbaryl surface water monitoring study being conducted by the registrant (LOD, 0.002 ppb; LOQ 0.030 ppb) is similar to the GC/ MS method used for the NAWQA program. In addition to the GC/ MS method used in the NAWQA program, carbaryl was also analyzed by HPLC/ photodiode­ array detection in a limited number of samples with a MDL of 0.008 (Werner et al., 1996). Therefore, the quantification limits reported for the GC/ MS method used to generate a majority of the carbaryl data in the NAWQA database is very similar to the quantification limits for available HPLC methods. See the discussion section at the end of this response document for a summary of the available NAWQA data obtained by the GC/ MS and HPLC/ PDA methods. EFED Response: EFED has concerns that poor detection limits in the past may have underestimated the concentration of carbaryl in surface and groundwater. However, a sentence has been added to the paragraph stating "More recent studies using HPLC/ MS should provide better data on the true extent and magnitude of water contamination from the use of carbaryl." Page: 30 Paragraph: 4 Line: 4 EPA comment: More recent studies using HPLC/ MS should provide better data on the true extent and magnitude of water contamination from the use of carbaryl. Aventis' response: Aventis believes that our ongoing targeted surface water­ monitoring program using HPLC/ MS/ MS accurately reflects the extent and magnitude of carbaryl exposure in drinking water derived from surface water. EFED Response: EFED agrees that the ongoing study applies more appropriate analytical methods. The limitations of the study have been discussed elsewhere. 49 Drinking Water Modeling Page: 31 Paragraph: carried over from page 30 Line: 8 EPA comment: A partial list of input parameters for the PRZM/ EXAMS modeling are given in Table 4. Aventis' response: The partial list of input parameters in Table 4 includes multiple conservative assumptions likely to lead to significant over­ estimation of the potential surface water concentrations of carbaryl. EFED Response: The modeling was done following EFED policy and standard procedures. EFED concurs with the registrant that the PRZM/ EXAMS model includes a number of conservative assumptions. Page: 31 Paragraph: 2 Line: 1 EPA comment: For the Index Reservoir scenario using maximum label rates, acute EEC values ranged from 19 µg/ L from sugar beets to 494 µg/ L for oranges (Table 6). Aventis' response: Table 6 on page 33 shows a concentration of 19 µg/ L for sugar beets treated with the maximum label rate of 2 x 1.5 lb ai, not 10 as stated in this sentence. A low EEC value of 9 µg/ L for sugar beets results from the "maximum reported" application scenario of 1 x 1.2 lb ai/ A. EFED Response: EFED concurs with the registrant's comment. The text had been revised to present more generalized ranges and reads ". . . acute EEC values ranged from about 10 µg/ L from sugar beets to about 500 µg/ L from citrus (Table 6)." Page: 31 Paragraph: 2 Line: 3 EPA comment: Chronic EECs ranged from about 1 to 28 µg/ L. 50 Aventis' response: Table 6 on page 33 shows that this is correct when considering all of the model scenarios. However, either the same maximum label rate reference should be used as in the preceding sentence (in which case the minimum chronic EEC would be 2), or the basis for the preceding sentence should be changed from the maximum label rate to include all application scenarios to keep the comparisons consistent. EFED Response: EFED concurs with the registrant's comments. The text has been revised and now reads "Chronic EECs ranged from about 2 to 28 µg/ L." Page: 31 Paragraph: 2 Line: 6 EPA comment: It is highly unlikely that any but the most extensive targeted monitoring would capture the actual peak concentrations. Aventis' response: The role of a peak concentration in dietary exposure assessment is undergoing reexamination within EPA. The current policy of EPA appears to define a certain percentile as an appropriate value for use in screening assessments, but the exact percentile to be used is being currently set by EPA management. (The most recent documents from EPA cite the 95 th or 99 th percentile.) For more comprehensive assessments, a distribution of values is preferred. EFED Response: EFED further qualifies its statement by saying "The results of the modeling provide a very conservative, though not unreasonable, estimate of possible concentrations in drinking water. A more detailed assessment of the source of water used to provide drinking water and the relationship between the areas where carbaryl is used and surface water sources is required to more accurately evaluate possible human exposures." Page: 31 Paragraph: 2 Line: 7 EPA comment: The results of the modeling provide a conservative, though not unreasonable, estimate on possible concentrations drinking water.( sic) Aventis' response: The modeling, performed according to EPA procedures, provides an upper bound estimate on potential concentrations in drinking water from surface water. Whether the modeling estimates are reasonable depends on the specific assumptions. For carbaryl, the three­ year monitoring program (conducted according to EPA and ILSI guidance available at the time 51 the study was started) shows that the model calculations are unreasonable. These conservative assumptions include a 3x factor on both the aerobic soil and aerobic aquatic half lives, assuming the maximum drift rate for aerial applications throughout the county (in Florida citrus almost all applications are by air blast with ground equipment), and the application rate over a watershed. The conservative nature of the application assumption alone probably results in an overprediction by at least two orders of magnitude. The modeling calculations assume an application rate of 17.4 lbs/ acre of watershed annually. In Hardee County, the county with the highest usage of carbaryl, the average use rate on a countywide basis is only 0.31 lb/ acre (See Appendix II). In Manatee County, the county with the highest usage containing a watershed used to supply drinking water, the average rate on a countywide basis is 0.027 lb/ acre. EFED Response: EFED concurs with the registrant's comments and as noted in the previous response, the text has been revised and now reads "The results of the modeling provide a [very] conservative, though not unreasonable, estimate of possible concentrations [in] drinking water." Page: 31 Paragraph: 2 Line: 8 EPA comment: A more detailed assessment of the source of water used to provide drinking water and the relationship between the areas where carbaryl is used and surface water sources is required to more accurately evaluate possible human exposures. Aventis' response: As mentioned by EPA in this document, ground water is the source of the majority of Florida drinking water. Many of the counties with the highest use of carbaryl contain no watersheds used to provide drinking water. As discussed more fully in Appendix I, the watershed supplying the Manatee County Water Treatment Plant appears to have the most carbaryl usage of drinking water watersheds in Florida. EFED Response: The registrant's response is expressing their perspective on the likelihood that watersheds in particular areas serve as drinking water sources; the comments do not reflect an error in the EFED risk assessment. 52 Water Treatment Effects Page: 31 Paragraph: 3 Line: 8 EPA comment: Since relatively (sic) few water treatment facilities in the U. S. use ozone the limited data available do not indicate that carbaryl is likely to be degraded in the majority of treatment plants. Aventis' response: The monitoring program conducted by the registrant shows that removal occurs in some treatment plants. The effect of treatment seemed to be greater in systems using carbon treatment. EFED Response: The design of the water monitoring study does not allow the results to be used to evaluate treatment. For example, raw and treated water samples were not collected from the same mass of water, and treated water was not analyzed for all sampling periods. Treated water was found to have higher concentration in at least one case. The limitations of the study have been discussed elsewhere. Page: 33 Table 6 EPA comment: Drinking Water EECs (Table 6 entitled) Aventis' response: Many of the comments for this table are similar to those for the EECs for ecological risk found in Table 5. The PRZM model input parameters for the Index Reservoir scenarios were received as an electronic copy of a draft of Appendix B. These input files are very useful for assessing the scenarios that have been modeled. It would be useful to add another column to Table 6 to specify which method of application was used to generate the EECs (and thus the application efficiency and spray drift values). It would be of benefit for the Agency to state which of the carbaryl labels were used to develop the "maximum" label application rate scenarios. There are a number of errors in the input parameters (noted below) that would lead to changes in the calculated EECs and therefore the risk quotients for these uses. The model parameters listed in the electronic draft of Appendix B show that the "average" scenarios for citrus and apples were conducted using aerial applications. Few applications to these crops are made aerially. Therefore, the model results over­ estimate the contributions from spray drift since the "average" applications to these crops are made using ground airblast equipment with a spray drift of 6.3% versus aerial applications with a spray drift of 16%. 53 The "maximum label rate" application scenario for apples that is allowed by the Sevin brand XLR PLUS label (E. P. A. Reg. No 264­ 333), the Sevin brand 80WSP and CHIPCO Sevin brand 80WSP labels (E. P. A. Reg. No 264­ 526) and the CHIPCO Sevin brand SL label (E. P. A. Reg. No 264­ 335) is 5 applications at 3 lb ai/ A/ application made every 14 days. The scenario used in the model applies less than the maximum amount of product allowed by the labels. In addition, application timing was used in the modeling for the index reservoir scenario (applications made by air every 4 days) that would be a violation of the Aventis labels which restrict applications to a minimum of every 14 days. The "average" scenario for sweet corn in Ohio should be 3 applications at 1.1 lb ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not the 2 applications at 3.4 lb ai/ A/ application as listed in the table. The PRZM input file shows the correct inputs of 3 applications at 1.1 lb ai/ A/ application. The "average" scenario for sugar beets in Minnesota should be 1 application at 1.3 lb ai/ A/ application (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD") and not 1 application at 1.5 lb ai/ A/ application as listed in the table and the PRZM input file. The "Citrus" scenario would be more appropriately labeled Oranges. For the average scenario, the 3.4 lb ai/ A/ application rate listed in Table 5 is for oranges (as noted in the memo, "Average application rate from Quantitative Usage Analysis for Carbaryl, prepared July 21, 1998 by Frank Hernandez, OPP/ BEAD"), which is the highest "average" application rate for any type of citrus. Therefore, this "average" scenario for oranges is at the high end for all citrus and overestimates the EECs for use in the other citrus crops. "Average" application rates for other citrus as listed in the memo are: Lemons – 1.3 applications at 2.7 lb ai/ A/ appl Grapefruit – 1.6 applications at 1.4 lb ai/ A/ appl Citrus, other – 1.8 applications at 1.8 lb ai/ A/ appl EFED Response: EFED used available data from the Biological and Economic Assessment Division (BEAD) in 2001 to develop the risk assessment. However, the recommended changes would not substantially change EFED's risk assessment; therefore, the table has not been significantly revised other than changing "citrus" to read "oranges". Ground Water Resources Page: 34 Paragraph: carried over from page 33 Line: 3 EPA comment: U. S. EPA. Pesticides in Groundwater Database (Jacoby et al., 1992) 54 Aventis' response: This reference is not provided in the reference list. EFED Response: EFED concurs with the registrant's comments and the reference section has been revised to include the following reference: Jacoby, H., C. Hoheisel, J. Karrie, S. Lees, L. Davies­ Hilliard, P. Hannon, R. Bingham, E. Behl,, D. Wells, and E. Waldman, 1992. Pesticides in groundwater database: a compilation of monitoring studies: 1971­ 1991 National Summary. EPA 734­ 12­ 92­ 001. Page: 34 Paragraph: 3 Line: 3 EPA comment: Detections were from (sic) mainly from three use sites: wheat (5.8 % of well samples from wheat land use), orchards and vineyards (1.7 % of well samples from orchard and vineyard land use), and urban (1.8% of urban groundwater samples). Aventis' response: Updated information (noted below) is not summarized in the same manner as in this statement, so direct comparisons cannot be made easily. However, the updated information indicates a similar pattern of low concentrations of carbaryl detections in a limited number of ground water resources. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Detections were mainly from three use sites: wheat (5.8 % of well samples from wheat land use ), orchards and vineyards (1.7 % of well samples from orchard and vineyard land use), and urban (1.8% of urban groundwater samples). Data on pesticides in groundwater were reviewed by Kolpin et al. (1998) and updated information is available at: http:// water. wr. usgs. gov/ pnsp/ pestgw/." Page: 34 Paragraph: 3 Line: 6 EPA comment: Limitations in analytical methodology (described elsewhere) apply to groundwater sample analysis also suggesting that there (sic) actual maximum concentrations and extent of contamination may be significantly higher. Aventis' response: This statement is misleading and should be deleted. The validation of the most widely used GC/ MS method for the data contained in NAWQA show recoveries of 86 to 94% at spiking levels of 0.1 to 1.0 µg/ L with an MDL of 0.003 µg/ L. The HPLC method validation reported recoveries of 58 to 64% % at spiking levels of 0.1 to 1.0 µg/ L with an MDL of 0.018 µg/ L. Furthermore, using the GC/ MS method, a mean recovery of 115% was found for field matrix 55 spikes of carbaryl at spiking levels of 0.1 µg/ L. With the GC/ MS method MDL of 0.003 µg/ L and a mean recovery of 115% for the field matrix spikes, this method cannot reasonably be characterized as stated by EPA. Additional details of the method validations and field matrix spikes are provided in the `Discussion Section' at the end of this response. EFED Response: EFED has revised the text to read "Because of limitation in the analytical methods used there is some uncertainty in the quantitative accuracy of carbaryl analysis." Page: 34 Paragraph: 3 Line: last EPA comment: …and updated information is available at: . Aventis' response: This web page was last updated in 1998. A more recent update by Kolpin was posted June 11, 2001 at: http:// water. wr. usgs. gov/ pnsp/ pestgw/ and is the source of the updated information included in the `Discussion Section' at the end of this response. EFED Response: EFED concurs with the registrant's comment and the website has been updated to read " http:// water. wr. usgs. gov/ pnsp/ pestgw/". Surface Water Resources Monitoring Data Page: 34 Paragraph: 4 Line: 5­ 6 EPA comment: Because of limitation in the analytical methods used there is some question as to the accuracy of carbaryl analysis. Aventis' response: This generalized statement needs to be qualified or deleted. Whereas the authors of reports written as part of the NAWQA program have been clear about the potential limitations of the quantitative nature of the carbaryl data in the database, they have also been clear about the validity of the qualitative nature of the data. The use of the multi­ residue method in the NAWQA program does have some limitations as a result of the large numbers of diverse pesticides and degradation products that they are monitoring. However, the QC/ QA data generated as part of the NAWQA program (described in the discussion section on surface 56 water at the end of this response) demonstrate the validity of the detections of carbaryl in the studies. The monitoring study conducted by the registrant, and reported in this section, does not have the same potential limitations in the analytical method since the method is looking specifically for carbaryl. Therefore, the analytical method used by the registrant does not raise questions about the accuracy of the carbaryl analysis. EFED Response: EFED concurs with the registrant's comment and the text has been revised to read "Because of limitations in the analytical methods used there is some uncertainty in the quantitative accuracy of carbaryl analysis." Page: 34 Paragraph: 4 Line: 5­ 6 EPA comment: Poor analytical methods probably have resulted in lower detection rates and lower concentrations than actually present. Aventis' response: This generalized statement should be deleted for reasons provided above and in the discussion section. NAQWA (sic) EFED Response: EFED concurs with the registrant's comments and the sentence has been deleted. Additionally, all references to the National Water Quality Assessment (NAWQA) acronym have been corrected. Page: 34 ­ 35 Paragraph: 5 Lines: 5­ 8 EPA comment: Carbaryl analytical results are fairly poor, with a typical mean percent recovery of 24% ( F = 15) in laboratory quality control samples, and a method detection limit (MDL) of 0.003 ug/ L. This suggests that the values reported do not represent the maximum concentrations that exist, and that surface water contamination may be more widespread than the data show. Aventis' response: These statements are misleading and should be updated with further quality control data supplied by NAWQA. 57 A discussion of the analytical method used in the NAWQA program is presented in the USGS Open­ File Report 95­ 181 (see Zaugg et al. (1995) in references). The mean percent recovery of 24% noted above can be found in Table 9 of this report and is by no means "typical". A mean recovery value of 24% was reported for reagent­ grade water fortified at a level of 0.03 : g/ L with a method detection limit said to be 0.003 : g/ L. Additional recoveries for fortified water samples (reagent­ grade, ground and surface waters) ranged from 10 to 202% (see discussion section). The carbaryl data in thenot because the carbaryl concentrations are underestimated. Additional evaluations of field blank, field matrix spike and lab control spike samples as part of the NAWQA program can be found in a provisional report by Martin (1999). This report demonstrates the lack of detection of carbaryl in 100% of the field blanks, and median recoveries of 94.4% in 306 field matrix spikes and 93.0% in 1000 lab control spikes, each at spiking levels of 0.1 : g/ L. These data suggest an adequate level of detection of carbaryl in the method used in the NAWQA survey of surface and ground water. See the additional discussion at the end of this document for further information regarding recoveries in spiked surface and ground water. EFED Response: EFED has revised the text to read "Carbaryl is the second most widely detected insecticide after diazinon in the USGS NAWQA program (http:// water. usgs. gov/ nawqa/ nawqa_ home. html). Carbaryl was detected in 46% of 36 NAWQA study units between 1991 and 1998. The reported concentrations are believed to be reliable detections but have greater than average uncertainty in quantification. The data in the NAWQA database are amended with an "E" qualifier to indicate the variability found in the analysis. This suggests that the reported values may not represent the maximum concentrations that exist. Page: 35 Paragraph: 2 Line: 7 EPA comment: …at about 0.1 percent of the amount used in the basins (Larson et al., 1999) . The estimated carbaryl use on in agricultural applications is about 4 million pounds suggesting that 400,000 pounds are delivered to the nations streams draining agricultural areas. Aventis' response: This estimated use of carbaryl for agricultural applications over­ estimates the use of carbaryl by about 1 million pounds. BEAD and USGS data cited on pages 6 and 7 are consistent with lower total pounds of carbaryl applied. In addition, 0.1 percent of 4 million pounds would be 4,000 pounds, not 400,000 pounds. If the 1987 – 1996 average of 2.5 million pounds carbaryl is used in the calculation, the total load suggested to be delivered to streams draining agricultural areas would be 2,500 pounds. 58 EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "A significant portion of the total carbaryl applied was transported to streams. In areas with high agricultural use the load measured in surface waters was relatively consistent across the country at about 0.1 percent of the amount used in the basins (Larson et al., 1999) http:// water. wr. usgs. gov/ pnsp/ rep/ wrir984222/ load. html. The estimated carbaryl use on in agricultural applications is about 2.5 million pounds suggesting that 2,500 pounds are delivered to the nations streams draining agricultural areas. Registrant Monitoring Study Page: 35 Paragraph: 4 Line: 11 EPA comment: Carbaryl was analyzed by HPLC/ MS with a limit of detection… Aventis' response: The analytical method used by the registrant in the surface water monitoring study uses tandem mass spectrometry (MS/ MS) as the detection method. This type of detection involves quantification of "daughter" ions from a selected mass fragment and is more selective than an MS method. Therefore, to accurately reflect these differences, the method should be labeled as HPLC/ MS/ MS. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "Carbaryl was analyzed by HPLC/ MS/ MS with a limit of detection of 0.002 ppb (2 ppt) and a limit of quantitation (LOQ) of 0.030 ppb (30 ppt)." Page: 36 Paragraph: 3 Line: 9 EPA comment: In several cases finished water had higher concentration than raw water, and finished water had detectable carbaryl when the raw did not. The highest concentration measured was in finished water (0.18 ppb). Raw water sampled at the same time had much lower concentration (0.010). 59 Aventis' response: This statement is misleading and certainly does not consider the analytical uncertainty for concentrations below the level of quantification and near the level of detection. There were only two cases when finished water was greater than raw water when the concentrations in finished water were greater than 0.01 ppb (only one­ third of the quantification limit). One case was when the raw water was 0.009 ppb and the finished water was 0.011 ppb. These two analyses are essentially equivalent, especially considering that they are only about a third of the quantification limit. The other case was at the Deerfield community water system. This drinking water facility uses a small river without a reservoir as a source for a small Community Water System. Farms are located immediately upstream of the facility. The intake is also not continuous (shut down over weekends). Therefore, getting a matching sample is quite difficult, especially for a short duration spike as a result of spray drift, summer thunderstorm, or perhaps a spill that almost immediately enters the river a runoff event. The rarity of this event is demonstrated by the absence of residues of this magnitude the next year (2000). Samples collected through this time of the year in 2001 also do not indicate a similar event. Although the data from this site cannot be used to determine the peak concentration, the data provide a distribution of residues through the three year period which will define up to the 99 th percentile concentration of the distribution. The Deerfield, Michigan community water system is one of the systems in which the greatest variability of residues would be expected. Most of the other community water systems are located on larger rivers, lakes, or reservoirs. Because the design of study called for analysis of finished water only when there were residues in the raw water, there was only one finished sample analyzed when the raw water contained no residues. This sample was collected at the Deerfield community water system at the sampling interval after the finding of 0.16 ppb in the Deerfield system. The residue level in this sample was 0.004 ppb. The difference between 0.004 ppb and non­ detect is insignificant, and if real can probably be attributed to water at much higher concentrations remaining in the system from the previous week. EFED Response: The registrant's comments point out a major flaw in the water monitoring study design. The study should have analyzed finished water at all sampling times. Because of this and other shortcomings discussed previously, the results of this study cannot be used to evaluate the effects of treatment on carbaryl. Page: 36 Paragraph: 4 Line: 1 EPA comment: Non­ targeted monitoring, such as the NAWQA program, has shown much higher concentrations occur indicating that this study, while useful, can not be used to describe the overall distributions that occur throughout the entire use area. Aventis' response: 60 The targets of the drinking water monitoring conducted by the registrant and the NAWQA program are different. The NAWQA program characterized surface water concentrations within a study area while the Aventis drinking water monitoring measured residues in inlets and outlets of drinking water facilities. Also the drinking water monitoring program considered only use areas with drinking water supplies. However, for FQPA dietary assessments, the appropriate target is drinking water rather than surface water. The main reason why the drinking water monitoring study did not show residues as high as in the NAWQA program is the location of the sampling points. Drinking water supplies tend to be located on larger surface water bodies than NAWQA sampling points (or in other words, the intakes for community water systems tend to be downstream of NAWQA sampling points). This additional time allows for additional degradation and dilution to occur. Finding the highest concentration at the Deerfield, Michigan system is not surprising since this intake is on one of the smallest surface water bodies included in the monitoring study (see response to Page: 36, Paragraph: 3, Line: 9 above for a more detailed explanation). EFED Response: The registrant's comments express their perspective on non­ targeted monitoring studies and do not reflect an error in the risk assessment. Page: 36 Paragraph: 4 Line: 4 EPA comment: This study does not provide sufficient information to allow estimation of actual peak and mean concentrations that actually occur in all use areas. Aventis' response: Because most of the samples did not contain carbaryl residues, accurate estimates of the actual peak and mean concentrations can not be obtained. However, the distributions obtained from all sites can be used to define up to the 99 th percentile concentration. The average cannot be accurately determined; however, the time­ weighted average is only slightly above the limit of detection (and certainly less than 0.01 ppb) at all 20 sites. The peak concentration in this study was measured at a community water system on a small river. The registrant agrees that the sampling schedule was not adequate to determine the true peak in such systems. Most of the other community water systems are located on larger rivers, lakes, or reservoirs. Therefore, the peak values are not likely to be an order of magnitude greater than the amounts present in the collected samples. The distributions obtained in this study are suitable for use in dietary exposure assessments. When EPA policy establishes what percentile concentration is an appropriate regulatory endpoint, then these percentiles can be determined for each of the community water systems monitoring. These percentiles can then be compared with DWLOC values in screening assessments. 61 EFED Response: EFED has responded previously to the utility of Aventis' water monitoring study. Page: 37 Paragraph: 2 Line: 1 EPA comment: Only limited information was submitted on sampling site selection… Aventis' response: The summary in Appendix I of this response provides a description of the sites considered for the monitoring study and the rationale for the selection of the twenty sites. This information demonstrates that the community water systems selected for this study are representative of the systems that are most likely to contain the highest concentrations of carbaryl residues. EFED Response: EFED will review new submissions and data when available. This does not represent an error in the EFED document and so will not be addresses here. It will be addressed in an appropriate review document when it has been completed. Page: 37 Paragraph: 3 Line: 3 EPA comment: This should include an explanation of why this study did not observe concentrations as high as those found in other, non­ targeted studies, and how the results of this study can be related to concentrations that occur throughout the country. Aventis' response: The main reason why the drinking water monitoring study did not show residues as high as in the NAWQA program is the location of the sampling points. Drinking water supplies tend to be located on larger surface water bodies than NAWQA sampling points (or in other words, the intakes for community water systems tend to be downstream of NAWQA sampling points). This additional time allows for additional degradation and dilution to occur. Finding the highest concentration at the Deerfield, Michigan system is not surprising since this intake is on one of the smallest surface water bodies included in the monitoring study (see response to Page: 36, Paragraph: 3, Line: 9 above). Since the drinking water study targeted drinking water systems in high­ use watersheds, the data from this study are representative of the drinking water systems most likely to contain carbaryl. 62 EFED Response: EFED has already commented on the utility of Aventis' water­ monitoring study. Please refer to the previous discussions. Sacramento­ San Joaquin River Delta Page: 37 Paragraph: 4 Line: 4 ­ 5 EPA comment: Carbaryl was found to be the sole causative agent at one of 20 sites… The toxicity seemed to persist for several days… Aventis' response: The statement should be revised. The reference cited (Werner et al., 2000) lists carbaryl as "the primary toxicant" (not as the "sole causative agent"), even though an unknown was also found at the same time. No information about the "unknown" is provided. Both conclusions of "sole causative" and of "primary toxicant" cannot be substantiated without further evidence about the nature and concentration of the unknown. Actually, for another site the authors concluded about the unknown found there "in 3 of 21 samples, toxicity observed could not be entirely explained by the identified primary toxicants." Additionally, it is at least questionable if the analytical method employed would detect all potential toxicants beside the insecticides it was set up for. The toxicity seeming to persist is not explained or substantiated in the reference. The citation of such dubious results should be removed from the RED. EFED Response: EFED has revised the text; it now reads "Carbaryl was found to be the [primary] toxicant at one of 20 sites sampled in 1995, with concentration of 7.0 µg/ L." Furthermore, the reference cited (Werner, et al. 2000) is taken from a peer­ reviewed journal, i. e., Environmental Toxicology and Chemistry, which EFED does not consider to be a dubious source. 6.0 Hazard and Risk Assessment for Aquatic Organisms Hazard assessment for Aquatic organisms Estuarine/ Marine Fish Page: 39 Paragraph: 2 Line: 6 EPA comment: …carbaryl water concentration of 1.2 µg/ ml… 63 Aventis' response: To be consistent with the rest of the document the units should be presented in ppm (" carbaryl water concentration of 1.2 ppm") EFED Response: EFED concurs with the registrant's comments and the text has been revised to read "1.2 ppb". Aquatic Plants Page: 40 Paragraph: 2 Line: 6 EPA comment: Guideline 122­ 2 is not fulfilled. Aventis' response: The chapter should be revised. As detailed above (comments to Page 2 of the Memorandum), studies were submitted in 1992. The status for this requirement in an October 04, 2000 OPP Guideline Status Report (Chemical Review Management System) lists the guideline 122­ 2 status as "Acceptable/ Satisfied". EFED Response: As EFED has noted previously in its response to comments, EPA requires data on 5 aquatic plant species. The registrant has provided data on only two of the five species that were classified as acceptable and as having fulfilled guideline test requirements. Therefore, EFED is requesting that aquatic plant studies be repeated following EPA guidelines. Risk Assessment for Aquatic Organisms Page: 40 Paragraph: 4 Line: 3 EPA comment: …corresponding levels of concern (LOCs) is presented in Appendix D. Aventis' response: The risk quotients are currently listed in Appendix C. EFED Response: EFED concurs with the registrant's comments and the text has been revised; the sentence now reads "A detailed analyses of risk quotients (RQs) in relation to their corresponding levels of concern (LOCs) is presented in Appendix C." 64 Estuarine/ Marine Fish Page: 42 Paragraph: 1 Line: 17/ 18 EPA comment: Chronic toxicity studies with an estuarine/ marine fish species is required. Aventis' response: This requirement should be waived. Given the relatively short half­ life of carbaryl in the aquatic environment and the low acute risk, it is unlikely that estuarine/ marine fish species would be exposed to a chronic risk. EFED Response: This is not an error and is more appropriately addressed in a later phase of the reregistration process. Page: 42 Paragraph: 2 Line: 1 EPA comment: There is one carbaryl use in particular that presents a major acute and chronic risk to estuarine/ marine fish. Aventis' response: This sentence should be rephrased. While there might be an acute risk from the application to oyster beds, given that there is only one application every six years according to the reference cited by EPA, it is improbable that estuarine/ marine fish would be exposed to a chronic risk. EFED Response: In a study by Stonic (1999) application of carbaryl to mud flats in Willapa Bay, Washington, resulted in post­ spray carbaryl concentrations at sprayed sites ranging from 2,000 to 3,400 ppb by 2 days after treatment (DAT), 180 to 220 ppb by 30 DAT, and 86 ­ 120 ppb by 60 DAT. These data suggest that the potential for chronic exposure to estuarine/ marine fish is possible. However, EFED has rephrased the sentence to read "There is one carbaryl use in particular that represents a potential acute and chronic risk to estuarine/ marine fish." The full reference for these data is: Stonic, Cynthia. 1999. Screening Survey of Carbaryl (Sevin ™ ) and 1­ naphthol Concentrations in Willapa Bay Sediments. Washington State Department of Ecology. Publication No. 99­ 323. 65 7.0 Hazard and Risk Assessment for Terrestrial Organisms Hazard Assessment for Terrestrial Organisms Mammalian Page: 46 Paragraph: 4 Line: 1 EPA comment: With a rat LD50 of 307 mg/ kg… Aventis' response: Typographical error, the rat LD50 is 301 mg/ kg. EFED Response: EFED concurs with the registrant's comments and has corrected the text to indicate a rat LD50 of 301 mg/ kg. Risk Assessment for Terrestrial Organisms Avian Risk Nongranular Formulations Page: 47 Paragraph: 4 Line: 5 EPA comment: …levels of concern (LOCs) is presented in Appendix D. Aventis' response: The risk quotients are currently listed in Appendix C. EFED Response: EFED concurs with the registrant's comments and has revised the text to reflect that risk quotients and their associated levels of concern (LOCs) are presented in Appendix C. Page: 48 Paragraph: 1 Line: 3 EPA comment: … for 34 of 43 uses at maximum reported rates, and for 37 of 72 uses at "average" rates. (Appendix D, … Aventis' response: The risk quotients are currently listed in Appendix C. 66 EFED Response: EFED concurs with the registrant's comments and has revised the text to reflect that risk quotients and their associated levels of concern (LOCs) are presented in Appendix C. Granular Formulations Page: 48 Paragraph: 2 Line: 5 EPA comment: …for any of the granular carbaryl uses (Appendix D, Table 6). Aventis' response: The risk quotients are currently listed in Appendix C. EFED Response: EFED concurs with the registrant's comments and has revised the text to reflect that risk quotients and their associated levels of concern (LOCs) are presented in Appendix C. Mammalian Risk Risk to Herbivores/ Insectivores: Nongranular Formulations Risk Quotients for Herbivores/ Insectivores Based on Less than Maximum Label Use Rates Page: 48 Paragraph: 3 Line: 3 & 4 EPA comment: … (Appendix D, Table 10a) and maximum reported (Doane data) use rates data available for 43 uses (Appendix D, Table 10b) Aventis' response: The risk quotients are currently listed in Appendix C. EFED Response: EFED concurs with the registrant's comments and has revised the text to reflect that risk quotients and their associated levels of concern (LOCs) are presented in Appendix C. 67 Risk Quotients for Herbivores/ Insectivores Based on Maximum Label Use Rates Page: 48 Paragraph: 6 Line: 1 EPA comment: Carbaryl is moderately toxic to small mammals on an acute oral basis (rat LD50 = 307 mg/ kg) Aventis' response: Typographical error, the rat LD50 is 301 mg/ kg. By using the lower LD50 all acute mammalian risk quotients will change slightly. EFED Response: EFED concurs with the registrant's comments and has corrected the text to indicate a rat LD50 of 301 mg/ kg. The mammalian risk quotient tables in Appendix C and the ranges reported in the text have been revised to reflect the modest change in numbers. Page: 49 Paragraph: 1 Line: 3 EPA comment: …corresponding levels of concern (LOCs) is presented in Appendix D. Aventis' response: The risk quotients are currently listed in Appendix C. EFED Response: EFED concurs with the registrant's comments. The sentence has been revised to read "A detailed analysis of mammalian RQs in relation to their corresponding levels of concern (LOCs) is presented in Appendix C." Risk to Granivores: Nongranular Uses Chronic risk: Nongranular Uses Page: 50 Paragraph: 2 Line: 8 EPA comment: …summarized in Appendix D, Table 9. Aventis' response: The risk quotients are currently listed in Appendix C. 68 EFED Response: EFED concurs with the registrant's comments and has revised the text to reflect that risk quotients and their associated levels of concern (LOCs) are presented in Appendix C. Reproduction Effects Page: 50 & 51 Paragraph: 4 / 1 EPA comment: (Review of alleged reproduction effects of carbaryl). Aventis' response: The paragraphs should be changed. The literature cited in these paragraphs show ambivalent results. While some references seem to support the claim of reproductive effects, other references do not. The potential for reproductive effects in mammals was evaluated in the recently submitted 2­ generation study in rats. No reproductive effects were seen in this guideline study. The NOAEC of 75 ppm was based on pup mortality. EFED Response: EFED believes that the chronic effects cited from the open literature are legitimate. As stated previously, chronic reproductive tests have resulted in effects that support EFED's concerns regarding the endocrine disrupting potential of carbaryl. EFED believes that the chronic effects cited from rat developmental studies, i. e., reduced reproduction, disturbances in spermatogenesis, increased resorption of embryos, increased incidence of infertility in females and underdeveloped testes in males, also represent serious reproductive effects that support EFED's concerns regarding the chronic reproductive/ developmental toxicity of carbaryl. Just because one study failed to show similar effects to another, EFED does not believe that it would be reasonable to discount the validity of the earlier studies. If anything, the data strongly suggests that additional data are needed to better understand the likelihood of adverse effects. Page: 51 Paragraph: 4 EPA comment: Feeding 2 or 20 mg/ kg of carbaryl to pregnant rhesus monkeys (Macacca mulatta) Aventis' response: This paragraph should be deleted. As there are no native monkey species in the U. S., this reference is irrelevant for U. S. wildlife species. Additionally, the reference cited is only a brief abstract article consisting of one 17­ line paragraph. Such information should not be the basis for use in a RED risk assessment. 69 EFED Response: The basis for the EFED risk assessment is the mammalian acute (LD50 = 301 mg/ kg) and chronic (NOAEC = 80 ppm) rat toxicity data. The data from rhesus monkeys are used to further characterize risk. While the registrant is correct that rhesus monkeys are not native to the United States, these animals are routinely used in primate research and are considered reasonable surrogates for studying the effects of chemicals on humans. 9.0 References (non­ MRID) Some of the references cited in EPA's list are not full scientific articles, but only abstracts from meetings (e. g. DeNorsica, 1973; Doughtery et al. , 1971, Chapin et al. 1997). Such "publications" should not be used as references considered in risk assessments. Without a sufficient description of methods and a presentation of detailed results these studies cannot be evaluated to determine if the findings are or are not scientifically plausible. Similarly, at least three of the references (Gladenko et al. 1970, Krylova et al. 1975, Smirnov et al. 1971) cited as proof for reproductive toxicity are in Russian in Cyrillic writing making an appropriate and timely evaluation difficult. Due to the limited review time during the 30­ day comment period, the registrant could not peruse all references. A more detailed response will be provided during the 60­ day comment period. EFED Response: EFED has cited literature from peer­ reviewed journals and considers these sources to be reliable. Furthermore, the registrant is providing their perspective on open literature and is not citing a specific error in the risk assessment. Page: 59 EPA comment: Carmel, R. F., Imhoff, J. C., Hummel, P. R., Cheplick, J. M. and Donigan, A. S., 1997. Aventis' response: The first name should be Carsel. EFED Response: EFED concurs with the registrant's comment and has corrected the reference to reflect the correct spelling of the name "Carsel". 70 Page: 59 EPA comment: Nkedi­ Kizza and Brown (1988) Aventis' response: The date should be 1998. EFED Response: EFED concurs with the registrant's comment and has corrected the reference to reflect the correct date of publication, i. e., 1998. Appendix A: Environmental Fate Study Reviews (DERs) Page: 62 ff EPA comment: (Environmental fate DERs are included) Aventis' response: The DERs should not be included in the RED. Publication of DERs together with the RED is unusual and will put Aventis in a competitive disadvantage. EFED Response: EFED concurs with the registrant's comments that DERs should be made available to the public under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. EFED also wants to reduce the overall size and level of detail of its risk assessment for readability. EFED does not, however, take a position regarding Aventis' statement on "a competitive disadvantage" resulting from DER publication. 71 Appendix B: Refined Water Memo Aventis' response: This memo was provided as an electronic copy and needs to be inserted into the document. It included text that repeated several sections of the EFED document and it included PRZM input tables for the drinking water concentrations using the Index Reservoir scenario. It would have been of benefit to have the same PRZM inputs for the "standard pond" scenarios that were used to estimate surface water concentrations used in the aquatic risk assessments. EFED Response: The full text of the Refined Water Memo has been included in Appendix B of the EFED chapter. The memo includes both PRZM input and output files. Appendix C: Ecological Risk Assessment Toxicity Endpoints Used in the Risk Assessment Page: 129 (e­ version) EPA comment: Aventis' response: Mammalian acute oral LD50 rat = 307 mg/ kg The correct LD50 is 301 mg/ kg Mammalian chronic (reproduction) NOAEC rat = 80 ppm Th e r e s u l t o f t h e recently submitted 2­ generation rat study should be used (75 ppm) EFED Response: As indicated previously, EFED has corrected the typographical error regarding the mammalian acute oral LD50 of 301 mg/ kg. Additionally, EFED has already commented regarding the recently submitted 2­ generation rat study; even if the study is classified as acceptable, the change in NOAEC from 80 ppm to 75 ppm will not significantly affect the magnitude of the risk quotients. Neither of these changes have a marked impact on EFED's risk assessment. Avian Acute and Chronic Risk Page: 130 (e­ version) Paragraph: 1 Line: 1 EPA comment: Since the avian LC50 is greater than 5,000 ppm (Appendix E), 72 Aventis' response: The toxicity data are currently listed in Appendix D. EFED Response: EFED concurs with the registrant's comments and the text has been revised to read that toxicity data are listed in Appendix D. Page: 132 – 135 (e­ version) EPA comment: (Acute Risk Quotients in Tables 4 and 5, as well as throughout the document were a reference is made to these quotients) Aventis' response: As the acute risk quotients are calculated on the basis of an LC50 of > 5000 ppm, the quotients should be given as "< (value)", not just the value. The values should also be changed accordingly throughout the document where a reference is made to these quotients. EFED Response: EFED concurs with the registrant's comments and Appendix C Tables 4 and 5 have been revised to show that acute risk quotients are less than the values presented. No further changes were necessary in the text since acute avian risk quotients were reported as being less than levels of concern. Risk from Exposure to Non­ granular Products Page: 137 – 147 (e­ version) EPA comment: (Text and tables 7 ­ 10) Aventis' response: Text and tables should be revised. A rat LD50 of 307 mg/ kg was used to calculate the acute risk quotients. The correct value is 301 mg/ kg. For calculation of the chronic risk quotient a NOAEC of 80 ppm was taken from a developmental study. The NOAEC of 75 ppm from a more relevant 2­ generation rat study recently submitted should be used instead. EFED Response: As noted previously, the mammalian acute LD50 value has been corrected to 301 mg/ kg and the acute risk quotients have been revised. Additionally, the chronic risk quotients are still based on 73 a NOAEC of 80 ppm. The data from the 2­ generation rat study have not been reviewed; however, the change in NOAEC from 80 to 75 ppm will have no marked effect in EFED's risk assessment. Risk from Exposure to Granular Products Page: 147 & 148 (e­ version) EPA comment: (Text and Table 11) Aventis' response: Text and tables should be revised. A rat LD50 of 307 mg/ kg was used to calculate the acute risk quotients. The correct value is 301 mg/ kg. EFED Response: As noted previously, references to the rat LD50 have been corrected to represent a value of 301 mg/ kg. Table 11 has been corrected. Aquatic Plants Page: 152 (e­ version) EPA comment: Based on a single core aquatic plant toxicity study available… …recommended that toxicity studies with Lemna gibba, Anabaena flos­ aquae, Skeletonema costatum, and a freshwater diatom be submitted. Aventis' response: The respective studies were submitted to the Agency in 1992 (see comments above to Page 2 of the Memorandum for a complete list and status). EFED Response: As noted previously, EPA requires data on 5 aquatic plant species. Only two of the five species provided data that were classified as acceptable and as having fulfilled guideline test requirements. Therefore, EFED is requesting that aquatic plant studies are repeated following EPA guidelines. 74 Appendix D: Toxicity Assessment Page: 157 (e­ version) EPA comment: Table 1 (spelling of author in MRID No. 00160000) Aventis' response: The author of MRID No. 00160000 should be "Hudson et al. ". Also, it is not obvious why the same reference is one time classified "core" and six times "supplemental". The agency should reconsider if the use of a "supplemental" study (i. e., rock dove) in calculating all acute RQ values is justified. EFED Response: Table 1 has been revised to contain the correct spelling of the reference "Hudson et al." Study classifications reported in Table 1 are based on whether recommended species were used for testing. The only study reported in Table to use the recommended species, i. e., mallard ducks, is classified as core; the remaining studies did not use recommended species and thus are classified as supplemental. Birds, Chronic Toxicity Page: 158 (e­ version) Paragraph: 3 EPA comment: Bird kills attributed to carbaryl and involving blackbirds, ducks, starlings, grackles turkey, and cardinals have been reported in Pennsylvania, Virginia, New Jersey, North Carolina and Michigan (# 1002048­ 001, #1000802­ 001, #1007720­ 020, ## 1000799­ 003, #1004375­ 004). Aventis' response: The paragraph should be moved to the acute bird section. Also, only individuals familiar with this information will recognize the numbers as the incident numbers from the EIIS database. An appropriate reference should be inserted here and in similar citations. EFED Response: EFED concurs with the registrant's comments and the paragraph has been moved to the discussion on acute avian toxicity. Additionally, a reference has been inserted into the paragraph indicating that the information was based on 6( a) 2 ecological incident data. 75 Page: 158 Paragraph: 1 Line: 2 & 3 EPA comment: Exposure to carbaryl at levels equal to or greater than 1000 ppm in the mallard duck results in adverse reproduction effects, such as decrease in number of eggs produced include cracked eggs, fertility, embryonic mortality, and hatching success. Aventis' response: The sentence should be changed. The embryonic mortality and the hatching success were not different from the control. EFED Response: As stated previously, although the data evaluation record for the avian reproduction study lists increased embryonic mortality and reduced hatching success as significant effects, reference to these two effects has been deleted from the text since the original study by Fletcher was not available for secondary review. However, reduced egg production, increased incidence of cracked eggs and decreased fertility are reproductive effects that support EFED's concerns regarding the endocrine disrupting potential of carbaryl. Mammals, Acute and Chronic Page: 158 & 159 (e­ version) EPA comment: (rat LD50 of 307 mg/ kg, NOAEC 80 ppm) Aventis' response: The acute LD50 value for rat should be corrected to 301 mg/ kg, and the chronic NOEAC to 75 ppm from the 2­ generation rat study. EFED Response: As noted previously, the mammalian acute LD50 value has been corrected to 301 mg/ kg and the acute risk quotients have been revised. Additionally, the chronic risk quotients are still based on a NOAEC of 80 ppm. Data from the 2­ generation rat study have not been reviewed; however, the change in NOAEC from 80 to 75 ppm will have no marked effect in EFED's risk assessment. 76 Freshwater Fish, Acute Page: 161 (e­ version) EPA comment: Table 6 Aventis' response: The study classification of reference MRID 40098001 (Mayer & Ellersieck, 1986) should be reconsidered (and handled in a consistent fashion). A number of times the reference is classified "core", while in other instances the classification is "supplemental". The reference is an overview article with little description of test methods, analytical procedures, GLP, or study details. The results are generally listed in extensive tables (although summarized in the text for some chemicals). Such a review article cannot be regarded as a "core" study equivalent to the guideline studies that have to be prepared by registrants. Also, such studies with insufficient test method descriptions should not be used in a risk assessment as the primary source of information. A submission based on such data would have certainly been rejected by the Agency EFED Response: The classification of Mayer and Ellerieck (1986) data reported in Table 6 as either core or supplemental depends on whether EPA­ recommended species were used for testing. Unlike avian toxicity studies where only a limited number of species are recommended for testing, there is a broad range of fish species that EPA views as acceptable for testing. In Table 6, chinook salmon were the only species not recommended by EPA for testing; therefore, the data based on Chinook salmon were classified as supplemental. The only acceptable data available on technical grade carbaryl other than a study on largemouth bass by Johnson and Finley (1980) were from Mayer and Ellersieck (1986). The registrant is encouraged to submit data on the acute toxicity of technical grade carbaryl to address the uncertainties that they have identified. Freshwater Invertebrates, Acute Page: 163 (e­ version) EPA comment: Table 9 Aventis' response: The study classification of reference MRID 40098001 (Mayer & Ellersieck, 1986) should be reconsidered (and handled in a consistent fashion). A number of times the reference is classified "core", while in other instances the classification is "supplemental". The reference is a review article with little description of test methods, analytical procedures, GLP, or 77 study details. The results are generally listed in extensive tables (although summarized in the text for some chemicals). Such an overview article cannot be regarded as a "core" study equivalent to the guideline studies that have to be prepared by registrants. Also, such studies with insufficient test method descriptions should not be used in a risk assessment as the primary source of information. EFED Response: The classification of Mayer and Ellerieck (1986) data reported in Table 6 as either core or supplemental depends on whether EPA­ recommended species were used for testing. As with the freshwater fish studies discussed previously, the registrant is encouraged to submit data on the acute toxicity of technical grade carbaryl to address the uncertainties that they have identified. Estuarine and Marine Invertebrates, Acute Page: 165 (e­ version) EPA comment: Table 13, reference for glass shrimp: Mayer & Ellerersieck Aventis' response: The reference should be corrected in Mayer & Ellersieck. EFED Response: EFED concurs with the registrant's comments and the reference in Table 13 has been corrected to read "Mayer & Ellersieck (1986)." Page: 167 (e­ version) Table 15 EPA comment: Table 15, reference for MRID No. 00265665 Aventis' response: The reference for MRID No. 00265665 should also contain the citation of an author. EFED Response: The reference to MRID 00265665 (Eastern oyster LC50 = 2.5 ppm) has been deleted from Table 15. 78 DISCUSSION EFED Response: EFED has already responded to all of the issues discussed in this section. The reader is referred to earlier responses to comments. 1. Surface Water Concentrations Summary of Registrant Surface Water/ Drinking Water Monitoring Program In section V, page 31 EPA states that the modeling simulations provide a conservative, though not unreasonable, estimate on possible concentrations in drinking water. The data from the registrant drinking water monitoring program provide the best estimate of concentrations of carbaryl in drinking water. This study uses the sampling design for acute endpoints recommended in industry/ EPA meetings during 1999 (weekly sampling during times of peak concentrations over a three year period). Twenty sites representing the highest carbaryl use areas were selected based on the information provided in Appendix I. These included 16 sites in agricultural areas and 4 locations in urban areas. Samples were collected from the inlet and outlet water at each sampling interval. Outlet samples were only analyzed when residues were present in the inlet samples. The analytical method had a limit of quantification of 0.030 ppb and a limit of detection of 0.002 ppb. Table 1 summarizes the results of the monitoring at each of the 20 community water systems. The maximum concentration observed was 0.16 ppb (average of four samples, the highest was 0.18 ppb) in a finished water sample from the Deerfield community water system located on the River Raisin in Lenawee County, Michigan. There were only five other samples above the limit of quantification of 0.030 ppb. One was a raw water sample containing 0.31 ppb from the Little Potato Slough Mutual community water system near Lodi in San Joaquin County, California (the source is the Little Potato Slough). The corresponding finished water sample was 0.007 ppb. A second one was a raw water sample in Brockton, MA, which contained 0.031 ppb. No detectable residues were found in the corresponding finish water sample. The last three samples were from the Shades Mountain plant of the Birmingham community water system on the Cahaba River in Jefferson County, Alabama. Two were raw and finished samples of 0.038 and 0.032 ppb at the same sampling interval in 2001. The other sample was 0.035 ppb in the raw water in a 2000 sample (the corresponding finished sample did not contain carbaryl residues. All residues were transient so the time­ weighted average concentration of carbaryl in each of the years was 0.005 ppb or less at all 20 community water systems. 79 Table 1. Summary of Results from the Carbaryl Drinking Water Monitoring Study. Site Major Uses Maximum Concentration (ppt) T W A C o n c . (ppt)* in Outlet Water Inlet Water Outlet Water 1999 2000 2001* * 1999 2000 2001** 1999 2000 Manatee, FL citrus 9 3 ND 11 ND NA 1 1 West Sacramento, orchards, 3 24 ND 3 10 NA 1 1 Lodi, CA orchards, 12 31 ND 4 7 NA 1 1 Riverside, CA grapes, tree 8 ND ND ND NA NA 1 1 Lake Elsinore, citrus ND 3 6 NA NA Analysis 1 1 Corona, CA citrus ND ND ND NA NA NA 1 1 Beaumont, TX various ND ND ND NA NA NA 1 1 Point Comfort, rice, tree 18 5 ND ND ND NA 1 1 Penn Yan, NY grapes, ND 23 ND NA ND NA 1 1 Westfield, NY grapes, 21 5 ND ND 9 NA 1 1 Jefferson, OR vegetables, ND 10 ND NA ND NA 1 1 Coweta, OK pecans 4 ND *** ND NA *** 1 1 Pasco, WA apples, 2 3 ND ND ND NA 1 1 Manson, WA apples ND ND ND NA NA NA 1 1 Deerfield, MI vegetables 10 4 ND 160 ND NA 5 1 Brockton, MA cranberries 31 27 ND ND 3 NA 1 1 East P oint, G Ahome a nd18184 3 8 ND11 Midlothian, TX home and 14 ND 14 ND NA ND 1 1 Cary, NC home and 4 ND ND ND NA NA 1 1 Birmingham, AL home and 23 35 38 ND ND 32 1 1 * Annual Time Weighted Concentration, outlet values substituted for inlet values when available; values below the detection limit were considered to be half the detection limit. ** Results represent one to six months of sampling into the third year program. *** No results available for the third year of sampling. ND Not detected. NA No outlet samples analyzed due to carbaryl residues not being detected in inlet samples. 80 Summary of Surface Water Data from the NAWQA Program In Section 1 page 3, Section 4 page 28 and in Section 5 page 34, EPA has summarized the available surface water monitoring data from the NAWQA program as having detections in 46% of the 36 NAWQA study units between 1991 and 1998 with a maximum concentration of 5.5 ppb. The following tables summarize the carbaryl analyses presently available from this database. Table 2 is a summary of the carbaryl detections in the updated database analysis recently reported by Larson (2001). This analysis was conducted only for samples collected during a oneyear period of the most intensive sampling from each of the sampling sites. Numerous samples were excluded from this analysis as described by Larson: "A few sites with sufficient sampling for pesticides were excluded from the analysis, in order to minimize bias caused by over­ representation of a particular land use or agricultural setting. … The sampling requirements for a site to be included in the analysis were a minimum of 8 samples collected in 6 or more months during the 1­ year period. In addition, samples must have been collected during the expected period of elevated pesticide concentrations. At most of the sites used in this analysis, 20 to 30 samples were collected during the selected 1­ year period.… Not all samples collected during the year at each site were used in the calculation of the summary statistics, however. Samples collected as part of a fixed­ frequency sampling schedule were included, along with a much smaller number of samples collected during selected high or low flow conditions. Samples collected over a storm hydrograph, or as part of a study of diurnal variability, were excluded in order to avoid bias resulting from repeated sampling during extreme conditions. " Table 2. Carbaryl Detections Reported in Pesticides in Streams Update (Larson, 2001) Site Type Number of Number Carbaryl Detection Frequency (%) Maximum All >= 0.01 >= 0.05 >= 0.10 Agricultural 62 1560 9.2 5. 7 1.8 0. 9 5.2 Urban Streams 22 611 43 37 19 12 3.2 Integrator A 31 595 15 11 2.7 1. 2 0.43 A Large streams and rivers Results in Table 3 and Table 4 show a breakdown of all the carbaryl analyses reported in the USGS NAWQA database, which was downloaded from their web site July 16, 2001. The data are reported separately for the GC/ MS and HPLC/ PDA analyses. 81 Table 3. Frequency of Carbaryl Detections by GC/ MS in Different Concentration Ranges Reported in the NAWQA Database as of July 16, 2001 Land Use Number <= MDL C >0.003 to >0.01 to 0.1 >0.1 to 1 ppb >1 ppb No. % No. % No. % No. % No. % All Samples 10379 8388 80.82 617 5.94 1065 10.26 283 2.73 26 0.25 Agricultural 4349 3888 89.40 188 4.32 225 5.17 46 1.06 2 0. 05 Urban 1763 921 52.24 161 9.13 463 26.26 195 11.06 23 1.30 Mixed A 3648 3022 82.84 247 6.77 345 9.46 33 0.90 1 0. 03 Other B 619 557 89.98 21 3.39 32 5.17 9 1. 45 0 0 A Large streams and rivers. Includes all of the "Integrator" sites listed in Larson, et al. ., 1999 and many more. B Includes forest, rangeland, mining, etc. C The method detection limit (MDL) for carbaryl analyzed by the GC/ MS method is 0.003 : g/ L, but updated MDLs presented in the database may be higher for some analyses and are included in this category. Table 4. Frequency of Carbaryl Detections by LC/ PDA in Different Concentration Ranges Reported in the NAWQA Database as of July 16, 2001 Land Use Number <= MDL C >0.008 to >0.01 to 0.1 >0.1 to 1 ppb >1 ppb No. % No. % No. % No. % No. % All Types 5516 5348 96. 95 9 0.16 93 1.69 54 0.98 12 0.22 Agricultural 2528 2509 99. 25 1 0. 04 13 0. 51 3 0.12 2 0. 08 Urban 1189 1064 89. 49 4 0.34 64 5.38 47 3.95 10 0.84 Mixed A 1523 1501 98. 56 4 0. 26 15 0. 98 3 0.2 0 0 Other B 27627499. 280 0 1 0. 3610. 360 0 A Large streams and rivers. Includes all of the "Integrator" sites listed in Larson, et al. ., 1999 and many more. B Includes forest, rangeland, mining, etc. C The method detection limit (MDL) for carbaryl analyzed by the LC/ PDA method is 0.008 : g/ L, but updated MDLs presented in the database may be higher for some analyses and are included in this category. Summary of Carbaryl Analytical Methods used in the NAWQA Program In a number of instances throughout their review, EPA has made reference to the "poor recovery" for carbaryl noted in a NAWQA summary document (Larson, 1999). In this document, reference is made to mean percent recovery of 24% for carbaryl with a method detection limit (MDL) of 0.003 ppb. The Agency cites this low mean recovery several times as evidence that the concentrations of carbaryl reported in the database widely underestimate the actual concentrations of carbaryl in the water samples. This claim is misleading and should be removed from each location in the draft RED for reasons discussed below. Two analytical methods were developed as part of the NAWQA program and both of them have been used in the analysis of carbaryl. The first method, used for a majority of the NAWQA data reported for carbaryl, is a GC/ MS method with an MDL of 0.003 ppb (Zaugg, et al., 1995). The second method, used for a limited number of samples in which carbaryl was analyzed, is an 82 LC/ Photodiode­ Array (PDA) method with an MDL of 0.008 ppb (Werner et al. ., 1996). In the NAWQA database the quantitative data for carbaryl determined by the GC/ MS method are flagged with an "E", as are data for several other analytes, indicating that the analysts have noted "the potential for variable performance" in the analysis of carbaryl. None of the carbaryl data in the NAWQA database has been corrected for procedural recoveries that were noted in the documents described above. Both of these methods are discussed below in relation to the recoveries found for the methods and the potential impact this could have on the analytical data for carbaryl. Gas Chromatography/ Mass Spectroscopy Method The analytical method most used in the NAWQA program for the analysis of carbaryl in water samples is the GC/ MS method described by Zaugg, et al., 1995. In this multi­ residue method, the analytes are first removed from the water sample by sorption on a C­ 18 solid phase and are subsequently eluted from the solid phase, separated by GC and quantified by mass spectroscopy with selected ion monitoring. The identity of each analyte is confirmed by the appropriate combination of retention time and the ratios of three mass ions that are characteristic for the analyte. The recoveries for carbaryl spiked at different levels into three different types of water and analyzed by the GC/ MS method are shown in Table 5 Mean percent recoveries of 151 and 202% were found for carbaryl fortified at 0.1 and 1.0 : g/ L in reagent grade water. A preliminary MDL of 0.046 : g/ L was calculated for the 0.1 : g/ L spiking level. Mean percent recoveries of 10 and 75% were found for carbaryl fortified at 0.1 and 1.0 : g/ L in a surface water sample collected from the South Platte River. However, carbaryl was detected at 0.18 : g/ L in this water, or nearly twice the low spike level, raising questions about the validity of this result. Mean percent recoveries of 94 and 86% were found for carbaryl fortified at 0.1 and 1.0 : g/ L in a ground water sample collected from a well in Denver. A mean recovery value of 24% was reported for reagent­ grade water fortified at a level of 0.03 : g/ L with a method detection limit calculated at 0.003 : g/ L. Table 5. Recovery and Precision for Multiple Determinations of Carbaryl in GC/ MS Method for Carbaryl Spiked in Different Water Samples Water type Spike Concentration Mean Recovery (%) MDL Calculated Reagent Grade 0. 1 151 0.046 Reagent Grade 1. 0 202 ­ Surface A 0.1 10 ­ Surface A 1.0 75 ­ Ground B 0.1 94 ­ Ground B 1.0 86 ­ Reagent Grade 0. 03 24 0. 003 A Surface water was collected from the South Platte River near Henderson, Colorado. This water was found to contain significant concentrations of several pesticides including 0.18 : g/ L carbaryl. This concentration was subtracted from the values determined to give corrected results. B Ground water was collected from the Denver Federal Center Well 15. 83 Whereas the values reported by Zaugg, et al. (1995) are of interest in validating the analytical method, they are not as useful in evaluating the validity of the data contained in the NAWQA database. Therefore, quoting the mean recovery value of 24% for reagent grade water spiked with carbaryl at 0.03 : g/ L as evidence that the concentrations reported in the database underestimate the actual concentrations of carbaryl present in the water samples is misleading. A more useful measure of the validity of the values in the database lies with the quality control checks that have been incorporated into the analysis of samples in the NAWQA program. In a preliminary report, Martin (1999) reported the quality control data collected as part of the NAWQA surface and ground water programs by the 1991 NAWQA Study Unit teams or the National Water Quality Laboratory (NWQL) during 1992 to 1996. The data that were compiled includes field blanks, laboratory control spikes and field matrix spikes, which are defined below by Martin. "Field blanks were collected at the field site with pesticide­ grade blank water and are exposed to the field and laboratory environments and equipment similarly to environmental samples. Field blanks measure the frequency and magnitude of contamination (one type of positive bias) in environmental water samples from sources in the field and/ or laboratory. Contamination is the main cause of falsepositive detections (detecting a pesticide in a sample when, in truth, it is absent)." "Laboratory control spikes measure the bias and variability of the analytical method at a particular concentration. One laboratory control spike is measured in each analytical set of environmental samples. The laboratory control spike has the target pesticides spiked into pesticide­ grade blank water at the laboratory and extracted, processed, and analyzed like environmental samples. Laboratory control spikes analyzed by GCMS were spiked at 0.1 µg/ L…" "Field matrix spikes measure the bias and variability of the analytical method PLUS any potential effects caused by (1) degradation of pesticides during shipment to the laboratory, (2) inferences in the determination of pesticides from unusual characteristics of the environmental water sample (" matrix effects"), and (3) other chemical processes that cause bias or variability in the measurements of pesticides in environmental water samples. Field matrix spikes analyzed by GCMS were spiked at 0.1 µg/ L,…" All of the carbaryl analyses in the field blanks, field matrix spikes and lab control spikes were conducted following the same method described by Zaugg et al., 1995 that was used to generate a majority of the carbaryl data contained in the NAWQA database. The data below were excerpted from Tables 1 to 4 of the Martin report. Carbaryl is found in these tables under parameter 82680. Out of 145 samples taken as ground water field blanks, carbaryl was not detected in any of the samples indicating a lack of false positives. Out of 171 samples taken as surface water field 84 blanks, carbaryl was reported in two samples (1.2% false positives) at reported concentrations of 0.009 and 0.012 : g/ L. A summary of the results for the field matrix spikes and the lab control spikes is presented in Table 6 Mean recovery for the 306 field matrix spikes was 115% of the spiking level of 0.1 : g/ L with a median recovery of 94.4% and a 90 th percentile recovery of 200%. This indicates the potential for the method to over­ estimate the concentration of carbaryl present in the water samples and is consistent with the initial data reported for the reagent water samples by Zaugg et al. (1995). Mean recovery for the 1000 lab control spikes was 99.6% of the spiking level of 0.1 : g/ L with a median recovery of 93% and a 90 th percentile recovery of 185%. These data suggest an adequate level of detection of carbaryl in QC samples that were analyzed as part of the same process used in the NAWQA survey of pesticides in surface and ground water. 85 Table 6. Percent Recoveries of Carbaryl Detected by the NAWQA GC/ MS Method in Laboratory Control Spikes and Field Matrix Spikes at a Spiking level of 0.1 : g/ L Sample Type Number of 10 th Median Mean 90 th Maximum Field Matrix Spike 306 40 94.4 115.0 199.9 456 Laboratory Control 1000 20 93.0 99.6 185.1 329 The following disclaimer was taken verbatim from the provisional report by Martin (1999) and pertains to the data provided above on the recovery of carbaryl in the field matrix spike samples. "The field matrix­ spike data have not been reviewed thoroughly, are provisional, and are subject to change. Further review of the field­ spike data is expected to identify spikes that have extremely high or low recoveries because the spikes either were improperly collected or incorrectly documented in the NAWQA QC data base. The expected result of further review is a data set of field matrix spikes with fewer extreme values than the provisional data set described in this paper; consequently, the provisional data set provides a conservative estimate of the quality of the NAWQA pesticide data. Interpretations of field matrix spike data in this paper are not expected to change greatly as a result of further review of the data, however, the statistics and confidence limits reported in the text and tables will change on further review (especially for pesticides with low numbers of field spikes [less than 50])." High­ Performance Liquid Chromatography/ Photodiode­ Array Method Another analytical method used in the NAWQA program for the analysis of carbaryl in water samples is the LC/ PDA method described by Werner, et al., 1996. This method was used for the analysis of carbaryl in a limited number of samples as noted above. In this multi­ residue method, the analytes are first removed from the water sample by sorption on a Carbopak­ B solid phase extraction cartridge and are subsequently eluted from the solid phase, separated by HPLC and quantified by light absorption using a photodiode­ array detector. The identity of each analyte is confirmed by the appropriate combination of retention time and light absorption characteristics. The recoveries for carbaryl spiked at different levels into three water samples and analyzed by this method is shown in Table 7 The recoveries ranged from 58% to 84% for the different water and spiking levels. Laboratory control spikes in organic­ free water resulted in a mean recovery of 61% over a two­ year sampling period. These results indicate reasonable levels of carbaryl recovery from each of the different types of water evaluated for the method. 86 Table 7. Recovery and Precision for Multiple Determinations of Carbaryl in LC/ PDA Method for Carbaryl Spiked in Different Water Samples Water type Spike Concentration Mean Recovery (%) MDL Calculated Organic­ Free 0.1 82 0. 008 Organic­ Free 1.0 70 ­ Surface A 0.1 84 0. 016 Surface A 1.0 84 ­ Ground B 0.1 58 0. 018 Ground B 1.0 64 ­ Organic­ Free 0.5 61 C ­ A Surface water was collected from the South Platte River at Englewood, Colorado. B Ground water was collected from Jefferson County, Colorado (Arvada Well 14). C National Water Quality Laboratory results produced using 5 operators and 7 instruments over 2 years (about 350 data points). Summary of Surface Water Data from the California DPR Surface Water Database In Section 5 pages 34 to 37 EPA has summarized surface water monitoring data from various sources. One source not included in this discussion is the California Surface Water Monitoring Database. The number of analyses and the detections of carbaryl residues reported in the database are summarized in Table 8. Carbaryl was detected at levels above the LOQ in only 5.1% of the 2,690 samples analyzed. The mean concentration of carbaryl in the 140 samples above the LOQ was 0.42 ppb. The highest concentration of carbaryl that was detected was 8.4 ppb. An analysis of the data in the California Department of Pesticide Regulation's surface water database as of July 15, 2000 was conducted for carbaryl. The following summary of the contents of the database is adapted from information provided by the California DPR. The database contains monitoring results for pesticides in samples taken from California rivers, creeks, urban streams, agricultural drains, the Delta, and urban stormwater runoff. As of July 15, 2000, the database contained the results of 30 studies conducted by federal, state, and local agencies, private industry, and an environmental group. A total of 4,660 samples were taken in 16 counties from January 1991 through March 2000. Each record in the database is the result of one analysis for a pesticide active ingredient or breakdown product. The database contains a total of 92,296 analytical records. Only information on the analytical detection of carbaryl in these water samples is summarized in Table 8 below. Table 8. Carbaryl Detections Reported in California DPR Surface Water Monitoring Database Land Use Number <= LOQ >0.003 to >0.01 to 0.1 >0.1 to 1 ppb >1 ppb No. % No. % No. % No. % No. % All Samples 2690 2553 94.91 13 0.48 55 2.04 55 2.04 14 0.52 Concentrations of analytical results that are reported below the limit of quantification are reported as a zero in the database concentration field. The LOQs for the different methods used to generate the data contained in the database ranged from 0.003 to 0.5 : g/ L, with a majority of the samples analyzed with an LOQ of 0.05 : g/ L or less (Table 9) . 87 Table 9. Limits of Quantification for Carbaryl Analytical Methods Reported in California DPR Surface Water Monitoring Database LOQ ( : g/ L) 0.003 0.041 0.044 0.05 0.07 0.1 0. 5 Number of 267 238 168 1353 92 53 146 88 2. Ground Water Concentrations In Section 5 page 34 EPA summarized information on the detection of carbaryl in groundwater from the EPA Pesticides in Groundwater Database, the EPA STORET database and the NAWQA database. Each of the databases shows a pattern of very low levels of carbaryl detection in few groundwater resources. These analyses confirm several statements made by the Agency that carbaryl has limited potential to impact groundwater resources. However, on page 2 of the Memorandum issued June 28, 2001, in conjunction with the EFED RED chapter for carbaryl, EPA is requiring additional information on "Surface and groundwater monitoring in urban and suburban use areas (non­ guideline)." Based on the characteristics of carbaryl and the available data demonstrating limited impact of carbaryl on ground water resources, additional studies to evaluate the potential for carbaryl to contaminate groundwater are unnecessary and unwarranted. Summary of Ground Water Data from the NAWQA Program In Section 5, pages 33 ­ 34, EPA has summarized ground water monitoring data available for carbaryl. The database that contains the most extensive evaluation of the impact of the most recent uses of carbaryl on ground water is the NAWQA database. One deficiency of the NAWQA program is that samples are targeted to agricultural and urban areas but not to areas treated with the specific chemical being analyzed. However, given the use patterns of carbaryl, the use of carbaryl has certainly occurred near a number of these wells. Another deficiency is that when residues are found, that while they may be representative of residues in ground water, they may not be representative of residues in ground water used for drinking water due to the location of the sampled wells relative to potable drinking water wells. EPA cited a 1998 review of the NAWQA database by Kolpin and stated: "Carbaryl was detected at greater than the detection limit (0.003 µg/ L) in 1.1 % of groundwater samples from 1034 sites across the U. S. by U. S. G. S. NAQWA (sic) program. The maximum observed concentration was 0.021 µg/ L." This 1998 analysis has been extended by additional study data collected by the NAWQA program. The additional data continue to show a limited number of low level detections of carbaryl in ground water samples. Table 10 below summarizes a more recent provisional review by Kolpin (2001) of the updated NAWQA database. Not all of the water samples were used to calculate the summary statistics as noted by Kolpin: "To preclude bias in these summary statistics from wells that were sampled more than once, the data set was condensed such that each well had a single pesticide analysis. This generally was the first sample collected. However, subsequent samples were selected if these samples contained more pesticide data (i. e., a larger number of pesticides were analyzed). Wells that were designed to be a part of both a land­ use study and a major aquifer survey were used in each summary. Because of 89 uncertainties in the source of water and contributing land­ use area, springs and drains were excluded from these summaries." Table 10. Carbaryl Detections Reported in Pesticides in Ground Water Update (Kolpin, 2001) Site Type Number Carbaryl Detection Frequency (%) Maximum All >= 0.01 >= 0.05 >= 0.10 Agricultural Land­ 1244 0.40 0.16 0.0 0. 0 0.019 Urban Land­ Use 634 2.1 1. 3 0.0 0. 0 0.031 Major Aquifers 1849 0.59 0.54 0.05 0.05 0.539 90 REFERENCES Burgos, W. D., J. T. Novak and D. F. Berry. 1996. Reversible Sorption and Irreversible Binding of Naphthalene and " ­Naphthol to Soil: Elucidation of Processes. Environ. Sci. Technol., 30: 1205­ 1211. Burgos, W. D., D. F. Berry, A. Bhandair, and J. T. Novak. 1999. Impact of Soil­ Chemical Interactions on the Bioavailability of Naphthalene and 1­ Naphthol. Water Research, 33: 3789­ 3795. Hassett, J. J., W. L. Banwart, S. G. Wood, and J. C. Means. 1981. Sorption of " ­naphthol: Implications concerning the limits of hydrophobic sorption. Soil Sci. Soc. Am. J 45( 1): 38­ 42. Kolpin, D. W. June 11, 2001. Pesticides in Ground Water, Summary statistics; Results of the National Water Quality Assessment Program (NAWQA), 1992­ 1998. Available for download from http:// water. wr. usgs. gov/ pnsp/ pestgw/. Larson, S. J. June 11, 2001. Pesticides in Streams, Summary statistics; Results of the National Water Quality Assessment Program (NAWQA), 1992­ 1998. Available for download from http:// water. wr. usgs. gov/ pnsp/ pestsw/. Martin, J. D. October 27, 1999 .Quality of Pesticide Data for Environmental Water Samples Collected for the National Water­ Quality Assessment Program, 1992­ 96 and Examples of the Use of Quality­ Control Information in Water­ Quality Assessments. Available for review at: http:// water. wr. usgs. gov/ pnsp/ rep/ qcsummary/ McCall, P., D. Laskowski, R. Swann, and H. Dishburger. 1980. Measurement of Sorption Coefficients of Organic Chemicals and Their Use in Environmental Fate Analysis. In: Test Protocols for Environmental Fate & Movement of Toxicants. Proceedings of a Symposium, Association of Official Analytical Chemists, 94th Annual Meeting, October 21, 22, 1980. pp 89­ 109. Werner, I., L. A. Denovic, V. Conner, V. De Vlaming, H. Bailey and D. E. Hinton. 2000. InsecticideCaused Toxicity to Ceriodaphnia dubia (Cladocera) in the Sacramento­ San Joaquin River Delta, California. Environmental Toxicology and Chemistry, 19: 215­ 227. Werner, S. L., M. R. Burkhardt and S. N. DeRusseau. 1996. METHODS OF ANALYSIS BY THE U .S. GEOLOGICAL SURVEY NATIONAL WATER QUAL I T Y LABORATORY— DETERMINATION OF PESTICIDES IN WATER BY CARBOPAK­ B SOLIDPHASE EXTRACTION AND HIGH­ PERFORMANCE LIQUID CHROMATOGRAPHY. U. S. Geological Survey Open­ File Report 96­ 216, 42 pp. Available for download from http:// wwwnwql. cr. usgs. gov/ Public/ pubs/ OFR96­ 216/ OFR96­ 216. html. 91 Zaugg, S. D., M. W. Sandstrom, S. G. Smith and K. M. Fehlberg. 1995. METHODS OF ANALYSIS BY THE U. S. GEOLOGICAL SURVEY NATIONAL WATER QUALITY LABORATORY— DETERMINATION OF PESTICIDES IN WATER BY C­ 18 SOLID­ PHASE EXTRACTION AND CAPILLARY­ COLUMN GAS CHROMATOGRAPHY/ MASS SPECTROMETRY WITH SELECTED­ ION MONITORING. U. S. Geological Survey Open­ File R e p o r t 9 5 ­1 8 1 , 4 9 p p . A v a i l a b l e f o r d o w n l o a d f r o m http:// wwwnwql. cr. usgs. gov/ Public/ pubs/ OFR95­ 181/ OFR95­ 181. html. 92 Confidential Business Attachment APPENDIX 1 Surface Water Monitoring for Residues of Carbaryl in High Use Areas of the United States (Stone Environmental, Inc. Report #99­ 1005­ F) (hard copy provided). 93 Confidential Business Attachment APPENDIX 2 Calculation of County Average Carbaryl Use Rates (hard copy provided)

epa

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regulations

EPA-HQ-OPP-2002-0138-0019

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES CERTIFIED MAIL June 25, 2002 Danielle LaRochelle Registration Product Manager Aventis CropScience USA P. O. Box 12014 2 T. W. Alexander Drive Research Triangle Park, NC 27709 Re: Second Error Correction of Carbaryl Risk Assessments Dear Ms. LaRochelle: Within two weeks from the date of this letter, please identify and comment on any errors in the enclosed risk assessment documents for carbaryl, addressing only typographic, mathematical, or computational­ type errors. The enclosed documents include the human health and the environmental fate and effects risk assessments. Also enclosed for your reference are supporting documents for the human health risk assessment. Last August, Aventis completed its first error correction review of these documents. As a courtesy, EPA is offering Aventis a second error correction review of these documents because of substantive changes described later in this letter. On receiving your error correction submission, the Agency will evaluate your comments and will revise the risk assessments as necessary. At this phase, EPA will not address comments concerning matters of policy, interpretation, or applicability of data. Aventis will have ample opportunity to submit such comments during the 60­ day public comment period that will begin in the next few weeks. As part of your two week review, please also inform the Agency in writing of any claims of confidential business information (CBI) contained in these documents. If we do not receive notice in writing of any such claims within the two weeks, we will assume the document is free of CBI. Please send, in writing, the results of your error correction and CBI review to: Anthony Britten US EPA (7508C) 1200 Pennsylvania Avenue, N. W. Washington, D. C. 20460 E­ mail Address: britten. anthony@ epa. gov Fax: (703) 308­ 8005 2 Background EPA is offering this second courtesy error review because of substantive changes to the risk assessments. These changes were prompted by new data Aventis submitted since its first error correction review. The new data includes a two­ generation rat reproduction study, data from a developmental neurotoxicity study, and three dermal studies. EPA also rereviewed carbaryl under the latest cancer assessment guidelines. The two weeks offered for this error review coincides with the time necessary to publish the Federal Register notice announcing the start of the Phase 3 public comment period. The publication process is now underway. Two weeks is also the period EPA usually offers for a second review of typographic, mathematical or computational­ type errors. As part of its Phase 1 error review, Aventis submitted substantive comments to the Agency. EPA generally does not consider substantive comments received during Phase 1. However, in this case, EPA considered the comments while awaiting and then analyzing the new data from Aventis. EPA will specifically respond to these comments in a document prepared at the end of phase 3. You need not resubmit your substantive comments. Please keep your review in the next two weeks focused solely on typographic, mathematical or computational­ type errors. Again, Aventis will also have the full 60­ days of Phase 3 to submit further substantive comments, which EPA will address in its next revision of the risk assessments. The appropriate level of detail for your error response would be the amount of information that would fit in the margins of a pen­ and­ ink markup. In fact, a pen­ and­ ink markup would be the preferred response. Please complete your review of the comprehensive risk assessments before focusing attention on the supporting documents. Prioritizing your review in this way will help ensure the most significant corrections are made in a timely way. Sending corrections "piecemeal" is also recommended. Adopting these standards of review should allow both Aventis and EPA enough time to correct the enclosed documents before their release for Phase 3 public comment. If you have questions about this request, please contact Anthony Britten, the Chemical Review Manager for carbaryl, at (703) 308­ 8179. Sincerely, // signed by Anthony Britten for// Betty Shackleford, Acting Associate Director Special Review and Reregistration Division Enclosures

epa

2024-06-07T20:31:42.533337

regulations

EPA-HQ-OPP-2002-0138-0020

Supporting & Related Material

July 18, 2002 Mr. Anthony Britten, SRRD Document Processing Desk (7504C) Office of Pesticide Programs U. S. Environmental Protection Agency Room 266A, Crystal Mall 2 1921 Jefferson Davis Highway Arlington, Virginia 22202 Dear Mr. Britten, Re: Carbaryl; Chemical number 56801; EPA Reg. No. 264­ 324 Error Correction of Carbaryl Risk Assessments Attached are our comments on the error correction review of the revised HED and EFED Risk Assessments for Carbaryl. We have also included some comments on certain supporting documents for the HED Chapter. One issue of concern was noted during our review of the risk assessments. It appears that the Agency intends to include the Data Evaluation Records (DERs) for a number of carbaryl studies in the draft EFED Chapter which will be made available to the public for the 60­ day comment period. We believe that it is inappropriate to include the DERs in the RED document. A sufficiently detailed summary of study findings is already provided in the EFED Chapter. The summary of endpoints that is included in the draft Carbaryl EFED Chapter is typical of other Draft EFED REDs that have been issued recently and provides sufficient information to allow the reader to determine the endpoints that were selected for modeling and the justification for their selection. The inclusion of the more detailed information present in the DERs is unnecessary. We have reviewed the dockets for many of the RED documents that have recently been issued (many other insecticides and several fungicides) and none of them include DERs in any of the preliminary Environmental Fate and Effects Assessments. DERs should be made available to the public through the regular procedure under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. The inclusion of the DERs in the docket that is publicly available circumvents this process and is a departure from the procedures that have been followed until now by the Agency. It is unclear why the Agency chose to change their policy for only certain DERs for a single product when adequate summary information is already provided in the text of the Carbaryl EFED Chapter. This issue deserves careful consideration before the Agency makes the decision to amend their existing policy on providing this type of information to the public. Your help in ensuring that July 12, 2002 Mr. Anthony Britten Page 2 of 2 accepted procedures are followed for the public review of the Carbaryl RED Chapters is greatly appreciated. Sincerely, Danielle A. Larochelle Registration Manager Corr. # daL018­ 02 CARBARYL PC Code No. 056801; Case 0080 Human Health Risk Assessment and Supporting Documents – Phase 1 Error Correction – July 12, 2002 Aventis CropScience P. O. Box 12014, 2 T. W. Alexander Drive Research Triangle Park, NC 27709 CARBARYL Human Health Risk Assessment and Supporting Documents ­ Phase 1 Error Correction TABLE OF CONTENTS TABLE OF CONTENTS ................................................................................................................ 2 HUMAN HEALTH RISK ASSESSMENT, JUNE 7, 2002............................................................ 3 General..................................................................................................................................... 3 1.0 Executive Summary.......................................................................................................... 3 Dietary Risk Estimates.................................................................................................... 3 Aggregate Risks and DWLOCs...................................................................................... 3 Issues for Considerations ................................................................................................ 4 4.0 Non­ Occupational Risk Assessment and Characterization............................................... 4 4.1 Summary of Registered Uses................................................................................... 4 4.2 Dietary Risk Assessment ......................................................................................... 5 4.3 Estimated Environmental Concentrations in Water......................................... 5 4.3.1 Environmental Fate Characteristics ....................................................... 5 4.4 Residential Risk Assessment ........................................................................... 6 4.4.2.2 Residential Handler Cancer Risks ...................................................... 6 4.4.3 Residential Postapplication Risk Assessment........................................ 6 5.0 Aggregate Risk Assessments and Risk Characterization.................................................. 7 5.1 Calculation of Aggregate Risks and DWLOCs....................................................... 7 5.7 Summary of Aggregate Risks .................................................................................. 7 7.1 Occupational Handler Risk Assessment .................................................................. 8 REVISED PRODUCT AND RESIDUE CHEMISTRY CHAPTERS FOR THE REREGISTRATION ELIGIBILITY DECISION; MAY 30, 2002........................................ 9 General..................................................................................................................................... 9 Product Chemistry Chapter of the RED Document................................................................. 9 Manufacturing­ Use Products .......................................................................................... 9 Residue Chemistry Chapter of the RED Document ................................................................ 9 Regulatory Background ................................................................................................ 10 Summary of Science Findings ...................................................................................... 10 GLN 860.1200: Directions for Use............................................................... 10 GLN 860.1380: Storage Stability Data ­ Plants............................................ 10 GLN 860.1500: Crop Field Trials................................................................. 10 GLN 860.1520: Processed Food/ Feed .......................................................... 11 GLN 860.1480: Meat, Milk, Poultry, Eggs .................................................. 11 Tolerance Reassessment Summary............................................................................... 12 Table C. Tolerance Reassessment Summary for Carbaryl ........................... 12 Miscellaneous Typographical Errors ............................................................................ 12 3 Human Health Risk Assessment, June 7, 2002 General Several References Throughout the Document EPA statement: The company name of the registrant is listed throughout the document as Aventis Corporation, Aventis Crop Sciences, Aventis Crop Science, and Aventis Crop Science Corporation. Aventis' comment: Reference should be either to Aventis or Aventis CropScience. 1.0 Executive Summary Dietary Risk Estimates Page 7; Paragraph 3; Lines 4­ 6 EPA statement: "In livestock commodities, carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, 5­ methoxy­ 6­ dydroxy carbaryl and all residues which can be hydrolyzed to carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, 5­ methoxy­ 6­ hydroxy carbaryl under acidic conditions …." Aventis' comment: Add "and" before "5­ methoxy­ 6­ hydroxy carbaryl under acidic conditions ….". Aggregate Risks and DWLOCs Page 11; Paragraph 4; Lines 9­ 14 EPA statement: "Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment (133% of aPAD). However, the risk picture could substantively change if residential risks are refined based on updated use information from the carbaryl use survey yet to be submitted to the Agency, and the Agency uses the CMBS data even with the caveats associated with that study." Aventis' comment: This statement is inconsistent with information presented elsewhere in the HED Chapter. As written, the statement implies that the Agency has not yet approved the use of the CMBS data in the dietary risk assessment for carbaryl. However, EPA states in the Hazard Characterization section of the Executive Summary, page 6, paragraph 2, line 9, "Dietary exposures were calculated using FDA and PDP monitoring data, a carbamate market basket survey, and …" which indicates that the EPA approved the use of the CMBS data. In addition, it is stated on pages 8 and 31 (Footnotes) and page 37, first paragraph: "At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in 4 dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. Hence, the use of these data in this assessment should be considered with associated caveats …" Issues for Considerations Page 16, Paragraph 1, Lines 19­ 26 EPA statement: It should also be noted that Aventis Crop Sciences is in the process of conducting biological monitoring studies in residences where there have been carbaryl applications (sampling urine from children) and also for field workers during harvesting and hand thinning operations in apples and cherries. Preliminary results from these studies, based on personal communication with Aventis scientists (they have not been submitted to the Agency yet), indicate body burden levels similar to those calculated by the Agency for risk assessment purposes. For example, the turf risk assessments completed by the Agency are intended to provide upper percentile exposures. The data from the monitored children appear to indicate similar results a the upper percentiles. Aventis' comment: This statement does not accurately reflect the true scope of the study and would be misleading. The comment would be more accurate as follows: "It should also be noted that Aventis CropScience has completed and is in the process of submitting to the Agency a biomonitoring study of individuals in residences following the application by a member of the household to the lawn and either the vegetable garden or ornamental flowers. A biomonitoring study of for field workers during harvesting and hand thinning operations in apples and cherries will also be submitted to the Agency. Based on personal communication with Aventis scientists, preliminary results from the residential biomonitoring study indicate that the highest percentiles of the distribution of the younger children in the homes were similar to those predicted in the Agency's turf risk assessment for toddlers that are intended to represent the higher percentiles of the exposure distribution." 4.0 Non­ Occupational Risk Assessment and Characterization 4.1 Summary of Registered Uses Page 28; Table 3: Technical and Manufacturing Carbaryl Products Aventis' comment: Carbaryl – Technical Products ¨ EPA Registration No. 45735­ 24 (99%), Carbaryl 99% Technical Grade Insecticide, Burlington Scientific Corporation, should be added to the list of registered carbaryl technical. ¨ EPA Registration No. 264­ 325 (97.5%), Aventis CropScience, should be included in the list of manufacturing­ use products. 5 Carbaryl – Manufacturing­ Use Products ¨ EPA Registration No. 5481­ 190 (46% FI), AMVAC Chemical corporation , is an active registration and should be added to the list of Manufacturing­ Use Products. (It is listed in Table 1, page 2, of the Product and Residue Chemistry Chapters) ¨ EPA Registration No. 4816­ 270 (97.5%) is no longer active; it was transferred to EPA Registration No. 432­ 982 (97.5%), Aventis Environmental Science USA LP, on February 22, 2000. ¨ EPA Registration No. 4816­ 407 (1%) is no longer active; it was transferred to Reg. No. 432­ 1006 on February 22, 2000 and subsequently transferred to Reg. No. 73049­ 238, Valent Bioscience Corporation, on June 27, 2001 (neither 4816­ 407 or 432­ 1006 are active). ¨ As stated above, EPA Registration No. 264­ 325 (97.5%), Aventis CropScience, should be added to the list of manufacturing­ use products. 4.2 Dietary Risk Assessment Page 31; Paragraph 1; Lines 3­ 5 EPA statement: Carbaryl is used late in the season at maximal seasonal rates of 6­ 12 lb ai/ acre. [Note: A Special Local Needs registration in California uses 16 lb ai/ acre as a maximum rate on citrus.] Aventis' comment: The Section 3 registration of carbaryl products cover the use on citrus at the rate of 5­ 16 lbs ai/ acre in the state of California only. 4.3 Estimated Environmental Concentrations in Water 4.3.1 Environmental Fate Characteristics Section 4.3.1, Pages 39­ 40 Aventis' comment: The text in section 4.3.1 does not include the revisions that were made to the EFED draft Chapter and is inconsistent. For example: ¨ on Page 39, first paragraph of Section 4.3.1, first sentence "Carbaryl and its degradate 1­ naphthol are fairly mobile but are not likely to persist or accumulate in the environment." ¨ on Page 40, Paragraph 1, last sentence "Carbaryl is mobile to very mobile in the environment (Kf = 1.7 to 3.2)." The information in the EFED chapter has been revised to ¨ "Carbaryl is considered to be moderately mobile in soils" and the Kf range is 1.7 to 3.5 (EFED Chapter, Page 20 – Table 3; Page 22 – Mobility). ¨ "… literature information suggest that it [1­ naphthol] is less persistent and less mobile than parent carbaryl.""( EFED Chapter, Page 26, 1­ Naphthol Fate and Transport). 6 Section 4.3.1, Paragraphs 2 and 3 (pages 39­ 40) EPA statement: In these 2 paragraphs, the chemical name for the major carbaryl degradation product is typed as "1­ napthol". Aventis' comment: Correct spelling is "1­ naphthol". 4.4 Residential Risk Assessment 4.4.2.2 Residential Handler Cancer Risks Page 52; Paragraph 1; Lines 11­ 12 EPA statement: "…[ Note: Scenarios where risks are still of concern (i. e., <1x10 ­6 ) are highlighted in the table.]. Aventis' comment: (i. e., "<" 1x10 ­6 ) should be corrected to (i. e., ">" 1x10 ­6 ). 4.4.3 Residential Postapplication Risk Assessment Page 59; Paragraph 1; Lines 4­ 6 EPA statement: These levels were The Agency instead considers them a qualitative indicator that exposures in the general population are likely to occur. Aventis' comment: Words are missing from the first part of the sentence. Page: 59 Paragraph: 2 Lines: 1­ 6 EPA statement: Aventis Crop Science is in the process of conducting a biomonitoring study with children who live in households where carbaryl has been used. Based on discussions with Aventis, the preliminary results indicate that levels at the highest percentiles of the distribution are similar to those predicted in the Agency's turf risk assessment for toddlers which are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission Aventis' comment: The statement does not accurately reflect the true scope of the study and would be misleading. The comment would be more accurate as follows: Aventis CropScience has completed and is in the process of submitting to the Agency a biomonitoring study of individuals in residences following the application by a member of the household to the lawn and either the vegetable garden or ornamental flowers. Based on discussions with Aventis, preliminary results indicate that the highest percentiles of the distribution of the younger children in the homes were similar to those predicted in the Agency's turf risk assessment for toddlers that are 7 intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission. 5.0 Aggregate Risk Assessments and Risk Characterization 5.1 Calculation of Aggregate Risks and DWLOCs Page 72; Paragraph 2; Lines 6­ 11 EPA statement: "Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment. However, the risk picture could substantively change if residential risks are refined based on updated use information from the carbaryl use survey yet to be submitted to the Agency and the Agency chooses to regulate using the results of the CMBS." Aventis' comment: This statement is inconsistent with information presented elsewhere in the HED Chapter. As written, the statement implies that the Agency has not yet approved the use of the CMBS data in the dietary risk assessment for carbaryl. However, EPA states in the Hazard Characterization section of the Executive Summary, page 6, paragraph 2, line 9, "Dietary exposures were calculated using FDA and PDP monitoring data, a carbamate market basket survey, and …" which indicates that the EPA approved the use of the CMBS data. In addition, it is stated on pages 8 and 31 (Footnotes) and page 37, first paragraph: "At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. Hence, the use of these data in this assessment should be considered with associated caveats …" 5.7 Summary of Aggregate Risks Page 76; Paragraph 2; Lines 3­ 4 continued on page 77 EPA statement: "Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment. However, the risk picture could substantively change if residential risks are refined based on updated use information from the carbaryl use survey yet to be submitted to the Agency and the Agency chooses to regulate using the results of the CMBS." Aventis' comment: This statement is inconsistent with information presented elsewhere in the HED Chapter. As written, the statement implies that the Agency has not yet approved the use of the CMBS data in the dietary risk assessment for carbaryl. However, EPA states in the Hazard Characterization section of the Executive Summary, page 6, 8 paragraph 2, line 9, "Dietary exposures were calculated using FDA and PDP monitoring data, a carbamate market basket survey, and …" which indicates that the EPA approved the use of the CMBS data. In addition, it is stated on pages 8 and 31 (Footnotes) and page 37, first paragraph: "At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. Hence, the use of these data in this assessment should be considered with associated caveats …" 7.1 Occupational Handler Risk Assessment Page: 83; Paragraph 5; Lines 9­ 10 and Footnote EPA statement: There are no data compensation issues with any of these data. 11 . (Footnote) 11 Non­ ORETF data included in MRIDs 451672­ 01 and 452507­ 01 were from studies submitted by Aventis CropScience. The propoxur trigger sprayer study has a signed PHED data waiver but has not been included into PHED. Aventis' comment: Aventis concurs that there are no data compensation issues. However, the rationale presented for the propoxur trigger sprayer study is not accurate. The PHED data waiver is applicable only when the data are in PHED and not when cited outside of PHED. The propoxur study does not trigger data compensation because the study is the property of Bayer CropScience which has recently acquired Aventis CropScience. 9 Revised Product and Residue chemistry Chapters for the Reregistration Eligibility Decision; May 30, 2002 General Several References Throughout the Document EPA statement: The company name of the registrant is listed throughout the document as Aventis Ag Company. Aventis' comment: Reference should be to Aventis CropScience. Product Chemistry Chapter of the RED Document Manufacturing­ Use Products Page 2; Table 1 – Registered Carbaryl Manufacturing­ Use Products Aventis' comment: ¨ EPA Registration No. 45735­ 24 (99%), Carbaryl 99% Technical Grade Insecticide, Burlington Scientific Corporation, should be added to the list of registered carbaryl technical. ¨ EPA Registration No. 4816­ 270 (97.5%) is no longer active; it was transferred to EPA Registration No. 432­ 982 (97.5%), Aventis Environmental Science USA LP, on February 22, 2000. ¨ EPA Registration No. 4816­ 407 (1%) is no longer active; it was transferred to Reg. No. 432­ 1006 on February 22, 2000 and subsequently transferred to Reg. No. 73049­ 238, Valent Bioscience Corporation, on June 27, 2001 (neither 4816­ 407 or 432­ 1006 are active). ¨ The name of the registrant for EPA Registration No. 769­ 971 is Value Gardens Supply, LLC. Corresponding corrections should be made to the Product Chemistry Section of the Memorandum for this Chapter and in other sections of the Product Chemistry Chapter of the Reregistration Eligibility Decision (RED) Document. Residue Chemistry Chapter of the RED Document Several References Throughout the Document EPA statement: The company name of the registrant is listed throughout the document as Aventis Ag Company, Aventis Ag Co., and Aventis Crop Science. Aventis' comment: Reference should be to Aventis CropScience. 10 Regulatory Background Page 2; Paragraph 2; Line 5 EPA statement: "… but should not delay on the reregistration eligibility decisions for carbaryl." Aventis' comment: Remove "on" from the sentence . "… but should not delay on the reregistration …" Summary of Science Findings GLN 860.1200: Directions for Use Page 3; Table A1. Carbaryl EPs with Food/ Feed Uses Registered to Aventis Ag Company EPA statement: EPA Registration No. 264­ 430 is listed in this table. Aventis' comment: The registration of SEVIN® brand Granular Carbaryl Insecticide For Outdoor Home Use, EPA Registration No. 264­ 430, was transferred to Aventis Environmental Science, EPA Registration No. 432­ 885 on February 9, 2000. GLN 860.1380: Storage Stability Data ­ Plants Page 6; Paragraph 1; Lines 2­ 3 EPA statement: Additional data are required depicting the storage stability of carbaryl per se in an oilseed, processed commodities of an oily crop, and a dried fruit stored for up to 10 months. Aventis' comment: Inconsistencies are noted between the information presented in the section "Summary of Science Findings" and Table B. Residue Chemistry Science Assessments for Reregistration of Carbaryl (page 63) Paragraph 1 of the "GLN 860.1380: Storage Stability Data – Plants" section indicates the need for storage stability data for dried fruit (in addition to other items). Table B data requirements (page 63 along with footnote #14 on page 73) does not request storage stability data for dried fruit; neither does the 4 th paragraph on page 6 (GLN 860.1380). GLN 860.1500: Crop Field Trials Page 7; Paragraph 5 EPA statement: 11 "In addition, conclusions regarding the adequacy of the data for alfalfa, apples, potatoes … are contingent upon receipt and acceptance of adequate supporting storage stability data." Aventis' comment: The statement is inconsistent with information elsewhere in the document. There is no requirement for storage stability data on apples in the "GLN 860.1380: Storage Stability Data – Plants" section (page 6) nor in Table B (page 63 along with footnote #14 on page 73). Page 8; Paragraph 14; Line 4 EPA statement: "However, additional residue data are required if the registrant seeks tolerances for residues in/ on succulent, shelled pea and bean commodities." (Also stated in the Memorandum on page 3, paragraph 3). Aventis' comment: This statement is in contradiction with paragraph 6 of this section: " … adequate magnitude of the residue data are available on the following crops: …….. beans (dried and succulent), … peas (dried and succulent .…" and Table B requirements for crop field trials (page 65). Also, MRID 43984701 (succulent bean) and MRID 43703102 (Fresh pea) were found to be acceptable. GLN 860.1520: Processed Food/ Feed Page 9; Paragraph 1; Lines 4­ 6 EPA statement: Based on the available processing studies, tolerances are required for residues in citrus fruit oil, raisins , wet apple pomace, and rice hulls only. Aventis' comment: EPA requests processed commodity tolerances for (among other commodities) wet apple pomace and raisins (see also Table C, page 85). Calculations according to the 860.1520 Guidelines indicates that processed commodity tolerances are not needed for these commodities. The Agency's statement appears to be the result of a mathematical or computational type error since the 860.1520 Guidelines are rather clear on determination of need for processed commodity tolerances. GLN 860.1480: Meat, Milk, Poultry, Eggs Page 11; Paragraph 3; Line 5 EPA statement: "The calculation of the maximum dietary is tentative ...". Aventis' comment: Add the word "burden" to the statement "The calculation of the maximum dietary (burden) is tentative ...". 12 Page 11; Paragraph 4; Lines 1­ 2 EPA statement: "… tolerances for residues of carbaryl per se in livestock (excluding swine) commodities should be reassessed ...". Aventis' comment: The tolerance expression in GLN 860.1480 should be modified to agree with the one in GLN 860.1300 (page 4): "... tolerances for ruminant meat and milk should be expressed as residues of free and conjugated carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, and 5­ methoxy­ 6­ hydroxy carbaryl." Tolerance Reassessment Summary Table C. Tolerance Reassessment Summary for Carbaryl Tolerance Listed Under 40 CFR §180.169( a); Page 79 Aventis' comment: Under the commodity "Corn, forage", Comments on "Corn, sweet, forage" : should read "Residue data indicate that the tolerance for sweet corn forage should be increased." (i. e., replace "field" with "sweet" in sentence). Miscellaneous Typographical Errors ­ Under "REGULATORY BACKGROUND", paragraph 3 of section, line 5 (page 2): remove "on" from the sentence "... should not delay on the reregistration ...". ­ Under "SUMMARY OF SCIENCE FINDINGS, GLN 860.1500: Crop Field Trials", paragraph 4, line 5, page 7: remove period (.) after "ppm" in "... current tolerance of 10 ppm. and all residue data ...". Also in memorandum, page 3, paragraph 1. ­ Under "SUMMARY OF SCIENCE FINDINGS, GLN 860.1520: Processed Food/ Feed", paragraph 2, line 2 (page 9): add "to" to the statement "... when this concentration factor is applied (to) the HAFT residue ...". ­ Footnotes to Table B. Residue Chemistry Science Assessment for Reregistration of Carbaryl: #38: correct the spelling of "canceled". ­ Table C. Tolerance Reassessment Summary of Carbaryl, under the commodity "Sorghum, stover" (under "Comments": correct spelling of sorghum). CARBARYL PC Code No. 056801; Case 0080 Revised EFED Risk Assessment of Carbaryl in Support of the Reregistration Eligibility Decision (RED) – Phase 1 Error Correction – July 12, 2002 Aventis CropScience P. O. Box 12014, 2 T. W. Alexander Drive Research Triangle Park, NC 27709 CARBARYL Revised EFED Risk Assessment of Carbaryl in Support of the Reregistration Eligibility Decision (RED) ­ Phase 1 Error Correction TABLE OF CONTENTS TABLE OF CONTENTS ................................................................................................................ 2 ENVIRONMENTAL FATE AND ECOLOGICAL RISK ASSESSMENT FOR THE REREGISTRATION OF CARBARYL.................................................................................. 3 General..................................................................................................................................... 3 1.0 Summary and Environmental Risk Conclusions .............................................................. 3 Fate and Water Assessment ............................................................................................ 3 3.0 Integrated Risk Characterization....................................................................................... 3 Introduction..................................................................................................................... 3 4.0 Environmental Fate Assessment ....................................................................................... 4 Exposure Characterization.............................................................................................. 4 5.0 Drinking Water Assessment ............................................................................................. 5 Drinking Water Modeling............................................................................................... 5 Appendix D: Toxicity Assessment ......................................................................................... 5 Toxicity to Terrestrial Animals....................................................................................... 5 3 Environmental Fate and Ecological Risk Assessment for the Reregistration of Carbaryl General Several References Throughout the Document EPA statement: The company name of the registrant is listed throughout the document as Aventis Corporation, Aventis Crop Sciences, Aventis Crop Science, and Aventis Crop Science Corporation. Aventis' comment: Reference should be either to Aventis or Aventis CropScience. 1.0 Summary and Environmental Risk Conclusions Fate and Water Assessment Page: 4 Paragraph: 1 Line: 16 EPA statement: …to those reported n non­ targeted… Aventis' comment: extra "n" in sentence 3.0 Integrated Risk Characterization Introduction Page: 8 Paragraph: 1 Line: 8 EPA statement: alkaline (pH half­ life = 5 hours environments. Aventis' comment: alkaline (pH half­ life = 3.2 hours) environments. half­ life is 3.2 not 5 hours as noted elsewhere in the document. Missing closing parenthesis. 4 4.0 Environmental Fate Assessment Exposure Characterization Page: 17 Paragraph: 3 Line: last sentence EPA statement: Detailed discussion and reviews (DERs) of the studies that are included in this assessment are attached in Appendix A. Aventis' comment: It is inappropriate to include the DERs in the RED. A sufficiently detailed summary of study findings is already included in the EFED Chapter. The summary of endpoints that is included in the draft Carbaryl EFED Chapter is typical of other Draft EFED REDs that have been issued recently and provides sufficient information to allow the reader to determine the endpoints that were selected for modeling and the justification for their selection. The inclusion of the more detailed information present in the DERs is unnecessary. We have reviewed the dockets for many of the RED documents that have recently been issued (many other insecticides and several fungicides) and none of them include DERs in any of the preliminary Environmental Fate and Effects Assessments. DERs should be made available to the public through the regular procedure under the Freedom of Information Act after they have been reviewed and cleared for confidential business information. The inclusion of the DERs in the docket that is publicly available circumvents this process and is a departure from the procedures that have been followed until now by the Agency. It is unclear why the Agency chose to change their policy for only certain DERs for a single product when adequate summary information is already provided in the text of the Carbaryl EFED Chapter. Page: 17 Paragraph: 4 Line: 4 EPA statement: lower levels (generally less than 0.01 µ/ L). Aventis' comment: value missing units ­ (generally less than 0.01 µg/ L). Persistence Microbially­ Mediated Processes Page: 22 Paragraph: 2 Line: 1 EPA statement: A number of soil microorganisms 5 Aventis' comment: "microorga nisms" 5.0 Drinking Water Assessment Drinking Water Modeling Page: 33 Table 6 EPA statement: Crop name – Sugar Beats (MN) Aventis' comment: Correct spelling is Sugar Beets Appendix D: Toxicity Assessment Toxicity to Terrestrial Animals Mammals, Acute and Chronic Page: 237 above Table 4 EPA statement: "Although at this time two­ generation rat reproduction study data are not available, …" Aventis' comment: A two­ generation rat reproduction study has been submitted and found to be acceptable by the Agency (MRID# 45448101).

epa

2024-06-07T20:31:42.536893

regulations

EPA-HQ-OPP-2002-0138-0021

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Office of Prevention, Pesticides and Toxic Substances August 6, 2002 SUBJECT: Carbaryl: Agency Response To Aventis Crop Science Error Correction Comments On Revised HED Risk Assessment and Supporting Documents, DP Barcode: D284591, PC Code: 056801 FROM: Jeffrey L. Dawson, Chemist/ Risk Assessor Reregistration Branch 1 Health Effects Division (7509C) THRU: Whang Phang, PhD, Branch Senior Scientist Reregistration Branch 1 Health Effects Division (7509C) TO: Anthony Britten, Chemical Review Manager Reregistration Branch 3 Special Review & Reregistration Division (7508C) Attached is the Agency's response to 30 day error correction comments provided by Aventis Crop Science on the previous version of the human health effects risk assessment (D281420/ June 7, 2002). The registrant comments were included in the document entitled Human Health Risk and Supporting Documents ­ Phase 1 Error Correction (Date: July 12, 2002). The Agency's human health risk assessment was updated based on a number of the comments and re­ issued on July 30, 2002 (D284580). The intent of this document is to illustrate how the comments were considered in the revisions to the risk assessment. The comments addressed the risk assessment, the product and residue chemistry chapter, and the occupational and residential risk assessment. Note that only the Agency risk assessment and not the supporting documents have been updated at this point. The Agency response is provided for each set of comments, respectively, in Sections 1, 2, and 3 of this document below. 2 Section 1: Human Health Risk Assessment The Aventis Crop Science comments on the human health risk assessment are presented below as well as the Agency's responses to each. Aventis Crop Science Comment 1: EPA statement: The company name of the registrant is listed throughout the document as Aventis Corporation, Aventis Crop Sciences, Aventis Crop Science, and Aventis Crop Science Corporation. Aventis' comment: Reference should be either to Aventis or Aventis CropScience. Agency Response To Aventis Crop Science Comment 1: The Agency has used Aventis Crop Science throughout the document. Aventis Crop Science Comment 2: 1.0 Executive Summary Dietary Risk Estimates (Page 7; Paragraph 3; Lines 4­ 6) EPA statement: "In livestock commodities, carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, 5­ methoxy­ 6­ dydroxy carbaryl and all residues which can be hydrolyzed to carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, 5­ methoxy­ 6­ hydroxy carbaryl under acidic conditions …." Aventis' comment: Add "and" before "5­ methoxy­ 6­ hydroxy carbaryl under acidic conditions ….". Agency Response To Aventis Crop Science Comment 2: The "and" has been added. 3 Aventis Crop Science Comment 3: 1.0 Executive Summary Aggregate Risks and DWLOCs (Page 11; Paragraph 4; Lines 9­ 14) EPA statement: "Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment (133% of aPAD). However, the risk picture could substantively change if residential risks are refined based on updated use information from the carbaryl use survey yet to be submitted to the Agency, and the Agency uses the CMBS data even with the caveats associated with that study." Aventis' comment: This statement is inconsistent with information presented elsewhere in the HED Chapter. As written, the statement implies that the Agency has not yet approved the use of the CMBS data in the dietary risk assessment for carbaryl. However, EPA states in the Hazard Characterization section of the Executive Summary, page 6, paragraph 2, line 9, "Dietary exposures were calculated using FDA and PDP monitoring data, a carbamate market basket survey, and …" which indicates that the EPA approved the use of the CMBS data. In addition, it is stated on pages 8 and 31 (Footnotes) and page 37, first paragraph: "At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. Hence, the use of these data in this assessment should be considered with associated caveats …" Agency Response To Aventis Crop Science Comment 3: The Agency has considered this and other comments related to the use and interpretation of the carbamate market basket survey results in a similar fashion. The intent of the Agency in any risk assessment is to present as broad a picture as possible to risk managers so they can make the most informed decisions possible given the resources available. This approach is very consistent with the Agency's available guidelines for exposure assessment and risk characterization. In this case, both the CMBS and the PDP data (as well as the other data used in the Agency's dietary risk assessment) were considered to be acceptable for use in the risk assessment. However, both sources of data have associated uncertainties such as the rubbing issue in the CMBS. Additionally, it should be noted that if the Agency considers multiple sources of data acceptable for risk assessment, it does not mean that the 4 Agency would disregard other sources of information. This is particularly true when each one is considered to be of high quality yet still has uncertainties associated with its use. As such, the Agency has retained the comparative risk analyses based on the use, or not, of the CMBS in the recently revised risk assessment (D284580/ July 30, 2002). Aventis Crop Science Comment 4: 1.0 Executive Summary Issues for Consideration (Page 16, Paragraph 1, Lines 19­ 26) EPA statement: It should also be noted that Aventis Crop Sciences is in the process of conducting biological monitoring studies in residences where there have been carbaryl applications (sampling urine from children) and also for field workers during harvesting and hand thinning operations in apples and cherries. Preliminary results from these studies, based on personal communication with Aventis scientists (they have not been submitted to the Agency yet), indicate body burden levels similar to those calculated by the Agency for risk assessment purposes. For example, the turf risk assessments completed by the Agency are intended to provide upper percentile exposures. The data from the monitored children appear to indicate similar results a the upper percentiles. Aventis' comment: This statement does not accurately reflect the true scope of the study and would be misleading. The comment would be more accurate as follows: "It should also be noted that Aventis CropScience has completed and is in the process of submitting to the Agency a biomonitoring study of individuals in residences following the application by a member of the household to the lawn and either the vegetable garden or ornamental flowers. A biomonitoring study of field workers during harvesting and hand thinning operations in apples and cherries will also be submitted to the Agency. Based on personal communication with Aventis scientists, preliminary results from the residential biomonitoring study indicate that the highest percentiles of the distribution of the younger children in the homes were similar to those predicted in the Agency's turf risk assessment for toddlers that are intended to represent the higher percentiles of the exposure distribution." Agency Response To Aventis Crop Science Comment 4: The Agency replaced the text in the revised assessment with that suggested by Aventis Crop Science. 5 Aventis Crop Science Comment 5: 4.0 Non­ Occupational Risk Assessment and Characterization 4.1 Summary of Registered Uses (Page 28; Table 3: Technical and Manufacturing Carbaryl Products) Aventis' comment: Carbaryl – Technical Products ° EPA Registration No. 45735­ 24 (99%), Carbaryl 99% Technical Grade Insecticide, Burlington Scientific Corporation, should be added to the list of registered carbaryl technical. ° EPA Registration No. 264­ 325 (97.5%), Aventis CropScience, should be included in the list of manufacturing­ use products. Carbaryl – Manufacturing­ Use Products ° EPA Registration No. 5481­ 190 (46% FI), AMVAC Chemical corporation , is an active registration and should be added to the list of Manufacturing­ Use Products. (It is listed in Table 1, page 2, of the Product and Residue Chemistry Chapters) ° EPA Registration No. 4816­ 270 (97.5%) is no longer active; it was transferred to EPA Registration No. 432­ 982 (97.5%), Aventis Environmental Science USA LP, on February 22, 2000. ° EPA Registration No. 4816­ 407 (1%) is no longer active; it was transferred to Reg. No. 432­ 1006 on February 22, 2000 and subsequently transferred to Reg. No. 73049­ 238, Valent Bioscience Corporation, on June 27, 2001 (neither 4816­ 407 or 432­ 1006 are active). ° As stated above, EPA Registration No. 264­ 325 (97.5%), Aventis CropScience, should be added to the list of manufacturing­ use products. Agency Response To Aventis Crop Science Comment 5: The suggested modifications have been made to the risk assessment. Aventis Crop Science Comment 6: 4.0 Non­ Occupational Risk Assessment and Characterization 4.2 Dietary Risk Assessment (Page 31; Paragraph 1; Lines 3­ 5) EPA statement: Carbaryl is used late in the season at maximal seasonal rates of 6­ 12 lb ai/ acre. [Note: A Special Local Needs registration in California uses 16 lb ai/ acre as a maximum rate on citrus.] 6 Aventis' comment: The Section 3 registration of carbaryl products cover the use on citrus at the rate of 5­ 16 lbs ai/ acre in the state of California only. Agency Response To Aventis Crop Science Comment 6: The suggested modifications have been made to the risk assessment. Aventis Crop Science Comment 7: 4.0 Non­ Occupational Risk Assessment and Characterization 4.3 Estimated Environmental Concentrations in Water 4.3.1 Environmental Fate Characteristics (Section 4.3.1, Pages 39­ 40) Aventis' comment: The text in section 4.3.1 does not include the revisions that were made to the EFED draft Chapter and is inconsistent. For example: ° on Page 39, first paragraph of Section 4.3.1, first sentence "Carbaryl and its degradate 1­ naphthol are fairly mobile but are not likely to persist or accumulate in the environment." ° on Page 40, Paragraph 1, last sentence "Carbaryl is mobile to very mobile in the environment (Kf = 1.7 to 3.2)." The information in the EFED chapter has been revised to ° "Carbaryl is considered to be moderately mobile in soils" and the Kf range is 1.7 to 3.5 (EFED Chapter, Page 20 – Table 3; Page 22 – Mobility). ° "… literature information suggest that it [1­ naphthol] is less persistent and less mobile than parent carbaryl."( EFED Chapter, Page 26, 1­ Naphthol Fate and Transport). Agency Response To Aventis Crop Science Comment 7: The suggested modifications have been made to the risk assessment. 7 Aventis Crop Science Comment 8: 4.0 Non­ Occupational Risk Assessment and Characterization 4.3 Estimated Environmental Concentrations in Water 4.3.1 Environmental Fate Characteristics (Section 4.3.1, Paragraphs 2 and 3 (pages 39­ 40)) EPA statement: In these 2 paragraphs, the chemical name for the major carbaryl degradation product is typed as "1­ napthol". Aventis' comment: Correct spelling is "1­ naphthol". Agency Response To Aventis Crop Science Comment 8: The suggested modifications have been made to the risk assessment. Aventis Crop Science Comment 9: 4.0 Non­ Occupational Risk Assessment and Characterization 4.4 Residential Risk Assessment 4.4.2.2 Residential Handler Cancer Risks (Page 52; Paragraph 1; Lines 11­ 12) EPA statement: "…[ Note: Scenarios where risks are still of concern (i. e., <1x10 ­6 ) are highlighted in the table.]. Aventis' comment: (i. e., "<" 1x10 ­6 ) should be corrected to (i. e., ">" 1x10 ­6 ). Agency Response To Aventis Crop Science Comment 9: The suggested modifications have been made to the risk assessment. 8 Aventis Crop Science Comment 10: 4.0 Non­ Occupational Risk Assessment and Characterization 4.4 Residential Risk Assessment 4.4.3 Residential Postapplication Risk Assessment (Page 59; Paragraph 1; Lines 4­ 6) EPA statement: These levels were The Agency instead considers them a qualitative indicator that exposures in the general population are likely to occur. Aventis' comment: Words are missing from the first part of the sentence. Agency Response To Aventis Crop Science Comment 10: The suggested modifications have been made to the risk assessment. Aventis Crop Science Comment 11: 4.0 Non­ Occupational Risk Assessment and Characterization 4.4 Residential Risk Assessment 4.4.3 Residential Postapplication Risk Assessment (Page: 59 Paragraph: 2 Lines: 1­ 6) EPA statement: Aventis Crop Science is in the process of conducting a biomonitoring study with children who live in households where carbaryl has been used. Based on discussions with Aventis, the preliminary results indicate that levels at the highest percentiles of the distribution are similar to those predicted in the Agency's turf risk assessment for toddlers which are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission Aventis' comment: The statement does not accurately reflect the true scope of the study and would be misleading. The comment would be more accurate as follows: Aventis CropScience has completed and is in the process of submitting to the Agency a biomonitoring study of individuals in residences following the application by a member of the household to the lawn and either the vegetable garden or ornamental flowers. Based on discussions with Aventis, preliminary results indicate that the highest percentiles of the distribution of the younger children in the homes were similar to those predicted in the Agency's turf risk assessment for toddlers that are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission. 9 Agency Response To Aventis Crop Science Comment 11 The suggested modifications have been made to the risk assessment. Aventis Crop Science Comment 12: 5.0 Aggregate Risk Assessments and Risk Characterization 5.1 Calculation of Aggregate Risks and DWLOCs (Page 72; Paragraph 2; Lines 6­ 11) EPA statement: "Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment. However, the risk picture could substantively change if residential risks are refined based on updated use information from the carbaryl use survey yet to be submitted to the Agency and the Agency chooses to regulate using the results of the CMBS." Aventis' comment: This statement is inconsistent with information presented elsewhere in the HED Chapter. As written, the statement implies that the Agency has not yet approved the use of the CMBS data in the dietary risk assessment for carbaryl. However, EPA states in the Hazard Characterization section of the Executive Summary, page 6, paragraph 2, line 9, "Dietary exposures were calculated using FDA and PDP monitoring data, a carbamate market basket survey, and …" which indicates that the EPA approved the use of the CMBS data. In addition, it is stated on pages 8 and 31 (Footnotes) and page 37, first paragraph: "At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. Hence, the use of these data in this assessment should be considered with associated caveats …" Agency Response To Aventis Crop Science Comment 12: Please refer to the Agency response to Aventis Crop Science comment 3 above. Aventis Crop Science Comment 13: 5.0 Aggregate Risk Assessments and Risk Characterization 5.7 Summary of Aggregate Risks (Page 76; Paragraph 2; Lines 3­ 4 continued on page 77) EPA statement: "Additionally, acute dietary risks were also exceeded for infants and children (1 to 6 years old) at the 99.9 th percentile when the Carbamate Market Basket Survey (CMBS) was not considered in the assessment. However, the risk picture 10 could substantively change if residential risks are refined based on updated use information from the carbaryl use survey yet to be submitted to the Agency and the Agency chooses to regulate using the results of the CMBS." Aventis' comment: This statement is inconsistent with information presented elsewhere in the HED Chapter. As written, the statement implies that the Agency has not yet approved the use of the CMBS data in the dietary risk assessment for carbaryl. However, EPA states in the Hazard Characterization section of the Executive Summary, page 6, paragraph 2, line 9, "Dietary exposures were calculated using FDA and PDP monitoring data, a carbamate market basket survey, and …" which indicates that the EPA approved the use of the CMBS data. In addition, it is stated on pages 8 and 31 (Footnotes) and page 37, first paragraph: "At the present time, information from the industry­ sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. Hence, the use of these data in this assessment should be considered with associated caveats …" Agency Response To Aventis Crop Science Comment 13: Please refer to the Agency response to Aventis Crop Science comment 3 above. Aventis Crop Science Comment 14: 7.1 Occupational Handler Risk Assessment (Page: 83; Paragraph 5; Lines 9­ 10 and Footnote) EPA statement: There are no data compensation issues with any of these data. 11 . (Footnote) 11 Non­ ORETF data included in MRIDs 451672­ 01 and 452507­ 01 were from studies submitted by Aventis CropScience. The propoxur trigger sprayer study has a signed PHED data waiver but has not been included into PHED. Aventis' comment: Aventis concurs that there are no data compensation issues. However, the rationale presented for the propoxur trigger sprayer study is not accurate. The PHED data waiver is applicable only when the data are in PHED and not when cited outside of PHED. The propoxur study does not trigger data compensation because the study is the property of Bayer CropScience which has recently acquired Aventis CropScience. Agency Response To Aventis Crop Science Comment 14: The suggested modifications have been made to the risk assessment. 11 Section 2: Product and Residue Chemistry This section addresses the comments received from Aventis Crop Science pertaining to the product and residue chemistry supporting document (D283328). This document has not been altered at this point to reflect the changes suggested by the registrant, Aventis Crop Sciences. Rather, specific changes which could impact the results of the risk assessment were considered and the appropriate modifications were made to the risk assessment. The Agency response to comments provided by Aventis will serve as errata to the product and residue chemistry chapter (D283328). Aventis Crop Science Comment 15: General several References Throughout the Document EPA statement: The company name of the registrant is listed throughout the document as Aventis Ag Company. Aventis' comment: Reference should be to Aventis CropScience. [Note: This issue was repeated in the Aventis Crop Science comments pertaining to the product and residue chemistry chapters. It is only addressed here.] Agency Response To Aventis Crop Science Comment 15: The suggested modifications will be made to the product and residue chemistry chapter (D283328) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect the suggested change. Aventis Crop Science Comment 16: Product Chemistry Chapter/ Manufacturing­ Use Products (Page 2; Table 1 – Registered Carbaryl Manufacturing­ Use Products) Aventis' comment: ° EPA Registration No. 45735­ 24 (99%), Carbaryl 99% Technical Grade Insecticide, Burlington Scientific Corporation, should be added to the list of registered carbaryl technical. ° EPA Registration No. 4816­ 270 (97.5%) is no longer active; it was transferred to EPA Registration No. 432­ 982 (97.5%), Aventis Environmental Science USA LP, on February 22, 2000. 12 ° EPA Registration No. 4816­ 407 (1%) is no longer active; it was transferred to Reg. No. 432­ 1006 on February 22, 2000 and subsequently transferred to Reg. No. 73049­ 238, Valent Bioscience Corporation, on June 27, 2001 (neither 4816­ 407 or 432­ 1006 are active). ° The name of the registrant for EPA Registration No. 769­ 971 is Value Gardens Supply, LLC. Corresponding corrections should be made to the Product Chemistry Section of the Memorandum for this Chapter and in other sections of the Product Chemistry Chapter of the Reregistration Eligibility Decision (RED) Document. Agency Response To Aventis Crop Science Comment 16: The suggested modifications will be made to the product and residue chemistry chapter (D283328) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect the suggested change. Aventis Crop Science Comment 17: Regulatory Background (Page 2: Paragraph 2: Line 5) EPA statement: "... but should not delay on the reregistration eligibility decisions for carbaryl." Aventis' comment: Remove "on" from the sentence, "... but should not delay on the reregistration..." Agency Response To Aventis Crop Science Comment 17: The Agency is unclear about this comment but will review the affected text and make appropriate changes. Aventis Crop Science Comment 18: Summary of Science Findings GLN 860.1200: Directions for Use (Page 3: Table A1. Carbaryl EPs with Food/ Feed Uses Registered to Aventis Ag Company) EPA statement: EPA Registration No. 264­ 430 is listed on this table. Aventis' comment: The registration of Sevin Brand Granular Carbaryl Insecticide For Outdoor Home Use, EPA Registration No. 264­ 430, was transferred to Aventis Environmental Science, EPA Registration No. 432­ 885 on February 9, 2000. 13 Agency Response To Aventis Crop Science Comment 18: The appropriate changes to the product and residue chemistry chapter will be made after verification by the chemical review manager. There is no anticipated impact on the results of the risk assessment. Aventis Crop Science Comment 19: GLN 860.1380: Storage Stability Data ­ Plants (page 6: Paragraph 1; Lines 2­ 3) EPA statement: Additional data are required depicting the storage stability of carbaryl per se in an oilseed, processed commodities of an oily crop, and a dried fruit stored up to 10 months. Aventis' comment: Inconsistencies are noted between the information presented in the section "Summary of Science Findings" and Table B. Residue Chemistry Science Assessments for Reregistration of Carbaryl (page 63) Paragraph 1 of the "GLN 860.1380: Storage Stability Data ­ Plants" section indicates the need for storage stability data for dried fruit (in addition to other items). Table B data requirements (page 63 along with footnote #14 on page 73) does not request storage stability data for dried fruit; neither does the 4 th paragraph on page 6 (GLN 860.1380). Agency Response To Aventis Crop Science Comment 19: The appropriate modifications will be made to the product and residue chemistry chapter (D283328) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect appropriate changes. Aventis Crop Science Comment 20: GLN 860.1500: Crop Field Trials (Page 7, paragraph 5) EPA statement: "In addition, conclusions regarding the adequacy of the data for alfalfa, apples, potatoes... are contingent upon receipt and acceptance of adequate supporting storage stability data." Aventis' comment: The statement is inconsistent with information elsewhere in the document. There is no requirement for storage stability data on apples in the "GLN 860.1380: Storage Stability Data ­ Plants" section (page 6) nor in Table B (page 63 along with footnote #14 on pate 73). 14 Agency Response To Aventis Crop Science Comment 20: The appropriate modifications will be made to the product and residue chemistry chapter (D283328) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect appropriate changes. Aventis Crop Science Comment 21: GLN 860.1500: Crop Field Trials (Page 8, paragraph 14, Line 4) EPA statement: "However, additional residue data are required if the registrant seeks tolerances for residues in/ on succulent, shelled pea and bean commodities." (Also stated in the Memorandum on page 3, paragraph 3). Aventis' comment: This statement is in contradiction with paragraph 6 of this section: "... adequate magnitude of the residue data are available on the following crops: ... beans (dried and succulent), ... peas (dried and succulent..." and Table B requirements for crop field trials (page 65). Also, MRID 43984701 (succulent bean) and MRID 43703102 (fresh pea) were found to be acceptable. Agency Response To Aventis Crop Science Comment 21: The appropriate modifications will be made to the product and residue chemistry chapter (D283328) if and when the document is reissued after verification by the chemical review manager. There is no anticipated impact on the results of the risk assessment. Aventis Crop Science Comment 22: GLN 860.1520: Processed Food/ Feed (page 9, paragraph 1, lines 4­ 6) EPA statement: Based on the available processing studies, tolerances are required for residues in citrus fruit oil, raisins, wet apple pomace, and rice hulls only. Aventis' comment: EPA requests processed commodity tolerances for (among other commodities) wet apple pomace and raisins (see also Table C, page 85). Calculations according to the 860.1520 Guidelines indicate that processed commodity tolerances are not needed for these commodities. The Agency's statement appears to be the result of a mathematical or computational type error since the 860.1520 Guidelines are rather clear on determination of need for processed commodity tolerances. 15 Agency Response To Aventis Crop Science Comment 22: The appropriate modifications will be made to the product and residue chemistry chapter (D283328) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect appropriate changes. Aventis Crop Science Comment 23: GLN 860.1480: Meat, Milk, Poultry, Eggs (page 11: paragraph 3, line 5) EPA statement: "The calculation of the maximum dietary is tentative..." Aventis' comment: Add the word "burden" to the statement "The calculation of the maximum dietary (burden) is tentative...". Agency Response To Aventis Crop Science Comment 23: The Agency will add the word "burden" to the text of the document. Aventis Crop Science Comment 24: GLN 860.1480: Meat, Milk, Poultry, Eggs (page 11: paragraph 4, lines 1­ 2) EPA statement: "... tolerances for residues of carbaryl per se in livestock (excluding swine) commodities should be reassessed..." Aventis' comment: The tolerance expression in GLN 860.1480 should be modified to agree with the one in GLN 860.1300 (page 4): "... tolerances for ruminant meat and milk should be expressed as residues of free and conjugated carbaryl, 5,6­ dihydro­ 5,6­ dihydroxy carbaryl, and 5­ methoxy­ 6­ hydroxy carbaryl." Agency Response To Aventis Crop Science Comment 24: The appropriate modifications will be made to the product and residue chemistry chapter (D283328) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect appropriate changes. 16 Aventis Crop Science Comment 25: Tolerance Reassessment Summary, Table C. Tolerance Reassessment Summary For Carbaryl, Tolerance Listed Under 40 CFR §180.169 (a), page 79 Aventis' comment: Under the commodity "Corn, forage", Comments on "Corn, sweet, forage": should read "Residue data indicate that the tolerance for sweet corn forage should be increased." (i. e., replace "field" with "sweet" in the sentence). Agency Response To Aventis Crop Science Comment 25: The appropriate modifications will be made to the product and residue chemistry chapter (D283328) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect appropriate changes. 17 Section 3: Occupational & Residential Exposure This section addresses the comments received from Aventis Crop Science pertaining to the occupational and residential exposure supporting document (D281418). This document has not been altered at this point to reflect the changes suggested by the registrant, Aventis Crop Sciences. Rather, specific changes which could impact the results of the risk assessment were considered and the appropriate modifications were made to the risk assessment. The Agency response to comments provided by Aventis will serve as errata to the occupational and residential exposure/ risk assessment chapter (D281418). Aventis Crop Science Comment 26: General, Several References Throughout the Document EPA statement: The company name of the registrant is listed throughout the document as Aventis Corporation and Aventis Crop Science. Aventis' comment: Reference should either to Aventis or Aventis CropScience. Agency Response To Aventis Crop Science Comment 26: The suggested modifications will be made to the occupational and residential exposure chapter (D281418) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect the suggested change. Aventis Crop Science Comment 27: Executive Summary (Page 10, paragraph: 3, Lines 16­ 20) EPA comment: [Note: The Aventis Corporation is in the process of conducting a biomonitoring study with children who live in households where carbaryl has been used. Preliminary results indicate that levels at the highest percentiles of the distribution were similar to those predicted in the Agency's turf risk assessment for toddlers which are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission.] Aventis's response: The statement does not accurately reflect the true scope of the study and would be misleading. The comment would be more accurate as follows: Aventis Crop Science has completed and is in the process of submitting to the Agency a biomonitoring study of individuals in residences following the application by a member of the household to the lawn and either the vegetable garden or ornamental 18 flowers. Preliminary results indicate that the highest percentiles of the distribution of the younger children in the homes were similar to those predicted in the Agency's turf risk assessment for toddlers that are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission. Agency Response To Aventis Crop Science Comment 27: The suggested modifications will be made to the occupational and residential exposure chapter (D281418) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect the suggested change. Aventis Crop Science Comment 28: 1.0 Occupational and Residential Exposure/ Risk Assessment 1.5 Summary of Use Patterns and Formulations 1.5.1 End­ Use Products (page 15, table 2) Aventis' comment: Carbaryl – Technical Products ° EPA Registration No. 45735­ 24 (99%), Carbaryl 99% Technical Grade Insecticide, Burlington Scientific Corporation, should be added to the list of registered carbaryl technical. ° EPA Registration No. 264­ 325 (97.5%), Aventis CropScience, should be included in the list of manufacturing­ use products. Carbaryl – Manufacturing­ Use Products ° EPA Registration No. 5481­ 190 (46% FI), AMVAC Chemical corporation , is an active registration and should be added to the list of Manufacturing­ Use Products. (It is listed in Table 1, page 2, of the Product and Residue Chemistry Chapters) ° EPA Registration No. 4816­ 270 (97.5%) is no longer active; it was transferred to EPA Registration No. 432­ 982 (97.5%), Aventis Environmental Science USA LP, on February 22, 2000. ° EPA Registration No. 4816­ 407 (1%) is no longer active; it was transferred to Reg. No. 432­ 1006 on February 22, 2000 and subsequently transferred to Reg. No. 73049­ 238, Valent Bioscience Corporation, on June 27, 2001 (neither 4816­ 407 or 432­ 1006 are active). ° As stated above, EPA Registration No. 264­ 325 (97.5%), Aventis CropScience, should be added to the list of manufacturing­ use products. 19 Agency Response To Aventis Crop Science Comment 28: The suggested modifications will be made to the occupational and residential exposure chapter (D281418) if and when the document is reissued pending verification by the chemical review manager. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect the suggested change. [Note: This comment was also addressed above in the risk assessment section.] Aventis Crop Science Comment 29: 1.5.3 Registered Use Categories and Sites (page 20, animal uses) EPA statement: Poultry (Chickens, ducks, geese, game birds, turkeys) Livestock (cattle, sheep, horses, etc.) Aventis' comment: Both uses should be removed from the list of registered uses. Aventis voluntarily requested the deletion of the use on poultry. A Federal Register Notice dated October 24, 2001 announced receipt by the Agency of an application from Aventis Crop Science to delete this use. The use on livestock (cattle, sheep, horses, etc.) is no longer registered. Aventis will not support the reregistration of this use. Agency Response To Aventis Crop Science Comment 29: The suggested modifications will be made to the occupational and residential exposure chapter (D281418) if and when the document is reissued once the suggested changes are verified by the chemical review manager. It should be noted that an August 1, 2002 review of the Agency's REFs system still had active registrations listed for both poultry and unspecified livestock and horses. There were some registrations for cattle that were listed as inactive. Aventis Crop Science Comment 30: 1.5.3 Registered Use Categories and Sites (page 21, aquatic food crop) EPA statement: Aquatic sites ­ commercial fishery water systems Aventis' comment: This use is not listed on Aventis Carbaryl product labels. 20 Agency Response To Aventis Crop Science Comment 30: The use likely attributed to this site is from EPA Reg. No. 264­ 316, SLN WA­ 900013 which is for Sevin Brand 80S Carbaryl Insecticide For Control Of Ghost and Mud Shrimp in Oyster Beds in Washington state. Aventis Crop Science Comment 31: 1.5.3 Registered Use Categories and Sites (page 21, aquatic non­ food industrial) EPA statement: Aquatic sites ­ drainage systems Aventis' comment: This use is not listed on Aventis carbaryl products labels. Agency Response To Aventis Crop Science Comment 31: The suggested modifications will be made to the occupational and residential exposure chapter (D281418) if and when the document is reissued once the suggested changes are verified by the chemical review manager and another review of available labels is completed. It should be noted that an August 1, 2002 review of the Agency's REFs system still had an active registration for this site. Aventis Crop Science Comment 32: 2.0 Occupational Exposures and Risks 2.1 Occupational Handler Exposures and Risks 2.1.2 Data and Assumptions For Handler Exposure Scenarios (page 36, paragraph 1, lines 1 ­ 4) EPA statement: There are no data compensation issues associated with the use of nonORETF data... and the propoxur trigger sprayer study has a signed PHED data waiver but just has not been included into PHED at this time. Aventis' response: Aventis concurs that there are no data compensation issues. However, the rationale for the propoxur trigger sprayer study is not correct. The PHED data waiver is applicable only when the data are in PHED and not when cited outside of PHED. The propoxur study does not trigger data compensation because the study is the property of Bayer Crop Science which has acquired Aventis Crop Science. 21 Agency Response To Aventis Crop Science Comment 32: The suggested modifications will be made to the occupational and residential exposure chapter (D281418) if and when the document is reissued. Otherwise the Agency acknowledges this comment and has altered the overall risk assessment document to reflect the suggested change. [Note: This comment was also addressed above in the risk assessment section.] Aventis Crop Science Comment 33: 3.0 Residential and Other Non­ Occupational Exposures and Risks 3.1 Residential Handler Exposures and Risks 3.1.2 Data and Assumptions For Handler Exposure Scenarios (page 99, paragraph: 2, line 9) EPA statement: "Longitudinal data, however, were not available to establish that such populations definitively exist." Aventis' comment: The following should be added after this sentence to accurately reflect the submission of Residential Exposure Joint Venture data for carbaryl that covers use patterns by the same individuals between May and August. "Note: Aventis has recently submitted an analysis of longitudinal residential use patterns of carbaryl that monitored the use of carbaryl within several thousand households between the months of May through August." Agency Response To Aventis Crop Science Comment 33: At the time the occupational and residential exposure/ risk assessment was completed, the Residential Exposure Joint Venture data for carbaryl had not yet been submitted by Aventis Crop Science. The Agency will review this information, both in the context of a deterministic and a probabilistic risk assessment strategy. Results from this study will be incorporated into any revisions to the human health risk assessment and the occupational and residential exposure/ risk assessment documents as appropriate. 22 Aventis Crop Science Comment 34: 3.0 Residential and Other Non­ Occupational Exposures and Risks 3.1 Residential Handler Exposures and Risks 3.1.2 Data and Assumptions For Handler Exposure Scenarios (pages 104­ 105, Discussion of OMA004) EPA statement: The discussion presents exposure data for Dial­ type (DTS) Homeowner Hose­ End sprayers and Ready­ to­ Use Sprayers. However, Table 23 and subsequent risk and exposure tables only present exposure estimates based on the DTS sprayer. Aventis' response: The RTU sprayer is an important component of the carbaryl market and was developed as an exposure mitigation product that eliminates the homeowner's need to pour concentrated formulations of carbaryl. The OMA004 study demonstrated significant reductions in the exposure to homeowners and the presentation of the resultant RTU hose­ end sprayer data, exposure, and risk is essential to the residential handler section. Agency Response To Aventis Crop Science Comment 34: The Agency did not include a quantitative analysis based on the ready­ to­ use (no mixing/ loading) product because it is unclear if the packaging used in the study is similar to the containers used for carbaryl and it is also not clear what percentage of the market for carbaryl is accounted for by the no­ mix containers. The Agency calculated risk estimates based solely on the hose­ end sprayer data that required users to add concentrated formulation to the device. Both sets of information will be considered in any risk management decision. The Agency used the following unit exposures in its assessment (i. e., the open mixing data from ORETF Study OMA004): ° Dermal geo. mean for a person wearing shorts and a short­ sleeved shirt: 11 mg/ lb ai ° Inhalation geo. mean for a person not wearing a respirator: 16 µg/ lb ai [Dermal exposure drives the overall risk estimate so any change in dermal exposure would clearly and proportionally alter the overall risk estimate. The total MOE (includes both dermal and inhalation exposures) for broadcast applications to lawns is 25 while the MOE for spot treatments is 495 (Agency target is 100).] The unit exposure values from ORETF Study OMA004 where no mixing dial type sprayers were used are as follows: ° Dermal geo. mean for a person wearing shorts and a short­ sleeved shirt: 2.6 mg/ lb ai ° Inhalation geo. mean for a person not wearing a respirator: 11 µg/ lb ai 23 If the MOE for broadcast applications is adjusted for changes in the dermal exposure estimate, then the MOE would be ~106 (25* 11/ 2.6) which exceeds Agency targets. This information will be considered in the risk management decisions as well as the feasability of using the no­ mix containers in 100 percent of the carbaryl market. Aventis Crop Science Comment 35: 3.2 Residential Postapplication Exposures and Risks 3.2.2 Data and Assumptions For Residential Postapplication Exposure Scenarios (Page: 122 Paragraph: 5 Lines: 1­ 6) EPA statement: Aventis Crop Science is in the process of conducting a biomonitoring study with children who live in households where carbaryl has been used. Preliminary results indicate that levels at the highest percentiles of the distribution were similar to those predicted in the Agency's turf risk assessment for toddlers which are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission Aventis' comment: The statement does not accurately reflect the true scope of the study and would be misleading. The comment would be more accurate as follows: Aventis CropScience has completed and is in the process of submitting to the Agency a biomonitoring study of individuals in residences following the application by a member of the household to the lawn and either the vegetable garden or ornamental flowers. Preliminary results indicate that the highest percentiles of the distribution of the younger children in the homes were similar to those predicted in the Agency's turf risk assessment for toddlers that are intended to represent the higher percentiles of the exposure distribution. A more detailed analysis will be completed upon submission. Agency Response To Aventis Crop Science Comment 35: The suggested modifications have been made to the risk assessment. Aventis Crop Science Comment 36: 3.2.4 Residential Postapplication Exposure and Noncancer Risk Estimates (page 132 and 135, Tables 26 and 28) EPA comment: The residential turf (lawncare) scenario does not differentiate between liquid spray and granular formulation applications. 24 Aventis' response: There is significant differences in the postapplication exposure potential following a liquid spray application compared to a granular application. ORETF data submitted to the Agency indicate that transferable residues following a granular application are about 10 times less than a liquid spray application . In addition, ORETF has recently conducted a large postapplication exposure study in Moses Lake, Washington that will provide both adult Jazzercise and Children's Activity Pattern (CHAPs) transfer coefficients. Although the Moses Lake data have not yet been submitted, the conduct of the study should be referenced and the tables should differentiate between the very different liquid spray and granular lawn postapplication exposure scenarios. Agency Response To Aventis Crop Science Comment 36: The Agency acknowledges this comment and will incorporate data from this study as appropriate in the risk assessment and risk management process. It should be noted that even there appears to be differences between TTR (turf transferable residues) levels after liquid or granular formulation applications, Aventis Crop Science only completed a TTR study using a liquid formulation of carbaryl.

epa

2024-06-07T20:31:42.558340

regulations

EPA-HQ-OPP-2002-0142-0001

Rule

1-Methylcycloropene; Exemption from the Requirement of a Tolerance

48796 Federal Register / Vol. 67, No. 144 / Friday, July 26, 2002 / Rules and Regulations * * * * * [ FR Doc. 02 18867 Filed 7 25 02; 8: 45 am] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 180 [ OPP 2002 0142; FRL 7187 4] 1­ Methylcyclopropene; Exemption from the Requirement of a Tolerance AGENCY: Environmental Protection Agency ( EPA). ACTION: Final rule. SUMMARY: This regulation establishes an exemption from the requirement of a tolerance for residues of 1­ Methylcyclopropene ( 1­ MCP) in or on fruits and vegetables when used as a post harvest plant growth regulator, i. e., for the purpose of inhibiting the effects of ethylene. AgroFresh, Inc. ( formerly BioTechologies for Horticulture) submitted a petition to EPA under the Federal Food, Drug, and Cosmetic Act, as amended by the Food Quality Protection Act of 1996, requesting an exemption from the requirement of a tolerance. This regulation eliminates the need to establish a maximum permissible level for residues of 1­ MCP. DATES: This regulation is effective July 26, 2002. Objections and requests for hearings, identified by docket ID number OPP 2002 0142, must be received on or before September 24, 2002. ADDRESSES: Written objections and hearing requests may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit IX. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, your objections and hearing requests must identify docket ID number OPP 2002 0142 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By mail: Driss Benmhend, c/ o Product Manager ( PM) 90, Biopesticides and Pollution Prevention Division ( 7511C), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 308 9525; e­ mail address: Benmhend. driss@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? You may be affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Categories NAICS codes Examples of potentially affected entities Industry 111 Crop production 112 Animal production 311 Food manufacturing 32532 Pesticide manufacturing This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in the table could also be affected. The North American Industrial Classification System ( NAICS) codes have been provided to assist you and others in determining whether or not this action might apply to certain entities. If you have questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up the entry for this document under the `` Federal Register Environmental Documents.'' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. A frequently updated electronic version of 40 CFR part 180 is available at http:// www. access. gpo. gov/ nara/ cfr/ cfrhtml_ 00/ Title_ 40/ 40cfr180_ 00. html. 2. In person. The Agency has established an official record for this action under docket ID number OPP 2002 0142. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. II. Background and Statutory Findings In the Federal Register of June 21, 2000 ( 65 FR 38550) ( FRL 6589 5), EPA issued a notice pursuant to section 408( d)( 3) of the Federal Food, Drug, and Cosmetic Act ( FFDCA), 21 U. S. C. 346a( d)( 3), as amended by the Food Quality Protection Act ( FQPA) ( Public Law 104 170), announcing the filing of a pesticide tolerance petition ( PP OF6144) by AgroFrech, Inc. ( formerly BioTechnologies for Horticulture, Inc.), 100 Independence Mall West, Philadelphia, PA 19106 2399. As required by section 408( d)( 2)( A)( i)( I), this notice included a summary of the petition prepared by the petitioner AgroFresh, Inc. There were no comments received in response to the notice of filing. Section 408( c)( 2)( A)( i) of the FFDCA allows EPA to establish an exemption from the requirement for a tolerance ( the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is `` safe.'' Section 408( c)( 2)( A)( ii) defines `` safe'' to mean that `` there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.'' This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408( b)( 2)( C) requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to `` ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue. . . .'' Additionally, section 408( b)( 2)( D) requires that the Agency consider `` available information'' concerning the cumulative effects of a particular pesticide's residues and `` other substances that have a common mechanism of toxicity.'' EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. First, VerDate Jul< 19> 2002 18: 20 Jul 25, 2002 Jkt 197001 PO 00000 Frm 00054 Fmt 4700 Sfmt 4700 E:\ FR\ FM\ 26JYR1. SGM pfrm17 PsN: 26JYR1 48797 Federal Register / Vol. 67, No. 144 / Friday, July 26, 2002 / Rules and Regulations EPA determines the toxicity of pesticides. Second, EPA examines exposure to the pesticide through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings. III. Toxicological Profile Consistent with section 408( b)( 2)( D) of FFDCA, EPA has reviewed the available scientific data and other relevant information in support of this action and considered its validity, completeness, and reliability and the relationship of this information to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children. The end­ use product, a white powder, when mixed with water or a buffer solution releases the gas 1­ MCP. The active ingredient acts an inhibitor to ethylene, by blocking the attachment of ethylene to tissue, and thus, prolongs the life of the food commodity treated. Toxicity studies submitted in support of the tolerance exemption petition, and the Agency reviews are compiled in the official record established for this action under the docket ID number OPP 2002 0142. 1. Acute toxicity ( MRIDs 444647 04 to 08). 1­ MCP exhibits low acute toxicity. It is a category IV biopesticide. The rat oral LD50 is greater than 5,000 milligrams/ kilograms ( mg/ kg), the rabbit dermal LD50 is greater than 2,000 mg/ kg and the rat inhalation LC50 is greater than 2.5 milligram/ liter ( mg/ L) ( or greater than 1,126 parts per million ( ppm) v/ v active ingredient in air). No deaths or clinical signs of systemic toxicity were observed following these acute exposures. 1­ MCP produces minimal irritation of skin and eyes in rabbits and 1­ MCP is not a skin sensitizer. No hypersensitivity incidents were observed following exposure to 1­ MCP. 2. Genotoxicity ( MRID 444647 09). 1­ MCP was not mutagenic when tested as a gas in several short­ term in vitro/ in vivo assays, including a bacterial reverse mutation assay ( Ames test), an in vitro mammalian point mutation assay in Chinese hamster ovary cells, an in vitro cytogenetics assay in human lymphocytes and an in vivo mouse micronucleus assay following inhalation exposure. In addition, 1­ MCP is not mutagenic when tested as a suspension in cell media in the Ames test and in the in vitro mouse lymphoma forward mutation assay ( MRID 444647 10) and is not mutagenic in the in vivo mouse micronucleus assay ( MRID 444747 11) following oral exposure ( gavage). 3. Developmental toxicity ( MRID 454586 08). 1­ MCP produces no developmental toxicity when tested in a standard developmental toxicity study in the rat via inhalation at concentrations up to and including 2.3 mg a. i./ L ( or 543 mg a. i./ kg/ day, 6 hr exposure/ day). The no observed adverse effect level ( NOAEL) for maternal toxicity was 0.24 mg a. i./ L ( 56 mg a. i./ kg/ day, 6 hr exposure/ day). 4. Subchronic toxicity ( MRID 456090­ 01). 1­ MCP was tested in a 90 day inhalation study at doses of 0.05, 0.24 and 2.3 mg a. i./ kg in the rat. The NOAEL is 0.05 mg a. i./ L ( equivalent to 9 to 15 mg a. i./ kg/ day), based on minimal to mild effects on spleen and kidney histopathology at 0.24 mg a. i./ L ( equivalent to 39 to 66 mg a. i./ kg/ day). In this study there was no evidence of neurotoxicity, no effects on the respiratory tract and no effects on pathology of any endocrine or reproductive organs up to and including the highest dose tested of 2.3 mg a. i./ L ( or equivalent to 380 to 640 mg a. i./ kg/ day). 5. AgroFresh ( the applicant) submitted a waiver request for the immune response data requirements based on the current toxicological data submitted on 1­ MCP. The review of the 3 month inhalation rat study ( mentioned in the previous paragraph) indicates, no effects on thymus weight and no effects on the histopathology of the thymus, bone marrow or spleen that would be attributed to an impact on the immune system were seen. There were no effects on white blood cell differential parameters ( including monocytes, lymphocytes, segmented neutrophils or eosinophils) and no basophils were observed which may be indicative of an allergic reaction. The Agency concluded that 1­ MCP did not induce dysfunction or inappropriate suppressive responses in components of the immune system. As a result, immune response data requirements were waived. 6. Other. 1­ MCP has a mode of action in plants which is a non­ persistent and non­ toxic mode of action. 1­ MCP prevents the natural chemical, ethylene, from binding to ethylene receptors in plants. This mode of action is not relevant in animals, since ethylene receptors are not present in animal tissues. IV. Aggregate Exposures In examining aggregate exposure, FFDCA section 408 directs EPA to consider available information concerning exposures from the pesticide residue in food and all other nonoccupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings ( residential and other indoor uses). A. Dietary Exposure 1. Food From food and feed uses. The primary source for human exposure to 1­ MCP will be from ingestion of the following raw food commodities and the processed food commodities derived from: apples, melons, tomatoes, pears, avocadoes, mangoes, papayas, kiwifruit, plums, apricots and persimmons. Studies submitted ( MRID 456090 02) showed residues in treated apples to be extremely low ( average residue was 0.004 ppm using an exaggerated treatment rate of 1,200 parts per billion ( ppb) versus the 1,000 ppb proposed label rate). A worst­ case scenario ( using the 0.004 ppm average residue concentration found in treated apples and assuming that concentration is present in 100% of the diet regardless of crops treated) indicates that a daily diet of 1.5 kg/ day could contain 0.006 mg 1­ MCP. For the general population ( assuming an average body weight of 60 kg), this would represent a daily intake of 0.0001 mg 1­ MCP/ kg body weight which is 90,000 to 150,000­ fold less than the 9­ 15 mg/ kg NOAEL indicated in the 90 day inhalation study. Residues in other treated commodities are expected to be similar or even lower since the highest treatment rate is recommended for apples. Processing would be expected to further lower the residue levels in processed food commodities. 2. Drinking water exposure. Since 1­ MCP will only be used on postharvested fruits and vegetables in enclosed storage areas, there is little if any, potential for drinking water exposure. B. Other Non­ Occupational Exposure The potential for non­ dietary exposure to 1­ MCP for the general population, is unlikely because potential use sites are commercial, agricultural, and horticultural. 1­ MCP is currently registered for indoor, nonfood commercial use on flowers and ornamentals. The Agency has approved that use, based on the data submitted that show little potential for significant non­ occupational exposure to the general population. 1. Dermal exposure. 1­ MCP will only be sold enclosed in a generator for treatment of raw agricultural commodities. The generator will not release 1­ MCP until the applicator has exited the storage area and entrances to the treatment area have been sealed. At VerDate Jul< 19> 2002 18: 20 Jul 25, 2002 Jkt 197001 PO 00000 Frm 00055 Fmt 4700 Sfmt 4700 E:\ FR\ FM\ 26JYR1. SGM pfrm17 PsN: 26JYR1 48798 Federal Register / Vol. 67, No. 144 / Friday, July 26, 2002 / Rules and Regulations the end of the treatment period, the storage area will be vented before workers are permitted to reenter the area. This label mitigating language would eliminate the potential for dermal exposure to handlers or applicators. 2. Inhalation exposure. As mentioned in the previous paragraph, the use of this product according to the label instructions would result in little, if any, inhalation exposure to handlers or applicators. V. Cumulative Effects The Agency has considered the cumulative effects of 1­ MCP and other substances in relation to a common mechanism of toxicity. These considerations include the possible cumulative effects of such residues on infants and children. There is no indication of mammalian toxicity at the maximum doses tested, of this or other products containing 1­ MCP. VI. Determination of Safety for U. S. Population, Infants and Children 1. U. S. population. There is reasonable certainty that no harm will result from aggregate exposure to residues of 1­ MCP to the U. S. population. This includes all anticipated dietary exposures and all other exposures for which there is reliable information. The Agency has arrived at this conclusion based on the very low levels of mammalian toxicity ( no toxicity at the maximum doses tested, Toxicity Categories III and IV) and the minimum exposure associated with 1­ MCP's use. 2. Infants and children. FFDCA section 408 provides that EPA shall apply an additional tenfold margin of exposure ( safety) for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the data base unless EPA determines that a different margin of exposure ( safety) will be safe for infants and children. Margins of exposure ( safety) are often referred to as uncertainty ( safety) factors. In this instance, based on all the available information, the Agency concludes that 1­ MCP is practically non­ toxic to mammals, including infants and children. Thus, there are no threshold effects of concern and, as a result the provision requiring an additional margin of safety does not apply. Further, based on the lack of observed developmental toxicity and extremely low exposure, there is reasonable certainty that no harm to infants, children, or adults will result from aggregate exposure to 1­ MCP residues. Exemption of 1­ MCP from the requirements of a tolerance should pose no significant risk to humans or the environment VII. Other Considerations A. Endocrine Disruptors EPA is required under the FFDCA as amended by FQPA to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) `` may have an effect in humans that is similar to an effect produced by a naturally­ occurring estrogen, or other such endocrine effects as the Administrator may designate.'' Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there is no scientific basis for including, as part of the program, the androgen­ and thyroid hormone systems in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program( EDSP). When the appropriate screening and/ or testing protocols being considered under the Agency's Endocrine Disruptor Screening Program have been developed, 1­ MCP may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption. Based on available data, no endocrine system­ related effects have been identified with consumption of 1­ MCP. In addition, 1­ MCP does not share any structural similarity to any known endocrine disruptive chemical. B. Analytical Method( s) EPA is establishing an exemption from the requirement of a tolerance without any numerical limitation for the reasons stated above, including 1­ MCP's lack of mammalian toxicity. For the same reasons, the Agency has concluded that an analytical method is not required for enforcement purposes for 1­ MCP. C. Codex Maximum Residue Level No Codex maximum residue levels are established for residues of 1­ MCP in or on any food or feed crop. There are no established tolerances or exemptions from tolerance for 1­ MCP in the United States. The Agency has classified 1­ MCP as a biochemical pesticide. VIII. Conclusions Based on the toxicology data submitted, there is reasonable certainty no harm will result from aggregate exposure of residues of 1­ MCP to the U. S. population, including infants and children, when the proposed product is used in accordance with label instructions and good agricultural practices. This includes all anticipated dietary exposures and all other exposures for which reliable data were submitted, accepted and reviewed. The Agency has arrived at this conclusion based on the data submitted demonstrating no toxicity at the maximum doses tested. As a result, EPA establishes an exemption from tolerance requirements pursuant to FFDCA 408( c) and ( d) for residues of 1­ MCP in or on all food commodities. IX. Objections and Hearing Requests Under section 408( g) of the FFDCA, as amended by the FQPA, any person may file an objection to any aspect of this regulation and may also request a hearing on those objections. The EPA procedural regulations which govern the submission of objections and requests for hearings appear in 40 CFR part 178. Although the procedures in those regulations require some modification to reflect the amendments made to the FFDCA by the FQPA of 1996, EPA will continue to use those procedures, with appropriate adjustments, until the necessary modifications can be made. The new section 408( g) provides essentially the same process for persons to `` object'' to a regulation for an exemption from the requirement of a tolerance issued by EPA under new section 408( d), as was provided in the old FFDCA sections 408 and 409. However, the period for filing objections is now 60 days, rather than 30 days. A. What Do I Need to Do to File an Objection or Request a Hearing? You must file your objection or request a hearing on this regulation in accordance with the instructions provided in this unit and in 40 CFR part 178. To ensure proper receipt by EPA, you must identify docket ID number OPP 2002 0142 in the subject line on the first page of your submission. All requests must be in writing, and must be mailed or delivered to the Hearing Clerk on or before September 24, 2002. 1. Filing the request. Your objection must specify the specific provisions in the regulation that you object to, and the grounds for the objections ( 40 CFR VerDate Jul< 19> 2002 18: 20 Jul 25, 2002 Jkt 197001 PO 00000 Frm 00056 Fmt 4700 Sfmt 4700 E:\ FR\ FM\ 26JYR1. SGM pfrm17 PsN: 26JYR1 48799 Federal Register / Vol. 67, No. 144 / Friday, July 26, 2002 / Rules and Regulations 178.25). If a hearing is requested, the objections must include a statement of the factual issues( s) on which a hearing is requested, the requestor's contentions on such issues, and a summary of any evidence relied upon by the objector ( 40 CFR 178.27). Information submitted in connection with an objection or hearing request may be claimed confidential by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. A copy of the information that does not contain CBI must be submitted for inclusion in the public record. Information not marked confidential may be disclosed publicly by EPA without prior notice. Mail your written request to: Office of the Hearing Clerk ( 1900), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. You may also deliver your request to the Office of the Hearing Clerk in Rm. C400, Waterside Mall, 401 M St., SW., Washington, DC 20460. The Office of the Hearing Clerk is open from 8 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The telephone number for the Office of the Hearing Clerk is ( 202) 260 4865. 2. Tolerance fee payment. If you file an objection or request a hearing, you must also pay the fee prescribed by 40 CFR 180.33( i) or request a waiver of that fee pursuant to 40 CFR 180.33( m). You must mail the fee to: EPA Headquarters Accounting Operations Branch, Office of Pesticide Programs, P. O. Box 360277M, Pittsburgh, PA 15251. Please identify the fee submission by labeling it `` Tolerance Petition Fees.'' EPA is authorized to waive any fee requirement `` when in the judgement of the Administrator such a waiver or refund is equitable and not contrary to the purpose of this subsection.'' For additional information regarding the waiver of these fees, you may contact James Tompkins by phone at ( 703) 305 5697, by e­ mail at tompkins. jim@ epa. gov, or by mailing a request for information to Mr. Tompkins at Registration Division ( 7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. If you would like to request a waiver of the tolerance objection fees, you must mail your request for such a waiver to: James Hollins, Information Resources and Services Division ( 7502C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 3. Copies for the Docket. In addition to filing an objection or hearing request with the Hearing Clerk as described in Unit IX. A., you should also send a copy of your request to the PIRIB for its inclusion in the official record that is described in Unit I. B. 2. Mail your copies, identified by docket ID number OPP 2002 0142, to: Public Information and Records Integrity Branch, Information Resources and Services Division ( 7502C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. In person or by courier, bring a copy to the location of the PIRIB described in Unit I. B. 2. You may also send an electronic copy of your request via e­ mail to: oppdocket epa. gov. Please use an ASCII file format and avoid the use of special characters and any form of encryption. Copies of electronic objections and hearing requests will also be accepted on disks in WordPerfect 6.1/ 8.0 or ASCII file format. Do not include any CBI in your electronic copy. You may also submit an electronic copy of your request at many Federal Depository Libraries. B. When Will the Agency Grant a Request for a Hearing? A request for a hearing will be granted if the Administrator determines that the material submitted shows the following: There is a genuine and substantial issue of fact; there is a reasonable possibility that available evidence identified by the requestor would, if established resolve one or more of such issues in favor of the requestor, taking into account uncontested claims or facts to the contrary; and resolution of the factual issues( s) in the manner sought by the requestor would be adequate to justify the action requested ( 40 CFR 178.32). X. Regulatory Assessment Requirements This final rule establishes an exemption from the tolerance requirement under FFDCA section 408( d) in response to a petition submitted to the Agency. The Office of Management and Budget ( OMB) has exempted these types of actions from review under Executive Order 12866, entitled Regulatory Planning and Review ( 58 FR 51735, October 4, 1993). Because this rule has been exempted from review under Executive Order 12866 due to its lack of significance, this rule is not subject to Executive Order 13211, Actions Concerning Regulations That Significantly Affect Energy Supply, Distribution, or Use ( 66 FR 28355, May 22, 2001). This final rule does not contain any information collections subject to OMB approval under the Paperwork Reduction Act ( PRA), 44 U. S. C. 3501 et seq., or impose any enforceable duty or contain any unfunded mandate as described under Title II of the Unfunded Mandates Reform Act of 1995 ( UMRA) ( Public Law 104 4). Nor does it require any special considerations under Executive Order 12898, entitled Federal Actions to Address Environmental Justice in Minority Populations and Low­ Income Populations ( 59 FR 7629, February 16, 1994); or OMB review or any Agency action under Executive Order 13045, entitled Protection of Children from Environmental Health Risks and Safety Risks ( 62 FR 19885, April 23, 1997). This action does not involve any technical standards that would require Agency consideration of voluntary consensus standards pursuant to section 12( d) of the National Technology Transfer and Advancement Act of 1995 ( NTTAA), Public Law 104 113, section 12( d) ( 15 U. S. C. 272 note). Since tolerances and exemptions that are established on the basis of a petition under FFDCA section 408( d), such as the tolerance exemption in this final rule, do not require the issuance of a proposed rule, the requirements of the Regulatory Flexibility Act ( RFA) ( 5 U. S. C. 601 et seq.) do not apply. In addition, the Agency has determined that this action will not have a substantial direct effect on States, on the relationship between the national government and the States, or on the distribution of power and responsibilities among the various levels of government, as specified in Executive Order 13132, entitled Federalism ( 64 FR 43255, August 10, 1999). Executive Order 13132 requires EPA to develop an accountable process to ensure `` meaningful and timely input by State and local officials in the development of regulatory policies that have federalism implications.'' `` Policies that have federalism implications'' is defined in the Executive order to include regulations that have `` substantial direct effects on the States, on the relationship between the national government and the States, or on the distribution of power and responsibilities among the various levels of government.'' This final rule directly regulates growers, food processors, food handlers and food retailers, not States. This action does not alter the relationships or distribution of power and responsibilities established by Congress in the preemption provisions of FFDCA section 408( n)( 4). For these same reasons, the Agency has determined that this rule does not have any `` tribal implications '' as described in Executive Order 13175, entitled Consultation and Coordination with VerDate Jul< 19> 2002 18: 20 Jul 25, 2002 Jkt 197001 PO 00000 Frm 00057 Fmt 4700 Sfmt 4700 E:\ FR\ FM\ 26JYR1. SGM pfrm17 PsN: 26JYR1 48800 Federal Register / Vol. 67, No. 144 / Friday, July 26, 2002 / Rules and Regulations Indian Tribal Governments ( 65 FR 67249, November 6, 2000). Executive Order 13175, requires EPA to develop an accountable process to ensure `` meaningful and timely input by tribal officials in the development of regulatory policies that have tribal implications.'' `` Policies that have tribal implications'' is defined in the Executive order to include regulations that have `` substantial direct effects on one or more Indian tribes, on the relationship between the Federal Government and the Indian tribes, or on the distribution of power and responsibilities between the Federal Government and Indian tribes.'' This rule will not have substantial direct effects on tribal governments, on the relationship between the Federal Government and Indian tribes, or on the distribution of power and responsibilities between the Federal government and Indian tribes, as specified in Executive Order 13175. Thus, Executive Order 13175 does not apply to this rule. XI. Submission to Congress and the Comptroller General The Congressional Review Act, 5 U. S. C. 801 et seq., as added by the Small Business Regulatory Enforcement Fairness Act of 1996, generally provides that before a rule may take effect, the agency promulgating the rule must submit a rule report, which includes a copy of the rule, to each House of the Congress and to the Comptroller General of the United States. EPA will submit a report containing this rule and other required information to the U. S. Senate, the U. S. House of Representatives, and the Comptroller General of the United States prior to publication of this final rule in the Federal Register. This final rule is not a `` major rule'' as defined by 5 U. S. C. 804( 2). List of Subjects in 40 CFR Part 180 Environmental protection, Administrative practice and procedure, Agricultural commodities, Pesticides and pests, Reporting and recordkeeping requirements. Dated: July 16, 2002. Marcia E. Mulkey, Director, Office of Pesticide Programs. Therefore, 40 CFR chapter I is amended as follows: PART 180 [ AMENDED] 1. The authority citation for part 180 continues to read as follows: Authority: 21 U. S. C. 321( q), 346( a) and 374. 2. Section 180.1220 is added to subpart D to read as follows: § 180.1220 1­ Methylcyclopropene; exemption from the requirement of a tolerance. An exemption from the requirement of a tolerance is established for residues of 1­ Methylcyclopropene in or on fruits and vegetables when used as a post harvest plant growth regulator, i. e., for the purpose of inhibiting the effects of ethylene. [ FR Doc. 02 18868 Filed 7 25 02; 8: 45am] BILLING CODE 6560 50 S DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Medicare & Medicaid Services 42 CFR Part 405 [ CMS 3074 F2] RIN 0938 AK98 Medicare Program; End­ Stage Renal Disease: Removing of Waiver of Conditions for Coverage Under a State of Emergency in the Houston, Texas Area AGENCY: Centers for Medicare & Medicaid Services ( CMS). ACTION: Final rule. SUMMARY: This final rule removes an emergency waiver of the Medicare endstage renal disease ( ESRD) conditions for coverage granted to permit the transplant team of an approved renal transplant center to furnish kidney transplant services in three specific hospitals in the Houston, Texas area during a state of emergency. The state of emergency has ceased, the primary kidney transplant center in the area is now fully operational, and the effective period of the waiver provisions has expired. EFFECTIVE DATE: July 26, 2002. FOR FURTHER INFORMATION CONTACT: Rachael Weinstein, ( 410) 786 6775 SUPPLEMENTARY INFORMATION I. Provisions of This Rule On June 20, 2001, we published a final rule in the Federal Register ( 66 FR 33030 33031) that granted an emergency waiver of the Medicare endstage renal disease ( ESRD) conditions of coverage to permit the transplant team of an approved renal transplant center to furnish covered kidney transplant services in three specific hospitals in the Houston, Texas area during a state of emergency. The state of emergency ( a natural disaster due to flooding) resulted in a severe health and safety threat to hospitals in the entire Houston, Texas area, including ESRD facilities that were approved to furnish kidney transplant services. Waivers of the conditions of coverage were granted to Memorial Hermann­ Memorial City Hospital, Memorial Hermann Southwest Hospital, and Memorial Hermann Southeast Hospital to permit an approved transplant team to furnish kidney transplant services in the three hospitals, effective June 15, 2001, through the earlier of December 15, 2001, or until Memorial Hermann Hospital, the primary kidney transplant center, reopened. Memorial Hermann Hospital is now reopened. In the June 20, 2001 final rule, we amended the Medicare regulations to include a new § 405.2175 that incorporated the waiver provisions. In § 405.2175, we specified that we would publish a rule removing the waiver provisions from the regulations after the waiver expired. The waiver has expired and we are removing the provisions from the Medicare regulations. II. Waiver of Proposed Rulemaking and Delay of Effective Date We ordinarily publish a notice of proposed rulemaking in the Federal Register and invite public comment on a proposed rule. The notice of proposed rulemaking includes a reference to the legal authority under which the rule is proposed, and the terms and substances of the proposed rule or a description of the subjects and issues involved. This procedure can be waived, however, if an agency finds good cause that a noticeand comment procedure is impracticable, unnecessary, or contrary to the public interest and incorporates a statement of the findings and its reasons in the rule issued. Further, we generally provide for final rules to be effective no sooner than 30 days after the date of publication unless we find good cause under 5 U. S. C. 553( d)( 3) to waive the 30­ day delay of the effective date. The purpose of the 30­ day waiting period between publication of an administrative agency final rule and its effective date is to give affected parties reasonable time to adjust their behavior before the final rule takes place. The state of emergency under which we granted a waiver of the ESRD conditions of coverage is now over in the Houston, Texas area, and Memorial Hermann Hospital is reopened to furnish kidney transplant services. We announced in the June 20, 2001 final rule our intention to remove the VerDate Jul< 19> 2002 18: 20 Jul 25, 2002 Jkt 197001 PO 00000 Frm 00058 Fmt 4700 Sfmt 4700 E:\ FR\ FM\ 26JYR1. SGM pfrm17 PsN: 26JYR1

epa

2024-06-07T20:31:42.571802

regulations

EPA-HQ-OPP-2002-0146-0003

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM SUBJECT: TRED for Tebuthiuron (Chemical # 105501, DP Barcode D279066) FROM: Mark Corbin, Environmental Scientist Environmental Risk Branch 1 Environmental Fate and Effects Division (7507C) THRU: Dana Spatz, Acting Branch Chief Environmental Risk Branch 1 Environmental Fate and Effects Division (7507C) TO: Daniel Helfgot Special Review Branch Special Review and Reregistration Division (7508C) Wilhelmena Livingston Special Review Branch Special Review and Reregistration Division (7508C) EFED has completed a drinking­ water assessment for the reassessment of tolerances for the herbicide Tebuthiuron. This assessment considers Tebuthiuron, and to the extent possible, the degradate "Compound 104," which the Health Effects Division has determined is of toxicological concern. Compound 104 was the only degradate of Tebuthiuron of toxicological concern that was detected in the environmental fate studies reviewed. Tier II (PRZM version 3.12/ EXAMS version 2.97.5) surface water modeling for Tebuthiuron use on rangeland/ pasture at 4 pounds active ingredient per acre (lbs ai/ A) using the index reservoir predicts the 1 in 10 year annual maximum (acute) concentration of 15.1 : g/ L. The 1 in 10 year annual average concentration (non­ cancer chronic) of Tebuthiuron is predicted to be 1.5 : g/ L . The 36 year annual average concentration (cancer chronic) of Tebuthiuron is predicted to be 0.6 : g/ L. SCIGROW (version 2.1) modeling estimates the acute and chronic concentration of Tebuthiuron residues in shallow groundwater is 181 : g/ L. Monitoring data was evaluated from the USGS NAWQA program and from preliminary data from the USGS Reservoir Pilot Monitoring Project. Both surface and ground water data from the NAWQA program were evaluated for annual maximum (peak) and time weighted mean concentrations. Only surface water data was available from the USGS Reservoir Pilot Monitoring study which was also evaluated for annual N N S N CH 3 CH 3 C H 3 C H 3 O N H CH 3 maximum and time weighted mean concentrations. EFED proposes using the estimated environmental concentrations (EECs) from modeling as upper bound estimates of exposure. Acute (annual maximum) concentrations and chronic (time weighted mean) concentrations from monitoring data are summarized below. In general these concentrations are less than the estimates from modeling. EFED proposes using the model results as acute and chronic EECs for the risk assessment because Tebuthiuron is persistent and data from edge of field runoff studies conducted in the 1980's indicate concentrations higher than those found in the NAWQA and USGS Reservoir studies can occur. Drinking water environmental concentrations for Compound 104 cannot be estimated due to a lack of fate and monitoring data . Compound 104 was detected at a maximum concentration of 0.004 mg/ L in ground water in a Small Scale Retrospective study (MRID 42390901) submitted in 1992. However the concentrations were detected four years after application of Tebuthiuron and may not be representative of the maximum concentrations present beneath the site after application. Compound 104 was detected at 6.9% of applied parent at the end of the aerobic soil metabolism study but was noted to still be increasing at the end of the study. It is suspected that the percent applied of Compound 104 would have increased if the experiment had run longer. Compound 104 appears to have similar mobility to Tebuthiuron and has a long half life. Therefore, EFED is unable to estimate how much degradate might have been produced if the study had run longer. Introduction Tebuthiuron is a non­ selective herbicide used primarily on pastureland, rights­ of­ way, and other non­ agricultural sites. Tebuthiuron is used predominantly in Texas, Oklahoma, and New Mexico based on information provided by the registrant and BEAD. Information on publically supplied drinking water available from the USGS (Selley, et al, 1998; "Estimated Use of Water in the United States in 1995". USGS Circular 1200) was reviewed. Both surface and ground water sources are used for publically supplied water in Texas, Oklahoma and New Mexico. Ground water provides approximately 89% of New Mexico's public water, while surface water provides 66% and 83% of public water to Texas and Oklahoma respectively. Reviewing population served information indicates that 88% of New Mexico's population relies on ground water while 58% of Texas and 74% of Oklahoma's population rely on surface water. Chemical Name: N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea Compound 104: N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N­ methylurea Chemical Structure: Environmental Fate As reported in the 1994 RED Tebuthiuron is persistent and mobile, and that the "principal route of dissipation appears to be transport to ground and surface water." This assessment was based on a suite of required environmental fate studies that lacked only a field dissipation study. This study has since been submitted and reviewed and found to be marginally acceptable with field dissipation half lives of 385 days (Florida), 770 days (California), and 575 days (Nebraska). The quickest observed route of Tebuthiuron degradation in laboratory studies was soil photolysis (half­ life 39.7 days.) Tebuthiuron is stable in laboratory studies to hydrolysis, aqueous photolysis, and aerobic aquatic metabolism. Tebuthiuron was also stable during a 9­ month aerobic soil metabolism study, with a calculated half­ life of 35.4 months. Soil partition coefficients (Kd) from adsorption/ desorption studies were 0.11, 0.62, 0.82 and 1.82, indicating that Tebuthiuron is very mobile over a range of soil types. The corresponding Koc values relating to these studies ranged from 31 to 151, with a median of 76 l/ kg. The soil adsorption of Tebuthiuron appears to be related to the amount of organic carbon in the soil. Degradate 104 (Compound 104 was the only degradate of Tebuthiuron of toxicological concern that was detected in the environmental fate studies reviewed) was at 6.9% and rising by the end of the study. That is the highest concentration of any degradate in any lab study. Based on data reviewed at the time of the RED, the degradate appears to have similar mobility to parent Tebuthiuron. For full details of the environmental fate assessment for Tebuthiuron, see the 1994 Reregistration Eligibility Document, which can be found on the internet at http:// www. epa. gov/ pesticides/ reregistration/ status. htm. SURFACE WATER MONITORING DATA ASSESSMENT National NAWQA Data The United States Geological Survey (USGS) is collecting surface and ground water data from selected watersheds in order to catalog the quality of water resources in the United States. The National Water Quality Assessment (NAWQA) program began in 1991 and consists of chemical, biological and physical water quality data from 59 study units across the United States. EFED evaluated the occurrence of Tebuthiuron in surface water from the national data set. Tebuthiuron was detected in surface water from locations in 30 states. Compared with current usage which is predominantly located in Texas, Oklahoma, and New Mexico, the occurrence in so many locations is reflective of past usage due to the persistence of Tebuthiuron. Tebuthiuron was detected above the limit of detection in 1155 samples from a total national dataset of 6625 samples (17.4%). This rate of detection is greater than for most pesticides included as analytes, in spite of its limited use. EFED analyzed the occurrence of Tebuthiuron in surface water from each sampling location within each state on an annual basis. Each year of data from an individual sample location was evaluated and the annual maximum concentration and time weighted mean were calculated. For the purposes of this assessment only the upper bound time weighted mean concentration from the NAWQA data is presented. The upper bound annual time weighted mean concentrations were estimated by setting detections at or below the detection limit at the value of the detection limit. Analysis of the national NAWQA surface water data set for Tebuthiuron is presented below. The annual maximum concentrations ranged from 2.83 to 0.003 (estimated below limit of quantitation) : g/ L and the upper bound time weighted means ranged from 0.26 to 0.00 : g/ L. No degradate data was available in this dataset for analysis. The annual maximum concentrations and time weighted mean concentrations were ranked and percentiles generated for the dataset. The results of the analysis are summarized in Table 1. Table 1 Summary of Percentiles for Surface Water Annual Maximum and Time Weighted Mean Tebuthiuron Concentrations from the National NAWQA Data. Percentile National NAWQA Annual Maximum ( : g/ L) National NAWQA Time Weighted Mean ( : g/ L) Maximum 2. 83 0. 26 99.9% 1.99 0.24 99% 0.21 0.06 95% 0.09 0.03 90% 0.06 0.02 50% 0.01 0.01 The analysis above includes the entire national NAWQA data which consists of surface water results from all 59 NAWQA study units. In order to assess the impact of high Tebuthiuron usage on the analysis, EFED completed an additional analysis focusing on only data from those study units located in areas of high Tebuthiuron usage. This focused assessment is intended to indicate if exposure to Tebuthiuron in surface water in those areas where the herbicide is used predominantly (i. e. Texas, Oklahoma, and New Mexico) is greater in these areas than on a national basis. The study units for the focused analysis were selected by overlaying Tebuthiuron usage data taken from registrant supplied information with the NAWQA study units. As with the national NAWQA, the focused NAWQA data annual maximum concentrations ranged from 2.83 to 0.01 : g/ L and the upper bound time weighted means ranged from 0.26 to 0.01 : g/ L. No degradate data was available in this dataset for analysis. The annual maximum concentrations and time weighted mean concentrations were ranked and percentiles generated for the dataset. The results of the analysis are summarized in Table 2. Analysis of surface water data from those locations where Tebuthiuron usage is higher indicates that while the range of concentrations is the same for both annual maximum and time weighted mean, the concentrations at the higher percentiles (> 90%) are higher for the focused data. Table 2 Summary of Percentiles for Surface Water Annual Maximum and Time Weighted Mean Tebuthiuron Concentrations from the Focused NAWQA Data. Percentile Focused NAWQA Annual Maximum ( : g/ L) Focused NAWQA Time Weighted Mean ( : g/ L) Maximum 2. 83 0. 26 99.9% 2.77 0.26 99% 2.27 0.25 95% 0.69 0.19 90% 0.33 0.05 50% 0.01 0.01 USGS Reservoir and Finished Water ­ Pilot Monitoring Study, 1999­ 2000 The USGS recently issued preliminary data from a cooperative study between the USGS and USEPA for "Pesticides in Water­ supply Reservoirs and Finished Drinking Water ­ A Pilot Monitoring Program". The study consists of the analysis of samples from 12 drinking water reservoirs across the United States (including Texas and Oklahoma). EFED has reviewed the preliminary data for the occurrence of Tebuthiuron. Tebuthiuron was analyzed in all samples using the same analytical methodology as the USGS NAWQA program (Schedule 2001). Degradates of Tebuthiuron were not analyzed in this study. Source water samples were collected from drinking water intakes within each reservoir and treated water samples were collected post­ treatment. Treated and intake samples were typically collected on the same date within several hours of each other. In addition, samples were collected and analyzed from the reservoir outfall (untreated) from selected locations. Several outfall locations coincide with source water intakes and therefore the intake and outfall samples are the same. Tebuthiuron was detected in 232 out of 627 analysis for a detection frequency of 37%. The highest peak concentration of Tebuthiuron was 0.032 : g/ L detected in the treated water of the Oklahoma Reservoir. The maximum concentrations and time weighted mean concentrations were calculated for each subset of the data (intake, treated, and outfall) for each location. The results are presented in Table 3 and 4. In addition, the maximum concentrations and time weighted mean concentrations were ranked and percentiles generated for the data set. The results of ranking are presented in Tables 5 and 6. Table 3 Summary of Time Weighted Mean Tebuthiuron Concentrations from the USGS Reservoir Data from 1999­ 2000. State Intake Sample Time Weighted Mean ( : g/ L) Treated Sample Time Weighted Mean ( : g/ L) Reservoir Outfall Time Weighted Mean ( : g/ L) SD 0.011 0.010 0.009 NY 0.010 0.011 OH 0.011 0.010 0.011 CA 0.009 0.010 TX 0.008 0.008 LA 0.010 0.010 0.010 NC 0.010 0.010 OK 0.018 0.020 0.011 MO 0.009 0.011 0.008 PA 0.008 0.008 SC 0.008 0.008 0.008 IN 0.011 0.011 0.006 Table 4 Summary of Maximum Tebuthiuron Concentrations from the USGS Reservoir Data from 1999­ 2000. State Intake Sample Maximum ( : g/ L) Treated Sample Maximum ( : g/ L) Reservoir Outfall Maximum ( : g/ L) SD 0.016 0.016 0.010 NY 0.016 0.016 OH 0.015 0.010 0.012 CA 0.012 0.018 TX 0.010 0.010 LA 0.016 0.016 0.010 NC 0.011 0.010 OK 0.030 0.032 0.024 MO 0.010 0.016 0.010 PA 0.020 0.010 SC 0.010 0.016 0.010 IN 0.016 0.016 0.020 Table 5 Summary of Percentiles for Surface Water Annual Time Weighted Mean Tebuthiuron Concentrations from the USGS Reservoir Data from 1999­ 2000. Percentile Time Weighted Mean Concentration from Intake Samples ( : g/ L) Time Weighted Mean Concentration from Treated Samples Time Weighted Mean Concentration from Outfall Samples ( : g/ L) Maximum 0. 018 0.020 0.011 99.9% 0.018 0.020 0.011 99% 0.017 0.019 0.011 95% 0.014 0.015 0.011 90% 0.011 0.011 0.011 50% 0.010 0.010 0.009 Table 6 Summary of Percentiles for Surface Water Maximum Tebuthiuron Concentrations from the USGS Reservoir Data from 1999­ 2000. Percentile Maximum Concentration from Intake Samples ( : g/ L) Maximum Concentration from Treated Samples ( : g/ L) Maximum Concentration from Outfall Samples ( : g/ L) Maximum 0. 030 0.032 0.024 99.9% 0.030 0.032 0.024 99% 0.029 0.030 0.024 95% 0.025 0.024 0.023 90% 0.020 0.018 0.022 50% 0.016 0.016 0.010 The data above indicate that Tebuthiuron is found at a high frequency of detection (greater than 17% in NAWQA data and greater than 37% in the USGS Reservoir data). The maximum concentration detected in these two studies is 2.83 ppb from the NAWQA study. Time weighting of these data indicate that long term exposure is generally less than 1 ppb. The high frequency of detection is likely a function of the persistence of Tebuthiuron in the environment. The low concentrations detected (compared with edge of field studies discussed below) may be a function of the use of Tebuthiuron which is focused on rangeland/ pasture which is typically in arid and semi­ arid environments and is not likely applied in proximity to surface water bodies assessed by NAWQA and USGS Reservoir studies. Additional Monitoring Data Four supplemental watershed/ runoff studies were conducted in Idaho, Oklahoma, Texas, and Arizona between 1980 and 1984. The four studies represent typical application scenarios for the time with variable rates of application between 1 and 3 lbs a. i./ acre. The maximum label rate is 4 lbs a. i./ acre suggesting that these studies do not represent a worse case scenario. Tebuthiuron was applied to varying percentages of four small watersheds ranging between 13 acres (Oklahoma) to 303 acres (Arizona). Surface water and "hydrosoil" samples were collected up to 9 months after application at the Idaho site (24 samples), 7 months after application at the Oklahoma site (7 samples), 7 months after application at the Texas site (6 samples), and 3 months after application at the Arizona site (53 samples). Analytical results from the four watershed/ runoff studies reported concentrations of Tebuthiuron in surface water ranging from less than 1 : g/ L (measured at the conclusion of the Texas study) up to 180 : g/ L (measured 5/ 5/ 81 in the Oklahoma study) and hydrosoil residues from < 50 : g/ L up to 140 : g/ L. EFED revisited the analytical data from the four runoff studies in Idaho, Oklahoma, Texas, and Arizona. Analysis of the data from 1980 through 1981 indicate that the maximum concentration detected for each site respectively is 180 : g/ L for Oklahoma, 14 : g/ L for Idaho, 70 : g/ L for Texas, and 54 : g/ L for Arizona. Time weighted mean concentrations were calculated for each dataset with the results showing 98 : g/ L in Oklahoma, 7 : g/ L in Idaho, 37 : g/ L in Texas, and 24 : g/ L in Arizona. These concentrations are higher than those observed in other surface water monitoring studies (NAWQA and USGS Reservoir Pilot Monitoring) and those concentrations predicted using PRZM/ EXAMS. The samples analyzed were collected from catchment/ weir ponds within a watershed unlike the other surface water monitoring data which is generally collected from flowing streams and drinking water reservoirs. The concentrations from these runoff studies are better compared to the edge of field effect predicted by PRZM/ EXAMS. The comparison with PRZM/ EXAMS suggests that the modeling may under predict the concentrations that would be expected in a waterbody adjacent to a treatment area. GROUND WATER MONITORING DATA ASSESSMENT A small scale retrospective ground water monitoring study was completed on a rangeland site at a ranch near Sarita, Texas. The study was conducted in a portion of a 540 acre area treated with Tebuthiuron in March 1986 by aerial broadcast in 70 foot wide strips. Tebuthiuron was applied at rates between 1.5 and 1.75 lbs a. i./ acre for rangeland brush control. Higher application up to 2 lbs a. i./ acre were applied in bands to thick stands of live oak and along fence lines. In some areas at the site overlap of rangeland and fence line treatments resulted in total application of up to 4 lbs a. i./ acre. A total of 16 soil borings, 14 test pits, and 5 ground water monitoring wells were performed to complete site characterization. The site characterization gives a high level of confidence that this study was performed with a reasonable "high exposure" scenario. The site is comprised of eolian sands over fluvial deposits. Monitoring wells were installed to avoid discontinuous, restrictive clay layers that are found beneath some portions of the site. Using the site characterization data, a study protocol was developed and field work began in May 1990 and included the installation of an additional 5 ground water monitoring wells. A program of ground water analysis was begun in which seven of the ten ground water monitoring wells were sampled every other month beginning in June 1990 and ending June 1991. Analysis of soil samples indicated that Tebuthiuron was still present in soil at depths greater than three feet below ground surface and appeared to be in contact with shallow ground water beneath portions of the study site. No degradate was detected in soil samples above the limit of detection of 0.01 mg/ L. The data suggest that Tebuthiuron is persistent and mobile in soil at the study site. Analysis of ground water samples collected beneath the study site indicate that Tebuthiuron was present above the limit of detection (0.001 mg/ L) in six of the seven wells at the site and was detected above the limit of quantitation (0.003 mg/ L) in three of the seven wells with a maximum concentration of 0.023 mg/ L four years after application. Compound 104 was detected above the limit of detection in three wells and was detected at concentrations above the limit of quantitation in one well with a maximum concentration of 0.004 mg/ L four years after application. This data indicate that Tebuthiuron and its primary degradate are persistent and mobile in ground water up to four years after application. NAWQA Data EFED evaluated the occurrence of Tebuthiuron in ground water from the national data set. Tebuthiuron was detected in 228 ground water samples out of a total of 5303 samples (4.3%). It is difficult to compare analytical results from ground water monitoring wells within a given geographic area. A significant amount of ancillary data is necessary in order to compare wells across an area. Examples of the data that is needed is aquifer type, well construction, and sampling methodology. Even with ancillary data it is difficult to compare analytical results within a region due to variations in geology, geochemistry of ground water, and groundwater usage patterns and history. Because this information is not readily available for this data set, EFED has conducted a general analysis of the data. The maximum concentration detected across all samples is 17.3 : g/ L with a detection limit of 0.010 : g/ L, while the average concentration among all reported Tebuthiuron data is 0.016 : g/ L. Depth to ground water across the entire NAWQA data ranged from near surface to greater than 600 feet below ground surface with an average depth of 33 feet below ground surface. Depth to ground water in the focused NAWQA study units from Texas, Oklahoma, and New Mexico ranged from 2 to 177 feet below ground surface with an average depth of 17 feet below ground surface. The depth to ground water data suggest that the peak and average concentrations are representative of the shallowest aquifers. SURFACE, GROUND AND DRINKING WATER ASSESSMENT Because Tebuthiuron is not included among regulated or unregulated chemicals required as analytes in testing of public drinking water supplies, drinking­ water monitoring results are not available. Therefore, drinking water exposure assessments are supplemented with modeling predictions. Surface water concentrations of Tebuthiuron were modeled using the PRZM/ EXAMS (Tier II) programs for pasture/ rangeland using EFEDs standard scenario for alfalfa in Texas. The alfalfa scenario was chosen because its hydrologic and agronomic practices closely match those of pasture/ rangeland. Groundwater concentrations were modeled using the SCI­ GROW program. Input parameters used Tier II (PRZM version 3.12/ EXAMS version 2.97.5) modeling were selecting using Agency guidance (" Guidance for Chemistry and Management Practice Input Parameters for Use in Modeling the Environmental Fate and Transport of Pesticides" dated August 6, 2000) and EFED calculated degradation rate constants from review of registrant submitted environmental fate studies. The assessment strategy was designed to assess concentrations of the parent compound alone. Tier II (PRZM­ EXAMS) surface water modeling for Tebuthiuron (parent only) using the index reservoir with the percent cropped area (PCA= 0.87 for default PCA) estimates the concentration of Tebuthiuron is not likely to exceed the concentrations in Table 7. Table 7. PRZM­ EXAMS Predicted Parent Tebuthiuron Concentrations in the Index Reservoir Simulation Scenarios Concentration ( : g/ L) 1 in 10 year Mean of Annual Means Crop and Location Scenario Peak 96 Hour 21 Day 60 Day 90 Day Annual Mean Pasture, Milam Co., TX Index Reservoir 17.4 16.6 13.2 8.1 6.0 1.7 0.7 Index Reservoir w/ PCA (0.87) 15.1 14.4 11.5 7.0 5.2 1.5 0.6 SCI­ GROW predicts a concentration of Tebuthiuron in shallow ground water of 181 µg/ L. Appendix A provides a detailed discussion of the modeling efforts for PRZM/ EXAMS and SCIGROW APPENDIX A MODELING DISCUSSION DRINKING WATER ASSESSMENT Uncertainties, Assumptions and Limitations Input parameters used in Tier II (PRZM/ EXAMS) modeling were selecting using Agency guidance (" Guidance for Chemistry and Management Practice Input Parameters for Use in Modeling the Environmental Fate and Transport of" dated August 6, 2000) and EFED calculated degradation rate constants from review of registrant submitted environmental fate studies. Tebuthiuron is used primarily on pasture and rangeland in Texas, Oklahoma, and New Mexico, therefore, only one scenario was simulated to estimate runoff concentrations. EFED selected a scenario in Texas for alfalfa representing an EFED standard scenario developed for use in modeling the respective crops. Alfalfa was selected as the scenario most closely representing pasture/ rangeland (the alfalfa scenario was developed based on a pasture setting). These scenarios were developed to approximately represent the 90 th percentile site for runoff vulnerability in a high usage state. Application timing was taken from registrant provided information and recent labels. The standard scenario for alfalfa is based on usage patterns in Milam County, Texas. The soil is a Lufkin sandy loam in Major Land Use Area (MLRA) 87. The Lufkin sandy loam is characterized as a Hydrologic Group D soil. The index reservoir represents potential drinking water exposure from a specific area with specific cropping patterns, weather, soils, and other factors (use of an index reservoir for areas with different climates, crops, pesticides used, sources of water, and hydrogeology creates uncertainties). If a community derives its drinking water from a large river, then the estimated exposure would likely be higher than the actual exposure. Conversely, a community that derives its drinking water from smaller bodies of water with minimal outflow would likely get higher drinking water exposure than estimated using the index reservoir. Areas with a less humid climate that use a similar reservoir and cropping patterns would likely get less pesticides in their drinking water than predicted levels. A single steady flow has been used to represent the flow through the reservoir. Discharge from the reservoir also removes chemical from it so this assumption will underestimate removal from the reservoir during wet periods and overestimates removal during dry periods. This assumption can both underestimate or overestimate the concentration in the pond depending upon the annual precipitation pattern at the site. The index reservoir scenario uses the characteristic of a single soil to represent the soil in the basin. In fact, soils can vary substantially across even small areas, and thus, this variation is not reflected in these simulations. The index reservoir scenario does not consider tile drainage. Areas that are prone to substantial runoff are often tile drained. This may underestimate exposure, particularly on a chronic basis. EXAMS is unable to easily model spring and fall turnover which results in complete mixing of the chemical through the water column at these times. Because of this inability, Shipman City Lake has been simulated without stratification. There is data to suggest that Shipman City Lake does indeed stratify in the deepest parts of the lake at least in some years. This may result in both over and underestimation of the concentration in drinking water depending upon the time of the year and the depth the drinking water intake is drawing from. PRZM/ EXAMS is a field­ scale model which treats watersheds as large fields. It assumes that the entire area of the watershed is planted with the crop of interest (i. e., 100% crop coverage). This assumption may not hold for areas larger than a few hectares, such as watersheds containing drinking water reservoirs. Therefore, pesticide concentrations (peak and/ or long­ term average) were estimated with PRZM/ EXAMS (the index reservoir modification changes the surface water body parameters used in EXAMS) and the model results from PRZM/ EXAMS were adjusted by a factor that represents the maximum percent crop area found for the crop or crops being evaluated. Percent crop areas (PCAs) were derived on a watershed basis with GIS tools using 1992 Census of Agriculture data and 8­ digit Hydrologic Unit Code (HUC) coverage for the coterminous United States. The maximum PCA derived from this project was selected to represent the modeled crop or crops. The PCA assumes the distribution of the crops within a county is uniform and homogeneous throughout the county area. Distance between the treated fields and the water body is not addressed. The PCA is a watershed­ based modification. Implicit in its application is the assumption that currently­ used field­ scale models reflect basin­ scale processes consistently for all pesticides and uses. In other words, we assume that the large field simulated by the coupled PRZM and EXAMS models is a reasonable approximation of pesticide fate and transport within a watershed that contains a drinking water reservoir. If the models fail to capture pertinent basin­ scale fate and transport processes consistently for all pesticides and all uses, the application of a factor that reduces the estimated concentrations predicted by modeling could, in some instances, result in inadvertently passing a chemical through the screen that may actually pose a risk. Some preliminary assessments made in the development of the PCA suggest that PRZM/ EXAMS may not be realistically capturing basin­ scale processes for all pesticides or for all uses. A preliminary survey of water assessments which compared screening model estimates to readily available monitoring data suggest uneven model results. In some instances, the screening model estimates are more than an order of magnitude greater than the highest concentrations reported in available monitoring data; in other instances, the model estimates are less than monitoring concentrations. Because of these concerns, the SAP recommended using the PCA only for "major" crops in the South. For other crops, development of PCAs will depend on the availability of relevant monitoring data that could be used to evaluate the result of the PCA adjustment. Table A­ 1. Input Parameters for Tebuthiuron for PRZM (Version 3.12) for Index Reservoir and PCA. Variable Description Variable (Units) Input Value Source of Info/ Reference Application date( s) (day/ mo/ yr) APD, APM, IAPYR (day/ mo/ yr) 1 times per year Product label or location­ specific Incorporation depth DEPI (cm) 0 Product label Application rate TAPP (kg a. i. ha ­1 ) 4.48 Aerial granular Product label Application efficiency APPEFF (decimal) 1.00 Spray Drift Task Force Data Spray drift fraction: For aquatic ecological exposure assessment, use 0.05 for aerial spray; 0.01 for ground spray. For drinking water assessment, use 0.16 for aerial 0.064 for ground spray. DRFT (decimal) 0.00 Spray Drift Task Force Data Foliar extraction FEXTRA (frac./ cm rain) 0.5 (default) Default or field data Decay rate on foliage PLDKRT (day ­1 ) 0.0 (default) Default or field data Volatilization rate from foliage PLVKRT (day ­1 ) 0.0 (default) Default or field data Plant uptake factor UPTKF (frac. of evap) 0.0 (default) Default or field data Dissolved phase pesticide decay rate in surface horizon (aerobic soil metabolism) DWRATE (surface) (day ­1 ) T1/ 2 => 1060 days Rate constant = 0.00065/ day MRID 41328001 Adsorbed phase pesticide decay rate in surface horizon (aerobic soil metabolism) DSRATE (surface) (day ­1 ) T1/ 2 => 1060 days Rate constant = 0.00065/ day MRID 41328001 Dissolved phase pesticide decay rate in subsequent subsurface horizons (aerobic or anaerobic soil metabolism) DWRATE (subsurface horizons) (day ­1 ) T1/ 2 => 1060 days Rate constant = 0.00065/ day MRID 41328001 Adsorbed phase pesticide decay rate in subsequent subsurface horizons (aerobic or anaerobic soil metabolism) DSRATE (subsurface horizons) (day ­1 ) T1/ 2 => 1060 days Rate constant = 0.00065/ day MRID 41328001 Pesticide partition or distribution coefficients for each horizon (Leaching/ Adsorption/ Desorption) Kd 0.84 Average Kd MRID 40768401 Table A­ 2. Input Parameters for Tebuthiuron. chm Files Used in EXAMS (Version 2.97. 5) for Index Reservoir and PCA. Variable Description Variable (Units) Input Value Source of Info/ Reference Henry's law constant HENRY (atm­ m 3 mole ­1 ) 2.4 x 10 ­10 Atm m 3 /mol From registrant or product chemistry Bacterial biolysis in water column (aerobic aquatic metabolism) KBACW (cfu/ mL) ­1 hour ­1 30 days Rate constant =0.00096/ hr MRID 41372501 Bacterial biolysis in benthic sediment (anaerobic aquatic or aerobic aquatic metabolism) KBACS 1 (cfu/ mL) ­1 hour ­1 365 days MRID 41913101 Direct photolysis (aqueous photolysis) KDP (hour ­1 ) T1/ 2 =30 days Rate constant =0.00096/ hr MRID 41365101 Base hydrolysis KBH (mole ­1 hour ­1 ) 30 days (stable) Rate constant =0.00096/ hr 1994 RED Neutral hydrolysis KNH (mole ­1 hour ­1 ) 30 days (stable) Rate constant =0.00096/ hr 1994 RED Acid hydrolysis KAH (mole ­1 hour ­1 ) 30 days (stable) Rate constant =0.00096/ hr 1994 RED Partition coefficient for sediments (Leaching/ Adsorption/ Desorption) need Kd from soil closest to crop scenario KPS (mL g ­1 or L kg ­1 ) Kd = 0.84 Average Kd MRID 40768401 Molecular weight MWT (g mole ­1 ) 228.3 From registrant or product chemistry Aqueous solubility (Multiply water solubility by 10) SOL (mg L ­1 ) = 0.800 2,500 ppm @ 20° C From registrant or product chemistry Vapor pressure VAPR (torr) 2 x 10 ­6 Torr From registrant or product chemistry Sediment bacteria temperature coefficient QTBAS 2 Standard value Water bacteria temperature coefficient QTBAW 2 Standard value Table A­ 3. PRZM­ EXAMS Predicted Tebuthiuron Concentrations in the Index Reservoir Simulation Scenarios Concentration ( : g/ L) 1 in 10 year Mean of Annual Means Crop and Location Scenario Peak 96 Hour 21 Day 60 Day 90 Day Annual Mean Pasture, Milam Co., TX Index Reservoir 17.4 16.6 13.2 8. 1 6.0 1. 7 0.7 Index Reservoir w/ PCA (0.87) 15.1 14.4 11.5 7. 0 5.2 1. 5 0.6 TX Alfalf ­ 08/ 06/ 2001 " Texas Claypan Area, Milam County, Texas; MLRA J­ 87" *** Record 3: 0.71 0.36 0 25 1 1 *** Record 6 ­­ ERFLAG 4 *** Record 7: 0.43 0.109 1 172.8 4 1 600 *** Record 8 1 *** Record 9 1 0.25 100 100 1 90 88 89 0 76 *** Record 9a­ d 1 26 0101 1601 0102 1602 0103 1503 1603 0104 1604 0105 1605 0106 1506 1606 0107 1607 .003 .003 .003 .004 .004 .004 .003 .001 .000 .001 .001 .000 .001 .001 .000 .000 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 0108 1608 0109 1609 0110 1610 0111 1611 0112 1612 .001 .000 .000 .001 .001 .002 .002 .002 .003 .003 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 *** Record 10 ­­ NCPDS, the number of cropping periods 36 *** Record 11 300847 201047 010848 1 300848 201048 010849 1 300849 201049 010850 1 300850 201050 010851 1 300851 201051 010852 1 300852 201052 010853 1 300853 201053 010854 1 300854 201054 010855 1 300855 201055 010856 1 300856 201056 010857 1 300857 201057 010858 1 300858 201058 010859 1 300859 201059 010860 1 300860 201060 010861 1 300861 201061 010862 1 300862 201062 010863 1 300863 201063 010864 1 300864 201064 010865 1 300865 201065 010866 1 300866 201066 010867 1 300867 201067 010868 1 300868 201068 010869 1 300869 201069 010870 1 300870 201070 010871 1 300871 201071 010872 1 300872 201072 010873 1 300873 201073 010874 1 300874 201074 010875 1 300875 201075 010876 1 300876 201076 010877 1 300877 201077 010878 1 300878 201078 010879 1 300879 201079 010880 1 300880 201080 010881 1 300881 201081 010882 1 300882 201082 010883 1 *** Record 12 ­­ PTITLE Tebuthiuron ­ 1 applications @ 4.48 kg/ ha *** Record 13 36 1 0 0 *** Record 15 ­­ PSTNAM Tebuthiuron *** Record 16 050648 0 8 2 4.48 1 0 050649 0 8 2 4.48 1 0 050650 0 8 2 4.48 1 0 050651 0 8 2 4.48 1 0 050652 0 8 2 4.48 1 0 050653 0 8 2 4.48 1 0 050654 0 8 2 4.48 1 0 050655 0 8 2 4.48 1 0 050656 0 8 2 4.48 1 0 050657 0 8 2 4.48 1 0 050658 0 8 2 4.48 1 0 050659 0 8 2 4.48 1 0 050660 0 8 2 4.48 1 0 050661 0 8 2 4.48 1 0 050662 0 8 2 4.48 1 0 050663 0 8 2 4.48 1 0 050664 0 8 2 4.48 1 0 050665 0 8 2 4.48 1 0 050666 0 8 2 4.48 1 0 050667 0 8 2 4.48 1 0 050668 0 8 2 4.48 1 0 050669 0 8 2 4.48 1 0 050670 0 8 2 4.48 1 0 050671 0 8 2 4.48 1 0 050672 0 8 2 4.48 1 0 050673 0 8 2 4.48 1 0 050674 0 8 2 4.48 1 0 050675 0 8 2 4.48 1 0 050676 0 8 2 4.48 1 0 050677 0 8 2 4.48 1 0 050678 0 8 2 4.48 1 0 050679 0 8 2 4.48 1 0 050680 0 8 2 4.48 1 0 050681 0 8 2 4.48 1 0 050682 0 8 2 4.48 1 0 050683 0 8 2 4.48 1 0 *** Record 17 0 1 0 *** Record 19 ­­ STITLE Lufkin Sandy Loam; HYDG: D *** Record 20 100 0 0 0 0 0 0 0 0 0 *** Record 26 0 0 0 *** Record 33 3 1 10 1.55 0.215 0 0 0 0.0006540.000654 0 0.1 0.215 0.105 1.16 0.84 2 8 1.55 0.215 0 0 0 0.0006540.000654 0 1 0.215 0.105 1.16 0.84 3 82 1.6 0.32 0 0 0 0.0006540.000654 0 2 0.32 0.2 0.29 0.84 *** Record 40 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­ 7 YEAR PRCP TCUM 0 0 RUNF TCUM 0 0 INFL TCUM 1 1 ESLS TCUM 0 0 1.0E3 RFLX TCUM 0 0 1.0E5 EFLX TCUM 0 0 1.0E5 RZFX TCUM 0 0 1.0E5 SET MODE = 3 CHEM NAME IS Tebuthiuron Read ENV c:\ mark\ przmexam\ exam\ irtxalf. exv SET MWT(*) = 228.3 SET SOL(*,*) = 2500.0 SET PRBEN = 0.05 SET VAPR( 1)= 0.20E­ 05 SET KBACW(*,*, 1)= 0.00096 SET KBACS(*,*, 1)= 0.0 SET QTBAS(*,*, 1)= 2.0 SET QTBAW(*,*, 1)= 2.0 SET KDP(*, 1)= 0.00096 SET KBH(*,*, 1)= 0.000 SET KNH(*,*, 1)= 0.000 SET KAH(*,*, 1)= 0.000 SET KPS(*, 1)= 0.84 SET YEAR1 = 1948 READ PRZM P2E­ C1. D48 RUN READ PRZM P2E­ C1. D49 CONTINUE READ PRZM P2E­ C1. D50 CONTINUE READ PRZM P2E­ C1. D51 CONTINUE READ PRZM P2E­ C1. D52 CONTINUE READ PRZM P2E­ C1. D53 CONTINUE READ PRZM P2E­ C1. D54 CONTINUE READ PRZM P2E­ C1. D55 CONTINUE READ PRZM P2E­ C1. D56 CONTINUE READ PRZM P2E­ C1. D57 CONTINUE READ PRZM P2E­ C1. D58 CONTINUE READ PRZM P2E­ C1. D59 CONTINUE READ PRZM P2E­ C1. D60 CONTINUE READ PRZM P2E­ C1. D61 CONTINUE READ PRZM P2E­ C1. D62 CONTINUE READ PRZM P2E­ C1. D63 CONTINUE READ PRZM P2E­ C1. D64 CONTINUE READ PRZM P2E­ C1. D65 CONTINUE READ PRZM P2E­ C1. D66 CONTINUE READ PRZM P2E­ C1. D67 CONTINUE READ PRZM P2E­ C1. D68 CONTINUE READ PRZM P2E­ C1. D69 CONTINUE READ PRZM P2E­ C1. D70 CONTINUE READ PRZM P2E­ C1. D71 CONTINUE READ PRZM P2E­ C1. D72 CONTINUE READ PRZM P2E­ C1. D73 CONTINUE READ PRZM P2E­ C1. D74 CONTINUE READ PRZM P2E­ C1. D75 CONTINUE READ PRZM P2E­ C1. D76 CONTINUE READ PRZM P2E­ C1. D77 CONTINUE READ PRZM P2E­ C1. D78 CONTINUE READ PRZM P2E­ C1. D79 CONTINUE READ PRZM P2E­ C1. D80 CONTINUE READ PRZM P2E­ C1. D81 CONTINUE READ PRZM P2E­ C1. D82 CONTINUE READ PRZM P2E­ C1. D83 CONTINUE Tebuthiuron on Pasture in Texas WATER COLUMN DISSOLVED CONCENTRATION (PPB) YEAR PEAK 96 HOUR 21 DAY 60 DAY 90 DAY YEARLY ­­­­ ­­­­ ­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ ­­­­­ 1948 4.558 4.303 3.627 2.252 1.678 0.491 1949 1.216 1.148 0.928 0.598 0.445 0.137 1950 10.440 9.861 7.831 4.873 3.605 0.958 1951 21.420 20.230 16.060 9.896 7.466 2.015 1952 9.117 8.612 6.840 4.257 3.149 0.871 1953 1.768 1.667 1.292 0.788 0.586 0.179 1954 0.148 0.139 0.109 0.072 0.056 0.023 1955 9.022 8.536 6.810 4.244 3.140 0.854 1956 0.178 0.168 0.133 0.082 0.065 0.034 1957 9.876 9.328 7.405 4.575 3.386 0.872 1958 4.589 4.334 3.435 2.109 1.567 0.455 1959 4.282 4.044 3.158 1.989 1.485 0.430 1960 17.050 16.270 12.910 7.886 5.853 1.724 1961 5.934 5.671 4.674 2.912 2.156 0.707 1962 16.330 15.490 12.420 7.693 5.694 1.553 1963 0.679 0.642 0.511 0.314 0.233 0.095 1964 9.273 8.762 7.099 4.369 3.235 0.870 1965 1.998 1.887 1.499 0.933 0.697 0.201 1966 3.022 2.854 2.266 1.400 1.041 0.291 1967 3.743 3.509 2.710 1.747 1.370 0.391 1968 0.294 0.282 0.225 0.138 0.103 0.049 1969 9.944 9.392 7.351 4.667 3.694 1.060 1970 0.232 0.227 0.206 0.167 0.143 0.055 1971 8.399 7.933 6.245 3.891 2.909 0.808 1972 5.950 5.620 4.455 2.741 2.031 0.587 1973 3.450 3.304 2.655 1.641 1.215 0.354 1974 1.165 1.108 0.878 0.558 0.431 0.139 1975 4.268 4.034 3.206 1.986 1.470 0.438 1976 5.716 5.398 4.275 2.646 1.968 0.585 1977 0.300 0.283 0.222 0.136 0.109 0.057 1978 18.300 17.290 13.730 8.536 6.323 1.642 1979 2.098 1.967 1.660 1.234 1.057 0.346 1980 0.203 0.191 0.150 0.099 0.078 0.034 1981 33.920 32.280 25.780 15.920 11.780 3.384 1982 5.063 4.782 4.043 2.524 1.871 0.570 1983 2.171 2.050 1.633 1.031 0.765 0.224 SORTED FOR PLOTTING ­­­­­­ ­­­ ­­­­­­­ PROB PEAK 96 HOUR 21 DAY 60 DAY 90 DAY YEARLY ­­­­ ­­­­ ­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ 0.027 33.920 32.280 25.780 15.920 11.780 3.384 0.054 21.420 20.230 16.060 9.896 7.466 2.015 0.081 18.300 17.290 13.730 8.536 6.323 1.724 0.108 17.050 16.270 12.910 7.886 5.853 1.642 0.135 16.330 15.490 12.420 7.693 5.694 1.553 0.162 10.440 9.861 7.831 4.873 3.694 1.060 0.189 9.944 9.392 7.405 4.667 3.605 0.958 0.216 9.876 9.328 7.351 4.575 3.386 0.872 0.243 9.273 8.762 7.099 4.369 3.235 0.871 0.270 9.117 8.612 6.840 4.257 3.149 0.870 0.297 9.022 8.536 6.810 4.244 3.140 0.854 0.324 8.399 7.933 6.245 3.891 2.909 0.808 0.351 5.950 5.671 4.674 2.912 2.156 0.707 0.378 5.934 5.620 4.455 2.741 2.031 0.587 0.405 5.716 5.398 4.275 2.646 1.968 0.585 0.432 5.063 4.782 4.043 2.524 1.871 0.570 0.459 4.589 4.334 3.627 2.252 1.678 0.491 0.486 4.558 4.303 3.435 2.109 1.567 0.455 0.514 4.282 4.044 3.206 1.989 1.485 0.438 0.541 4.268 4.034 3.158 1.986 1.470 0.430 0.568 3.743 3.509 2.710 1.747 1.370 0.391 0.595 3.450 3.304 2.655 1.641 1.215 0.354 0.622 3.022 2.854 2.266 1.400 1.057 0.346 0.649 2.171 2.050 1.660 1.234 1.041 0.291 0.676 2.098 1.967 1.633 1.031 0.765 0.224 0.703 1.998 1.887 1.499 0.933 0.697 0.201 0.730 1.768 1.667 1.292 0.788 0.586 0.179 0.757 1.216 1.148 0.928 0.598 0.445 0.139 0.784 1.165 1.108 0.878 0.558 0.431 0.137 0.811 0.679 0.642 0.511 0.314 0.233 0.095 0.838 0.300 0.283 0.225 0.167 0.143 0.057 0.865 0.294 0.282 0.222 0.138 0.109 0.055 0.892 0.232 0.227 0.206 0.136 0.103 0.049 0.919 0.203 0.191 0.150 0.099 0.078 0.034 0.946 0.178 0.168 0.133 0.082 0.065 0.034 0.973 0.148 0.139 0.109 0.072 0.056 0.023 1/ 10 17.425 16.576 13.156 8.081 5.994 1.667 MEAN OF ANNUAL VALUES = 0.652 STANDARD DEVIATION OF ANNUAL VALUES = 0.696 UPPER 90% CONFIDENCE LIMIT ON MEAN = 0.824 RUN No. 2 FOR Tebuthiuron INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APPL (#/ AC) APPL. URATE SOIL SOIL AEROBIC RATE NO. (#/ AC/ YR) KOC METABOLISM (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 4.000 1 4.000 72.0 1060.0 GROUND­ WATER SCREENING CONCENTRATIONS IN PPB ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 181.451200 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ A= 1055.000 B= 77.000 C= 3.023 D= 1.886 RILP= 6.390 F= 1.657 G= 45.363 URATE= 4.000 GWSC= 181.451200

epa

2024-06-07T20:31:42.582761

regulations

EPA-HQ-OPP-2002-0146-0004

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: February 20, 2002 SUBJECT: Addendum to Drinking Water Assessment for the Tolerance Reassessment (TRED) for Tebuthiuron FROM: Mark Corbin, Environmental Scientist Environmental Risk Branch 1 Environmental Fate and Effects Division (7507C) THRU: Dana Spatz, Acting Branch Chief Environmental Risk Branch 1 Environmental Fate and Effects Division (7507C) TO: Paula Deschamp Reregistration Branch II Health Effects Division (7509C) Wilhelmena Livingston Special Review Branch Special Review and Reregistration Division (7508C) EFED has completed an addendum to the drinking­ water assessment for the reassessment of tolerances for the herbicide tebuthiuron submitted to the Health Effects Division (HED). This assessment considers tebuthiuron and its degradates which the Health Effects Division (HED) has determined are of toxicological concern. Compound 104 was identified by the MARC as the only environmental fate degradate of tebuthiuron of toxicological concern. However, insufficient fate data was available for compound 104. Therefore, EFED elected to model total tebuthiuron residues (TTR) using a cumulative residue approach. The assessment strategy adopted in this addendum was designed to assess concentrations of the TTR (tebuthiuron plus compound 104, compound 105, compound 106, compound 107, compound 108, and compound 109) which were detected in the environmental fate studies. The name and chemical structure of the degradates are attached as Appendix A. A cumulative residue approach was employed to provide conservative estimated concentrations in drinking water for tebuthiuron and its degradation products. In this approach, the fate parameters necessary for Tier II modeling are estimated from the total residue data in the environmental fate studies previously submitted. For tebuthiuron, total residue data was evaluated for the aerobic soil metabolism (MRID 41328001) half life, aqueous photolysis (MRID 41305101) half life, aerobic aquatic (MRID 41372501) half life, anaerobic soil metabolism (MRID 41328002) half life, and hydrolysis half lives. Additional fate data (including Koc, Henry's Law constant, vapor pressure, solubility, and molecular weight) were estimated for Compound 104 using published software (Estimation Programs Interface (EPI), Version 3.04, 1999) which estimates fate parameter using published equations. Compound 104 was used as a reference degradate because it was the degradate detected at the highest concentration in the environmental fate studies, is expected to be a highly mobile tebuthiuron residue in soil and aquatic environments based in its chemical structure and the fact that it was the only degradate detected in a Small Scale Retrospective Monitoring study. More detail on EPI estimation techniques may be found at http:// syrres. com/ interkow/ epi. htm. As with parent tebuthiuron, surface water concentrations of TTR were modeled using the PRZM/ EXAMS (Tier II) programs for pasture/ rangeland using EFEDs standard scenario for alfalfa in Texas. The alfalfa scenario was chosen because its hydrologic and agronomic practices are expected to approximate those of pasture/ rangeland. Groundwater concentrations were modeled using the SCI­ GROW program. Input parameters used Tier II (PRZM version 3.12/ EXAMS version 2.97.5) modeling were selecting using Agency guidance (" Guidance for Chemistry and Management Practice Input Parameters for Use in Modeling the Environmental Fate and Transport of Pesticides" dated August 6, 2000) and EFED calculated degradation rate constants from review of registrant submitted environmental fate studies as note above. Tier II (PRZM version 3.12/ EXAMS version 2.97.5) surface water modeling for TTR due to use of tebuthiuron use on rangeland/ pasture at 4 pounds active ingredient per acre (lbs ai/ A) using the index reservoir and a PCA of 0.87 predicts the 1 in 10 year annual maximum (acute) concentration of 15.52 : g/ L. The 1 in 10 year annual average concentration (non­ cancer chronic) of tebuthiuron is predicted to be 4.31 : g/ L . The 36 year annual average concentration (cancer chronic) of tebuthiuron is predicted to be 1.96 : g/ L. SCI­ GROW (version 2.1) modeling estimates the acute and chronic concentration of TTR in shallow groundwater is 245 : g/ L. A comparison of the TTR concentrations compared with the parent only values previously submitted are presented in Table 1. A more detailed modeling discussion is presented in Appendix B. Table 1. Comparison of PRZM­ EXAMS Predicted Total Tebuthiuron Residue (TTR) Concentrations with Predicted Parent Tebuthiuron Concentrations in the Index Reservoir Simulation Scenarios Concentration ( : g/ L) 1 in 10 year Mean of Annual Means Crop and Location Scenario Peak 96 Hour 21 Day 60 Day 90 Day Annual Mean Pasture, Milam Co., TX Total Residues w/ PCA (0.87) 15.5 15.3 14.3 12.2 10.9 4.3 2.0 Parent Only w/ PCA (0.87) 15.1 14.4 11.5 7.0 5.2 1.5 0.6 Appendix B provides a detailed discussion of the modeling efforts for PRZM/ EXAMS, and SCIGROW APPENDIX A DEGRADATE NAMES and STRUCTURES N N S N CH 3 CH 3 C H 3 C H 3 O NH 2 Table 1. Degradates of Tebuthiuron with maximum applied detected in each study: Parent / Degradate Name and Structure Percent of Applied Dose MRID # Study Type Reported Values Maximum Day *104: N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ methylurea ND N/ A N/ A hydrolysis ND N/ A 41305101 aqueous photolysis 6.8 14 41050201 soil photolysis 6.9 270 41328001 aerobic soil Nmetabolism 2.9 60 41328002 anaerobic soil metabolism 1.5 21 41372501 aerobic aquatic metabolism ND N/ A 41913101 anaerobic aquatic metabolism ND N/ A 40768401 batch equilibrium N/ A N/ A N/ A laboratory volatility N/ A N/ A N/ A field volatility 22.9 408 43318101 terrestrial field dissipation 2.2 (edible) 21 40819501 bioaccumulation in fish 105: N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N methylurea ND N/ A N/ A hydrolysis ND N/ A 41305101 aqueous photolysis 3.5 19 41050201 soil photolysis 0.4 90 41328001 aerobic soil metabolism 0.2 60 41328002 anaerobic soil metabolism 0.4 28 41372501 aerobic aquatic metabolism ND N/ A 41913101 anaerobic aquatic metabolism ND N/ A 40768401 batch equilibrium Parent / Degradate Name and Structure Percent of Applied Dose MRID # Study Type Reported Values Maximum Day N N S N H CH 3 C H 3 C H 3 O NH 2 N/ A N/ A N/ A laboratory volatility N/ A N/ A N/ A field volatility ND N/ A 43318101 terrestrial field dissipation 4.7 (edible) 21 40819501 bioaccumulation in fish 106: N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl] urea ND N/ A N/ A hydrolysis ND N/ A 41305101 aqueous photolysis 2.7 5 41050201 soil photolysis ND N/ A 41328001 aerobic soil metabolism ND N/ A 41328002 anaerobic soil metabolism ND N/ A 41372501 aerobic aquatic metabolism ND N/ A 41913101 anaerobic aquatic metabolism ND N/ A 40768401 batch equilibrium N/ A N/ A N/ A laboratory volatility N/ A N/ A N/ A field volatility ND N/ A 43318101 terrestrial field dissipation ND N/ A 40819501 bioaccumulation in fish 107: 5­( 1,1­ Dimethylethyl)­ 2­ methylamino­ 1,3,4­ thiadiazole ND N/ A N/ A hydrolysis ND N/ A 41305101 aqueous photolysis ND N/ A 41050201 soil photolysis 1.1 270 41328001 aerobic soil metabolism ND N/ A 41328002 anaerobic soil metabolism Parent / Degradate Name and Structure Percent of Applied Dose MRID # Study Type Reported Values Maximum Day N N S NH 2 CH 3 C H 3 C H 3 0.3 21 41372501 aerobic aquatic metabolism ND N/ A 41913101 anaerobic aquatic metabolism ND N/ A 40768401 batch equilibrium N/ A N/ A N/ A laboratory volatility N/ A N/ A N/ A field volatility ND N/ A 43318101 terrestrial field dissipation ND N/ A 40819501 bioaccumulation in fish 108: 2­ dimethylethyl­ 5­ amino­ 1,3,4­ thiadiazole ND N/ A N/ A hydrolysis ND N/ A 41305101 aqueous photolysis ND N/ A 41050201 soil photolysis 0.6 270 41328001 aerobic soil metabolism ND N/ A 41328002 anaerobic soil metabolism 0.1 7 41372501 aerobic aquatic metabolism ND N/ A 41913101 anaerobic aquatic metabolism ND N/ A 40768401 batch equilibrium N/ A N/ A N/ A laboratory volatility N/ A N/ A N/ A field volatility ND N/ A 43318101 terrestrial field dissipation ND N/ A 40819501 bioaccumulation in fish Parent / Degradate Name and Structure Percent of Applied Dose MRID # Study Type Reported Values Maximum Day N N S N CH 3 CH 3 C H 3 C H 3 O N H OH N N S N CH 3 CH 3 C H 3 C H 3 O N H CH 3 N N S N CH 3 CH 3 C H 3 O N H CH 3 OH *109: N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ hydroxymethyl­ methylurea ND N/ A N/ A hydrolysis ND N/ A 41305101 aqueous photolysis ND N/ A 41050201 soil photolysis N'ND N/ A 41328001 aerobic soil Nmetabolism 0.2 60 41328002 anaerobic soil metabolism 0.3 7 41372501 aerobic aquatic metabolism ND N/ A 41913101 anaerobic aquatic metabolism ND N/ A 40768401 batch equilibrium N/ A N/ A N/ A laboratory volatility N/ A N/ A N/ A field volatility ND N/ A 43318101 terrestrial field dissipation 40.1 (edible) 21 40819501 bioaccumulation in fish Attachment 1: Additional structures of tebuthiuron and its metabolites: Tebuthiuron (103): [N­[ 5­( 1,1­ dimethylethyl 1,3,4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea Matrices: grass forage and hay, ruminant and milk 103 (OH): N­[ 5­( 2­ hydroxy­ 1,1­ dimethylethyl 1,3,4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea Matrices: ruminant and milk N N S N CH 3 CH 3 C H 3 O NH 2 OH N N S N CH 3 CH 3 C H 3 O N H OH OH N N S N C CH3 H3C CH3 H C O N CH3 H Tebuthiuron 105 N N S N C CH3 H3C CH3 H CH3 Tebuthiuron 107 104 (OH): N­[ 5­( 2­ hydroxy­ 1,1­ dimethylethyl 1,3,4­ thiadiazol­ 2­ yl]­ N­ methylurea Matrices: milk A [109 (OH)]: N­[ 5­( 2­ hydroxy­ 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N hydroxymethyl­ N­ methylurea Matices: milk 105: N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl N'­ methylurea Matrices: water 107: 5­( 1,1­ Dimethylethyl)­ 2­ methylamino­ 1,3,4­ thiadi azol e Matr ices :wat er and tissu es cc: SF, RF, List A files, S. Piper, M. Corbin RDI: FBSuhre: /01; MARC: /01 7509C: CEB: CM­ 2: Room 810F: 308­ 2717: Tebuthiuron APPENDIX B MODELING DISCUSSION DRINKING WATER ASSESSMENT Uncertainties, Assumptions and Limitations Input parameters used in Tier II (PRZM/ EXAMS) modeling were selecting using Agency guidance (" Guidance for Chemistry and Management Practice Input Parameters for Use in Modeling the Environmental Fate and Transport of" dated August 6, 2000) and EFED calculated degradation rate constants from review of registrant submitted environmental fate studies. Tebuthiuron is used primarily on pasture and rangeland in Texas, Oklahoma, and New Mexico, therefore, only one scenario was simulated to estimate runoff concentrations. EFED selected a scenario in Texas for alfalfa representing an EFED standard scenario developed for use in modeling the respective crops and is expected to be the standard scenario in the tebuthiuron use with the highest runoff potential. Alfalfa was selected as the scenario most closely representing pasture/ rangeland (the alfalfa scenario was developed based on a pasture setting). These scenarios were developed to approximately represent the 90 th percentile site for runoff vulnerability in a high usage state. Application timing was taken from registrant provided information and recent labels. The standard scenario for alfalfa is based on usage patterns in Milam County, Texas. The soil is a Lufkin sandy loam in Major Land Use Area (MLRA) 87. The Lufkin sandy loam is characterized as a Hydrologic Group D soil. Uncertainties, Assumptions and Limitations There are several uncertainties and assumptions in the assessment of tebuthiuron and its degradates. Primary among these is the lack of environmental fate data for the transformation products of tebuthiuron. In order to address this uncertainty, EFED has conducted the Tier II modeling (PRZM/ EXAMS) on the summed tebuthiuron residues (tebuthiuron and its identifiable degradation products including compound 104, compound 105, compound 106, compound 107, compound 108, and compound 109) instead of individual residues. Although the persistence of the tebuthiuron residues was estimated from registrant submitted environmental fate data, the mobility of tebuthiuron residues was estimated using the degradate compound 104 (N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N­ methylurea) as a reference compound. This compound was used to assess mobility because it was the degradate detected at the highest concentration in the environmental fate studies, is expected to be a highly mobile tebuthiuron residue in soil and aquatic environments, and was the only degradate detected in a Retrospective Ground Water Study. EFED used the lowest Kd/ Koc value for tebuthiuron as the Kd/ Koc for Compound 104. Physical chemistry parameters were estimated for compound 104 (Estimation Programs Interface (EPI), Version 3.04, 1999) and degradation rate constants were estimated by performing linear regression on the total residues (Microsoft Excel 2000) from several fate studies. Table A­ 1. Input Parameters for Total Tebuthiuron Residues for PRZM (Version 3.12) for Index Reservoir and PCA. Variable Description Variable (Units) Input Value Source of Info/ Reference Application date( s) (day/ mo/ yr) APD, APM, IAPYR (day/ mo/ yr) 1 times per year Product label or location­ specific Incorporation depth DEPI (cm) 0 Product label Application rate TAPP (kg a. i. ha ­1 ) 4.48 Aerial granular Product label Application efficiency APPEFF (decimal) 1.00 Spray Drift Task Force Data Spray drift fraction: For aquatic ecological exposure assessment, use 0.05 for aerial spray; 0.01 for ground spray. For drinking water assessment, use 0.16 for aerial 0.064 for ground spray. DRFT (decimal) 0.00 Spray Drift Task Force Data Foliar extraction FEXTRA (frac./ cm rain) 0.5 (default) Default or field data Decay rate on foliage PLDKRT (day ­1 ) 0.0 (default) Default or field data Volatilization rate from foliage PLVKRT (day ­1 ) 0.0 (default) Default or field data Plant uptake factor UPTKF (frac. of evap) 0.0 (default) Default or field data Dissolved phase pesticide decay rate in surface horizon (aerobic soil metabolism) DWRATE (surface) (day ­1 ) T1/ 2 => 2832 days Rate constant = 0.000245/ day MRID 41328001 Adsorbed phase pesticide decay rate in surface horizon (aerobic soil metabolism) DSRATE (surface) (day ­1 ) T1/ 2 => 2832 days Rate constant = 0.000245/ day MRID 41328001 Dissolved phase pesticide decay rate in subsequent subsurface horizons (aerobic or anaerobic soil metabolism) DWRATE (subsurface horizons) (day ­1 ) T1/ 2 => 2832 days Rate constant = 0.000245/ day MRID 41328001 Adsorbed phase pesticide decay rate in subsequent subsurface horizons (aerobic or anaerobic soil metabolism) DSRATE (subsurface horizons) (day ­1 ) T1/ 2 => 2832 days Rate constant = 0.000245/ day MRID 41328001 Pesticide partition or distribution coefficients for each horizon (Leaching/ Adsorption/ Desorption) Kd 0.11 Lowest Kd MRID 40768401 Table A­ 2. Input Parameters for Tebuthiuron. chm Files Used in EXAMS (Version 2.97. 5) for Index Reservoir and PCA. Variable Description Variable (Units) Input Value Source of Info/ Reference Henry's law constant HENRY (atm­ m 3 mole ­1 ) 7.58 x 10 ­11 Atm m 3 /mol EPI Bacterial biolysis in water column (aerobic aquatic metabolism) KBACW (cfu/ mL) ­1 hour ­1 683 days Rate constant =0.000042/ hr MRID 41372501 Bacterial biolysis in benthic sediment (anaerobic aquatic or aerobic aquatic metabolism) KBACS 1 (cfu/ mL) ­1 hour ­1 0 days (stable) MRID 41913101 Direct photolysis (aqueous photolysis) KDP (hour ­1 ) T1/ 2 =0 days (stable) MRID 41365101 Base hydrolysis KBH (mole ­1 hour ­1 ) 0 days (stable) 1994 RED Neutral hydrolysis KNH (mole ­1 hour ­1 ) 0 days (stable) 1994 RED Acid hydrolysis KAH (mole ­1 hour ­1 ) 0 days (stable) 1994 RED Partition coefficient for sediments (Leaching/ Adsorption/ Desorption) need Kd from soil closest to crop scenario KPS (mL g ­1 or L kg ­1 ) Kd = 0.11 Lowest Kd MRID 40768401 Molecular weight MWT (g mole ­1 ) 214.3 EPI Aqueous solubility (Multiply water solubility by 10) SOL (mg L ­1 ) = 0.800 2790 ppm @ 20° C EPI Vapor pressure VAPR (torr) 7.5 x 10 ­7 Torr EPI Sediment bacteria temperature coefficient QTBAS 2 Standard value Water bacteria temperature coefficient QTBAW 2 Standard value TX Alfalf ­ 08/ 06/ 2001 " Texas Claypan Area, Milam County, Texas; MLRA J­ 87" *** Record 3: 0.71 0.36 0 25 1 1 *** Record 6 ­­ ERFLAG 4 *** Record 7: 0.43 0.109 1 172.8 4 1 600 *** Record 8 1 *** Record 9 1 0.25 100 100 1 90 88 89 0 76 *** Record 9a­ d 1 26 0101 1601 0102 1602 0103 1503 1603 0104 1604 0105 1605 0106 1506 1606 0107 1607 .003 .003 .003 .004 .004 .004 .003 .001 .000 .001 .001 .000 .001 .001 .000 .000 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 0108 1608 0109 1609 0110 1610 0111 1611 0112 1612 .001 .000 .000 .001 .001 .002 .002 .002 .003 .003 .110 .110 .110 .110 .110 .110 .110 .110 .110 .110 *** Record 10 ­­ NCPDS, the number of cropping periods 36 *** Record 11 300847 201047 010848 1 300848 201048 010849 1 300849 201049 010850 1 300850 201050 010851 1 300851 201051 010852 1 300852 201052 010853 1 300853 201053 010854 1 300854 201054 010855 1 300855 201055 010856 1 300856 201056 010857 1 300857 201057 010858 1 300858 201058 010859 1 300859 201059 010860 1 300860 201060 010861 1 300861 201061 010862 1 300862 201062 010863 1 300863 201063 010864 1 300864 201064 010865 1 300865 201065 010866 1 300866 201066 010867 1 300867 201067 010868 1 300868 201068 010869 1 300869 201069 010870 1 300870 201070 010871 1 300871 201071 010872 1 300872 201072 010873 1 300873 201073 010874 1 300874 201074 010875 1 300875 201075 010876 1 300876 201076 010877 1 300877 201077 010878 1 300878 201078 010879 1 300879 201079 010880 1 300880 201080 010881 1 300881 201081 010882 1 300882 201082 010883 1 *** Record 12 ­­ PTITLE Tebuthiuron ­ 1 applications @ 4.48 kg/ ha *** Record 13 36 1 0 0 *** Record 15 ­­ PSTNAM Tebuthiuron *** Record 16 050648 0 8 2 4.48 1 0 050649 0 8 2 4.48 1 0 050650 0 8 2 4.48 1 0 050651 0 8 2 4.48 1 0 050652 0 8 2 4.48 1 0 050653 0 8 2 4.48 1 0 050654 0 8 2 4.48 1 0 050655 0 8 2 4.48 1 0 050656 0 8 2 4.48 1 0 050657 0 8 2 4.48 1 0 050658 0 8 2 4.48 1 0 050659 0 8 2 4.48 1 0 050660 0 8 2 4.48 1 0 050661 0 8 2 4.48 1 0 050662 0 8 2 4.48 1 0 050663 0 8 2 4.48 1 0 050664 0 8 2 4.48 1 0 050665 0 8 2 4.48 1 0 050666 0 8 2 4.48 1 0 050667 0 8 2 4.48 1 0 050668 0 8 2 4.48 1 0 050669 0 8 2 4.48 1 0 050670 0 8 2 4.48 1 0 050671 0 8 2 4.48 1 0 050672 0 8 2 4.48 1 0 050673 0 8 2 4.48 1 0 050674 0 8 2 4.48 1 0 050675 0 8 2 4.48 1 0 050676 0 8 2 4.48 1 0 050677 0 8 2 4.48 1 0 050678 0 8 2 4.48 1 0 050679 0 8 2 4.48 1 0 050680 0 8 2 4.48 1 0 050681 0 8 2 4.48 1 0 050682 0 8 2 4.48 1 0 050683 0 8 2 4.48 1 0 *** Record 17 0 1 0 *** Record 19 ­­ STITLE Lufkin Sandy Loam; HYDG: D *** Record 20 100 0 0 0 0 0 0 0 0 0 *** Record 26 0 0 0 *** Record 33 3 1 10 1.55 0.215 0 0 0 0.00022 0.00022 0 0.1 0.215 0.105 1.16 0.11 2 8 1.55 0.215 0 0 0 0.00022 0.00022 0 1 0.215 0.105 1.16 0.11 3 82 1.6 0.32 0 0 0 0.00022 0.00022 0 2 0.32 0.2 0.29 0.11 *** Record 40 0 YEAR 10 YEAR 10 YEAR 10 1 1 1 ­­­­­ 7 YEAR PRCP TCUM 0 0 RUNF TCUM 0 0 INFL TCUM 1 1 ESLS TCUM 0 0 1.0E3 RFLX TCUM 0 0 1.0E5 EFLX TCUM 0 0 1.0E5 RZFX TCUM 0 0 1.0E5 SET MODE = 3 CHEM NAME IS Tebuthiuron 104 Read ENV c:\ mark\ przmexam\ exam\ irtxalf. exv SET MWT(*) = 214.3 SET SOL(*,*) = 2790.0 SET PRBEN = 0.05 SET VAPR( 1)= 7.50E­ 07 SET HENRY( 1) = 7.58E­ 11 SET KBACW(*,*, 1)= 0.000042 SET KBACS(*,*, 1)= 0.0 SET QTBAS(*,*, 1)= 2.0 SET QTBAW(*,*, 1)= 2.0 SET KDP(*, 1)= 0.0 SET KBH(*,*, 1)= 0.000 SET KNH(*,*, 1)= 0.000 SET KAH(*,*, 1)= 0.000 SET Koc( 1)= 15.69 SET YEAR1 = 1948 READ PRZM P2E­ C1. D48 RUN READ PRZM P2E­ C1. D49 CONTINUE READ PRZM P2E­ C1. D50 CONTINUE READ PRZM P2E­ C1. D51 CONTINUE READ PRZM P2E­ C1. D52 CONTINUE READ PRZM P2E­ C1. D53 CONTINUE READ PRZM P2E­ C1. D54 CONTINUE READ PRZM P2E­ C1. D55 CONTINUE READ PRZM P2E­ C1. D56 CONTINUE READ PRZM P2E­ C1. D57 CONTINUE READ PRZM P2E­ C1. D58 CONTINUE READ PRZM P2E­ C1. D59 CONTINUE READ PRZM P2E­ C1. D60 CONTINUE READ PRZM P2E­ C1. D61 CONTINUE READ PRZM P2E­ C1. D62 CONTINUE READ PRZM P2E­ C1. D63 CONTINUE READ PRZM P2E­ C1. D64 CONTINUE READ PRZM P2E­ C1. D65 CONTINUE READ PRZM P2E­ C1. D66 CONTINUE READ PRZM P2E­ C1. D67 CONTINUE READ PRZM P2E­ C1. D68 CONTINUE READ PRZM P2E­ C1. D69 CONTINUE READ PRZM P2E­ C1. D70 CONTINUE READ PRZM P2E­ C1. D71 CONTINUE READ PRZM P2E­ C1. D72 CONTINUE READ PRZM P2E­ C1. D73 CONTINUE READ PRZM P2E­ C1. D74 CONTINUE READ PRZM P2E­ C1. D75 CONTINUE READ PRZM P2E­ C1. D76 CONTINUE READ PRZM P2E­ C1. D77 CONTINUE READ PRZM P2E­ C1. D78 CONTINUE READ PRZM P2E­ C1. D79 CONTINUE READ PRZM P2E­ C1. D80 CONTINUE READ PRZM P2E­ C1. D81 CONTINUE READ PRZM P2E­ C1. D82 CONTINUE READ PRZM P2E­ C1. D83 CONTINUE QUIT Tebuthiuron Total Residues on Texas Pasture WATER COLUMN DISSOLVED CONCENTRATION (PPB) YEAR PEAK 96 HOUR 21 DAY 60 DAY 90 DAY YEARLY ­­­­ ­­­­ ­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ 1948 4.843 4.762 4.514 3.926 3.511 1.338 1949 1.543 1.517 1.432 1.234 1.107 0.705 1950 10.530 10.350 9.641 8.230 7.331 2.902 1951 21.930 21.560 20.080 17.130 15.440 6.395 1952 10.370 10.200 9.497 8.111 7.227 3.798 1953 2.216 2.179 2.030 1.734 1.548 1.066 1954 0.491 0.484 0.454 0.396 0.357 0.204 1955 9.048 8.910 8.335 7.126 6.350 2.446 1956 1.610 1.586 1.486 1.289 1.160 0.578 1957 9.920 9.753 9.082 7.767 6.923 2.612 1958 5.094 5.008 4.668 3.991 3.558 1.841 1959 4.532 4.455 4.146 3.628 3.253 1.520 1960 17.620 17.320 16.200 13.840 12.340 5.088 1961 7.075 6.996 6.646 5.702 5.085 2.951 1962 16.710 16.490 15.500 13.260 11.820 4.894 1963 3.133 3.085 2.892 2.508 2.258 1.199 1964 9.535 9.374 8.756 7.494 6.681 2.599 1965 2.535 2.493 2.322 1.984 1.777 1.143 1966 3.153 3.100 2.888 2.471 2.210 0.974 1967 3.887 3.820 3.553 3.140 2.905 1.274 1968 1.029 1.013 0.950 0.823 0.742 0.414 1969 9.976 9.808 9.127 7.989 7.465 2.969 1970 2.528 2.490 2.333 2.022 1.820 0.853 1971 8.444 8.302 7.727 6.693 6.009 2.374 1972 6.418 6.310 5.879 5.030 4.486 2.192 1973 3.866 3.801 3.562 3.046 2.715 1.372 1974 1.297 1.287 1.211 1.038 0.929 0.537 1975 4.384 4.313 4.019 3.434 3.060 1.313 1976 5.983 5.882 5.528 4.736 4.233 1.850 1977 1.284 1.265 1.185 1.028 0.925 0.516 1978 18.350 18.040 16.800 14.350 12.800 4.902 1979 3.417 3.359 3.221 2.890 2.624 1.952 1980 0.888 0.875 0.821 0.713 0.642 0.342 1981 33.960 33.630 31.500 26.900 23.960 9.423 1982 6.936 6.820 6.522 5.625 5.022 3.505 1983 2.598 2.554 2.384 2.044 1.827 1.059 SORTED FOR PLOTTING ­­­­­­ ­­­ ­­­­­­­ PROB PEAK 96 HOUR 21 DAY 60 DAY 90 DAY YEARLY ­­­­ ­­­­ ­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ 0.027 33.960 33.630 31.500 26.900 23.960 9.423 0.054 21.930 21.560 20.080 17.130 15.440 6.395 0.081 18.350 18.040 16.800 14.350 12.800 5.088 0.108 17.620 17.320 16.200 13.840 12.340 4.902 0.135 16.710 16.490 15.500 13.260 11.820 4.894 0.162 10.530 10.350 9.641 8.230 7.465 3.798 0.189 10.370 10.200 9.497 8.111 7.331 3.505 0.216 9.976 9.808 9.127 7.989 7.227 2.969 0.243 9.920 9.753 9.082 7.767 6.923 2.951 0.270 9.535 9.374 8.756 7.494 6.681 2.902 0.297 9.048 8.910 8.335 7.126 6.350 2.612 0.324 8.444 8.302 7.727 6.693 6.009 2.599 0.351 7.075 6.996 6.646 5.702 5.085 2.446 0.378 6.936 6.820 6.522 5.625 5.022 2.374 0.405 6.418 6.310 5.879 5.030 4.486 2.192 0.432 5.983 5.882 5.528 4.736 4.233 1.952 0.459 5.094 5.008 4.668 3.991 3.558 1.850 0.486 4.843 4.762 4.514 3.926 3.511 1.841 0.514 4.532 4.455 4.146 3.628 3.253 1.520 0.541 4.384 4.313 4.019 3.434 3.060 1.372 0.568 3.887 3.820 3.562 3.140 2.905 1.338 0.595 3.866 3.801 3.553 3.046 2.715 1.313 0.622 3.417 3.359 3.221 2.890 2.624 1.274 0.649 3.153 3.100 2.892 2.508 2.258 1.199 0.676 3.133 3.085 2.888 2.471 2.210 1.143 0.703 2.598 2.554 2.384 2.044 1.827 1.066 0.730 2.535 2.493 2.333 2.022 1.820 1.059 0.757 2.528 2.490 2.322 1.984 1.777 0.974 0.784 2.216 2.179 2.030 1.734 1.548 0.853 0.811 1.610 1.586 1.486 1.289 1.160 0.705 0.838 1.543 1.517 1.432 1.234 1.107 0.578 0.865 1.297 1.287 1.211 1.038 0.929 0.537 0.892 1.284 1.265 1.185 1.028 0.925 0.516 0.919 1.029 1.013 0.950 0.823 0.742 0.414 0.946 0.888 0.875 0.821 0.713 0.642 0.342 0.973 0.491 0.484 0.454 0.396 0.357 0.204 1/ 10 17.839 17.536 16.380 13.993 12.478 4.958 MEAN OF ANNUAL VALUES = 2.253 STANDARD DEVIATION OF ANNUAL VALUES = 1.941 UPPER 90% CONFIDENCE LIMIT ON MEAN = 2.732 RUN No. 1 FOR Compound 104 INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APPL (#/ AC) APPL. URATE SOIL SOIL AEROBIC RATE NO. (#/ AC/ YR) KOC METABOLISM (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .276 1 .276 16.0 2832.0 GROUND­ WATER SCREENING CONCENTRATIONS IN PPB ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 245.181800 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ A= 1500.000 B= 20.960 C= 3.176 D= 1.321 RILP= 8.508 F= 2.949 G= 888.340 URATE= .276 GWSC= 245.181800

epa

2024-06-07T20:31:42.591300

regulations

EPA-HQ-OPP-2002-0146-0005

Supporting & Related Material

OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 TXR No: 0050572 March 20, 2002 Memorandum SUBJECT: TEBUTHIURON (PC Code: 105501) Toxicology Disciplinary Chapter for the Tolerance Reassessment Eligibility Decision Document FROM: Robert Fricke, Ph. D. Reregistration Branch 2 Health Effects Division (7509C) THRU: Alan Nielsen, Branch Senior Scientist Reregistration Branch 2 Health Effects Division (7509C) TO: Paula Deschamp, Risk Assessor Reregistration Branch 2 Health Effects Division (7509C) DP Barcode: D277101 Submission: S596544 Action Requested: Review toxicology studies submitted by the registrant and prepare the toxicology chapter to support Tolerance Reassessment Eligibility Decision (TRED) for tebuthiuron. Attached is the updated toxicology chapter summarizing the findings of the toxicology studies. TEBUTHIURON PC Code: 105501 Toxicology Disciplinary Chapter for the Tolerance Reassessment Eligibility Decision (TRED) Document February 20, 2002 Prepared by: Robert F. Fricke, Ph. D. Reregistration Branch 2 Health Effects Division Mail Code 7509C Peer reviewed by: Yung Yang, Ph. D. Toxicology Branch Health Effects Division Mail Code 7509C Robert F. Fricke, Toxicologist Yung Yang, Toxicologist TABLE OF CONTENTS 1 HAZARD CHARACTERIZATION ........................................ 1 2 REQUIREMENTS .................................................... 2 3 DATA GAPS ......................................................... 3 4 HAZARD ASSESSMENT ............................................... 3 4.1 Acute Toxicity .................................................... 3 4.2 Subchronic Toxicity ............................................... 3 4.2.1 870.3100 90­ Day Oral Toxicity ­ Rat ......................... 3 4.2.2 870.3150 90­ Day Oral Toxicity ­ Dog ........................ 4 4.2.3 870.3200 21/ 28­ Day Dermal Toxicity ­ Rabbit .................. 4 4.2.4 870.3250 90­ Day Dermal Toxicity ........................... 4 4.2.5 870.4365 90­ Day Inhalation Toxicity ......................... 5 4.3 Prenatal Developmental Toxicity ...................................... 5 4.3.1 870.3700a Prenatal Developmental Toxicity Study ­ Rat ........... 5 4.3.2 870.3700b Prenatal Developmental Toxicity Study ­ Rabbit ......... 6 4.4 Reproductive Toxicity .............................................. 7 4.4.1 870.3800 Two­ Generation Reproduction and Fertility Effects ­ Rat .. 7 4.5 Chronic Toxicity .................................................. 8 4.5.1 870.4300 Combined Chronic Toxicity/ Carcinogenicity StudyCD SD) BR Rats ................................. 8 4.5.2 870.4100b Chronic Toxicity ­ Dog ............................ 9 4.6 Carcinogenicity .................................................. 10 4.6.1 870.4200b Carcinogenicity Study ­ Crl: CD­ 1 (ICR) BR Mouse ..... 10 4.6.2 870.4300 Carcinogenicity Study­ CD( SD) BR Rats .............. 11 4.7 Mutagenicity .................................................... 11 4.8 Neurotoxicity ................................................... 13 4.8.1 870.6100 Delayed Neurotoxicity Study ­ Hen .................. 13 4.8.2 870.6200a Acute Neurotoxicity Screening Battery ............... 14 4.8.3 870.6200b Subchronic Neurotoxicity Screening Battery ........... 14 4.8.4 870.6300 Developmental Neurotoxicity Study ................. 14 4.9 Metabolism ..................................................... 14 4.9.1 870.7485 Metabolism ­ Rat ............................... 14 4.10 Special Studies .................................................. 14 5 TOXICITY ENDPOINT SELECTION .................................... 14 5.1 Dermal Absorption ............................................... 15 5.2 Classification of Carcinogenic Potential ................................ 15 5.2.1 Conclusions and Classification of Carcinogenic Potential ........... 15 5.2.2 Quantification of Carcinogenic Potential ........................ 15 6 FQPA CONSIDERATIONS ............................................ 15 6.1 Special Sensitivity to Infants and Children .............................. 15 6.2 Recommendation for a Developmental Neurotoxicity Study ................ 15 7 OTHER ISSUES ..................................................... 15 8 REFERENCES ...................................................... 15 9 APPENDICES ....................................................... 19 9.1 Toxicity Profile Summary Tables ..................................... 19 9.1.1 Acute Toxicity Table ....................................... 19 9.1.2 Subchronic, Chronic, and Other Toxicity Table ................... 19 9.2 Summary of Toxicological Dose and Endpoints for Tebuthiuron for Use in Human Risk Assessment ................................................. 22 Tebuthiuron (105501) RED Toxicology Chapter 1 1 HAZARD CHARACTERIZATION The toxicological database for tebuthiuron is not considered adequate for hazard characterization, however the database will support the Tolerance Reassessment Eligibility Decision (TRED) for the current registered uses. Hazard characterization was not possible because of datagaps which include a developmental toxicity study in rabbit, a chronic feeding/ carcinogenicity study in the rat and oncogenicity study in the mouse; all of these studies were found to be unacceptable. The requirement for a developmental neurotoxicity study is being held in reserve, pending submission of the rabbit developmental toxicity study. Additionally, the Health Effects Division's Hazard Identification Assessment Review Committee (HIARC) determined that a 28­ day inhalation is required to provide better hazard characterization. The acute toxicity studies indicate that tebuthiuron, technical, is more toxic for oral (Toxicity Category II) exposure than for either dermal (Toxicity Category IV) or inhalation (Toxicity Category III). Tebuthiuron is not an eye or skin irritant and not a skin sensitizer. In the 21­ day dermal toxicity study in rabbits, no dermal or systemic toxicity was observed at 1000 mg/ kg/ day (limit dose). Although the most consistent toxicological effect was decreased body weight, histopathological changes in the pancreas were observed in both the subchronic and chronic toxicity studies in the rat. Pancreatic acinar cells of both sexes showed vacuolation, which was described as generally slight or affecting only a few cells; males also had increased relative spleen and prostate gland weights. In a rat developmental study, however, pancreatic tissue appeared normal. Subchronic and chronic toxicity studies were available for the dog. In a subchronic study, anorexia, with resulting weight loss, and clinical chemistry effects (increased blood urea nitrogen and alkaline phosphatase) were observed at 50 mg/ kg/ day. In a chronic (1­ year) study clinical signs of toxicity (emesis anorexia, and diarrhea ), decreased body weight, increased ALT and ALP (males only), increased absolute and relative liver weights, and increased relative kidney (females only) thyroid (males only) weights. At the doses tested, neither the rat nor mouse showed any treatment­ related increase in the incidence of neoplasms. However, the HIARC (TXR No. 0050450, dated February 5, 2002) concluded that the dose levels were too low to assess the carcinogenic potential of tebuthiuron. Tebuthiuron was not mutagenic in bacteria or in cultured mammalian cells. There was also no indication of a clastogenic effect up to toxic doses in vivo. Results from the rat developmental and reproductive toxicity studies indicated that there was no evidence (qualitative or quantitative) for increased susceptibility following in utero and/ or pre post­ natal exposure. The rabbit developmental toxicity study was found to be unacceptable; susceptibility can not be evaluated in rabbits. In a rat metabolism study with 14 C­ tebuthiuron, absorption was complete; excretion was rapid both sexes, but was delayed during the first 12 hours post­ dose, indicating saturation of Tebuthiuron (105501) RED Toxicology Chapter 2 biotransformation or excretion. At termination, no significant amounts of residual radioactivity in any tissue examined, but the skin showed the highest amounts relative to other tissues. Six metabolites of tebuthiuron were identified. The major urinary metabolite was identified as hydroxylated tebuthiuron metabolites. 2 REQUIREMENTS The requirements (CFR §158.340, revised as of July 1, 1999) for Food and Non­ Food Use for tebuthiuron, technical, are summarized in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Study Required Satisfied 870.1100 Acute Oral Toxicity ....................... 870.1200 Acute Dermal Toxicity ..................... 870.1300 Acute Inhalation Toxicity ................... 870.2400 Primary Eye Irritation ..................... 870.2500 Primary Dermal Irritation ................... 870.2600 Dermal Sensitization ...................... Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 870.3100 Oral Subchronic (Rodent) ................... 870.3150 Oral Subchronic (Non­ Rodent) ............... 870.3200 21­ Day Dermal ........................... 870.3250 90­ Day Dermal ........................... 870.3465 28­ Day inhalation 870.3465 90­ Day Inhalation ........................ Yes Yes Yes No Yes No Yes Yes Yes No a 870.3700a Developmental Toxicity (Rodent) ............. 870.3700b Developmental Toxicity( Non­ rodent) ......... 870.3800 Reproduction ............................ Yes Yes Yes Yes No a Yes 870.4100a Chronic Toxicity (Rodent) ................... 870.4100b Chronic Toxicity (Non­ rodent) ................ 870.4200a Oncogenicity (Rat) ......................... 870.4200b Oncogenicity (Mouse) ...................... 870.4300 Chronic/ Oncogenicity ...................... Yes Yes Yes Yes Yes No a Yes No a No a No a 870.5100 Mutagenicity— Gene Mutation ­ bacterial ....... 870.5300 Mutagenicity— Gene Mutation ­ mammalian ..... 870.5375 Mutagenicity– in vitro cytogenicity 870.5385 Mutagenicity— Mammalian bone marrow chromosomal aberration test ................. 870.5550 Mutagenicity— UDS in Mammalian cells in vitro 870.5900 In vitro sister chromatid exchange assay ........ Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes 870.6100a Acute Delayed Neurotox. (Hen) ............... 870.6100b 90­ Day Neurotoxicity (Hen) .................. 870.6200a Acute Neurotox. Screening Battery (Rat) ........ 870.6200b 90 Day Neuro. Screening Battery (Rat) ......... 870.6300 Developmental Neurotoxicity ................. No No No No Yes b No a 870.7485 General Metabolism ........................ 870.7600 Dermal Penetration ........................ Yes No Yes Yes a The HIARC determined that these studies must be repeated b The HIARC determined that this study is held in reserve pending submission of a rabbit developmental toxicity study Tebuthiuron (105501) RED Toxicology Chapter 3 3 DATA GAPS 28­ day inhalation study in the rat (870.3465) Developmental toxicity study in the rabbit (870.3700b) Chronic feeding/ oncogenicity study in the rat (870.4300) Oncogenicity study in the mouse (870.4200) Developmental neurotoxicity study (870.6300) (held in reserve) 4 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of data base for acute toxicity: The database for acute toxicity is considered adequate. The acute toxicity studies indicate that tebuthiuron, technical, is more toxic for oral (Toxicity Category II) exposure than for either dermal (Toxicity Category IV) or inhalation (Toxicity Category III). The primary eye and skin irritation studies were both Toxicity Category IV; no dermal sensitization occurred with tebuthiuron in guinea pigs. Acute Toxicity of Tebuthiuron, Technical Guideline No. Study Type MRID No. Results Toxicity Category 870.1100 Acute Oral (Rat) 40583901 LD50 =477.5 mg/ kg (%%) 387.5 mg/ kg (&&) II 870.1200 Acute Dermal (Rabbit) 40583902 LD50 => 5000 mg/ kg (%%and &&) IV 870.1300 Acute Inhalation (Rat) 00155730 LC50 = 3.696 mg/ L III 870.2400 Primary Eye Irritation 40583903 Slight irritation IV 870.2500 Primary Skin Irritation 40583902 Non­ irritating IV 870.2600 Dermal Sensitization 40583904 Non­ sensitizer 4.2 Subchronic Toxicity Adequacy of data base for subchronic toxicity: With the exception of the 28­ day inhalation study, the database for subchronic toxicity is considered adequate. Subchronic studies in both the rat and dog, as well as a 28­ dy dermal toxicity study, were considered to be acceptable. 4.2.1 870.3100 90­ Day Oral Toxicity ­ Rat Executive Summary: In a subchronic toxicity study (MRID 00020662), Harlan SpragueDawley rats (10/ sex/ dose) were fed diets containing tebuthiuron (purity not given) at 0, 400, 1000 or 2500 ppm (0, 20, 50 or 125 mg/ kg/ day) for three months. High dose males and females showed decreased body weights, increased relative liver, kidney, gonad Tebuthiuron (105501) RED Toxicology Chapter 4 weights; males also had increased relative weights for spleen, prostate gland and moderate vacuolization of the pancreatic acinar cells. The LOAEL was established at 125 mg/ kg/ day, based on increased relative organ weights and increased incidence of vacuolization of the pancreatic acinar cells; the NOAEL was established at 50 mg/ kg/ day. This study is classified as Acceptable/ Guideline and satisfies the requirements for a subchronic toxicity study [870.3100 (§ 82­ 1a)] in rats. 4.2.2 870.3150 90­ Day Oral Toxicity ­ Dog Executive Summary: In a subchronic toxicity study (MRID 00020663), beagle dogs (2/ sex/ dose) were dosed (capsule) with tebuthiuron (purity not given) at 0, 12.5, 25 or 50 mg/ kg/ day for 90 days. Clinical signs were limited to high dose dogs, which had anorexia; all animals survived to terminal sacrifice. High­ dose females had body weight losses of 5%. Transient increases (up to 4­ fold) in alkaline phosphatase activity were observed in high­ dose animals; other clinical chemistry parameters were unaffected by treatment. Relative liver weights were slightly increased in one male and female in the high­ dose group, however, gross and histopathological observations did not show any treatmentrelated effects in these animals. The LOAEL was established at 50 mg/ kg/ day, based on decreased body weight and increased alkaline phosphatase activity; the NOAEL was established at 25 mg/ kg/ day. This study is classified as Acceptable/ Guideline and satisfies the requirements for a subchronic toxicity study [870.3150 (§ 82­ 1b)] in dogs. 4.2.3 870.3200 21/ 28­ Day Dermal Toxicity ­ Rabbit Executive Summary: In a dermal toxicity study (MRID 00149733, 00160796) New Zealand White rabbits were treated for 21 days with tebuthiuron (purity not given) at 0 or 1000 (limit dose) mg/ kg/ day. No treatment­ related toxicity was observed. The LOAEL was not established; the NOAEL was established at 1000 mg/ kg/ day (limit dose) This study is classified as Acceptable/ Guideline and satisfies the requirements for a 21­ day dermal toxicity study [870.3200 (§ 82­ 2)] in rabbits. 4.2.4 870.3250 90­ Day Dermal Toxicity No study available, not required 4.2.5 870.4365 90­ Day Inhalation Toxicity Tebuthiuron (105501) RED Toxicology Chapter 5 No study available. A 28­ day inhalation study has been identified as a data gap by the HIARC. 4.3 Prenatal Developmental Toxicity Adequacy of data base for Prenatal Developmental Toxicity: The data base for prenatal developmental toxicity is not complete. The developmental toxicity study in the rabbit was found to be unacceptable; the requirement for a developmental neurotoxicity study is being held in reserve pending submission of this study. In the rat developmental toxicity study, no qualitative/ quantitative evidence of increased susceptibility was observed. 4.3.1 870.3700a Prenatal Developmental Toxicity Study ­ Rat Executive Summary: In a developmental toxicity study (MRID 00020803, 40485801), 25 presumed pregnant Harlan rats per group were administered tebuthiuron (purity not given; Lot No. 1093­ 316A­ 259) at dietary concentrations of 0, 600, 1200, or 1800 ppm (0, 37, 72, or 110 mg/ kg/ day, respectively) on gestation days (GD) 6­ 15, inclusive. On GD 20, dams were sacrificed and subjected to gross necropsy; pancreatic tissue was saved from 10 females/ group for histopathological examination. Fetal sex, weight, and viability were determined and each fetus was examined for external abnormalities. Approximately onethird of all fetuses were fixed in Bouin's solution for subsequent visceral examination and the remainder were cleared for skeletal examination. All dams survived to terminal sacrifice. No treatment­ related clinical signs of toxicity were observed in any group. Body weights, body weight gains, and food consumption by the low­ and mid­ dose groups were similar to the controls throughout the study. No treatment­ related lesions were observed in any dam at necropsy. Pancreatic tissue, as evaluated by both gross and microscopic examination, appeared normal. For the high­ dose group, absolute body weights were slightly reduced on GD 16 to 93% of the control level due to reduced body weight gains during the entire treatment interval. Body weight gains by the high­ dose dams were 21% of the control level during GD 6­ 10 and 57% of the control level during GD 11­ 15. During the treatment interval, food consumption by the high­ dose group was 71% of the control amount for GD 6­ 10 and 95% of the control amount for GD 11­ 15. Compensatory weight gain and food consumption was observed in the high­ dose group during the post­ treatment interval. The maternal toxicity LOAEL is 1800 ppm (110 mg/ kg/ day) based on decreased body weight gains and food consumption. The maternal toxicity NOAEL is 1200 ppm (72 mg/ kg/ day). No differences were observed between the treated and control groups for pregnancy rate, number of corpora lutea/ dam, number of implantation sites/ dam, pre­ or post­ implantation losses, number of fetuses/ litter, fetal body weights, or fetal sex ratios. No dead fetuses were observed. Tebuthiuron (105501) RED Toxicology Chapter 6 The total number of fetuses( litters) available for examination for malformations/ variations in the control, low­, mid­, and high­ dose groups was 259( 23), 263( 21), 300( 23), and 258( 21), respectively. No treatment­ related abnormalities were found in any fetus. In the control, low­, mid­, and high­ dose groups, the total number of fetuses( litters) with external, visceral, or skeletal malformations/ variations was 3( 2), 4( 4), 11( 7), and 4( 3), respectively. Hydronephrosis was a common finding in fetuses from control and treated groups. The developmental toxicity NOAEL is $ $1800 ppm (110 mg/ kg/ day) and the developmental toxicity LOAEL was not identified. This study is classified as Acceptable/ Guideline and satisfies the requirements for a developmental toxicity study [870.3700 (§ 83­ 3a)] in rats. 4.3.2 870.3700b Prenatal Developmental Toxicity Study ­ Rabbit Executive Summary: In a developmental toxicity study (MRID 00020644), 15 presumed pregnant Dutch belted rabbits per group were administered tebuthiuron (96.5% a. i.; Lot No.: B30­ 23­ 149) by gavage at doses of 0, 10, or 25 mg/ kg/ day on gestation days (GD) 6­ 18, inclusive. Details of the purity and composition and of the insemination procedure were given in MRID 41122401. On GD 28, all surviving does were sacrificed and examined grossly. Litters were weighed and each fetus examined for viability, sex, and external malformations/ variations. The fetuses were killed, examined viscerally by fresh dissection (including the brain), and the carcasses processed for skeletal examination. Doses for the study were selected on the basis of a preliminary range­ finding study (MRID 40776301). In this study, mated rabbits (4/ group) were administered 5, 10, 20, 25, 50, or 100 mg/ kg/ day on GD 6­ 18. Three animals in the 100 mg/ kg/ day group died or were killed moribund on GD 8­ 10. Overall body weight changes for the treated groups were 140, 5, ­37, ­72, ­103, and ­480 g, respectively. From the range­ finding study, the percentage of resorptions in the 25, 50, and 100 mg/ kg/ day groups was 68.8, 66.7, and 100%.. In the main study, premature deaths of several animals were considered incidental to treatment. No clinical signs of toxicity were observed in any animal. No effects on body weights, body weight changes, or food consumption were noted for the treated groups as compared with the controls. No treatment­ related lesions were found at gross necropsy. The maternal toxicity NOAEL was established at 25 mg/ kg/ day; the LOAEL for maternal toxicity was not established. No differences between the treated and control groups were noted for pregnancy rate or numbers of corpora lutea, implantations, fetuses/ litter, or resorptions. Although the mean fetal body weights in the high­ dose group were significantly lower than the control value, the decreases were attributed to increased liter size. Tebuthiuron (105501) RED Toxicology Chapter 7 The total number of fetuses( litters) examined in the control, low­, and high­ dose groups was 48( 11), 58( 11), and 68( 12), respectively. No treatment­ related external, visceral, or skeletal malformations/ variations were observed in this study. The developmental toxicity NOAEL is established at 25 mg/ kg/ day; the LOAEL was not established. This study is classified as Unacceptable/ Guideline and does not satisfy the guideline requirements for a developmental toxicity study [870.3700 (§ 83­ 3b)] in rabbits. 4.4 Reproductive Toxicity Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered complete and no additional studies are required at this time. 4.4.1 870.3800 Two­ Generation Reproduction and Fertility Effects ­ Rat Executive Summary: In a two­ generation reproduction study (MRID 00090108), tebuthiuron (Lot No. 00880­ 1L­ 1, X­ 35920, 98.0% a. i.) was fed to groups of 25 male and 25 female Wistar rats per dose at dietary concentrations of 0, 100, 200, and 400 ppm. The dietary levels corresponded to doses of 6­ 7, 13­ 14, and 26­ 28 mg/ kg/ day, respectively, for F0 and F1 males and 7­ 8, 14­ 15, and 30­ 31 mg/ kg/ day, respectively, for F0 and F1 females averaged over the premating period only. Adult rats of both generation were fed the treated or control diets during the premating period (98 days for F0 and 124 days for F1 rats) and during mating, gestation, and lactation of two litters per generation. Pups from the F1a litters were selected to parent the F2 generation. No treatment­ related deaths, clinical signs of toxicity, gross lesions, or microscopic lesions were observed in adult rats of either generation. No treatment­ related effects were observed on body weight, body weight gain, food consumption, or food efficiency in F0 male rats, F1 male rats, or F0 female rats fed any dose at any time during the study including the premating, mating, gestation, and lactation periods. F1 females in the 200 and 400 ppm groups had mean weekly body weights 7­ 9% (not biologically significant) and 8­ 13% (p< 0.01 or <0.05), respectively, less than the control group throughout the premating period starting with day 21 for the 200 ppm group and day 7 for the 400 ppm group. Weight gain over the entire premating period was 7% (N. S.) less than controls for 200 ppm group F1 females and 14% (p< 0.05) less for the 400 ppm group. Cumulative food consumption was not significantly affected, but food efficiency was reduced by 13% (p< 0.01) for 400 ppm group F1 females. The decreased body weights and weight gain did not extend into the gestation or lactation period for F2a litters. The parental systemic LOAEL was established at 400 ppm (30 mg/ kg/ day) for female rats based on deceases in body weight and weight gain; NOAEL was established at 200 ppm (14 mg/ kg/ day). Parental effect levels were not established for adult male rats in this study. Tebuthiuron (105501) RED Toxicology Chapter 8 No effects were observed on reproductive parameters as measured by sperm morphology, fertility index for females, and the number of litters produced. A reproductive LOAEL was not established; the NOAEL was established at 400 ppm (30 mg/ kg/ day). The F1a , F1b , F2a , or F2b offspring/ litters were not affected by treatment with tebuthiuron in the diet. The mean litter size at birth, litter size throughout lactation, survival indices (live birth, viability, and lactation), and pup weights and pup weight gain throughout lactation were not statistically different between treated and control groups. Dosing was considered to be barely adequate for assessing reproductive and offspring toxicity. The offspring LOAEL was not established; the NOAEL was established at 400 ppm (30 mg/ kg/ day). This study is classified Acceptable/ Guideline and satisfies the guideline requirement for a two­ generation reproductive study (OPPTS 870.3800, §83­ 4) in the rat. 4.5 Chronic Toxicity Adequacy of data base for chronic toxicity: The data base for chronic toxicity is not complete; datagaps include a chronic feeding/ carcinogenicity study in the rat. It should be noted that initial review of the carcinogenicity studies in the rat and mouse by the RfD Committee on August 28, 1992 did not consider the doses to be adequate based on the absence of systemic effects. On February 25, 1993, however, the RfD Committee (Second RfD/ Peer review report of Tebuthiuron, memo dated March 1, 1993) reconvened and found the rat carcinogenicity study to be acceptable; the committee felt that the doses were considered adequate, or at least approaching an adequate dose, for carcinogenicity testing in rats based on body weight gain decrease. Even though the Committee found the mouse carcinogenicity study to be unacceptable (inadequate dose levels), they concluded that treatment did not seem to alter the tumor profile for this strain of mouse and indicated that there would be no need for another study. 4.5.1 870.4300 Combined Chronic Toxicity/ Carcinogenicity Study­ CD( SD) BR Rats Executive Summary: In a chronic toxicity/ carcinogenicity study (MRID 00020714), tebuthiuron (> 97% a. i., lot number, 6SG43 and B30­ 23­ 149) was administered to male and female Wistar rats (40/ group/ sex) at dietary concentrations of 400, 800, or 1600 ppm (20, 40, and 80 mg/ kg/ day, based on the default food factor of 0.05). Two control groups of 60 male and 60 female Wistar rats administered untreated basal diet. No interim sacrifice was conducted for this study. Two replicate studies were carried out. No treatment­ related effects were reported for clinical signs, mortality, or clinical pathology in male or female rats receiving any dose of the test material. The mortality rates for all groups was high. During the first year of treatment, 10­ 19% of males died Tebuthiuron (105501) RED Toxicology Chapter 9 while at the end on the study, only 26% of all rats remained alive. Pneumonia affected the majority of animals in all groups at various times during the study; antibiotic treatment was required during one episode. Absolute body weights presented graphically indicated that high­ dose males and females weighed less than controls throughout most of the study. The magnitude of the reduction in absolute body weight could not be determined for assessment of statistical or toxicologic significance. A 15% reductions in body weight in high­ dose females was observed at study termination. Food consumption was measured but not reported. Relative kidney weights were depressed in high­ dose male rats, but no histopathological correlates were observed. Each animal was necropsied, but gross findings were not tabulated. Vacuolization of pancreatic acinar cells (generally slight or affecting only a few cells) was observed in 11 males and 13 females receiving the high­ dose and in none of the controls of either sex. Only selected histopathological data were presented in the summary tables of the study report; therefore, a complete assessment of histopathological findings could not be conducted. No treatment­ related neoplasms were reported; common neoplasms included pituitary adenomas and mammary fibroadenomas in female rats. The microscopic findings in the pancreatic acinar cells were generally slight, affected only a few cells, and caused no physiological effect on glucose levels. Based on the results of this study (decreased terminal body weight in females), the LOAEL for systemic toxicity was established at 80 mg/ kg/ day; a LOAEL was not established im males. The NOAEL was established at 40 mg/ kg/ day in females at 80 mg/ k/ day in females. The HIARC (TXR No. 0050450, dated February 5, 2002) determined that doses used in this study were not considered to be adequate for the evaluation of the carcinogenic potential of tebuthiuron. This chronic toxicity/ carcinogenicity study in the rat is Unacceptable/ Guideline and does not satisfy the guideline requirement for a chronic toxicity/ carcinogenicity oral study [OPPTS 870.4300 (§ 83­ 5)] in the rat. 4.5.2 870.4100b Chronic Toxicity ­ Dog Executive Summary: In a one­ year chronic toxicity study, tebuthiuron (98.9% a. i., Batch No. X­ 35920) was administered daily by capsule to groups of 4 male and 4 female beagle dogs at doses of 0, 12.5, 25.0, or 50.0 mg/ kg/ day (MRID 00146801). All animals survived to scheduled termination. Clinical signs of toxicity in high­ dose animals included anorexia, emesis, and diarrhea. Absolute body weights for females and food consumption for males and females were not affected by treatment. Body weights of the high­ dose males were less than those of the controls throughout most of the study with statistical significance attained occasionally. Overall weight gains by the high­ dose males and females were 67% and 82%, respectively, of the control levels. No treatment­ related ophthalmological lesions, changes in urinalysis parameters, or microscopic lesions were Tebuthiuron (105501) RED Toxicology Chapter 10 noted and gross necropsy was unremarkable. Thrombocyte counts were significantly (p # 0.05) increased in high­ dose males at 6 and 12 months as compared with the controls. Alanine aminotransferase (ALT) levels were increased in males after 1 month and in females after 3 months to 186­ 529% and 228­ 407%, respectively, of the control group levels. In addition, alkaline phosphatase (AP) levels in males were increased to 283­ 408% of the control levels at 6 and 12 months. Statistical significance was not attained at all timepoints for the increases in enzyme levels due to large variability between individual animals. Absolute liver weights were significantly (p # 0.05) increased in the high­ dose males and females. No other differences in absolute organ weights were found. Also for the highdose groups, significant (p # 0.05) differences in organ weights relative to final body weight included increased relative liver weights in males and females, increased relative kidney weights in females, and increased relative thyroid weights in males. The LOAEL was established at 50 mg/ kg/ day based on clinical signs (anorexia, emesis, and diarrhea), decreased body weight gains, increased alanine aminotransferase and alkaline phosphatase (males only) levels, increased absolute and relative liver weights, increased relative kidney weights (females only), and increased relative thyroid weights (males only). The NOAEL was established at 25 mg/ kg/ day. This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a chronic toxicity study in dogs [OPPTS 870.4100 (83­ 1b)] . 4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The database for carcinogenicity is considered inadequate. The HIARC (TXR No. 0050450, dated February 5, 2002) reevaluated the classification and concluded that the carcinogenic potential of tebuthiuron can not be determined due to inadequate carcinogenicity studies. 4.6.1 870.4200b Carcinogenicity Study ­ Crl: CD­ 1 (ICR) BR Mouse Executive Summary: In a carcinogenicity study (MRID 00020717) Tebuthiuron (> 97% a. i., lot # B30­ 23­ 149) was administered to groups of 80 Harlan ICR mice/ sex/ dose in pelleted diet at dose levels of 400, 800, or 1600 ppm (60, 120, or 240 mg/ kg /day based on the default food factor of 0.15) for 2 years. The control group, consisting of 120 males and 120 females was fed untreated pelleted diet. Animals were equally subdivided by dose and sex into two substudies; the second substudy was started 1 week after the first. It should be noted that animals were not assigned by body weight. Although there was a statistically significant decrease (32.4 g, 12%) in the terminal body weights of high­ dose females in one of the substudies (M9153), this is likely due to the higher body weight (36.7 g) of the control females in this substudy. The terminal body Tebuthiuron (105501) RED Toxicology Chapter 11 weight of the control females in the other substudy was 34.1 g. There were no compound related effects on mortality, clinical signs, hematology or clinical chemistry, organ weights, or gross or microscopic pathology. The LOAEL for systemic toxicity was not established. The NOAEL was established at 1600 ppm (240 mg/ kg/ day). At the doses tested, there was no treatment related increase in tumor incidence when compared to that of controls. Dosing was not considered adequate based on the absence of systemic effects. This carcinogenicity study in Unacceptable/ Guideline and does not satisfy guideline requirements for a carcinogenicity study in the rat. 4.6.2 870.4300 Carcinogenicity Study­ CD( SD) BR Rats Executive Summary: See section 4.5.1 (870.4300). Adequacy of the Dose Levels Tested: At the doses tested, there was no treatment related increase in tumor incidence when compared to that of controls. Dosing was not considered adequate based on the absence of systemic effects. 4.7 Mutagenicity Adequacy of data base for Mutagenicity: The database for mutagenicity is considered adequate. The submitted test battery satisfies the Pre­ 1991 mutagenicity initial testing battery guidelines. There is no evidence of gene mutations in bacteria or mammalian cells, chromosome aberrations in mammalian cells or unscheduled DNA syntheses in cultured rat hepatocytes. No further testing is required at this time. Gene Mutation 870.5100 Bacterial reverse gene mutation assay MRID 00141691 Acceptable/ Guideline In a reverse gene mutation assay in bacteria, S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed to Tebuthiuron (98.0%, lot number X­ 35920) in dimethylsulfoxide (DMSO) at concentrations of 100, 500, 1000, 2500, or 5000 :g/ plate in the presence and absence of mammalian metabolic activation (S9­ mix). Triplicate plates were utilized for each test concentration. Tebuthiuron was tested up to the limit dose. No increase in mutant frequency was noted in any strain with or without metabolic activation. The solvent and positive control values were appropriate in the respective strains. There was no evidence of induced mutant colonies over background in strains TA98, TA100, TA1535, TA1537 and TA1538 with or without S9 activation. Tebuthiuron (105501) RED Toxicology Chapter 12 870.5100 Bacterial reverse gene mutation assay MRID 00141690 Acceptable/ Guideline In a reverse gene mutation assay in bacteria, S. typhimurium strains G46, TA1535, TA100, C3076, TA1537, D3052, TA1538, and TA98 and E. coli strains WP2 and WP2 uvrA­ were exposed to tebuthiuron (98.0%, lot number X­ 35920) in dimethylsulfoxide (DMSO) over a concentration range of 0.1 to 1000 :g/ mL, in a gradient plate assay, in the presence and absence of mammalian metabolic activation (S9­ mix). No increase in mutant frequency was noted in any S. typhimurium or E. coli tester strain with or without metabolic activation. The solvent and positive control values were appropriate in the respective strains. There was no evidence of induced mutant colonies over background in S. typhimurium strains G46, TA1535, TA100, C3076, TA1537, D3052, TA1538, and TA98 and E. coli strains WP2 and WP2 uvrA­ with or without S9 activation. 870.5300 In vitro mammalian cell gene mutation MRID 00145041 Acceptable/ Guideline In a mammalian cell gene mutation assay in vitro, cultures of mouse lymphoma L5178Y TK+/­ cells were exposed to Tebuthiuron (98.0%, lot No. X­ 35920) in dimethylsulfoxide at concentrations of 100, 200, 300, 400, 500, 600, 700, or 800 :g/ mL in an initial assay the absence of mammalian metabolic activation (S9­ mix), and at concentrations of 10, 100, 200, 300, 400, 500, 750, or 1000 :g/ mL in an initial assay in the presence of S9 mix. Due to cytotoxicity, the nonactivated assay was repeated at concentrations of 10, 100, 200, 400, 500, 600, 700, and 800 :g/ mL, and the activated assay was repeated at concentrations of 1, 10, 100, 200, 400, 500, 600, or 700 :g/ mL. Tebuthiuron technical was tested up to concentrations limited by cytotoxicity. Relative growth ranged from 57% to 13% (at 100 to 800 :g/ mL) in the absence of metabolic activation in the initial assay and from 28% to 6% (at 10 to 750 :g/ mL) in the presence of metabolic activation in the initial assay. In the initial nonactivated assay, mutation indices of 2.0 and 2.4 were detected at 700 and 800 :g/ mL, respectively. In a repeat nonactivated assay, mutation indices of 2.0, 2.0, and 2.7 occurred at 200, 400, and 500 :g/ mL, respectively. Mutations were not induced at any concentration with activation. The ethyl methane sulfonate (without S9) and 3­ methylcholanthrene (with S9­ mix) positive controls responded appropriately. Tebuthiuron was considered weakly mutagenic in the absence of metabolic activation. No evidence of an increased mutant frequency was observed in the presence of metabolic activation. Tebuthiuron (105501) RED Toxicology Chapter 13 Cytogenetics 870.5375 In vitro mammalian cell chromosome aberration MRID 41134101 Acceptable/ Guideline In a mammalian chromosome aberration assay, Chinese Hamster Ovary (CHO) cell cultures were exposed to Tebuthiuron (99.08%, lot number 729AS7) in dimethylsulfoxide at concentrations of 0, 1650, 1800, or 1950 :g/ mL for 4 hours in the absence of exogenous metabolic activation (S9­ mix) or to 1350, 1450, or 1550 :g/ mL for 4 hours in the presence of activation (followed by an additional 19­ hour incubation in fresh medium). Tebuthiuron was tested up to concentrations limited by cytotoxicity. A preliminary cytotoxicity test showed survival ranging from 15% at 2285 :g/ mL to 115% at 1000 :g/ mL under nonactivated conditions and 39% at 1750 :g/ mL and 55% at 1500 :g/ mL. A significant (p< 0.01) increase in the percent of cells with aberrations was noted in nonactivated cultures at 1950 :g/ mL (15 &19% for treated duplicate cultures vs. 5% for vehicle controls) and activated cultures at 1550 :g/ mL (15 &18% for treated duplicate cultures vs. 5­ 6% for vehicle controls). The predominant types of aberrations were chromosome and chromatid breaks. No significant increases were observed at lower concentrations; however, rare complex aberrations, such as triradials, quadriradials and complex rearrangements were noted, providing further support for clastogenicity. Positive control values were acceptable. There was evidence of an increase in structural chromosomal aberrations over background in the presence and absence of metabolic activation. Other Genotoxicity 870.5550 Unscheduled DNA synthesis in mammalian cell culture MRID 40750901 Acceptable/ Guideline In an unscheduled DNA synthesis assay, primary rat hepatocyte cultures were exposed to Tebuthiuron (99.1% a. i.; Lot No. 729AS7) in dimethylsulfoxide at eight concentrations ranging from 300 to 800 :g/ mL for 20 hours. Tebuthiuron was tested to the limit of cytotoxicity (cytotoxicity was observed at $900 :g/ mL). UDS activity was evaluated at concentrations up to 800 :g/ mL and there was no evidence of induction of UDS. The solvent (1% DMSO) and positive control (N­ methyl­ N'­ nitrosoguanidine 1 :g/ mL and 2­ acetoaminofluorene 0.05 :g/ mL) values were appropriate. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. 4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: No acute or subchronic neurotoxicity studies on Tebuthiuron are available. Evaluation of subchronic, chronic and reproduction toxicity, did not reveal any treatment­ related effects on the central or peripheral nervous system of mice, rats, or rabbits. No changes in clinical signs, brain weights, gross necropsy results or histopathological results suggested any part of the nervous system as a target organ. However, the HIARC meeting on December 13, 2001 and January 17, 2002 determined that a developmental neurotoxicity study should be held in reserve, pending submission of a developmental toxicity study in the rabbit (TXR No. 0050450, dated Tebuthiuron (105501) RED Toxicology Chapter 14 February 5, 2002). 4.8.1 870.6100 Delayed Neurotoxicity Study ­ Hen This study is not required. 4.8.2 870.6200a Acute Neurotoxicity Screening Battery This study is not required. 4.8.3 870.6200b Subchronic Neurotoxicity Screening Battery This study is not required. 4.8.4 870.6300 Developmental Neurotoxicity Study The requirement for this study is being held in reserve. 4.9 Metabolism Adequacy of data base for metabolism: The data base for metabolism is considered complete and no additional studies are required at this time. 4.9.1 870.7485 Metabolism ­ Rat Executive Summary: In a metabolism study (MRID 42711701, 43129701), male and female Fischer 344 rats were dose with 14 C­ tebuthiuron at a single low oral dose (10 mg/ kg), a repeated low oral dose (10 mg/ kg x 14 days), or a single high dose (100 mg/ kg). Absorption was complete at both the low and high dose. Terminal distribution data showed no significant amounts of residual radioactivity in any tissue examined, but the skin showed the highest amounts relative to other tissues. Excretion was rapid at both the low and high dose levels in both sexes, but was delayed during the first 12 hours postdose indicating saturation of biotransformation or excretion. From HPLC and mass spectral analysis of urine samples, 6 metabolites of tebuthiuron were identified. The major metabolite was identified as 109OH and/ or 104­ OH, both hydroxylated metabolites of tebuthiuron. This metabolite composed between 39.6­ 60.3% of the administered dose in 0­ 24 hour urine of male and female rats. The second most abundant metabolite was identified as metabolite 106 of tebuthiuron. This comprised between 9­ 15% of the administered dose in 0­ 24 hour urine of low dose rats, and between 55.6% and 57.3% of the administered dose for male and female rats, respectively. Two other metabolites identified, 104/ 109 and 103­ OH, comprised between 2­ 10% of the administered dose in male and female 0­ 24 hour urine. Feces contained minor amounts of 104­ OH and 109­ OH, accounting for an average of 3.5% of the administered dose. 4.10 Special Studies None 5 TOXICITY ENDPOINT SELECTION Tebuthiuron (105501) RED Toxicology Chapter 15 See Section 9.2 for Endpoint Selection Table 5.1 Dermal Absorption No study available. 5.2 Classification of Carcinogenic Potential 5.2.1 Conclusions and Classification of Carcinogenic Potential The HIARC (TXR No. 0050450, dated February 5, 2002) reevaluated the classification and concluded that the carcinogenic potential of tebuthiuron can not be determined due to inadequate carcinogenicity studies. 5.2.2 Quantification of Carcinogenic Potential Not applicable 6 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children The toxicological database is inadequate for FQPA assessment. The developmental toxicity study in the rabbit is unacceptable for the determination of susceptibility to the fetuses due to in utero tebuthiuron exposure. However, there is an adequate developmental toxicity study in the rat and a two­ generation reproductive toxicity study in the rat to assess the susceptibility of fetuses/ offspring to tebuthiuron. There is no qualitative/ quantitative evidence of increased susceptibility in 2­ generation reproduction study in the rat or the developmental toxicity study in the rat. In the developmental toxicity study in the rabbit, no maternal or developmental toxicity was observed at the highest dose tested. Because there was no toxicity observed at the highest dose tested, susceptibility could not be ascertained and the HIARC concluded that a new developmental toxicity in the rabbit is needed.. 6.2 Recommendation for a Developmental Neurotoxicity Study The FQPA Committee reserved the requirement of a developmental neurotoxicity study pending submission of a developmental toxicity study in rabbits. 7 OTHER ISSUES None 8 REFERENCES 00020662 Todd, G. C.; Gibson, W. R.; Kiplinger, G. F. (1972) The Toxicological Evaluation of EL­ 103 in Rats for 3 Months. (Unpublished study received Mar 13, 1973 under 1471­ 97; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Tebuthiuron (105501) RED Toxicology Chapter 16 Indianapolis, Ind.; CDL: 006422­ G) 00020663 Todd, G. C.; Gibson, W. R.; Kiplinger, G. F. (1972) The Toxicological Evaluation of EL­ 103 in Dogs for 3 Months. (Unpublished study received Mar 13, 1973 under 1471­ 97; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL: 006422­ H) 00020644 Todd, G. C., Markham, J. K., Adams, E. R., Owen, N. V., Gossett, F. O., and Morton, D. M. (1975) A teratology study with EL­ 103 in the rabbit. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study No. B­ 7014. April 1975. Unpublished. 00020714 Todd, G., W. Gibson, D. Hoffman, et al. 1976. The toxicological evaluation of tebuthiuron (EL­ 103) in rats for two years. Studies R­ 603 and R­ 613. Toxicology Division, Lilly Research Laboratories, Greenfield, IN, November, 1976. Unpublished. 00020717 Todd, G. C.; Gibson, W. R.; Hoffman, D. G.; et al. (1976) The Toxicological Evaluation of Tebuthiuron (EL­ 103) in Mice for Two Years: Toxicology Report # 8. (Unpublished study received Dec 1, 1976 under 1471­ EX­ 43; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL: 230139­ D) 00020803 Todd, G. C., Markham, J. K., Adams, E. R., Owen, N. V., Gibson, W. R., and Kiplinger, G. F. (1972) Rat teratology study with EL­ 103. The Lilly Toxicology Laboratories, Eli Lilly and Company, Greenfield, IN. Laboratory Study No. R632 September, 1972. Unpublished. 00090108 Adams, E. R., N. Owen, and J. Hoyt. 1981. A two­ generation reproduction study with tebuthiuron (Compound 75503) in the Wistar rat. Lilly Research Laboratories, Greenfield, IN. November, 1981. Study numbers R03780 and R08780. Unpublished 00141691 Rexroat, M. A., Todd, G. C. (1984). The effect of Tebuthiuron (Lilly Compound 75503) on the induction of reverse mutations in Salmonella typhimurium using the Ames test. Lilly Research Laboratories, Greenfield, IN. Study No. 840326AMS655. April, 1984. Unpublished 00145041 Oberly, T. J, Bewsey, B. J., Todd, G. C. (1984). The effect of Tebuthiuron (Lilly Compound 75503) on the induction of forward mutation at the thymidine kinase locus of L5178Y mouse lymphoma cells. Lilly Research Laboratories, Greenfield, IN. Study Nos. 840410 MLA655, 84060MLA655, 840612MLA655. Unpublished. 00146801 Todd, G. (1985). The toxicity evaluation of tebuthiuron (Lilly compound 75503) to Beagle dogs for one year. Lilly Research Laboratories, Greenfield, IN. Laboratory Study No. D04283. February 1985. MRID. Unpublished. 00149733 Brown, G. (1985) Subchronic (21­ Day) Dermal Toxicity Study in New Zealand White Rabbits with Technical Tebuthiuron: Study B01484. Unpublished study Tebuthiuron (105501) RED Toxicology Chapter 17 prepared by Lilly Research Laboratories. 211 p. 00160796 Negilski, D.; McGrath, J.; Young, S. (1986) Reply to U. S. EPA Recommendation To Upgrade the Current 21­ day Dermal Toxicity Study (BO1484) of Technical Tebuthiuron with Additional Doses to Establish a Systemic No­ effect Level. Unpublished study prepared by Eli Lilly and Co. 18 p. 40485801 Todd, G. C. and Higdon, G. L. (1972) A supplementary report of a rat teratology study with tebuthiuron (EL­ 103, compound 75503). Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Laboratory Study No. R­ 632. September, 1972. Unpublished. 40750901 Negilski. D. S, Garriot, M. L., Yount, D. J. (1988) . The effect of Tebuthiuron (EL­ 103, Compound 75503) on the induction of DNA synthesis in primary cultures of adult rat hepatocytes. Eli Lilly and Company, Greenfield, IN. Study Nos. 880510UDS0655 and 880517 UDS0655. Unpublished. 40776301 Negilski, D. S. and Higdon, G. L. (1988) A supplementary report in support of a teratology study with tebuthiuron (EL­ 103, Compound 75503) in the rabbit. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study No. B7014 June 8, 1988. Unpublished. 40870101 Negilski, D.; Todd, G. (1988) A Supplemental Inventory of Selected Tissues from Rats Given Diets Containing Tebuthiuron (...) for Two Years: Project ID: R­ 603 and R­ 613. Unpublished study prepared by Lilly Research Laboratories. 10 p. 41122401 Megilski, D. S., Rutherford, B. S., and Higdon, G. L. (1989) A supplementary report for a rabbit teratology study (B­ 7014) with tebuthiuron (EL­ 103, Compound 75503) ­ A response to the U. S. EPA's request for certain additional information to upgrade the rabbit teratology study from core supplementary to core minimum. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study No. B­ 7014. March 8, 1989. Unpublished. 41134101 Negilski, D. S., Garriot, M. L., Kindig, D. E. F. (1989) The effect of tebuthiuron (EL­ 103, Compound 075503) on the in vitro induction of chromosomal aberrations in Chinese Hamster Ovary cells. Lilly Research Laboratories, Greenfield, IN, Study Nos. 890111CTX655, 890125CTX655, 890201CAB655, 890228CAB655. April 12, 1989. Unpublished. 42711701 Eschbach, J.; Hackett, D. (1993) Absorption, Distribution and Elimination of (Carbon 14)­ Tebuthiuron in Rats: Lab Project Number: DR­ 0189­ 9383­ 001. Unpublished study prepared by Bio/ dynamics, Inc. 107 p. 43129701 Eschbach, J.; Hackett, D. (1994) Absorption, Distribution and Elimination of (carbon 14) Tebuthiuron in Rats: Addendum: Lab Project Number: DR/ 0189/ 9383/ 001. Unpublished study prepared by Bio/ dynamics, Inc. 10 p. USEPA Memorandum: Tebuthiuron oncogenicity studies, HED Project No. 9­ 0927, Tebuthiuron (105501) RED Toxicology Chapter 18 Caswell No. 366AA. From Quang Q. Bui, Head, Review Section I, Tox BranchHFAS HED to Robert Taylor, PM, # 25, Registration Division, November 30, 1988 (TXR No.: 007374) USEPA Memorandum: Tebuthiuron: Report of the Hazard Identification Assessment Review Committee, February 5, 2002 (TXR No 0050450) USEPA Memorandum: Tebuthiuron: Report of the FQPA Safety Factor Committee, February 12, 2002 (TXR No. 0050466) Tebuthiuron (105501) RED Toxicology Chapter 19 9 APPENDICES ­ Tables for Use in Risk Assessment 9.1 Toxicity Profile Summary Tables 9.1.1 Acute Toxicity Table ­ See Section 4.1 9.1.2 Subchronic, Chronic, and Other Toxicity Table Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90­ Day oral toxicityrat 00020662 (1972) Acceptable/ Guideline 0, 20, 50, 125 mg/ kg/ day NOAEL = 50 mg/ kg/ day LOAEL = 125 mg/ kg/ day, based on decreased body weight, increased relative liver, kidney, gonads, spleen (males only), and prostate and slight vacuolization of pancreatic acinar cells. 870.3150 90­ Day oral toxicitydog 00020663 (1972) Acceptable/ Guideline 0, 12.5, 25, 50 NOAEL = 25 mg/ kg/ day LOAEL = 50 mg/ kg/ day, based on decrease in body weight and increased alkaline phosphatase activity. 870.3200 21/ 28­ Day dermal toxicity­ rabbit 00149733 (1985) 00160796 (1986) Acceptable/ Guideline 0, 1000 mg/ kg/ day NOAEL = 1000 mg/ kg/ day (limit dose) 870.3250 90­ Day dermal toxicity No study available N/ A 870.3465 90­ Day inhalation toxicity No study available N/ A 870.4100 [83­ 1( b)] 1­ Year Feeding Study ­ Dog 00146801 (1985) Acceptable/ Guideline 0, 12.5, 25, 50 mg/ kg/ day NOAEL= 25 mg/ kg/ day LOAEL = 50 mg/ kg/ day based on clinical signs, decreased body wt, increased ALT and ALP (males only), increased absolute and relative livers and relative thyroid wt, (males only) wt, and increased absolute liver wt. 870.4200 [83­ 2 (b)] Oncogenicity Study ­ Mouse 00020717 (1986) Unacceptable/ Guideline 0, 60, 120, 240 mg/ kg/ day NOAEL= 240 mg/ kg/ day LOAEL = Not achieved Histopathology: None observed at doses tested, doses not high enough to assess carcinogenicity. Tebuthiuron (105501) RED Toxicology Chapter 20 Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.4300 [83­ 5( a)] Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat 00020714 (1976) 00098190 (1981) 40870101 (1988) Unacceptable/ Guideline 0, 20, 40, 80 mg/ kg/ day NOAEL = 40 mg/ kg/ day, females 80 mg/ kg/ day males LOAEL = 80 mg/ kg/ day, based on decreased terminal body weight in females not established in males Histopathology: None observed at doses tested, doses not high enough to assess carcinogenicity. 870.3700 [83­ 3( a)] Developmental Toxicity Study ­ Rat 00020803 (1972) 40485801 (1972) Acceptable/ Guideline 0, 37, 72, 110 mg/ kg/ day Maternal Systemic NOAEL= 72 mg/ kg/ day LOAEL = 110 mg/ kg/ day) based on decreased body weight gains and food consumption. Developmental NOAEL = 110 mg/ kg/ day LOAEL = not established 870.3700 [83­ 3( b)] Developmental Toxicity ­ Rabbit 00020644 (1975) 40776301 (1988) 41122401 (1989) Unacceptable/ Guideline 0, 10, or 25mg/ kg/ day Maternal Systemic NOAEL= 25 mg/ kg/ day LOAEL = not established Developmental NOAEL = 25 mg/ kg/ day LOAEL = not established 870.3800 [83­ 4] 2­ Generation Reproduction ­ Rat 00090108 (1981) Acceptable/ Guideline %% 0, 7, 14, and 26 mg/ kg/ day && 7, 14, and 30 mg/ kg/ day, Systemic NOAEL= 14 mg/ kg/ day LOAEL = 30 mg/ kg/ day, based on deceased in body weight and weight gain in F1 females. Parental effect levels were not established for adult male rats in this study. Reproductive NOAEL = 30 mg/ kg/ day LOAEL = not established Offspring NOAEL = 30 mg/ kg/ day LOAEL = not established 870.7600 (85­ 2) Dermal Penetration Rat No study available N/ A Tebuthiuron (105501) RED Toxicology Chapter 21 Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.7485 (85­ 1) Metabolism Study Rat 42711701 (1993) 43129701 (1994) Acceptable/ Guideline 10 or 100 mg/ kg, 1 day 10 mg/ kg/ day for 14 days Terminal distribution data showed no significant amounts of residual radioactivity in any tissue examined, but the skin showed the highest amounts relative to other tissues. Excretion was rapid at both the low and high dose levels in both sexes, but was delayed during the first 12 hours post­ dose, indicating saturation of biotransformation or excretion. Six metabolites of tebuthiuron were identified. The major metabolite in 0­ 24 hour urine of male (58.3%) and female (62.1%) rats was identified as hydroxylated tebuthiuron metabolites (# 109­ OH and /or #104­ OH). The second most abundant metabolite was identified as metabolite 106 of tebuthiuron. This comprised between 9­ 15% of the administered dose in 0­ 24 hour urine of low dose rats, and between 1 ­ 10% of the administered dose in high dose rats. Two other metabolites identified, 104/ 109 and 103­ OH, .comprised between 2­ 10% of the administered dose in male and female 0­ 24 hour urine. Feces contained minor amounts of 104­ OH and 109­ OH, accounting for an average of 3.5% of the administered dose. Tebuthiuron (105501) RED Toxicology Chapter 22 aPAD aRfD FQPA SF = cPAD cRfD FQPA SF = 9.2 Summary of Toxicological Dose and Endpoints for Tebuthiuron for Use in Human Risk Assessment Exposure Scenario Dose Used in Risk Assessment, UF 1 FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary females 13­ 50 years of age NOAEL = 25 mg/ kg/ day UF = 100 Acute RfD = 0.25 mg/ kg/ day FQPA SF 2 =3 = 0.083 mg/ kg/ day Developmental Toxicity Study Rabbit NOAEL of 25 mg/ kg/ day. LOAEL not established A range­ finding study showed increased early resorptions at 50 mg/ kg/ day Acute Dietary general population including infants and children N/ A N/ A No appropriate effects attributed to a single exposure was identified. Chronic Dietary all populations NOAEL= 14 mg/ kg/ day UF = 100 Chronic RfD = 0.14 mg/ kg/ day FQPA SF 3 = 1 = 0.14 mg/ kg/ day Two­ generation reproduction study in the rat LOAEL = 30 mg/ kg/ day, based on decreased body weight and feed consumption in F1 females Toxicological endpoints for occupational/ residential exposure risk assessments were not selected since tebuthiuron is scheduled for a Tolerance Reassessment Eligibility Decision (TRED) 1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose 2 Because there is a data gap for assessing susceptibility of fetuses following in utero exposure a FQPA safety factor of 3x will be used. 3 Because there was no susceptibility identified in the 2­ generation rat reproduction study (a long­ term study). the FQPA safety factor will be removed (1x).

epa

2024-06-07T20:31:42.611509

regulations

EPA-HQ-OPP-2002-0146-0006

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: April 3, 2002 SUBJECT: Tebuthiuron Acute and Chronic Dietary Exposure Assessments for the Tolerance Reassessment Eligibility Decision (TRED); PC codes 105501; DP Barcode D281821. FROM: Sheila Piper, Chemist Chemistry and Exposure Branch Health Effects Division (7509C) THROUGH: F. B. Suhre, Branch Senior Scientist Chemistry and Exposure Branch Health Effects Division (7509C) and Sherrie Kinard, Chemist Douglas Dotson, Chemist Dietary Exposure Science Advisory Council (DeSAC) Health Effects Division (7509C) TO: Paula Deschamp, Risk Assessor Reregistration Branch II Health Effects Division (7509C) and Wilhelmena Livingston, Chemical Review Manager Special Review Branch Special Review and Reregistration Division (7508C) The purpose of this memorandum is to summarize the results of the dietary risk assessment for the general U. S. population (chronic only) and females 13­ 50 years (acute) resulting from exposure to tebuthiuron through food. This risk assessment is an updated risk analysis that has been conducted for tebuthiuron. The most recent dietary risk assessment was conducted by J. M. Winterseen (09/ 01/ 93). DP Barcode: D281821 Dietary exposure assessment / 1 Tebuthiuron / 105501 1 aPAD/ cPAD = acute/ chronic Population Adjusted Dose = Acute or Chronic RfD FQPA Safety Factor 1 EPA Reviewer: Sheila Piper , Date April 3, 2002 STUDY TYPE: Tebuthiuron Acute and Chronic Dietary Exposure Assessments for the Tolerance Reregistration Eligibility Decision (TRED) PC codes 105501; DP Barcode D281821. ACTIVE INGREDIENT: Tebuthiuron SYNONYMS: Spike RESIDUE OF CONCERN: The residues of concern in livestock commodities are tebuthiuron and its metabolites 104, 106, 108, and 109; the terminal residues of concern in milk are tebuthiuron and metabolites 104, 104( OH), 106, 109 and 109( OH). Executive Summary A Tier 2 acute and a chronic dietary risk assessment were conducted for all supported currently registered tebuthiuron food uses. Dietary risk estimates are provided for the general U. S. population (chronic only) and females 13­ 50 (acute). This assessment concludes that for all included commodities, the acute risk estimates are below the Agency's level of concern (< 100% aPAD 1 ) at the 95 th exposure percentile for females 13­ 50 years (< 1% of the aPAD). This assessment also concludes that for all included commodities, the chronic risk estimates are below the Agency's level of concern (< 100% cPAD 1 ) for the general U. S. population (< 1% of the cPAD) and all population subgroups. I. Introduction Exposure to pesticides can occur through food, water, residential and occupational means. Risk assessment incorporates both exposure and toxicity of a given pesticide. The risk is expressed as a percentage of a dose that could be expressed as a daily or a long term dose, that poses no unreasonable adverse effects. This is called the population adjusted dose (PAD), and is expressed as %PAD. References are available on the DP Barcode: D281821 Dietary exposure assessment / 2 Tebuthiuron / 105501 2 EPA/ pesticides web site which discuss the acute and chronic risk assessments in more detail: "Available Information on Assessing Exposure from Pesticides, A User's Guide", 6/ 21/ 2000, web link: http:// www. epa. gov/ fedrgstr/ EPA­ PEST/ 2000/ July/ Day­ 12/ 6061. pdf ; or see SOP 99.6, 8/ 20/ 99. The purpose of this memorandum is to summarize the results of the dietary risk assessment for the U. S. population (chronic only) and females 13­ 50 (acute) resulting from exposure to tebuthiuron through food. This risk assessment is an updated risk analysis that has been conducted for tebuthiuron. The most recent dietary exposure analysis was conducted by J. M. Winterseen (09/ 01/ 93). II. Toxicological Information HED has completed the dietary risk assessment for tebuthiuron on the deliberations of the Hazard Identification Assessment Review Committee (HIARC) and hazard endpoints have been selected for both acute (one day) and chronic (long term) exposure intervals (Memorandum: R. Fricke dated February 5, 2002). On December 13, 2001 and January 17, 2002 the HIARC evaluated the results of a rabbit developmental toxicity study and its impact on the Food Quality Protection Act (FQPA) assessment and toxicity endpoint selection for tebuthiuron. An appropriate endpoint attributable to a single dose was not available in the database for an acute reference dose (general population). An appropriate acute endpoint (females 13+) attributable to a single dose at 25 mg/ kg/ day was selected for risk assessment, since there was no dose response in the observed early resorptions. In addition, the selection of the 25 mg/ kg/ day dose for risk assessment is supported by the NOAEL of 50 mg/ kg/ day in a rabbit developmental range­ finding study with a structurally related urea. For chronic reference dose, the NOAEL is 14 mg/ kg/ day from the twogeneration reproduction study based on decreased body weight, body weight gain and food consumption in F1 females at 30 mg/ kg/ day. The acute and chronic hazard endpoints selected for dietary exposure to tebuthiuron are listed in Table 1. In a meeting on February 4, 2002, the FQPA Safety Factor Committee recommended that the 10X FQPA Safety Factor (as required by the Food Quality Protection Act of August 3, 1996) be reduced to 3X for acute dietary exposure (females 13­ 50) and 1X for chronic dietary exposure (general population) when assessing the potential dietary risks posed by tebuthiuron use (C. Christensen, FQPA memo, 02/ 12/ 02). The basis and rationale for the 3x FQPA safety factor for females 13­ 50 years is due to a data gap for assessing susceptibility of fetuses DP Barcode: D281821 Dietary exposure assessment / 3 Tebuthiuron / 105501 3 following in utero exposure to tebuthiuron. For chronic dietary exposure to the general population, the FQPA safety factor will be reduced to 1x because there was no susceptibility identified in the 2­ generation rat reproduction study (a long­ term study). Table 1. Summary of Toxicological Dose and Endpoints for Tebuthiuron for Use in Dietary Exposure Assessment EXPOSURE SCENARIO DOSE (mg/ kg/ day) ENDPOINT STUDY Acute Dietary (Females 13­ 50) NOAEL= 25 UF = 100 FQPA= 3X Increased post­ implantation loss and fetal/ litter resorptions at 50 mg/ kg/ day (LOAEL). Developmental Toxicity Study in the Rabbit Acute RfD (Females 13­ 50 years old) = 0.25 mg/ kg/ day Acute PAD (females 13­ 50)= 0.083 mg/ kg/ day Acute Dietary (General Population) No appropriate effects attributed to a single exposure were identified. Chronic Dietary NOAEL = 14 UF = 100 FQPA= 1X Decreased body weight and feed consumption in F1 females at 30 mg/ kg/ day (LOAEL) 2­ Generation Reproduction Study in the Rat Chronic RfD = 0.14 mg/ kg/ day Chronic PAD (all population)= 0.14 mg/ kg/ day Cancer No endpoint for carcinogenicity due to inadequate carcinogenicity studies Category D or not classifiable as to human carcinogenicity Rat and mouse carcinogenicity studies III. Residue Information Tebuthiuron [N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea] is a relatively nonselective, soil activated herbicide registered for use to control broadleaf, woody weeds, grasses and brush on terrestrial feed crop sites (pastures and rangeland). Pelleted/ tableted (P/ T) is the only tebuthiuron formulation class registered for use on food/ feed crops. This formulation may be applied preplant, preemergence, postemergence, or postharvest. The registered mode of DP Barcode: D281821 Dietary exposure assessment / 4 Tebuthiuron / 105501 4 application is broadcast using ground or aerial equipment. Tolerances for residues of tebuthiuron have been established for grasses and livestock commodities (40 CFR §180.390). These tolerances are expressed in terms of the combined residues of N­[ 5­( 1,1­ diemthylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea and its metabolites containing the dimethylethyl thiadiazole moiety. Adequate enforcement methods are available for the determination of residues in/ on grasses and in animal tissues and milk. Tebuthiuron is a List A FIFRA reregistration chemical that was the subject of a Reregistration Standard Guidance Document dated 7/ 87. The Residue Chemistry Chapter of the Tebuthiuron Tolerance Reregistration Eligibility Decision (TRED) is being completed in conjunction with this document and reflects the evaluation of all the submissions made in response to the earlier reregistration documents. No monitoring data were available for tebuthiuron. An adequate method is available for the enforcement of plant commodity tolerances. A GLC with flame photometric detection is designated as Method II in PAM Vol. II. Tebuthiuron and metabolites 104 and 109 are thermally degraded on the GLC column and are determined as 104; metabolite 103( OH) is determined as 104( OH). A revised enforcement method for milk, to include hydrolysis steps and the determination of metabolites 104( OH) and 109( OH) is being requested. The stated detection limits are 0.1 ppm for tebuthiuron and metabolites 104 and 109, and 0.2 ppm for metabolite 103( OH). Residues in meat and milk were estimated using livestock feeding studies. The order of preference for the purpose of refining dietary exposure assessment is usually: monitoring data> field trial data> tolerance. The registrant submitted all field trial data for registered uses of tebuthiuron on plant commodities which reflect maximum application rates and shortest PHIs (S. Funk, D187699, 8/ 93). Metabolites C For dietary risk assessment, the Metabolism Committee concluded that the residues of concern in plants are the parent compound and its metabolites 103, 103( OH), 104, and 109. The residues of concern in livestock commodities (fat, meat, kidney, and liver) are tebuthiuron and its metabolites 104, 106, 108, and 109; the terminal residues of concern in milk are tebuthiuron and metabolites 104, 104( OH), 106, 109, and 109( OH). A poultry metabolism study is not required since grasses are not considered to be poultry feed items. DP Barcode: D281821 Dietary exposure assessment / 5 Tebuthiuron / 105501 5 Percent Crop Treated Information C An updated quantitative usage analysis for tebuthiuron was provided by BEAD based on data years 1996­ 99 (S. Smearman, Biological and Economic Analysis Division, 2/ 28/ 02). The percentage of the acres for each site treated in 1999, an average of less than 1 percent of rangeland/ pastureland acreage was treated up to an estimated maximum 2 percent of acres treated annually. For the miles of railroad rights of way and electric utility rights of way treated annually, the average percentage of miles treated was less than 1 percent, respectively. No information pertaining to the percent of area treated for industrial facilities or miles of pipeline rights of way was available, but based on the percentage of a. i. allocated to these sites it is assumed that the percent of area/ mileage treated also averages less than 1 percent. Processing Information C Processing factors were taken from the DEEM default values. Residue Estimates for Meat and Milk C The only source of dietary (food) exposure is the consumption of secondary residues in meat and milk from livestock fed tebuthiuron treated grass forage and hay. Tolerances in meat (2ppm) and milk (0.3 ppm) are established and in grass forage and hay at 10 ppm for residues of tebuthiuron and its metabolites containing the dimethyl thiadiazole moiety. C The residues of concern in livestock commodities (fat, meat, kidney, and liver) are tebuthiuron and its metabolites 104, 106, 108, and 109; the terminal residues of concern in milk are tebuthiuron and metabolites 104, 104( OH), 106, 109, and 109( OH). A poultry metabolism study is not required since grasses are not considered to be poultry feed items. C Feeding studies (S. Funk, Ruminant Feeding Study, D217379, 12/ 05/ 95) have demonstrated a transfer of tebuthiuron to animal tissue (meat, meat by­ products, etc.). The results of the ruminant feeding study conducted at a nominal 45 ppm tebuthiuron feeding level for 28 days show that the existing tolerances for milk and meat are inadequate and should be revised. The tolerances for meat (2 ppm) and fat (2 ppm) may DP Barcode: D281821 Dietary exposure assessment / 6 Tebuthiuron / 105501 6 be lowered to 1 ppm, but the tolerances for milk (0.3 ppm) and meat byproducts (2 ppm) must be increased to 0.8 ppm for milk and 5 ppm for meat byproducts. C A dietary burden of tebuthiuron for beef cattle (extrapolating to goats, sheep and horses) is based on the feed items of grass forage. For dairy cattle, the residues used were the average residues from grass forage field trials while for beef cattle the highest average field trial (HAFT) residue values were used. See Table 2 below. Table 2: Dietary Burden of Tebuthiuron to Beef and Dairy Cattle Commodity % DM a Beef Cattle Dairy Cattle Average Field Trial Data (ppm) b % Diet a Concentration (ppm) HAFT b (ppm) % Diet a Concentration c (ppm) Grass Forage 25 1.97 60 2.56 2.56 60 6.14 Corn grain 88 0 40 0 0 40 0 TOTAL ­ 100 2.56 100 6.14 a OPPTS Guideline 860.1000 b Beef cattle based on average field trial data; dairy cattle based on highest average field trial (HAFT) data c Ruminant contribution= [tolerance/ %DM] x %diet Dow Elanco dosed four groups of three dairy cows each for 28 days with gelatin capsules containing tebuthiuron at nominal dosage rates of 0 ppm, 45 ppm (9.5x), 135 ppm (28.5x), and 450 ppm (95x). Daily milk samples were collected, and within 24 hours of the last dosing the cows were sacrificed and tissues were collected. For beef cattle, the nominal dosage rates of 0 ppm, 45 ppm (7.3x), 135 ppm (22x), and 450 ppm (73x) were determined based on the dietary burden for beef cattle. Tissue samples (5 grams) were analyzed by Method GRM 94.01, which determines tebuthiuron and metabolites 104, 106, 108 and 109. Liver, kidney, muscle, or fat was hydrolyzed with 6N HCl which converts metabolite 109 to 104. The maximum incurred residues in various tissues at the 45 ppm feeding level, expressed as the sum of tebuthiuron, 104 + 109 as 104, and 106 + 108 as 106. Results of the analyses of bovine tissues are summarized in Table 3. DP Barcode: D281821 Dietary exposure assessment / 7 Tebuthiuron / 105501 7 Table 3: Residues of Tebuthiuron and Metabolites in Tissues from the Oral Administration of Tebuthiuron for 28 Days Diet (ppm tebuthiuron) Tissue Analyte Concentration 1 (ppm) Range 2 (ppm) Average 3 (ppm) 0 liver tebuthiuron <0.1 4 <0.1 4 104 + 109 5 0.032 ­ <0.05 4 0.039 + 0.010 6 106 + 108 7 0.104 ­ 0.368 0.201 + 0.14 kidney tebuthiuron 0.055 ­ <0.1 4 0.075 + 0.023 104 + 109 5 0.108 ­ <0.2 4 0.138 + 0.054 106 + 108 7 <0.1 4 ­ 0.19 0.248 + 0.19 muscle tebuthiuron <0.2 4 <0.2 4 104 + 109 5 <0.06 4 <0.06 4 106 + 108 7 <0.06 4 <0.06 4 fat tebuthiuron <0.01 4 0.01 4 104 + 109 5 0.006 ­ <0.01 4 0.007 + 0.002 106 + 108 7 <0.01 <0.01 45 liver tebuthiuron <0.1 <0.1 104 + 109 5 0.94 ­ 2.13 1.73 + 0.68 106 + 108 7 1.50 ­ 1.80 1.65 + 0.15 kidney tebuthiuron <0.1 <0.1 104 + 109 5 0.355 ­ 0.907 0.679 + 0.29 106 + 108 7 0.756 ­ 1.06 0.873 + 0.16 muscle tebuthiuron <0.2 <0.2 104 + 109 5 0.214 ­ 0.560 0.418 + 0.18 106 + 108 7 0.196 ­ 0.230 0.216 + 0.018 fat tebuthiuron <0.01 <0.01 104 + 109 5 0.12 ­ 0.38 0.206 + 0.15 106 + 108 7 0.033 ­ 0.164 0.093 + 0.066 135 liver tebuthiuron 0.098 ­ 0.265 0.154 + 0.096 104 + 109 5 4.46 ­ 8.23 6.96 + 2.16 106 + 108 7 2.76 ­ 3.67 3.35 + 0.51 kidney tebuthiuron 0.050 ­ 0.069 0.059 + 0.01 104 + 109 5 1.58 ­ 2.72 2.27 + 0.60 106 + 108 7 1.44 ­ 3.20 2.22 + 0.90 muscle tebuthiuron 0.120 ­ 0.140 0.13 + 0.01 104 + 109 5 1.32 ­ 2.86 2.26 + 0.82 106 + 108 7 0.466 ­ 0.816 0.601 + 0.19 DP Barcode: D281821 Dietary exposure assessment / 8 Tebuthiuron / 105501 Table 3: Residues of Tebuthiuron and Metabolites in Tissues from the Oral Administration of Tebuthiuron for 28 Days Diet (ppm tebuthiuron) Tissue Analyte Concentration 1 (ppm) Range 2 (ppm) Average 3 (ppm) 8 fat tebuthiuron 0.01 ­ 0.074 0.036 + 0.03 104 + 109 5 0.52 ­ 2.00 1.33 + 0.75 106 + 108 7 0.158 ­ 0.428 0.250 + 0.15 450 liver tebuthiuron 0.359 ­ 1.20 0.666 + 0.46 104 + 109 5 28.4 ­ 41.6 33.3 + 7.2 106 + 108 7 11.2 ­ 18.0 14.6 + 3.4 kidney tebuthiuron 0.107 ­ 0.244 0.155 + 0.77 104 + 109 5 10.5 ­ 15.4 13.5 + 2.1 106 + 108 7 5.79 ­ 8.78 6.80 + 1.7 muscle tebuthiuron 0.210 ­ 0.370 0.280 + 0.082 104 + 109 5 8.96 ­ 13.6 11.2 + 2.3 106 +108 7 2.68 ­ 3.95 3.11 + 0.73 fat tebuthiuron 0.064 ­ 0.140 0.100 + 0.038 104 + 109 5 5.03 ­ 6.64 5.61 + 0.89 106 + 108 7 0.830 ­ 1.26 1.01 + 0.22 1 Not corrected for concurrent method recovery. 2 Range of average of duplicate determinations for three cows. 3 Average of duplicate determinations for three cows. 4 "<" values are estimated limits of detection. 5 Results are expressed as 104 equivalents. 6 <0.01 values were assigned 0.01. 7 Results are expressed as 106 equivalents. Milk samples were analyzed for residues of tebuthiuron and metabolites 104, 106, 109, 104( OH), and 109( OH) using Method GRM 92.08. Metabolites 109 and 109( OH) were converted to metabolites 104 and 104( OH), respectively, in an initial acid hydrolysis. The hydrolysis product mixture was partitioned with ethyl acetate and purified on a neutral alumina solid phase extraction cartridge. A separate sample was required for metabolite 106. The maximum incurred residue in milk at the 45 ppm feeding level, expressed as the sum of tebuthiuron, 104 plus 109 as 104, 104( OH) plus 109( OH) as 104( OH), and 106. See Table 4. Table 4: Residues of Tebuthiuron and Metabolites in Milk Diet (ppm) Day 1 Analyte Concentration 2 (ppm) DP Barcode: D281821 Dietary exposure assessment / 9 Tebuthiuron / 105501 9 0 25 Tebuthiuron <0.04 3 28 104 + 109 <0.02 28 104( OH) + 109( OH) <0.01 28 106 <0.01 45 6 12 4 Tebuthiuron 0.017; 0.023 (< 0.14) 5 104 + 109 0.550; 0.726 22 104( OH) + 109( OH) 0.063; 0.116 5 106 0.118; 0.132 135 7 22 Tebuthiuron 5 0.227; 0.480 5 104 + 109 3.03; 3.38 22 104( OH) + 109( OH) 0.143; 0.188 5 106 0.507; 0.626 450 8 22 Tebuthiuron 1.47; 3.18 25 104 + 109 23.0; 40.8 22 104( OH) + 109( OH) 1.15; 1.64 28 9 106 4.13; 5.25 1 Day of plateau of residue, unless otherwise indicated. 2 Not corrected for concurrent method recovery. First entry is average of three cows; second entry is maximum residue. For 104 + 109, results are expressed as 104 equivalents. For 104( OH) + 109( OH), results are expressed as 104( OH) equivalents. 3 "<" values are estimated limits of detection. 4 Residues were lower on subsequent days, except one cow (0.035 ppm) on day 13. 5 Results were variable among cows on a given days and among different days. The residue ranged from 0.148 to 0.288 ppm on day 25, 0.205 ppm average, 112% recovery. 6 Actual feeding levels were 71, 51, and 56 ppm. 7 Actual feeding levels were 192, 197, and 136 ppm. 8 Actual feeding levels were 903, 587, and 646 ppm. 9 Residue may not have plateaued, but low recovery (40%) obscures trends. The average residues in various tissues at the 45 ppm (7.3x), 135 ppm (22x), and 450 ppm (73x) feeding levels, expressed as the sum of tebuthiuron, 104 + 109, and 106 + 108; and the total residues at 6.14 ppm tebuthiuron, assuming a linear regression relationship between diet intake and residues, are summarized in Table 5a. Table 5a: Average Residues for Each Tissue Based on Linear Regression Beef Cattle Diet (ppm) Liver (ppm) Muscle (ppm) Kidney (ppm) Fat (ppm) 45ppm (7.3x) 3.43 0.80 1.6 0. 31 DP Barcode: D281821 Dietary exposure assessment / 10 Tebuthiuron / 105501 10 135ppm (22x) 10.44 2.96 4.53 1.62 450ppm (73x) 48.57 14.55 19.79 6.72 Calculated Maximum at 6.14 ppm (1x) 0.646 0.193 0.264 0.090 For milk, the average residues in milk at the 45 ppm (9.5x), 135 ppm (28.5x), and 450 ppm (95x) feeding levels, expressed as the sum of tebuthiuron, 104 + 109, and 104( OH) + 109( OH), and 106; and the total residues at 4.73 ppm tebuthiuron, assuming a linear regression relationship between diet intake and residues, are summarized in Table 5b. Table 5b: Average Residues for Milk Based on Linear Regression Dairy Cattle Diet (ppm) Milk (ppm) 45ppm (9.5x) 0.748 135ppm (28.5x) 3.91 450ppm (95x) 29.75 Calculated Maximum at 4.73 ppm (1x) 0.296 Example: Calculation for Liver Step 1: The sum of the average of tebuthiuron residues, average 104 + 109 residues, and 106 + 108 residues are calculated from the feeding studies (see Table 4). Average refers to the average of duplicate analyses per each of the three cows. Please note the values using ½ LOD. 45 ppm: 0.05 ppm (parent) + 1.73 ppm (104 + 109) + 1.65 ppm (106 + 108)= 3.43 135 ppm: 0.129 ppm (parent) + 6.96 ppm (104 + 109) + 3.35 ppm (106 + 108)= 10.44 450 ppm: 0.668 ppm (parent) + 33.25 ppm (104 + 109) + 14.65 ppm (106 + 108)= 48.57 Step 2: The linear relationship (average residues versus beef cattle diets) for liver was derived from Table 5a using linear regression graph and equation to determine 1x. Table 6. Summary of Tebuthiuron and its Metabolites in Meat and Milk DP Barcode: D281821 Dietary exposure assessment / 11 Tebuthiuron / 105501 11 RAC Anticipated Residues Chronic (ppm) Acute (RDF) Liver 0. 006 (0.646 ppm x 1% CT) 0.013 (0.646 ppm x 2% CT) Kidney 0. 003 (0.264 ppm x 1% CT) 0.005 (0.264 ppm x 2% CT) Muscle 0.002 (0.193 ppm x 1% CT) 0.004 (0.193 ppm x 2% CT) Fat 0. 001 (0.090 ppm x 1% CT) 0.002 (0.090 ppm x 2% CT) Milk 0.003 (0.296 ppm x 1% CT) 0.006 (0.296 ppm x 2% CT) I. DEEM™ Program and Consumption Information Tebuthiuron acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model (DEEM™) software Version 7.74, which incorporates consumption data from USDA's Continuing Surveys of Food Intake by Individuals (CSFII), 1989­ 1992. The 1989­ 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive days, and therefore represent more than 30,000 unique "person days" of data. Foods "as consumed" (e. g., apple pie) are linked to raw agricultural commodities and their food forms (e. g., apples­ cooked/ canned or wheat­ flour) by recipe translation files internal to the DEEM software. Consumption data are averaged for the entire US population and within population subgroups for chronic exposure assessment, but are retained as individual consumption events for acute exposure assessment. For chronic exposure and risk assessment, an estimate of the residue level in each food or food­ form (e. g., orange or orange­ juice) on the commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms on the commodity residue list to arrive at the total estimated exposure. Exposure estimates are expressed in mg/ kg body weight/ day and as a percent of the cPAD. This procedure is performed for each population subgroup. DP Barcode: D281821 Dietary exposure assessment / 12 Tebuthiuron / 105501 12 For acute exposure assessments, individual one­ day food consumption data are used on an individual­ by­ individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic (Tier 1 or Tier 2) exposure assessment, or "matched" in multiple random pairings with residue values and then summed in a probabilistic (Tier 3/ 4) assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user (i. e., those who reported eating relevant commodities/ food forms) and a per­ capita (i. e., those who reported eating the relevant commodities as well as those who did not) basis. In accordance with HED policy, per capita exposure and risk are reported for all tiers of analysis. However, for tiers 1 and 2, significant differences in user vs. per capita exposure and risk are identified and noted in the risk assessment. II. Results/ Conclusions Acute Dietary Exposure Analysis A Tier 2 acute and chronic dietary risk assessments were conducted for all supported tebuthiuron food uses. Dietary risk estimates are provided for the general U. S. population (chronic only) and females 13­ 50 years (acute). This assessment concludes that for all included commodities, the acute risk estimates are below the Agency's level of concern (< 100% aPAD) at the 95 th exposure percentile for females 13­ 50 years (< 1% of the aPAD). This assessment also concludes that for all commodities, the chronic risk estimates are below the Agency's level of concern (< 100% cPAD) for the general U. S. population (< 1% of the cPAD) and all population subgroups. The results reported in Table 7 are for females 13­ 50 years only for acute dietary exposure analysis and Table 8 is the results of chronic dietary exposure analysis. Table 7. Results of Acute Dietary Exposure Analysis Population Subgroup 95 th Percentile 99 th Percentile 99.9 th Percentile Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % aPAD Females 13­ 50 years old 0.000078 <1 0.000121 <1 0.000207 <1 DP Barcode: D281821 Dietary exposure assessment / 13 Tebuthiuron / 105501 13 Chronic Dietary Exposure Analysis Table 8. Results of Chronic Dietary Exposure Analysis Population Subgroup Exposure (mg/ kg/ day) % cPAD U. S. Population (total) 0.000023 <1 All Infants (< 1 year) 0. 000036 <1 Children 1­ 6 years 0. 000083 <1 Children 7­ 12 years 0. 000043 <1 Females 13­ 50 0.000013 <1 Males 13­ 19 0.000025 <1 Males 20+ years 0. 000012 <1 Seniors 55+ 0.000012 <1 III. Discussion of Uncertainties C Residue Issues ­ The Agency notes that field trial data are generally considered by HED as an upper­ end or a worst case scenario of possible residues and are more suited to the requirements of tolerance setting, because it requires the highest rates of application and shortest PHI, than to the requirements of dietary exposure assessment (when the most realistic estimate is desired). IV. List of Attachments Attachment 1: Acute Residue Input Data for DEEM Analysis for Tebuthiuron Attachment 2: Acute Residue Analysis for Tebuthiuron Attachment 3: Chronic Residue Input Data for DEEM Analysis for Tebuthiuron Attachment 4: Chronic Residue Analysis for Tebuthiuron DP Barcode: D281821 Dietary exposure assessment / 14 Tebuthiuron / 105501 14 cc: S. Piper (CEB), RF RDI: ChemSAC: 3/ 27/ 02; Secondary Reviewers: 4/ 1/ 02; FBSuhre 4/ 8/ 02 7509C: CEB: CM­ 2: RM 810F: 308­ 2717: Tebuthiuron­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Attachment 1: Acute Residue Input Data for DEEM Analysis for Tebuthiuron U. S. Environmental Protection Agency Ver. 7.76 DEEM Acute analysis for TEBUTHIURON Residue file name: C:\ deem\ tebuthiruon\ tebuthiuronacute. RS7 Analysis Date 04­ 02­ 2002 Residue file dated: 04­ 02­ 2002/ 15: 58: 50/ 8 Reference dose: aRfD = 0.083 mg/ kg bw/ day NOEL = 25 mg/ kg bw/ day Comment: Assumes 3x factor for FQPA­ females 13­ 50 yrs only ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Food Crop Food Name Def Res Adj. Factors RDL Code Grp (ppm) #1 #2 Ind ­­­­ ­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­­ ­­­ 318 D Milk­ nonfat solids 0.296000 1.000 0.020 319 D Milk­ fat solids 0.296000 1.000 0.020 320 D Milk sugar (lactose) 0.296000 1.000 0.020 321 M Beef­ meat byproducts 0.646000 1.000 0.020 322 M Beef­ other organ meats 0.646000 1.000 0.020 323 M Beef­ dried 0.193000 1.920 0.020 324 M Beef­ fat w/ o bones 0.090000 1.000 0.020 325 M Beef­ kidney 0.264000 1.000 0.020 326 M Beef­ liver 0.646000 1.000 0.020 327 M Beef­ lean (fat/ free) w/ o bones 0.193000 1.000 0.020 328 M Goat­ meat byproducts 0.646000 1.000 0.020 329 M Goat­ other organ meats 0.646000 1.000 0.020 330 M Goat­ fat w/ o bone 0.090000 1.000 0.020 331 M Goat­ kidney 0.264000 1.000 0.020 332 M Goat­ liver 0.646000 1.000 0.020 333 M Goat­ lean (fat/ free) w/ o bone 0.193000 1.000 0.020 334 M Horsemeat 0.193000 1.000 0.020 336 M Sheep­ meat byproducts 0.646000 1.000 0.020 337 M Sheep­ other organ meats 0.646000 1.000 0.020 338 M Sheep­ fat w/ o bone 0.090000 1.000 0.020 339 M Sheep­ kidney 0.264000 1.000 0.020 340 M Sheep­ liver 0.646000 1.000 0.020 341 M Sheep­ lean (fat free) w/ o bone 0.193000 1.000 0.020 398 D Milk­ based water 0.296000 1.000 0.020 Attachment 2: Acute Residue Analysis for Tebuthiuron U. S. Environmental Protection Agency Ver. 7.76 DEEM ACUTE Analysis for TEBUTHIURON (1989­ 92 data) Residue file: tebuthiuronacute. RS7 Adjustment factor #2 used. Analysis Date: 04­ 02­ 2002/ 15: 54: 34 Residue file dated: 04­ 02­ 2002/ 15: 51: 52/ 8 NOEL (Acute) = 25.000000 mg/ kg body­ wt/ day Daily totals for food and foodform consumption used. Run Comment: "Assumes 3x factor for FQPA­ females 13­ 50 yrs" =============================================================================== DP Barcode: D281821 Dietary exposure assessment / 15 Tebuthiuron / 105501 15 Summary calculations (per capita): 95th Percentile 99th Percentile 99.9th Percentile Exposure % aRfD MOE Exposure % aRfD MOE Exposure % aRfD MOE ­­­­­­­­­­ ­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ ­­­­­­­­ Females 13+ (preg/ not nursing): 0.000109 0.13 229030 0.000128 0.15 195001 0.000195 0.24 128105 Females 13+ (nursing): 0.000118 0.14 211948 0.000183 0.22 136354 0.000195 0.23 128528 Females 13­ 19 (not preg or nursing): 0.000098 0.12 255390 0.000175 0.21 142798 0.000235 0.28 106564 Females 13­ 50 yrs: 0.000078 0.09 319551 0.000121 0.15 206558 0.000207 0.25 120907 Attachment 3: Chronic Residue Input Data for DEEM Analysis for Tebuthiuron U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for TEBUTHIURON 1989­ 92 data Residue file: C:\ deem\ tebuthiruon\ tebuthirchronic. RS7 Adjust. #2 used Analysis Date 04­ 02­ 2002 Residue file dated: 04­ 02­ 2002/ 15: 52: 42/ 8 Reference dose (RfD) = 0.14 mg/ kg bw/ day Comment: Assumes 1x factor for FQPA ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Food Crop RESIDUE Adj. Factors Code Grp Food Name (ppm) #1 #2 ­­­­ ­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­­ 318 D Milk­ nonfat solids 0.296000 1.000 0.010 319 D Milk­ fat solids 0.296000 1.000 0.010 320 D Milk sugar (lactose) 0.296000 1.000 0.010 321 M Beef­ meat byproducts 0.646000 1.000 0.010 322 M Beef­ other organ meats 0.646000 1.000 0.010 323 M Beef­ dried 0.193000 1.920 0.010 324 M Beef­ fat w/ o bones 0.090000 1.000 0.010 325 M Beef­ kidney 0.264000 1.000 0.010 326 M Beef­ liver 0.646000 1.000 0.010 327 M Beef­ lean (fat/ free) w/ o bones 0.193000 1.000 0.010 328 M Goat­ meat byproducts 0.646000 1.000 0.010 329 M Goat­ other organ meats 0.646000 1.000 0.010 330 M Goat­ fat w/ o bone 0.090000 1.000 0.010 331 M Goat­ kidney 0.264000 1.000 0.010 332 M Goat­ liver 0.646000 1.000 0.010 333 M Goat­ lean (fat/ free) w/ o bone 0.193000 1.000 0.010 334 M Horsemeat 0.193000 1.000 0.010 336 M Sheep­ meat byproducts 0.646000 1.000 0.010 337 M Sheep­ other organ meats 0.646000 1.000 0.010 338 M Sheep­ fat w/ o bone 0.090000 1.000 0.010 339 M Sheep­ kidney 0.264000 1.000 0.010 340 M Sheep­ liver 0.646000 1.000 0.010 341 M Sheep­ lean (fat free) w/ o bone 0.193000 1.000 0.010 398 D Milk­ based water 0.296000 1.000 0.010 DP Barcode: D281821 Dietary exposure assessment / 16 Tebuthiuron / 105501 16 Attachment 4: Chronic Residue Analysis for Tebuthiuron U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for TEBUTHIURON (1989­ 92 data) Residue file name: C:\ deem\ tebuthiruon\ tebuthirchronic. RS7 Adjustment factor #2 used. Analysis Date 04­ 02­ 2002/ 16: 03: 16 Residue file dated: 04­ 02­ 2002/ 15: 52: 42/ 8 Reference dose (RfD, Chronic) = .14 mg/ kg bw/ day COMMENT 1: Assumes 1x factor for FQPA =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Percent of Subgroup body wt/ day Rfd ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­ U. S. Population (total) 0.000023 0.0% U. S. Population (spring season) 0.000023 0.0% U. S. Population (summer season) 0.000022 0.0% U. S. Population (autumn season) 0.000024 0.0% U. S. Population (winter season) 0.000023 0.0% Northeast region 0.000023 0.0% Midwest region 0.000026 0.0% Southern region 0.000021 0.0% Western region 0.000023 0.0% Hispanics 0.000025 0.0% Non­ hispanic whites 0.000023 0.0% Non­ hispanic blacks 0.000020 0.0% Non­ hisp/ non­ white/ non­ black 0.000024 0.0% All infants (< 1 year) 0.000036 0.0% Nursing infants 0.000007 0.0% Non­ nursing infants 0.000048 0.0% Children 1­ 6 yrs 0.000083 0.1% Children 7­ 12 yrs 0.000043 0.0% Females 13­ 19 (not preg or nursing) 0.000019 0.0% Females 20+ (not preg or nursing) 0.000011 0.0% Females 13­ 50 yrs 0.000013 0.0% Females 13+ (preg/ not nursing) 0.000022 0.0% Females 13+ (nursing) 0.000019 0.0% Males 13­ 19 yrs 0.000025 0.0% Males 20+ yrs 0.000012 0.0% Seniors 55+ 0.000012 0.0% Pacific Region 0.000023 0.0% ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

epa

2024-06-07T20:31:42.630689

regulations

EPA-HQ-OPP-2002-0146-0007

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: April 9, 2002 SUBJECT: Tebuthiuron Residue Chemistry Chapter for the Tolerance Reassessment Eligibility Decision (TRED); PC codes 105501; DP Barcode D277103. FROM: Sheila Piper, Chemist Chemistry and Exposure Branch Health Effects Division (7509C) THROUGH: F. B. Suhre, Branch Senior Scientist Chemistry and Exposure Branch Health Effects Division (7509C) TO: Paula Deschamp, Risk Assessor Reregistration Branch II Health Effects Division (7509C) and Wilhelmena Livingston, Chemical Review Manager Special Review Branch Special Review and Reregistration Division (7508C) The Tolerance Reassessment Eligibility Document (TRED) for tebuthiuron has undergone secondary review in the branch and has been revised to reflect Agency policies. cc: S. Piper (CEB), RF RDI: ChemSAC: 3/ 27/ 02: Secondary Reviewers: 3/ 27/ 02: F. B. Suhre 4/ 8/ 02 7509C: CEB: CM­ 2: RM 810F: 308­ 2717: Tebuthiuron 2 N N S N CH 3 CH 3 C H 3 C H 3 O N H CH 3 TEBUTHIURON INTRODUCTION Tebuthiuron [N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea] is a relatively nonselective, soil activated herbicide registered for use to control broadleaf, woody weeds, grasses, and brush on terrestrial feed crop sites (pastures and rangeland) primarily in TX, OK, and NM. Tebuthiuron is also used on terrestrial non­ food crop such as airports/ landing fields, industrial areas, non­ agricultural rights­ of­ way, fencerows, hedgerows, and non­ agricultural uncultivated areas/ soil; there is no agricultural crop use of tebuthiuron except for range and pasture land uses. Pelleted/ tablets (P/ T) is the only tebuthiuron formulation class registered for use on food/ feed crops. The registered mode of application is broadcast using ground or aerial equipment (Source: LUIS General Chemical Report for Tebuthiuron, 5/ 20/ 92). There are no registered residential uses. GLN 860.1000: REGULATORY BACKGROUND Tolerances for residues of tebuthiuron have been established for grasses and animal commodities [40 CFR §180.390]. These tolerances are expressed in terms of the combined residues of N­[ 5 (1, 1diemethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea and its metabolites containing the dimethylethyl thiadiazole moiety. Adequate enforcement methods are available for the determination of residues in/ on grasses and in animal tissues and milk. Tebuthiuron was first registered by Elanco Products Company in 1974. The registration was later transferred to DowElanco (currently Dow AgroSciences LLC) in 1989. The Tebuthiuron Reregistration Standard Guidance Document was issued 7/ 87 for all pesticide products containing the active ingredient, tebuthiuron. The information contained in this document outlines the Residue Chemistry Science Assessments with respect to the reregistration of tebuthiuron. The summaries of residue chemistry guidelines and topics listed below are based on the present regulatory status where the only registered food/ feed use of tebuthiuron is on grasses grown in pasture and rangeland. The Agency reserves the right to require additional studies for each applicable residue chemistry guideline and topic if additional registrations on food/ feed crops other than pasture and rangeland grasses are sought, or if a tolerance change is proposed. 3 N N S N CH 3 CH 3 C H 3 O N H CH 3 OH N N S NH 2 CH 3 C H 3 C H 3 N N S N CH 3 CH 3 C H 3 C H 3 O NH 2 N N S N CH 3 CH 3 C H 3 C H 3 O N H OH N N S N CH 3 CH 3 C H 3 O NH 2 OH N N S N CH 3 CH 3 C H 3 O N H OH OH N N S N H CH 3 C H 3 C H 3 O NH 2 Figure A. The chemical structures of the metabolites of concern of tebuthiuron Structure Metabolite: Chemical name Structure Metabolite: Chemical name 103 (OH): N­[ 5­( 2­ hydroxy­ 1,1­ dimethylethyl)­ 1,3, 4 thiadiazol­ 2­ yl]­ N, N'­ dimethylurea 108: 2­ dimethylethyl­ 5­ amino­ 1, 3, 4­ thiadiazole 104: N­[ 5­( 1,1­ dimethylethyl)­ 1,3, 4­ thiadiazol­ 2­ yl N­ methylurea 109: N­[ 5­( 1,1­ dimethylethyl)­ 1,3, 4­ thiadiazol­ 2­ yl N'­ hydroxymethyl­ N­ methylurea 104 (OH): N­[ 5­( 2­ hydroxy­ 1,1­ dimethylethyl)­ 1, 3, 4 thiadiazol­ 2­ yl]­ N­ methylurea A [109 (OH)]: N­[ 5­( 2­ hydroxy­ 1,1­ dimethylethyl 1,3,4­ thiadiazol­ 2­ yl]­ N'­ hydroxymethyl­ N­ methylurea 106: N­[ 5­( 1,1­ dimethylethyl)­ 1,3, 4­ thiadiazol­ 2­ yl] urea 4 SUMMARY OF SCIENCE FINDINGS GLN 860.1200: Directions for Use Based on a search of OPP's REFs conducted on March 22, 2002, there are eight active Section 3 registrations for end­ use products containing tebuthiuron. End­ use formulations include granular, pelleted/ tablets, and wettable powder products which are applied using ground and aerial equipment. A summary of the currently registered end­ use products and use sites is given in the Table 1 below: Table 1: Current registered end­ use products and use sites Company EPA Reg. No. Formulation Class % ai Use Sites Rainbow Technology Corp 13283­ 18 Granular 2 Industrial areas (outdoor) Non­ agricultural rights­ of way/ fencerows/ hedgerows 13283­ 21 Granular 1 Industrial areas (outdoor) Non­ agricultural rights­ of way/ fencerows/ hedgerows SSI Maxim Company, Inc. 34913­ 10 Granular 5 Drainage systems Non­ agricultural uncultivated areas/ soils 34913­ 15 Granular 1 Non­ agricultural uncultivated areas/ soils 34913­ 16 Granular 2 Non­ agricultural uncultivated areas/ soils Dow AgroSciences LLC 62719­ 107 Wettable Powder 80 Drainage systems Non­ agricultural uncultivated areas/ soils 62719­ 121 Pelleted/ Tableted 20 Pasture/ rangeland Non­ agricultural uncultivated areas/ soils 62719­ 122 Pelleted/ Tableted 40 Pasture/ rangeland Non­ agricultural uncultivated areas/ soils The 20% and 40% P/ T formulations (EPA Reg. Nos. 62719­ 121 and 62719­ 122, dated 2/ 96) are registered for a single broadcast application to rangeland and forage grasses by aerial or ground equipment at 0. 5­ 4. 00 lb ai/ A. Tebuthiuron may be applied anytime but the recommended timing of application is prior to the resumption of active seasonal growth in the spring or before expected seasonal rainfall. The maximum recommended rate is 4.0 lb ai/ A for areas receiving >20 inches average annual rainfall, or 2.0 lb ai/ A for areas receiving <20 inches average annual rainfall. Application to ditches used to transport irrigation or potable water is prohibited. 1 MARC members (C. Olinger, L. Cheng, R. Loranger and D. Nixon) determined the residues of concern in the tolerance expression should also be included in the risk assessment. 5 GLN 860.1300: Nature of the Residue­ Plants The qualitative nature of the residue in grasses is adequately understood. The registrant (1976; MRID 00020756) submitted a "revised" metabolism study in which a [ 14 C] tebuthiuron solution (labeled in the 5­ position of the thiadiazole ring; specific activity of 16. 9 uCi/ mg) was applied to the surface of the soil in which 10­ week old tall fescue (0.374 lb ai/ A), little bluestem and indiangrass (0.75 lb ai/ A.) were grown. The residues of concern are the parent compound and its metabolites 103 (OH), 104, and 109 (N. Dodd, MRIDs 40985001­ 02, 6/ 22/ 89). MARC 1 revisited N. Dodd's memo, "Nature of the Residue in Milk and Bovine Tissues," dated 6/ 22/ 89 and determined the parent compound and its metabolites 103 (OH), 104, and 109 should also be included in the risk assessment (3/ 28/ 02). Tebuthiuron was the most abundant 14 C­ residue recovered in the organosoluble fraction of the grass extract. Other metabolites identified in the organosoluble fraction from all three grass species were 103( OH), 104, and 109. Approximately 39­ 86% of the total 14 C­ activity of all grasses was identified from the organosoluble fraction. The metabolites which were recovered and identified following acid hydrolysis of the aqueous fraction were 103( OH), 104, and l04( OH). The predominant conjugate in little bluestem was 103( OH) while 104 was the major conjugate in indiangrass. One additional metabolite, isopropyl 103, was found in the hydrolysates of the aqueous fraction of little bluestem. Based on the 14 C­ residues identified in the organosoluble and aqueous fractions, approximately 81­ 89, 58­ 70, and 78­ 80% of the total 14 C­ activity found in tall fescue, little bluestem, and indiangrass, respectively, was identified. In summary, two major metabolic pathways are involved: N­ demethylation of tebuthiuron to form 104 and alkyl hydroxylation of the dimethylethyl side chain to form 103( OH). The molecular structures of the metabolites of concern are presented in Figure A. GLN 860.1300: Nature of the Residue­ Livestock The qualitative nature of the residue in milk and ruminant tissues is adequately understood. The terminal residues of concern in fat, meat, kidney, and liver are tebuthiuron and its metabolites 104, 106, 108, and 109; the terminal residues of concern in milk are tebuthiuron and metabolites 104, 104 (OH), 106, 109, and A [109 (OH)] for the tolerance expression and risk assessment (N. Dodd, MRIDs 409850­ 02, 6/ 22/ 89). A poultry metabolism study is not required since grasses are not considered to be poultry feed items. A metabolism study was conducted on one cow in the study titled "Nature of [ 14 C] Tebuthiuron Residues in Bovine Tissue" (J. D. Magnussen and D. P. Rainey, Ph. D., Experiment ABC0413, Lilly Research Laboratories, January 24, 1989, MRID No. 409850­ 02). Capsules containing [ 14 C] tebuthiuron labeled in the 5­ position of the thiadiazole ring were placed directly into the rumen via a surgically fitted fistula. The 280 kg (approximately) cow was given one capsule every 6 12 hours (morning and evening) for 3 consecutive days. Each capsule contained 140 mg [ 14 C] tebuthiuron, which the petitioner has calculated to be a feeding rate of 50 ppm. The cow was sacrificed 12 hours after the final dose. The percentage of the total radioactivity which was identified was 82.7 percent in fat, 87.2 percent in lean, 83.2 percent in liver, and 91.0 percent in kidney. Of the total radioactivity in milk, 64. 2 to 68. 1 percent was not conjugated (i. e., extractable in acetonitrile or ethyl acetate). Between 25.4 and 29.6 percent were conjugated (i. e., polar). Most of the conjugated residues were released by enzyme or acid hydrolysis. Residues in milk (days 1, 2, and 3) as a percentage of total radioactivity were reported as follows: 1. 1 to 1. 2 percent, parent (103); 20.7 to 21.6 percent, 104; 21.0 to 26.3 percent, 106; 10.0 to 11.8 percent, 109; 2.2 to 3. 2 percent, 108; 1.0 to 1. 7 percent, 103( OH); 9. 6 to 16.3 percent, 104( OH); 7. 6 to 11.8 percent, Metabolite A or 109( OH); 1. 5 to 7.2 percent, Metabolite B; 1. 7 to 2.5 percent, Metabolite C; and 3. 3 to 5. 5 percent, other. The molecular structures of the metabolites of concern are presented in Figure A. GLN 860.1340: Residue Analytical Methods ­ Plants and Livestock An adequate method is available for the enforcement of plant commodity tolerances. A GLC method with flame photometric detection is designated as Method II in PAM Vol. II. Tebuthiuron and metabolites 104 and 109 are thermally degraded on the GLC column and are determined as 5­( 1, 1­ dimethylethyl)­ N­ methyl­ 1, 3, 4­ thiadiazol­ 2­ amine; metabolite 103 (OH) is determined as 5­( 2­ hydroxy­ 1, 1­ dimethylethyl)­ N­ methyl­ 1, 3, 4­ thiadiazol­ 2­ amine. The stated detection limits are 0. 1 ppm for tebuthiuron and metabolites 104 and 109, and 0. 2 ppm for metabolite 103 (OH). A revised enforcement method for milk, to include hydrolysis steps and the determination of metabolites 104 (OH) and A [109 (OH)], and a revised enforcement method for animal tissues, to include hydrolysis steps and the determination of metabolite 108, were submitted. GLN 860.1380: Storage Stability The available storage stability data indicate that residues of tebuthiuron and its metabolites containing the thiadiazole moiety [103 (OH), 104, and 109] are stable for up to ca. 29 months of frozen storage at ­20 C in/ on grass forage and hay. Tebuthiuron and its metabolites 104, 104( OH), 109, 109( OH), and 106 are stable in milk stored frozen for up to 6 months. These data are translated to meat and stability data for metabolite 108 (not found in milk) will not be required. The stability data fully support the ruminant feeding study and no additional data are required (S. Funk, D223089, 11/ 22/ 95). 7 GLN 860.1400: Water, Fish and Irrigated Crops Tebuthiuron is presently not registered for direct use on potable water and aquatic food and feed crops; therefore, no residue chemistry data are required under these guideline topics. GLN 860.1460: Food Handling Tebuthiuron is presently not registered for use in food­ handling establishments; therefore, no residue chemistry data are required under these guideline topics. GLN 860.1480: Magnitude of the Residue in Meat, Milk, Poultry and Eggs The reregistration requirements for data depicting magnitude of the residue in milk, eggs, and livestock tissues are fulfilled. The registrant submitted animal feeding study to reassess the adequacy of established tebuthiuron tolerances on animal commodities. A summary of the animal feeding data relative to the maximum theoretical dietary burden of tebuthiuron to beef cattle and dairy cattle are included in this document. Maximum Theoretical Dietary Burden An acceptable ruminant feeding study (S. Funk, D217379, 12/ 05/ 95) has been submitted. The results of the ruminant feeding study conducted at a nominal 45 ppm tebuthiuron feeding level (1. 5x) for 28 days show that the existing tolerances for milk and meat are inadequate and that they should be revised. The tolerances for meat and fat may be lowered, but the tolerances for milk and meat byproducts must be increased as follows: Commodity Existing Tolerance 1 (40 CFR § 180.390) Revised Tolerance 1 Milk 0. 3 0. 8 Ruminant 2 ,fat 2 1. 0 Ruminant 2 , mbyp 2 5.0 Ruminant 2 , meat 2 1.0 1 The tolerance is expressed in terms of tebuthiuron and its metabolites containing the dimethyethyl thiadiazole moiety. 2 Separate tolerances are established for cattle, goats, horses, and sheep. The feeding study have demonstrated a transfer of tebuthiuron to livestock tissue (meat, meat byproducts etc.). A dietary burden reflecting theoretical maximum exposures to tebuthiuron for 8 beef cattle (extrapolating to goats, sheep and horse) was based on reevaluated tolerances for grass forage and grass hay, 10 ppm each. Table 2: Maximum Ruminant Dietary Burden for Tebuthiuron Commodity Tolerance (ppm) %DM a Beef Cattle Dairy Cattle %Diet a Concentration b (ppm) %Diet a Concentration b (ppm) Grass Forage 10 25 60 24 60 24 Grass Hay 10 88 60 40 4.5 60 40 4.5 TOTAL ­ ­ 100 28.5 100 28.5 a As per Table 1 (OPPTS Guideline 860.1000) b Ruminant contribution= [tolerance/ %DM] x %diet No poultry or swine feed items are associated with the registered uses on grass; therefore, there is no reasonable expectation of detectable residues of tebuthiuron and its metabolites in poultry, swine, and eggs resulting from the use patterns being considered for reregistration. These uses for poultry, swine, and eggs can be classified under Category 3 of 40 CFR§ 180.6( a). GLN 860.1500: Magnitude of the Residue in Plants The 20% and 40% P/ T formulations (EPA Reg. Nos. 62719­ 121 and 62719­ 122, dated 8/ 12/ 91) are registered for a single broadcast application to rangeland and forage grasses by ground or air equipment at 0. 5­ 4. 00 lb ai/ A. Tebuthiuron may be applied anytime but the recommended timing of application is prior to the resumption of active seasonal growth in the spring or before expected seasonal rainfall. The maximum recommended rate is 4.0 lb ai/ A for areas receiving
20 inches average annual rainfall, or 2.0 lb ai/ A for areas receiving  20 inches average annual rainfall. Fresh grass samples were collected every two weeks for the first three months following application, and monthly for the following twenty­ one months in order to determine the maximum residue level that may occur at anytime following application. Hay samples were collected up to two years following the application. The maximum combined residues found in/ on grass forage were  9.5 ppm and < 8.0 ppm for hay samples (collected after the first cutting in the following season and then after the next two cuttings). Application to ditches used to transport irrigation or potable water is prohibited. Treated grasses may not be cut for hay for livestock feed for one year after treatment. The Agency considers restrictions against the grazing of treated rangeland to be impractical, and label revision is required. 9 Currently, HED's OPP Guidelines 860.1000 supports a 0­ day crop field residue data for grasses cut for grass forage and a reasonable interval before cutting for hay. Tebuthiuron was not sampled at a 0­ day time­ point in the forage grass residue study because sample timing was driven by formulation and use­ pattern considerations. Spike is an extruded pellet containing either 20% or 40% active ingredient. The pellets settle into the grass and plant litter and are difficult to find and essentially unavailable from a residue point of view. On bare ground there would be approximately 1 pellet per square foot per pound of a. i. applied. Residues do not appear in plants until the pellets have been activated by rainfall and the active ingredient washed into surface soil where it is taken up by plants (preferable until 0.5­ inches of rainfall had occurred). The registrant adjusted the sampling schedule within the test area reflecting the maximum residue levels occurring at any time after application were tested (N. Dodd, DEB No. 4587, 2/ 9/ 89). HED supports the registrant hay residue study protocol and specifically allowed hay sampling to begin 1 year after application. Spike 20P and 40P are used only for woody plant infestation (trees and brush). This will allow re­ vegetation with desirable grasses, but also because the sparse grass in such areas do not provide adequate nutritional levels for grazing or hay in that first year (N. Dodd, Tebuthiuron on Grass and Hay, Memorandum of Conference­ 4/ 6/ 89). All data requirements for the magnitude of the residue in plants have been evaluated and deemed acceptable. The conclusions regarding the reregistration eligibility of tebuthiuron on the crops listed in Table A are based on the use patterns registered by the basic producer, Dow AgroSciences LLC. When end­ use product DCIs are developed (e. g., at issuance of the RED), RD should require that all end­ use product labels (e. g. MAI labels, SLNs and products subject to the generic data exemption) be amended such that they are consistent with the basic producer labels. GLN 860.1520: Processed Food/ Feed No processed food/ feed studies were submitted by the registrant. GLNs 860.1850/ 1900: Confined/ Field Rotational Crops Grasses in rangeland are not rotated. Pastures on the other hand can vary from permanent (> 8 years), short term (2­ 4 years), long term (5­ 8 years), as well as temporary (< 1 year). A rotational pasture is one used for a few seasons and then plowed and planted to another crop. 10 The Quantitative Usage Analysis for Tebuthiuron indicates that the states with the most acres treated are in the Southwest U. S. (TX, OK, NM, and AZ). The grassland areas covered by these states include the Southern Plains and the Southwest Grasslands. These grassland areas are predominately rangeland that contains perennial native or introduced grasses, that have been invaded by woody perennial weedy shrubs which are very difficult to control. Pastures are mostly perennial grasses or legumes; however, we do not know if there are any significant pasture acreage planted to annual forages in this region. Therefore, confined field rotational crop studies will be conditionally required unless the registrant can provide information that pastureland in this area is either insignificant in acreage or is predominantly perennial grasses that are not rotated annually. 11 Table A. Range and Pasture Typical and Maximum Use Rates Use Site and Product Name Application Method and Equipment Registrant Maximum Application For Use Rate Parameters Label Maximum Application Per Use Registrant Typical Use Rate Reflecting Label Typical Use Rate Range and Pasture Spike 20P (20% pellet) Broadcast and spot treatment Applied by hand using canister delivery, ground and aerial application For vulnerable sites, maximum application rate is dependent upon annual precipitation: <20" in annual precipitation: no more than 1 lb a. i./ acre once every 3 years >20" in annual precipitation: no more than 2 lbs a. i./ acre once every 3 years For non­ vulnerable sites, maximum application rate is dependent upon annual precipitation: <20" in annual precipitation no more than 2 lbs once every 3 years and no more than two treatments totaling 6 lbs a. i./ acre in any 6year period. >20" in annual precipitation: no more than 4 lbs a. i./ acre once every 3 years and no more than two treatments totaling 6 lbs a. i./ acre in any 6­ year period For broadcast treatment, 4 lbs a. i./ acre For spot treatment when needed, 6 lbs a. i./ acre Typical application is once every 10­ 20 years 1.0­ 1.4 lbs for oak use 1. 5 lbs for desert species 0.3­ 0.5 lbs for sage NS (continued; footnotes follow) 12 TABLE B. RESIDUE CHEMISTRY SCIENCE ASSESSMENTS FOR REREGISTRATION OF TEBUTHIURON. GLN Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? References 1 860.1300: Plant Metabolism No 2 00020645, 00020756, 00020766 860.1300: Animal Metabolism No 00020648, 00020650, 00020651, 00020652, 00020721, 00020767, 00027805, 00027810, 00041675, 00106080, 40985001­ 40985002 3 860.1340: Residue Analytical Methods See footnote 4 00020656, 00020740, 00041673, 00094745, 00106080, PP# 7F1925, 41196901 5 , 43983701 4 , 43983702 4 860.1380: Storage Stability No 6 42630501 7 , 43439301 6 860.1500: Magnitude of the Residue in Plants Grass Forage, Fodder, and Hay Group Grass, forage 10 No 00020757, 00020764, 00041671, 00094745, 42630502 7 Grass, hay 10 No 00020705, 00094745, 42630502 7 860.1520: Magnitude of the Residue in Processed Food/ Feed N/ A 860.1480: Magnitude of the Residue in Meat, Milk, Poultry, and Eggs No 8 00041673, 00106080 860.1400: Magnitude of the Residue in Fish N/ A 860.1400: Nature and Magnitude of the Residue in Drinking and Irrigation Water N/ A 860.1460: Magnitude of the Residue in Food Handling Establishments N/ A 860.1550: Reduction of Residues N/ A 860.1850: Rotational Crops (Confined) See footnote 9 TABLE B. (continued). GLN Data Requirements Current Tolerances, ppm [40 CFR] Must Additional Data Be Submitted? References 1 13 1. Unless otherwise noted, references were reviewed in the Residue Chemistry Science Chapter of the Reregistration Standard dated 2/ 27/ 87. 2. CBRS No. 2959, 12/ 10/ 87, N. Dodd. 3. CBRS No. 4939, 6/ 22/ 89, N. Dodd. 4. Enforcement methods for milk and animal tissues have been proposed; independent laboratory validation is required. The registrant submitted submission MRIDs 43983701­ 02 which is under reviewed. 5. Data pertaining to multiresidue methodology testing of tebuthiuron and metabolites has been submitted and forwarded to FDA for review (M. Nelson to L. Sawyer, 9/ 1/ 89). 6. The stability data fully supports the ruminant feeding study, and no additional data are required (S. Funk, CBRS 16937, 11/ 22/ 95). 7. CBRS No. 11314, D187699, 5/ 20/ 93, S. Funk. 8. An adequate feeding study has been submitted (S. Funk, D217379, 12/ 95). 9. The confined field rotational crop studies will be conditionally required unless the registrant can provide information that pastureland in TX, OK, and NM is either insignificant in acreage or is predominantly perennial grasses that are not rotated annually. 860.1900: Rotational Crops (Field) See footnote 9 14 TOLERANCE REASSESSMENT SUMMARY HED has concluded that the tolerance expression for plants should include tebuthiuron and its metabolites N­[ 5­( 2­ hydroxy­ 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea [103 (OH)], N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea (104), and N­[ 5­( 1, 1dimethylethyl 1, 3, 4­ thiadiazol­ 2­ yl]­ N'­ hydroxymethyl­ N­ methylurea (109). The tolerance expression for livestock commodities should include tebuthiuron and its metabolites 104, N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl] urea (106), 2­ dimethylethyl­ 5­ amino­ 1,3,4­ thiadiazole (108), and 109. The terminal residues of concern in milk are tebuthiuron and metabolites 104, N­[ 5­( 2­ hydroxy­ 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea [104( OH)], 106, 109, and N­[ 5­( 2­ hydroxy­ 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N'hydroxymethyl N­ methylurea [109( OH)]. The adequacy of the established tolerances for milk, and the fat, meat, and meat byproducts of cattle, goats, hogs, horses, and sheep were from the results of the ruminant feeding study conducted at a nominal 45 ppm tebuthiuron feeding level (1. 5x) for 28 days (S. Funk, D217379, 12/ 05/ 95). The existing tolerances for milk (0. 3 ppm) and meat byproducts (2 ppm) should be increased to 0. 8 ppm for milk and 5 ppm for meat byproducts. The tolerance for meat (2 ppm) and fat (2 ppm) should be lowered to 1 ppm. Table C. Tolerance Reassessment Summary Commodity Current Tolerance (ppm) Tolerance Reassessment (ppm) Correct Commodity Definition Cattle, fat 2 1 Cattle, mbyp 2 5 Cattle, meat 2 1 Goats, fat 2 1 Goats, mbyp 2 5 Goats, meat 2 1 Horses, fat 2 1 Horses, mbyp 2 5 Horses, meat 2 1 Milk 0. 3 0. 8 Sheep, fat 2 1 Sheep, mbyp 2 5 Sheep, meat 2 1 HED recommends that the 40 CFR tolerance expression under §180.390 be modified as follows: 15 § 180.390 Tebuthiuron; tolerances for residues (a) Tolerances are established for the combined residues of the herbicide tebuthiuron N 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl­ N, N'­ dimethylurea) and its metabolites N­[ 5 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea, N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4thiadiazol 2­ yl] urea, 2­ dimethylethyl­ 5­ amino­ 1,3,4­ thiadiazole, and N­[ 5­( 1, 1dimethylethyl 1, 3, 4­ thiadiazol­ 2­ yl]­ N'­ hydroxymethyl­ N­ methylurea in or on the following raw agricultural commodities: Commodity Parts per million Cattle, fat 1 Cattle, mbyp 5 Cattle, meat 1 Goats, fat 1 Goats, mbyp 5 Goats, meat 1 Horses, fat 1 Horses, mbyp 5 Horses, meat 1 Sheep, fat 1 Sheep, mbyp 5 Sheep, meat 1 (b) A tolerance is established for the combined residues of the herbicide tebuthiuron N 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl­ N, N'­ dimethylurea) and its metabolites N­[ 5 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea, N­[ 5­( 2­ hydroxy­ 1, 1dimethylethyl 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea, N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4thiadiazol 2­ yl] urea, N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N'­ hydroxymethyl­ Ndimethylurea and N­[ 5­( 2­ hydroxy­ 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N'hydroxymethyl N­ methylurea in or on the following raw agricultural commodity: Commodity Parts per million Milk 0. 8 16 DIETARY EXPOSURE ASSESSMENT A refined acute and chronic dietary exposure assessment was conducted for tebuthiuron registered for foliar application to pastures and rangeland (secondary transfer to livestock commodities). Anticipated residues from field trial data and percent crop treated were utilized to estimate the dietary exposure to tebuthiuron in the diets of the U. S. Population (chronic) and females 13­ 50 years (acute only) [S. Piper, D281821, 04/ 2/ 02]. CODEX HARMONIZATION No Codex MRLs have been established or proposed for residues of tebuthiuron. Therefore, issues of compatibility with respect to U. S. tolerances and Codex MRLs do not exist. 17 AGENCY MEMORANDA CITED IN THIS DOCUMENT CBRS No.: 2959 Subject: EPA Registration No. 1471­ 101 (RCB No. 2959) ­ Data Waiver or Amendment Requested and Protocol Re: Tebuthiuron Reregistration (No Accession Number) From: N. Dodd To: R. Taylor and Toxicology Branch Dated: 12/ 10/ 87 MRID( s): None CBRS No.: None Subject: Tebuthiuron on Rangelands and Pastures­ Protocol for Magnitude of Residues Studies for Tebuthiuron Reregistration (No Accession Number) From: N. Dodd To: R. Taylor, Toxicology Branch II Dated: 2/ 9/ 89 MRID( s): None CBRS No.: None Subject:[ Multiresidue methodology testing of tebuthiuron and six of its metabolites.] From: M. Nelson To: L. Sawyer, FDA Dated: 9/ 1/ 89 MRID( s): 41196901 CBRS No. : 4939 Subject: EPA Registration No. 1471­ 101 (DEB No. 4939) ­ Tebuthiuron Reregistration ­ Nature of the Residue in Milk and Bovine Tissues. From: N. Dodd To: R. Taylor and Toxicology Branch II Dated: 6/ 22/ 89 MRID( s): 409850­ 01 and 409850­ 02. CBRS No.: 11235 DP Barcode: D187084 Subject: Tebuthiuron: Waiver Request for Grazing Study and Grazing Study Protocol; Draft of Enforcement Analytical Method for Milk; Schedule for Meat and Milk Analytical Methods; Schedule for Feeding Study. From: S. Funk To: P. Perreault Dated: 2/ 9/ 93 MRID( s): None 18 CBRS No.: 11314 DP Barcode: D187699 Subject: Tebuthiuron: List A; Chemical 105501; Case 0054. DowElanco Response to the Registration Standard Data Requirements for Grass Field Trials (171­ 4( k)) and Storage Stability for Forage and Hay (171­ 4( e)). MRID Nos. 42630501 and 42630502. From: S. Funk To: L. Rossi/ L. Propst Dated: 5/ 20/ 93 MRID( s): 42630501 and 42630502 CBRS No.: 15883 DP Barcode: D217379 Subject: Tebuthiuron: Ruminant Feeding Study (171­ 4 (j)). From: S. Funk To: L. Propst/ K. Rothwell Dated: 12/ 5/ 95 MRID( s): 43703201 CBRS No.: 16937 DP Barcode: D223089 Subject: Tebuthiuron Storage Stability in Support of the Ruminant Feeding Study (171­ 4( e; j)). From: S. Funk To: P. Deschamp Dated: 8/ 1/ 96 MRID( s): 43439301 CBRS No.: None DP Barcode: D281821 Subject: Tebuthiuron Acute and Chronic Dietary Exposure Assessments for the Tolerance Reassessment Eligibility Decision (TRED). From: S. Piper To: P. Deschamp/ W. Livingston Dated: 4/ 2/ 02 MRID( s): None

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EPA-HQ-OPP-2002-0146-0008

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N N S N O N 11­ 15­ 01 MEMORANDUM SUBJECT: Tebuthiuron. List A Reregistration Case 0054. PC Code 105501. Product Chemistry Chapter for the Tolerance Renewal Eligibility Decision [TRED] Document. DP Barcode D277104. FROM: K. Dockter, Chemist Reregistration Branch 2 Health Effects Division [7509C] THRU: Alan Nielsen, Branch Senior Scientist Reregistration Branch 2 Health Effects Division [7509C] TO: Paula Deschamp, Risk Assessor Reregistration Branch 2 Health Effects Division [7509C] Tebuthiuron {N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea} is a nonselective herbicide. Empirical formula: C9H16N4OS Molecular weight: 228.3 CAS Registry No.: 34014­ 18­ 1 PC Code: 105501 Chemical structure by J. Punzi A search of REFS conducted 10/ 12/ 01 identified a single tebuthiuron technical [T] registered under PC Code 105501, the Dow Agrosciences LLCo Spike* Technical 99 % T; EPA Reg. No. 2719­ 109. It is subject to a TRED. The Reregistration Eligibility Decision Document issued 6/ 94. 2 The Registration Standard issued 7/ 87. The product chemistry data base is essentially complete. There are no reported impurities of toxicological concern in tebuthiuron. The Series 830 physical and chemical properties are given in the table below. GLN MRID Data 6302 Color 40493802 off­ white 6303 Physical state " crystalline solid 6304 Odor " pungent 7200 MP " 161.5­ 164 C 7300 Bulk density " 0.579 g/ cc 7840 Water solubility " 2.5 mg/ mL @ 25 C 7950 vp " 2 x 10 ­6 mm Hg @ 25 C 7550 log Pow " 1.79 6313 Stability " stable for 3 yrs & for 6 mo. @ normal and elevated temperatures, respectively. No light instability or corrosiveness to metal has been observed. cc: Reg. Std. file, RF, Dockter, S. Piper, R. Fricke. RD\ I Tebuthiuron TRED Team. 7509C: RRB2: Rm712N: 57886: KD/ kd Tebuthiuron. TRED [982] = D277104. mem.

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EPA-HQ-OPP-2002-0146-0009

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES DATE: February 25, 2002 SUBJECT: Tebuthiuron. (List A, Case No. 0054) The Outcome of the HED Metabolism Assessment Review Committee Meeting Held on 01/ 22/ 02. Chemical 1105501. TXR# 0050409 FROM: Sheila Piper, Chemist, CEB/ HED (7509C) Mark Corbin, EPS, Environmental Risk Branch 1 (7507C) THROUGH: Francis B. Suhre, Branch Senior Scientist Chemistry and Exposure Branch Health Effects Division (7509C) TO: Yan W. Donovan, Chemist, RAB1/ HED (7509C) Executive Secretary, MARC Material Reviewed The Metabolism Assessment Review Committee (MARC) met on January 22, 2002 to consider the degradation of tebuthiuron [N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N, N'dimethylurea in water. Specifically, MARC was asked to determine which degradates should be included in the risk assessment. EFED supplied information that was presented to MARC (M. Corbin, 1/ 16/ 02) describing degradates found or having the potential to be found in soil and water. MARC Conclusions The Committee concluded that the parent compound and degradate 104 should be included in the drinking water risk assessment. Although, MARC expressed concern about the toxicity of other metabolites of tebuthiuron, the Committee did not recommend including them in a drinking water risk assessment because they are not likely to be present in drinking water. Supporting Reasons Page ­2­ N N S N CH 3 CH 3 C H 3 C H 3 O N H CH 3 N N S N CH 3 CH 3 C H 3 C H 3 O NH 2 The Committee considered the following information to arrive at the conclusion shown above: ­ Available data indicate that the parent and degradate 104 are persistent and mobile in the environment. Tebuthiuron is frequently detected in ground and surface water monitoring studies. The degradate 104 was detected in a retrospective ground water monitoring study and was a major degradate in a terrestrial field dissipation study accounting for up to 23% of the mass applied. The degradate 104 was also found in aerobic soil metabolism and soil photolysis studies comprising close to 7% of the mass applied. In addition, due to the structural similarity of degradate 104 to tebuthiuron (104 lacks an N­ methyl group) and lack of toxicity information on degradate 104, MARC assumes that it has similar toxicity to the parent. The chemical structures of tebuthiuron and degradate 104 Tebuthiuron: [N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl]­ N, N'­ dimethylurea] 104: N­[ 5­( 1,1­ dimethylethyl)­ 1,3,4­ thiadiazol­ 2­ yl N­ methylurea Individuals in Attendance 1. MARC Members Abdallah Khasawinah, Norman Birchfield, Christine Olinger, Rick Loranger, Leung Cheng, John Doherty, Bill Wassell, Yan Donovan, David Nixon, and Sheila Piper. 2. Scientists (non­ MARC members) Ken Dockter( RRB2), Robert Fricke( RRB2), Paula Deschamp( RRB2), and Mark Corbin( EFED). cc: SF, RF, List B File, S. Piper, P. Deschamp (RRB2), Mark Corbin (EFED) RDI: C. Olinger: 2/ 22/ 02; F. B. Suhre: 2/ 25/ 02 7509C: CEB1: CM­ 2: Room 810F: 308­ 2717: Tebuthiuron

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EPA-HQ-OPP-2002-0146-0010

Supporting & Related Material

1 THIS VERSION INCLUDES REVISIONS IN THE MUTACGENICITY AND DATAGAP SECTIONS TXR No: 0050672 DATE: April 16, 2002 MEMORANDUM SUBJECT: TEBUTHIURON ­ THIRD Report of the Hazard identification Assessment Review Committee FROM: Robert F. Fricke, Ph. D. Reregistration Branch 2 Health Effects Division (7509C) THROUGH: Jess Rowland, Co­ Chair and Elizabeth Doyle, Co­ Chair Hazard Identification Assessment Review Committee Health Effects Division (7509C) TO: Wilhelmena Livingston, Chemical Review Manager Special Review and Registration Division (7508C) PC CODE: 105501 On December 13, 2001, January 17, 2002 and February 12, 2002, the Hazard Identification assessment Review Committee (HIARC) reviewed the toxicology data base of tebuthiuron and selected endpoints/ doses the acute and chronic reference doses. The HIARC also evaluated the potential for increased susceptibility of infants and children from exposure to tebuthiuron as required by the Food Quality Protection Act (FQPA) of 1996. The conclusions drawn at these meetings are presented in this report. 2 Committee Members in Attendance Members in attendance: Ayaad Assaad, William Burnam, Jonathan Chen, Paula Deschamp Elizabeth Doyle (Co­ Chair) Pamela Hurley, John Liccione, Elizabeth Mendez, David Nixon Members in absentia:. Jess Rowland (Co­ Chair) Also in attendance: Susan Makris, and Pauline Wagner Data evaluation / presentation: Robert F. Fricke Reregistration Branch 2 3 N N S N CH 3 CH 3 C H 3 C H 3 O N H CH 3 Tebuthiuron (105501) 1 INTRODUCTION On December 13, 2001 and January 17, 2002 the Health Effects Division's (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for tebuthiuron with regard to the acute and chronic Reference Doses (RfD). The potential for increased susceptibility of infants and children from exposure to tebuthiuron was also evaluated. The HIARC met again on February 12, 2002 to discuss the need for an additional uncertainty factor due to the lack of an acceptable chronic toxicity/ carcinogenicity study in rats. The conclusions drawn at these meeting are presented in this report. 2 HAZARD IDENTIFICATION 2.1 Acute Reference Dose (RfD) ­ Females 13+ Study Selected: Rabbit Developmental Toxicity Guideline No.: 870.3700 (83­ 4b) Main and Range­ Finding studies MRID No.: 00020644, 40776301 Executive Summary: In a developmental toxicity study, 15 presumed pregnant Dutch belted rabbits per group were administered tebuthiuron (96.5% a. i.; Lot No.: B30­ 23­ 149) by gavage at doses of 0, 10, or 25 mg/ kg/ day on gestation days (GD) 6­ 18, inclusive. Doses were selected on the basis of preliminary studies summarized in MRID 40776301. Details of the purity and composition of the test article and of the insemination procedure were given in MRID 41122401. On GD 28, all surviving does were sacrificed and examined grossly. Litters were weighed and each fetus examined for viability, sex, and external malformations/ variations. The fetuses were killed, examined viscerally by fresh dissection (including the brain), and the carcasses processed for skeletal examination. Doses were selected on the basis of preliminary studies which were summarized in MRID 40776301. Mated rabbits (4/ group) were administered 5, 10, 20, 25, 50, or 100 mg/ kg/ day on GD 6­ 18. Three animals in the 100 mg/ kg/ day group died or were killed moribund on GD 8­ 10. Overall body weight changes for the treated groups were 140, 5, ­37, ­72, ­103, and 480 g, respectively. 4 In the main study, premature deaths of several animals were considered incidental to treatment. No clinical signs of toxicity were observed in any animal. No effects on body weights, body weight changes, or food consumption were noted for the treated groups as compared with the controls. No treatment­ related lesions were found at gross necropsy. No differences between the treated and control groups were noted for pregnancy rate or numbers of corpora lutea, implantations, fetuses/ litter, or resorptions. Although the mean fetal body weights of the high­ dose group were 83% of the control level, the decrease was due to a statistically significant (p # 0.01) negative correlation [increased litter size results in a significant decrease in fetal body weight] between litter size and fetal body weight. The total number of fetuses( litters) examined in the control, low­, and high­ dose groups was 48( 11), 58( 11), and 68( 12), respectively. No treatment­ related external, visceral, or skeletal malformations/ variations were observed in this study. From the range­ finding study, the percentage of early resorptions in the 25, 50, and 100 mg/ kg/ day groups was 68.8, 66.7, and 100%. Dose and Endpoint for Establishing RfD: 25 mg/ kg/ day, based on increased number of early resorptions. Uncertainty Factor( s): 100x (10x intraspecies variability, 10x interspecies extrapolation). Comments about Study/ Endpoint/ Uncertainty Factor( s): The HIARC considered the data of the main study and the range­ finding study to establish this endpoint. In the main study, no maternal or developmental toxicity was seen at the highest dose; the NOAEL was 25 mg/ kg/ day (HDT). In the range­ finding study, early resorptions were observed at 25 (69%), 50 (67%), and 100 (100%) mg/ kg/ day. Although the range­ finding study indicates that 25 mg/ kg/ day is an effect level, this dose (25 mg/ kg/ day) was selected for risk assessment, since there was no dose response in the observed early resorptions and because there was greater confidence in the results of the main study where no toxicity was seen at this dose (25 mg/ kg/ day) and thus was deemed to be an appropriate dose for risk assessment. In addition, the selection of the 25 mg/ kg/ day dose for risk assessment is supported by the NOAEL of 50 mg/ kg/ day in a rabbit developmental range­ finding study with a structurally related urea (UC 77179). This chemical had a toxicity profile similar to that of tebuthiuron. At 200 mg/ kg/ day decreased body weight gain, lethality and early resorption were observed. 5 2.2 Acute Reference Dose (RfD) ­ General Population An appropriate end point attributable to a single­ dose was not available in the database. The slight decrease (7%) in body weight gain seen on gestation day 16 in the rabbit study is not attributable to a single dose and no maternal toxicity was seen in the rabbit study. 2.3 Chronic Reference Dose (RfD) Proposed Study: Two­ Gen Repro ­ Rat Guideline No.: OPPTS 870.3800 (83.4) MRID No.: 00090108 Executive Summary: In a two­ generation reproduction study, tebuthiuron (Lot No. 00880­ 1L­ 1, X­ 35920, 98.0% a. i.) was fed to groups of 25 male and 25 female Wistar rats per dose at dietary concentrations of 0, 100, 200, and 400 ppm. The dietary levels corresponded to doses of 6­ 7, 13­ 14, and 26­ 28 mg/ kg/ day, respectively, for F0 and F1 males and 7­ 8, 14­ 15, and 30­ 31 mg/ kg/ day, respectively, for F0 and F1 females averaged over the premating period only. Adult rats of both generations were fed the treated or control diets during the premating period (98 days for F0 and 124 days for F1 rats) and during mating, gestation, and lactation of two litters per generation. Pups from the F1a litters were selected to parent the F2 generation. No treatment­ related deaths, clinical signs of toxicity, gross lesions, or microscopic lesions were observed in adult rats of either generation. No treatment­ related effects were observed on body weight, body weight gain, food consumption, or food efficiency in F0 male rats, F1 male rats, or F0 female rats fed any dose at any time during the study including the premating, mating, gestation, and lactation periods. F1 females in the 200 and 400 ppm groups had mean weekly body weights 7­ 9% (p # .05, not biologically significant) and 8­ 13% (p # 0.05), respectively, less than the control group throughout the premating period starting with day 14 (10%, NS) for the 200 ppm group and day 7 (12%, p # 0.05) for the 400 ppm group. Weight gain over the entire premating period was 7% (not significant) less than controls for 200 ppm group F1 females and 14% (p # 0.05) less for the 400 ppm group. Cumulative food consumption was not significantly affected, but food efficiency was reduced by 13% (p # 0.01) for 400 ppm group F1 females. The decreased body weights and weight gain did not extend into the gestation or lactation period for F2a litters. The parental systemic LOAEL for tebuthiuron is 400 ppm (30 mg/ kg/ day) based on deceases in body weight, body weight gain and food consumption of F1 females; the NOAEL is 200 ppm (14 mg/ kg/ day). Parental effect levels were not established for adult male rats in this study. No effects were observed on reproductive parameters as measured by sperm morphology, fertility index for females, and the number of litters produced. 6 Chronic R D 14 mg / kg /day( NOAEL) 100 (UF) 0.14 mg / kg / day f = = The reproductive LOAEL for tebuthiuron could not be established for this study. The NOAEL is $ 400 ppm (30 mg/ kg/ day). The F1a, F1b, F2a, or F2b offspring/ litters were not affected by treatment with tebuthiuron in the diet. The mean litter size at birth, litter size throughout lactation, survival indices (live birth, viability, and lactation), and pup weights and pup weight gain throughout lactation were not statistically different between treated and control groups. Pups in the 400 ppm group weighed about 5­ 14% less than the controls and gained slightly less weight than controls throughout lactation. Mean litter sizes in the 400 ppm group were larger than those for the control group and probably contributed to the lower body weights. Dosing was considered to be barely adequate for assessing reproductive and offspring toxicity. The offspring LOAEL could not be established for this study. The NOAEL is $ 400 ppm (30 mg/ kg/ day). This study is classified Acceptable/ Guideline and satisfies the guideline requirement for a two­ generation reproductive study (OPPTS 870.3800, §83­ 4) in the rat. Dose and Endpoint for Establishing RfD: Parental systemic NOAEL of 14 mg/ kg/ day based on decreased body weight, body weight gain and food consumption in F1 females at 30 mg/ kg/ day. Uncertainty Factor( s): 100x (10x intraspecies variability, 10x interspecies extrapolation. Co mments about Study/ Endpoint/ Uncertainty Factor( s): The HIARC noted that the chronic toxicity/ carcinogenicity study in rats is unacceptable since at the doses tested (0, 20, 40 or 80 mg/ kg/ day) no treatment­ related effects were seen for mortality, clinical signs or clinical pathology. Treatment had no effects on absolute body weight or body weight gains in males and there were minimal (15% reduction) changes in absolute body weights in females at termination. There were no effects on neoplastic and non­ neoplastic lesions in either sex. Because of the lack of systemic toxicity, the HIARC determined that the doses tested were inadequate to assess the chronic toxicity or the carcinogenic potential of tebuthiuron. The NOAEL of 14 mg/ kg/ day from the two­ generation reproduction study used for derivation of the chronic RfD is the lowest NOAEL in the database. In the 1­ year chronic study in dog, the NOAEL was 25 mg/ kg/ day and the LOAEL was 50 mg/ kg/ day. In the 78­ week carcinogenicity study in mice, the NOAEL was 240 mg/ kg/ day (HDT). The HIARC inferred that although a repeat study in rats at higher dose would provide hazard 7 characterization and evaluate the carcinogenic potential of this pesticide, but would not yield a dose that is lower than the dose that is used for derivation of the RfD. The chronic RfD is adequate to protect any adverse toxicity effects following exposure to tebuthiuron. The Committee therefore concluded that an additional uncertainty factor (for data gap) is not needed. The HIARC, however, determined that a repeat study is required to assess the carcinogenic potential of tebuthiuron and recommended that the request for this study should come as a Data Call In notice. 2.4 Occupational/ Residential Exposure Toxicological endpoints for occupational/ residential exposure risk assessments were not selected since tebuthiuron is scheduled for a Tolerance Reassessment Eligibility Decision (TRED) 3 CLASSIFICATION OF CARCINOGENIC POTENTIAL 3.1 Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No.: 0020714 Executive Summary: In a chronic toxicity/ carcinogenicity study, tebuthiuron (> 97% a. i., lot number, 6SG43 and B30­ 23­ 149) was administered to male and female Wistar rats (40/ group/ sex) at dietary concentrations of 400, 800, or 1600 ppm (20, 40, and 80 mg/ kg/ day, based on the default food factor of 0.05). Two control groups of 60 male and 60 female Wistar rats administered untreated basal diet. No interim sacrifice was conducted for this study. Two replicate studies were carried out. No treatment­ related effects were reported for clinical signs, mortality, or clinical pathology in male or female rats receiving any dose of the test material. The mortality rates for all groups was high. During the first year of treatment, 10­ 19% of males died while at the end on the study, only 26% of all rats remained alive. Pneumonia affected the majority of animals in all groups at various times during the study; antibiotic treatment was required during one episode. Absolute body weights presented graphically indicated that high­ dose males and females weighed less than controls throughout most of the study. The magnitude of the reduction in absolute body weight could not be determined for assessment of statistical or toxicologic significance. A 15% reductions in body weight in high­ dose females was observed at study termination. Food consumption was measured but not reported. Relative kidney weights were depressed in high­ dose male rats, but no histopathological correlates were observed. Each animal was necropsied, but gross findings were not tabulated. Vacuolization of pancreatic acinar cells (generally slight or affecting only a few cells) was observed in 11 males and 13 females receiving the high­ dose and in none of the controls of either sex. Only selected histopathological data were presented in the summary tables of the study report; therefore, a complete assessment of histopathological findings could not be conducted. No treatment­ related neoplasms were reported; common neoplasms included 8 pituitary adenomas and mammary fibroadenomas in female rats. The microscopic findings in the pancreatic acinar cells were generally slight, affected only a few cells, and caused no physiological effect on glucose levels. Based on the results of this study (decreased terminal body weight in females), the LOAEL for systemic toxicity was established at 80 mg/ kg/ day. The NOAEL was established at 40 mg/ kg/ day in females. A LOAEL was not established in males; the NOAEL was established at 80 mg/ k/ day. This chronic toxicity/ carcinogenicity study in the rat is Unacceptable/ Guideline and does not satisfy the guideline requirement for a chronic toxicity/ carcinogenicity oral study [OPPTS 870.4300 (§ 83­ 5)] in the rat. Adequacy of Dose Levels: The HIARC disagreed with the 1993 RfD conclusions that the doses tested approached an adequate dose because of the minimal change in female body weight. No decrease in body weight was observed in males, further, there was no systemic toxicity. The dose levels were selected from a 90­ day feeding study, where decreased body weight, organ weight changes and slight to moderate vacuolization of the pancreatic cells was seen at 2500 ppm. Based on the results of this study, animals could have been tested at higher doses. Discussion of Tumor Data: No treatment­ related neoplasms were reported at the doses tested. 3.2 Carcinogenicity Study in Mice MRID No. 00020717 Executive Summary: In a carcinogenicity study, tebuthiuron (> 97% a. i., lot # B30­ 23­ 149) was administered to groups of 80 Harlan ICR mice/ sex/ dose in pelleted diet at dose levels of 400, 800, or 1600 ppm (equivalent to 60, 120, or 240 mg/ kg bw/ day based on the default food factor of 0.15) for 2 years. The control group, consisting of 120 males and 120 females was fed untreated pelleted diet. Animals were equally subdivided by dose and sex into two substudies; the second substudy was started 1 week after the first. It should be noted that animals were not assigned by body weight. Although there was a statistically significant decrease (32.4 g, 12%) in the terminal body weights of high­ dose females in one of the substudies (M9153), this is likely due to the higher body weight (36.7 g) of the control females in this substudy. The terminal body weight of the control females in the other substudy was 34.1 g. There were no compound related effects on mortality, clinical signs, hematology or clinical chemistry, organ weights, or gross or microscopic pathology. 9 The LOAEL for systemic toxicity was not established in this study. The NOAEL was established at 1600 ppm (240 mg/ kg/ day). At the doses tested, there was no treatment related increase in tumor incidence when compared to that of controls. Dosing was not considered adequate based on the absence of systemic effects. This carcinogenicity study in the mouse is unacceptable/ guideline and does not satisfy guideline requirements for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice. Discussion of Tumor Data: No treatment­ related neoplasms were reported. Adequacy of the Dose Levels Tested: The HIARC disagreed with the 1993 RfD conclusions that the tumor profile would not change if the dose was increased. At 1600 ppm there was a 12% decrease in female body weight; males were unaffected by treatment. The dose levels were not considered adequate due to lack of significant toxicity at the highest dose tested. 3.3 Classification of Carcinogenic Potential The HIARC reevaluated the classification and concluded that the carcinogenic potential of tebuthiuron can not be determined due to inadequate carcinogenicity studies. The RfD Committee classified tebuthiuron as a "Group D" Carcinogen ­ Not classifiable as to human carcinogenicity (Second RfD/ Peer Review Report of Tebuthiuron, March 1, 1993). 4 MUTAGENICITY 4.1 Salmonella typhimurium/ Escherichia coli reverse gene mutation assay [OPPTS 870.5100 (§ 84­ 2)] MRID No: 00141691 Executive Summary: In a reverse gene mutation assay in bacteria , S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed to tebuthiuron (98.0%, lot number X­ 35920) in dimethylsulfoxide (DMSO) at concentrations of 100, 500, 1000, 2500, or 5000 : g/ plate in the presence and absence of mammalian metabolic activation (S9­ mix). Triplicate plates were utilized for each test concentration. The S9­ fraction was obtained from Aroclor 1254 induced rat liver. Tebuthiuron was tested up to the limit dose. No increase in mutant frequency was noted in any strain with or without metabolic activation. The solvent (DMSO) and positive control (2­ aminoanthracene, 2­ nitrofluorene, 9­ aminoacridine, N­ methyl­ N'nitro­ N­ nitroso guanidine values were appropriate in the respective strains. There was no evidence of induced mutant colonies over background in strains TA98, TA100, TA1535, TA1537 and TA1538 with or without S9 activation. 10 This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline [OPPTS 870.5100 (§ 84­ 2)] for in vitro mutagenicity (bacterial reverse gene mutation) assay. 4.2 Reverse Gene Mutation Assay in Bacteria [OPPTS 870.5100 (§ 84­ 2)] MRID No.: 00141690 Executive Summary: In a reverse gene mutation assay in bacteria, S. typhimurium strains G46, TA1535, TA100, C3076, TA1537, D3052, TA1538, and TA98 and E. coli strains WP2 and WP2 uvrA­ were exposed to tebuthiuron (98.0%, lot number X­ 35920) in dimethylsulfoxide (DMSO) over a concentration range of 0.1 to 1000 : g/ mL, in a gradient plate assay, in the presence and absence of mammalian metabolic activation (S9­ mix). The S9­ fraction was obtained from Aroclor 1254 induced rat liver. No increase in mutant frequency was noted in any S. typhimurium or E. coli tester strain with or without metabolic activation. The solvent (DMSO) and positive control (2­ aminoanthracene, N­ methyl­ N'nitro­ N­ nitrosoguanidine) values were appropriate in the respective strains. There was no evidence of induced mutant colonies over background in S. typhimurium strains G46, TA1535, TA100, C3076, TA1537, D3052, TA1538, and TA98 and E. coli strains WP2 and WP2 uvrA­ with or without S9 activation. This study is classified as Acceptable/ Nonguideline. 4.3 Mutagenicity­ in vitro Cytogenetic Assay [OPPTS 870.5375] MRID No.: 41134101 Executive Summary: In a mammalian chromosome aberration assay, Chinese Hamster Ovary (CHO) cell cultures were exposed to tebuthiuron (99.08%, lot number 729AS7) in dimethylsulfoxide at concentrations of 0, 1650, 1800, or 1950 : g/ mL for 4 hours in the absence of exogenous metabolic activation (S9­ mix) or to 1350, 1450, or 1550 : g/ mL for 4 hours in the presence of activation (followed by an additional 19­ hour incubation in fresh medium). The S9­ fraction was obtained from Aroclor 1254 induced male Fischer 344 rat liver. Tebuthiuron was tested up to concentrations limited by cytotoxicity. A preliminary cytotoxicity under nonactivated conditions showed survival of 15% at 2285 : g/ mL, 39% at 1750 : g/ mL, 55% at 1500 : g/ mL, and 115% at 1000 : g/ mL. A significant (p< 0.01) increase in the percent of cells with aberrations was noted in nonactivated cultures at 1950 : g/ mL (15 &19% for treated duplicate cultures vs. 5% for vehicle controls) and activated cultures at 1550 : g/ mL (15 &18% for treated duplicate cultures vs. 5­ 6% for vehicle controls). The predominant types of aberrations were chromosome and chromatid breaks. No significant increases were observed at lower concentrations; however, rare complex aberrations, such as triradials, quadriradials and complex rearrangements were noted, providing further support for clastogenicity. Cyclophosphamide and mitomycin C positive 11 control values were acceptable. There was evidence of an increase in structural chromosomal aberrations over background in the presence and absence of metabolic activation but only at cytotoxic concentrations. This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline OPPTS 870.5375 (84­ 2) for in vitro cytogenetic mutagenicity assay. 4.4 In vitro Bone Marrow Cytogenetic Assay [OPPTS 870.5300 (§ 84­ 2)] MRID No.: 00145041 Executive Summary: In a mammalian cell gene mutation assay in vitro, cultures of mouse lymphoma L5178Y TK+/­ cells were exposed to tebuthiuron (98.0%, lot No. X­ 35920) in dimethylsulfoxide at concentrations of 100, 200, 300, 400, 500, 600, 700, or 800 : g/ mL in an initial assay the absence of mammalian metabolic activation (S9­ mix), and at concentrations of 10, 100, 200, 300, 400, 500, 750, or 1000 : g/ mL in an initial assay in the presence of S9 mix. Due to cytotoxicity, the nonactivated assay was repeated at concentrations of 10, 100, 200, 400, 500, 600, 700, and 800 : g/ mL, and the activated assay was repeated at concentrations of 1, 10, 100, 200, 400, 500, 600, or 700 : g/ mL. The S9­ fraction was obtained from Aroclor 1254­ induced rats. Tebuthiuron technical was tested up to concentrations limited by cytotoxicity. Relative growth ranged from 57% to 13% (at 100 to 800 : g/ mL) in the absence of metabolic activation in the initial assay and from 28% to 6% (at 10 to 750 : g/ mL) in the presence of metabolic activation in the initial assay. In the initial nonactivated assay, mutation indices of 2.0 and 2.4 were detected at 700 and 800 : g/ mL, respectively. In a repeat nonactivated assay, mutation indices of 2.0, 2.0, and 2.7 occurred at 200, 400, and 500 : g/ mL, respectively. Mutations were not induced at any concentration with activation. The ethyl methane sulfonate (without S9) and 3­ methylcholanthrene (with S9­ mix) positive controls responded appropriately. Tebuthiuron was considered weakly mutagenic in the absence of metabolic activation. No evidence of an increased mutant frequency was observed in the presence of metabolic activation. This study is classified as Acceptable/ Guideline. It does satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5300 (§ 84­ 2)] for in vitro mutagenicity (mammalian forward gene mutation) data. 4.5 UDS Assay ­ Primary Rat Hepatocytes [OPPTS 870.5550 (§ 84­ 2)] MRID No.: 40750901 Executive Summary: In an unscheduled DNA synthesis assay primary rat hepatocyte cultures were exposed to tebuthiuron (99.1% a. i.; Lot No. 729AS7) in dimethylsulfoxide at eight concentrations ranging from 300 to 800 : g/ mL for 20 hours. Tebuthiuron was tested to the limit of cytotoxicity. Cytotoxicity was observed at $ 900 12 : g/ mL). UDS activity was evaluated at concentrations up to 800 : g/ mL and there was no evidence of induction of UDS. The solvent (1% DMSO) and positive control (N­ methyl­ N'nitrosoguanidine 1 : g/ mL and 2­ acetoaminofluorene 0.05 : g/ mL) values were appropriate. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. This study is classified as Acceptable/ Guideline. It does satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5550 (§ 84­ 2)] for other genotoxic mutagenicity data. 4.6 Sister Chromatid Exchange [OPPTS 870.5900 (§ 84­ 2)] MRID No.: 40750902 Executive Summary: In an in vivo cytogenetic assay measuring sister chromatid exchange (SCE) frequency in Chinese hamster bone marrow cells female Chinese hamsters (3/ group) were administered single oral doses of tebuthiuron (99.1%, Lot No. 729AS7) in 10% aqueous acacia at 3000, 4000, or 5000 mg/ kg. Tebuthiuron was tested up to cytotoxic concentrations. Hypoactivity was noted in all treatment groups and bone marrow cytotoxicity (as evidenced by an increase in the percent division metaphases) was observed at 5000 mg/ kg. There was no increase in the number of cells containing SCEs compared to controls at any concentration of tebuthiuron tested. Cyclophosphamide (50 mg/ kg) and vehicle control values were acceptable. There was no evidence of an increase in SCEs over background. This study is classified as Acceptable/ Guideline and satisfies the requirement for FIFRA Test Guideline [OPPTS 870.5915 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. 4.7 Conclusions: The submitted test battery satisfies the Pre­ 1991 mutagenicity initial testing battery guidelines. Tebuthiuron was not mutagenic in bacteria, but was weakly positive for gene mutations in cultured mouse lymphoma cells. The effect in mammalian cells was, however, confined to non­ activated test conditions. There was also some evidence of a clastogenic response at cytotoxic doses both with and without S9­ activation. Since an acceptable in vivo bone marrow cytogenetic assay is not available, final conclusions regarding the mutagenic potential of tebuthiuron can not be made at this time. 13 5 FQPA CONSIDERATIONS 5.1 Adequacy of the Data Base The toxicology data base is adequate for an FQPA assessment. The required developmental toxicity study in the rabbit does not meet guideline requirements. 6 FQPA CONSIDERATIONS 6.1 Neurotoxicity Data No acute or subchronic neurotoxicity studies on tebuthiuron are available. Evaluation of subchronic, chronic and reproduction toxicity, did not indicate any treatment­ related effects on the central or peripheral nervous system of mice, rats, or rabbits. No changes in clinical signs, brain weights, gross necropsy results or histopathological results suggested that any part of the nervous system as a target organ. 6.2 Developmental Toxicity 6.2.1 Prenatal Developmental Study ­ Rat MRID No: 00020803, 40485801 Executive Summary: In a developmental toxicity study, 25 presumed pregnant Harlan rats per group were administered tebuthiuron (purity not given; Lot No. 1093­ 316A­ 259) at dietary concentrations of 0, 600, 1200, or 1800 ppm on gestation days (GD) 6­ 15, inclusive. Doses to the animals were 0, 37, 72, or 110 mg/ kg/ day (calculated from body weight and feed consumption data), respectively. On GD 20, dams were sacrificed and subjected to gross necropsy; pancreatic tissue was saved from 10 females/ group for histopathological examination. Fetal sex, weight, and viability were determined and each fetus was examined for external abnormalities. Approximately one­ third of all fetuses were fixed in Bouin's solution for subsequent visceral examination and the remainder were cleared for skeletal examination. All dams survived to terminal sacrifice. No treatment­ related clinical signs of toxicity were observed in any group. Body weights, body weight gains, and food consumption by the low­ and mid­ dose groups were similar to the controls throughout the study. No treatment­ related lesions were observed in any dam at necropsy. Pancreatic tissue, as evaluated by both gross and microscopic examination, appeared normal. For the high­ dose group, absolute body weights were slightly reduced on GD 16 to 93% of the control level due to reduced body weight gains during the entire treatment interval. Body weight gains by the high­ dose dams were 21% of the control level during GD 6­ 10 and 57% of the control level during GD 11­ 15. During the treatment interval, food 14 consumption by the high­ dose group was 71% of the control amount for GD 6­ 10 and 95% of the control amount for GD 11­ 15. Compensatory weight gain and food consumption was observed in the high­ dose group during the post­ treatment interval. The maternal toxicity LOAEL is 1800 ppm (110 mg/ kg/ day) based on decreased body weight gains and food consumption. The maternal toxicity NOAEL is 1200 ppm (72 mg/ kg/ day). No differences were observed between the treated and control groups for pregnancy rate, number of corpora lutea/ dam, number of implantation sites/ dam, pre­ or postimplantation losses, number of fetuses/ litter, fetal body weights, or fetal sex ratios. No dead fetuses were observed. The total number of fetuses( litters) available for examination for malformations/ variations in the control, low­, mid­, and high­ dose groups was 259( 23), 263( 21), 300( 23), and 258( 21), respectively. No treatment­ related abnormalities were found in any fetus. In the control, low­, mid­, and high­ dose groups, the total number of fetuses( litters) with external, visceral, or skeletal malformations/ variations was 3( 2), 4( 4), 11( 7), and 4( 3), respectively. Hydronephrosis was a common finding in fetuses from control and treated groups The developmental toxicity NOAEL is $ 1800 ppm (110 mg/ kg/ day) and the developmental toxicity LOAEL was not identified. This study is classified as Acceptable/ Guideline and satisfies the requirements for a developmental toxicity study [870.3700 (§ 83­ 3a)] in rats. 6.2.2 Developmental Toxicity Study in the Rabbit MRID No.: 00020644 Executive Summary: In a developmental toxicity study (MRID 00020644), 15 presumed pregnant Dutch belted rabbits per group were administered tebuthiuron (96.5% a. i.; Lot No.: B30­ 23­ 149) by gavage at doses of 0, 10, or 25 mg/ kg/ day on gestation days (GD) 6­ 18, inclusive. Details of the purity and composition and of the insemination procedure were given in MRID 41122401. On GD 28, all surviving does were sacrificed and examined grossly. Litters were weighed and each fetus examined for viability, sex, and external malformations/ variations. The fetuses were killed, examined viscerally by fresh dissection (including the brain), and the carcasses processed for skeletal examination. Doses for the main study were selected on the basis of a preliminary range­ finding study (MRID 40776301). In this study, mated rabbits (4/ group) were administered 5, 10, 20, 25, 50, or 100 mg/ kg/ day on GD 6­ 18. Three animals in the 100 mg/ kg/ day group died or were killed moribund on GD 8­ 10. Overall body weight changes for the treated 15 groups were 140, 5, ­37, ­72, ­103, and ­480 g, respectively. The percentage of resorptions in the 25, 50, and 100 mg/ kg/ day groups was 68.8, 66.7, and 100%.. In the main study, premature deaths of several animals were considered incidental to treatment. No clinical signs of toxicity were observed in any animal. No effects on body weights, body weight changes, or food consumption were noted for the treated groups as compared with the controls. No treatment­ related lesions were found at gross necropsy. The maternal toxicity NOAEL was established at 25 mg/ kg/ day; the LOAEL for maternal toxicity was not established. No differences between the treated and control groups were noted for pregnancy rate or numbers of corpora lutea, implantations, fetuses/ litter, or resorptions. Although the mean fetal body weights in the high­ dose group were significantly lower than the control value, the decreases were attributed to increased liter size. The total number of fetuses( litters) examined in the control, low­, and high­ dose groups was 48( 11), 58( 11), and 68( 12), respectively. No treatment­ related external, visceral, or skeletal malformations/ variations were observed in this study. The developmental toxicity NOAEL is established at 25 mg/ kg/ day; the LOAEL was not established. This study is classified as Unacceptable/ Guideline and does not satisfy the guideline requirements for a developmental toxicity study [870.3700 (§ 83­ 3b)] in rabbits. 6.3 Reproductive Toxicity 6.3.1 Two­ Generation Reproduction ­ Rat MRID No: 90108 Executive Summary: In a two­ generation reproduction study, tebuthiuron (Lot No. 00880­ 1L­ 1, X­ 35920, 98.0% a. i.) was fed to groups of 25 male and 25 female Wistar rats per dose at dietary concentrations of 0, 100, 200, and 400 ppm. The dietary levels corresponded to doses of 6­ 7, 13­ 14, and 26­ 28 mg/ kg/ day, respectively, for F0 and F1 males and 7­ 8, 14­ 15, and 30­ 31 mg/ kg/ day, respectively, for F0 and F1 females averaged over the premating period only. Adult rats of both generation were fed the treated or control diets during the premating period (98 days for F0 and 124 days for F1 rats) and during mating, gestation, and lactation of two litters per generation. Pups from the F1a litters were selected to parent the F2 generation. 16 No treatment­ related deaths, clinical signs of toxicity, gross lesions, or microscopic lesions were observed in adult rats of either generation. No treatment­ related effects were observed on body weight, body weight gain, food consumption, or food efficiency in F0 male rats, F1 male rats, or F0 female rats fed any dose at any time during the study including the premating, mating, gestation, and lactation periods. F1 females in the 2 00 and 400 ppm groups had mean weekly body weights 7­ 9% and 8­ 13% (p< 0.01 or <0.05), respectively, less than the control group throughout the premating period starting with day 21 for the 200 ppm group and day 7 for the 400 ppm group. Weight gain over the entire premating period was 7% (N. S.) less than controls for 200 ppm group F1 females and 14% (p< 0.05) less for the 400 ppm group. Cumulative food consumption was not significantly affected, but food efficiency was reduced by 13% (p< 0.01) for 400 ppm group F1 females. The decreased body weights and weight gain did not extend into the gestation or lactation period for F2a litters. The parental systemic LOAEL for tebuthiuron is 400 ppm (30 mg/ kg/ day) for female rats based on deceases in body weight and weight gain; the corresponding NOAEL is 200 ppm (14 mg/ kg/ day). Parental effect levels were not established for adult male rats in this study. No effects were observed on reproductive parameters as measured by sperm morphology, fertility index for females, and the number of litters produced. The reproductive LOAEL for tebuthiuron could not be established for this study. The NOAEL is $ 400 ppm (30 mg/ kg/ day) The F1a, F1b, F2a, or F2b offspring/ litters were not affected by treatment with tebuthiuron in the diet. The mean litter size at birth, litter size throughout lactation, survival indices (live birth, viability, and lactation), and pup weights and pup weight gain throughout lactation were not statistically different between treated and control groups. Mean litter size in 400 ppm group was larger than those for the control group and probably contributed to the lower body weights. Dosing was considered to be barely adequate for assessing reproductive and offspring toxicity. The offspring LOAEL could not be established for this study. The NOAEL is $ 400 ppm. (30 mg/ kg/ day). This study is classified Acceptable/ Guideline and satisfies the guideline requirement for a two­ generation reproductive study (OPPTS 870.3800, §83­ 4) in the rat. 6.4 Additional Information from Literature Sources No studies available 17 6.5 Determination of Susceptibility There is no qualitative/ quantitative evidence of increased susceptibility following in utero exposure to rats or following pre/ post natal exposure to rats in the 2­ generation reproduction study. Susceptibility could not be assessed due to the lack of maternal or developmental toxicity at the highest dose tested.. 6.6 Evidence That Suggest Study Requiring a Developmental Neurotoxicity Study The need for a developmental neurotoxicity study is being held in reserve, pending submission of developmental toxicity studies in the rabbit (data gap). 6.7 Evidence That Do Not Suggest Requiring a Developmental Neurotoxicity Study: (1) No neurological signs or neuropathy were observed in any of the studies. (2) No increased susceptibility in rat developmental study. (3) No increased susceptibility the 2­ generation reproduction study in the rat. 7 HAZARD CHARACTERIZATION The toxicological database for tebuthiuron is not considered adequate for hazard characterization. The developmental toxicity studies in the rat and rabbit as well as the chronic feeding study in the rat and oncogenicity studies in the rat and mouse were found to be unacceptable. Further, because tebuthiuron was weakly positive for gene mutations in cultured mouse lymphoma cells, an in vivo mammalian bone marrow chromosomal aberration assay is also required. The acute toxicity studies indicate that tebuthiuron, technical, is more toxic for oral (Toxicity Category II) exposure than for either dermal (Toxicity Category IV) or inhalation (Toxicity Category III). The primary eye and skin irritation studies were both Toxicity Category IV; no dermal sensitization occurred with tebuthiuron in guinea pigs. Although the most consistent toxicological effect was decreased body weight, histopathological changes in the pancreas were observed in the rat. Vacuolation of pancreatic acinar cells was observed in both the subchronic and chronic feeding studies. Vacuolation was described as slight or affecting only a few cells. Subchronic feeding studies are available in the rat and dog, as well as a 21­ day dermal toxicity study in the rabbit. In the rat study, reduced body weight, increases in relative liver, kidney and gonad weights, and slight vacuolation of pancreatic acinar cells were observed in both sexes; males also had increased relative spleen and prostate gland weights. In the dog study, anorexia, 18 weight loss, increases in blood urea nitrogen and alkaline phosphatase, and increases in spleen and thyroid gland weights were observed. In the 21­ day dermal toxicity study in rabbits, no dermal or systemic toxicity was observed at 1000 mg/ kg/ day (limit dose). Tebuthiuron toxicity was also evaluated in a combined chronic toxicity/ oncogenicity study in the rat and a chronic feeding study in the dog. Decreased body weights were observed in both the rat and dog. Vacuolization of pancreatic acinar cells (generally slight or affecting only a few cells) was observed in rats, while increased liver and thyroid weights were observed in the dog. At the doses tested, neither the rat nor mouse showed any treatment­ related increase in the incidence of neoplasms. However, these dose levels were too low to assess the carcinogenic potential of tebuthiuron. Rat and rabbit developmental toxicity studies were carried out with tebuthiuron. In the rat, no compound­ related developmental effects were observed. In the rabbit susceptibility could not be evaluated due to lack of maternal and developmental toxicity at the high dose tested. In a two­ generation study in the rat, the only toxicological effect observed was a statistically and biologically significant decrease in the mean body weight of throughout the premating period; no offspring toxicity was seen. Tebuthiuron was not mutagenic in bacteria, but was weakly positive for gene mutations in cultured mouse lymphoma cells. The effect in mammalian cells was, however, confined to nonactivated test conditions. There was also some evidence of a clastogenic response at cytotoxic doses both with and without S9­ activation. Since an acceptable in vivo bone marrow cytogenetic assay is not available, final conclusions regarding the mutagenic potential of tebuthiuron can not be made at this time. 8 DATAGAPS The HIARC identified the following data gaps: 28­ day inhalation study in the rat ­ due to potential long­ term inhalation exposure based on the current use pattern.. Developmental toxicity study in the rabbit ­ the current study is unacceptable and is not adequate to assess susceptibility for FQPA. Chronic feeding/ oncogenicity study in the rat ­ doses tested were not adequate to assess the carcinogenic potential. Carcinogenicity study in the mouse ­ doses tested were not adequate to assess the carcinogenic potential. In vivo bone marrow chromosomal aberration test ­ Tier­ II test, required to verify the positive response in the in vitro chromosomal assay. Developmental neurotoxicity study ­ in Reserve pending submission of developmental 19 toxicity in the rabbit. 9 ACUTE TOXICITY Acute Toxicity of Tebuthiuron, Technical Guideline No. Study Type MRID No. Results Toxicity Category 870.1100 Acute Oral (Rat) 40583901 LD50 = 477.5 mg/ kg ( % % ) 387.5 mg/ kg ( & & ) II 870.1200 Acute Dermal (Rabbit) 40583902 LD50 = > 5000 mg/ kg ( % % and & & ) IV 870.1300 Acute Inhalation (Rat) 00155730 LC50 = 3. 696 mg/ L III 870.2400 Primary Eye Irritation 40583903 Slight irritation IV 870.2500 Primary Skin Irritation 40583902 Non­ irritating IV 870.2600 Dermal Sensitization 40583904 Non­ sensitizing – 20 10 SUMMARY OF TOXICOLOGY ENDPOINT SELECTION The doses and toxicological endpoints selected for Tebuthiuron EXPOSURE SCENARIO DOSE (mg/ kg/ day) ENDPOINT STUDY Acute Dietary (Females 13­ 50) NOAEL= 25 UF = 100 Increased post­ implantation loss and fetal/ litter resorptions at 50 mg/ kg/ day (LOAEL). Developmental Toxicity Study in the Rabbit Acute RfD (Females 13­ 50 years old) = 0.25 mg/ kg Acute Dietary (General Population) No appropriate effects attributed to a single exposure was identified. Chronic Dietary NOAEL = 14 UF = 100 Decreased body weight and feed consumption in F1 females at 30 mg/ kg/ day (LOAEL) 2­ Generation Reproduction Study in the Rat Chronic RfD = 0. 14 mg/ kg/ day Toxicological endpoints for occupational/ residential exposure risk assessments were not selected since tebuthiuron is scheduled for a Tolerance Reassessment Eligibility Decision (TRED)

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EPA-HQ-OPP-2002-0146-0011

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TXR NO. 0050466 February 12, 2002 MEMORANDUM SUBJECT: TEBUTHIURON­ Report of the FQPA Safety Factor Committee. FROM: Carol Christensen, Acting Executive Secretary FQPA Safety Factor Committee Health Effects Division (7509C) THROUGH: Ed Zager, Chairman FQPA Safety Factor Committee Health Effects Division (7509C) TO: Paula Deschamp, Risk Assessor Reregistration Branch II Health Effects Division (7509C) PC Code: 105501 The Health Effects Division (HED) FQPA Safety Factor Committee met on February 4 th , 2002 to evaluate the hazard and exposure data for tebuthiuron. The Committee recommend that the FQPA Safety Factor (as required by the FQPA) be reduced to 3x when assessing the exposure and risks of this chemical to human health. 2 I. HAZARD ASSESSMENT (Correspondence: R. Fricke to C. Christensen dated January 31, 2002) A. Adequacy of Database The Hazard Identification Assessment Review Committee (HIARC) met on December 13 th , 2001 and on January 7 th , 2002 to review the toxicological database of tebuthiuron. The toxicological database is adequate for FQPA assessment, however there are significant data gaps. The developmental toxicity study in the rabbit is unacceptable for the determination of susceptibility to the fetuses due to in utero tebuthiuron exposure. However, there is an adequate developmental toxicity study in the rat and a twogeneration reproductive toxicity study in the rat to assess the susceptibility of fetuses/ offspring to tebuthiuron. The Committee reserved the requirement of a developmental neurotoxicity study due to the data gap for a developmental toxicity study in rabbits. B. Determination of Susceptibility There is no qualitative/ quantitative evidence of increased susceptibility in the 2­ generation reproduction study in the rat or the developmental toxicity study in the rat. In the developmental toxicity study in the rabbit, no maternal or developmental toxicity was observed at the highest dose tested. Because there was no toxicity observed at the highest dose tested, susceptibility could not be ascertainted and the HIARC concluded that a new developmental toxicity in the rabbit is needed. II. EXPOSURE ASSESSMENT (Correspondence: S. Piper to C. Christensen dated January 31, 2002) A. Dietary Exposure Considerations Tebuthiuron is an herbicide registered for use on pastures and rangeland. The chemical is registered for a single broadcast application to rangeland and forage grasses by ground or air equipment with an application rate of 0.75­ 4.00 lb ai/ A. The recommended timing of application is prior to the resumption of active seasonal growth in the spring or before expected seasonal rainfall. Tolerances range from 0.8­ 5.0 ppm for secondary residues and 10 ppm for forage. There are no Codex MRLs established or proposed for residues of tebuthiuron. Therefore, issues of compatibility with respect to U. S. tolerances and Codex MRLs do not exist. The qualitative nature of the residue in grasses is adequately understood. The residues of concern are the parent compound and its metabolites 103( OH), 104, and 109. The terminal residues of concern in fat, meat, kidney, and liver are tebuthiuron and its metabolites 104, 106, 108 and 109; the terminal residues of concern in milk are 3 tebuthiuron and metabolites 104, 104( OH), 106, 109 and 109( OH). Tebuthiuron is a systemic soil herbicide that is absorbed mainly by the roots, with ready translocation. There are no monitoring data (PDP or FDA) for Tebuthiuron. Percent of crop treated information is available for use in the assessment. A DEEM Tier II analysis will likely be used to assess dietary exposure to this chemical using the results of field trial studies and percent of crop treated data. The Committee recognizes that further refinement to the dietary food exposure analyses may be required as the risk assessment is developed. Therefore, provided the final dietary food exposure assessment includes the metabolites of toxicological concern and does not underestimate the potential risk for infants and children, the safety factor recommendations of this Committee stand. B. Drinking Water Exposure Considerations The environmental fate database is essentially complete for parent tebuthiuron. Tebuthiuron water degradate 104 was detected at 6.9% and rising by the end of the study. The HED Metabolism Assessment and Review Committee (MARC) recommended degradate 104 be included in the water exposure and risk assessment. Based on the available data, the parent and degradate 104 are persistent and mobile. The quickest observed route of tebuthiuron degradation in laboratory studies was soil photolysis halflife 39.7 days.) Tebuthiuron has been assessed through a combination of modeling and analysis of surface water and ground water monitoring data. Drinking­ water monitoring results are not available for the chemical for direct quantitative incorporation into the exposure and risk assessment. Therefore, drinking water exposure assessments are supplemented with modeling predictions. Surface water concentrations of tebuthiuron were modeled using the PRZM/ EXAMS (Tier II) programs for pasture/ rangeland using EFED's standard scenario for alfalfa in Texas. Groundwater concentrations were modeled using the SCIGROW program. Input parameters used Tier II (PRZM version 3.12/ EXAMS version 2.97.5) modeling were selecting using Agency guidance and EFED calculated degradation rate constants from review of registrant submitted environmental fate studies. This assessment strategy was designed to assess concentrations of the parent compound. In order to account for the degradate of toxicological concern, EFED will complete modeling of the degradate using the total residue approach. Total residues (parent plus all degradates of toxicological concern) are summed from fate studies. In this case fate parameters are estimated for total residues for aerobic soil metabolism, aerobic aquatic metabolism, anaerobic soil metabolism, and photolysis. Other required fate parameters are conservatively estimated as stable in accordance with EFED guidance. This method 4 provides conservative estimates of total residues (parent plus degradates) in surface and ground water. Drinking water monitoring data support the results of the drinking water models. The FQPA Safety Factor Committee recognizes that further refinement to the dietary water exposure analyses may be required as the risk assessment is developed. Therefore, provided the final dietary water exposure assessment includes the metabolite of toxicological concern and does not underestimate the potential risk for infants and children, the safety factor recommendations of this Committee stand. C. Residential Exposure Considerations There are no registered residential uses for tebuthiuron. III. RISK CHARACTERIZATION A. FQPA Safety Factor Recommendation The Committee recommended that the FQPA Safety factor for enhanced sensitivity to infants and children (as required by FQPA) should be reduced (3x). A. Rationale for Reducing the FQPA Safety Factor The Committee concluded that the safety factor could be reduced for Tebuthiuron because: 1. There is no indication of quantitative or qualitative increased susceptibility of rats to in utero exposure; 2. There is no indication of quantitative or qualitative increased susceptibility of rat offspring seen in the two­ generation reproductive toxicity study; 3. The dietary (food and drinking water) exposure assessments will not underestimate the potential exposures for infants and children. However, the Committee decided that a factor is needed (3x) because of the data gap for a developmental toxicity study in the rabbit. 5 C. Application of the FQPA Safety Factor: Acute Dietary Exposure (Females 13­ 50): When assessing acute dietary exposure to females 13­ 50, the reduced FQPA safety factor of 3x will be used. This is because there is a data gap for assessing susceptibility of fetuses following in utero exposure to tebuthiuron. Chronic Dietary Exposure (General Population): When assessing chronic dietary exposure to the general population, the FQPA safety factor will be removed (1x). This is because there was no susceptibility identified in the 2­ generation rat reproduction study (a long­ term study).

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2024-06-07T20:31:42.662900

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EPA-HQ-OPP-2002-0146-0013

Supporting & Related Material

MEMORANDUM SUBJECT: Tebuthiuron Use Closure Memo (PC Code 105501) FROM: Michael McDavit, Acting Chief Special Review Branch TO: Margaret Stasikowski, Director Health Effects Division Elizabeth Leovey, Acting Director Environmental Fate and Effects Division This memo serves as the Tebuthiuron Use Closure Memo and clarifies Tebuthiuron uses for the TRED risk assessment. The SMART meeting for Tebuthiuron was held May 2, 2001. The updated Quantitative Usage Analysis (QUA) for Tebuthiuron, which is developed by the Economic Analysis Branch of the Biological and Economic Analysis Division is scheduled for completion on September 9, 2001. Attached is the most recent version of the QUA. Tebuthiuron is a relatively nonselective, soil activated herbicide that acts by inhibiting photosynthesis. It is used to control broadleaf and woody weeds, grasses, and brush on terrestrial feed crop sites (pastures and rangeland) primarily in Texas, Oklahoma, and New Mexico and on terrestrial non­ food crop sites including airports/ landing fields, outdoor industrial areas, nonagricultural rights­ of­ way, fencerows, hedgerows, uncultivated areas/ soils, and under paved roads and sidewalks in areas where no future landscaping is planned. Primary uses include rangelands and near railroads and other industrial facilities. Single active ingredient formulation include granular pelleted/ tableted, wettable powder, water dispersible granules and technical grade/ solid products. Three multiple active ingredient formulations (granulars) also are registered. All formulations may be applied as broadcast, banded or spot treatments using ground equipment. The pelleted/ tableted formulation also may be applied using aerial equipment. The LUIS report indicates no limit on the number of applications per season or crop cycle, but, the registrant provided information on the normal maximum and typical application use rates of Tebuthiuron at the SMART meeting. The attached tables reflect the use information (note: "NS" not specified) reflecting labeling current as of 02/ 21/ 2001 in the LUIS report and the registrants' use information. The risk assessment for Tebuthiuron will be based on the use sites listed in the LUIS report. Based on our understanding, this information will allow EFED to submit it's draft TRED chapter to SRRD on December 1, 2001, and HED to submit it's draft TRED chapter to SRRD on February 22, 2002, as it is currently scheduled. If you have any questions or concerns regarding this memorandum, please contact Wilhelmena Livingston at (703) 308­ 8025. cc: Paula Deschamp Virginia Dobozy Sheila Piper Ken Dockter Kevin Costello Mark Corbin Steve Smearman Dan Rosenblatt Range and Pasture Typical vs. Maximum Use Rates Use Site and Product Name Application Method and Equipment Registrant Maximum Application Per Use Rate Reflecting Label Maximum Application Per Use Registrant Typical Use Rate Reflecting Label Typical Use Rate Range and Pasture Oak Desert Species Sand Shinnery Spike 20P (20% pellet) Broadcast and spot treatment Applied by hand using canister delivery, ground and aerial application For vulnerable sites, maximum application rate is dependent upon annual precipitation: ° <20" in annual precipitation: no more than 1 lb a. i./ acre once every 3 years ° >20" in annual precipitation: no more than 2 lbs a. i./ acre once every 3 years For non­ vulnerable sites, maximum application rate is dependent upon annual precipitation: ° <20" in annual precipitation no more than 2 lbs once every 3 years and no more than two treatments totaling 6 lbs a. i./ acre in any 6­ year period ° >20" in annual precipitation: on more than 4 lbs a. i./ acre once every 3 years and no more than two treatments totaling 6 lbs a. i./ acre in any 6­ year period 4 lbs a. i./ acre/ NS for broadcast treatment 4 lbs a. i./ acre/ yr for spot treatment Typical application is once every 10­ 20 years 1.0­ 1.4 lbs for oak use 1.5 lbs for desert species 0.3­ 0.5 lbs for sand shinnery NS Industrial Vegetation Management Typical vs. Maximum Use Rates Use Site and Product Name Application Method and Equipment Registrant Maximum Application Per Use Rate Reflecting Label Maximum Application Per Use Registrant Typical Use Rate Reflectin g Label Typical Use Rate Industrial Vegetation Management Non­ Cropland Railroad Industrial General Woody Plant Spike 80DF (80% dry flowable) Broadcast/ Ban ded and spot Applied by backpack sprayer, handgun sprayer, and groundboom sprayer For vulnerable sites, maximum application rate is dependent upon annual precipitation: ° <20" in annual precipitation for broadcast/ banded and spot application: no more than 1 lb a. i./ acreonce every 3 years °> 20" in annual precipitation for broadcast/ banded and spot application no more than 2 lb a. i./ acreonce every 3 years For non­ vulnerable sites, maximum application rate is dependent upon annual ° <20" and >20" in annual precipitation for broadcast/ banded application for vegetation control: no more than 4 lbs a. i./ acre once every 3 years and no more than two treatments totaling 6 lbs. a. i./ acre in any 6­ year period; for total vegetation control and maintenance of bare ground (ground broadcast only) applied only once per year, however no more than 6 lbs a. i./ acre may be applied in any 3­ year period. ° <20" and >20" in annual precipitation for spot application no more than 6 lb a. i./ acre once every three years Maximum application rate is 6­ 8 lbs/ acre, depending on the use site Typically applied to railroad and industrial annually for 2­ 3 years followed by rotation to other products Typically applied to general woody plant once every 3 8 years 1.6­ 2.4 lbs for railroad use 1.6­ 2.4 lbs for industrial use 3­ 4 lbs for general woody plant use NS

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2024-06-07T20:31:42.667128

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EPA-HQ-OPP-2002-0146-0014

Supporting & Related Material

epa

2024-06-07T20:31:42.669559

regulations

EPA-HQ-OPP-2002-0146-0015

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES July 5, 2002 CERTIFIED MAIL Dear Registrant: This is to inform you that on July 5, 2002, the Environmental Protection Agency (hereafter referred to as EPA or the Agency) completed its "Report of FQPA Tolerance Reassessment Progress and Interim Risk Management Decision (TRED) for Tebuthiuron". A Notice of Availability, soliciting public comment for a 30 day period, will be published in the Federal Register (FR) Notice shortly. FFDCA, as amended, requires EPA to reassess all the tolerances for registered chemicals in effect on or before the date of the enactment of the Food Quality Protection Act (FQPA) in August of 1996 against the new safety standard adopted in the FQPA. In reassessing these tolerances, the Agency must consider, among other things, aggregate risks from non­ occupational sources of pesticide exposure, whether there is increased susceptibility to infants and children, and the cumulative effects of pesticides with a common mechanism of toxicity. The tolerances are considered reassessed once the safety finding has been made or a modification or revocation occurs. A reregistration eligibility decision (RED) for Tebuthiuron, was completed in April 1994, prior to FQPA enactment. Therefore, it needed to be updated to reassess the tolerances under the FQPA standard. The Agency has evaluated the dietary risk associated with Tebuthiuron and has determined that there is a reasonable certainty that no harm to any population subgroup will result from exposure to Tebuthiuron when considering dietary exposure and all other non­ occupational sources of pesticide exposure for which there is reliable information. Therefore, no mitigation measures are needed, and the tolerances established for residues of Tebuthiuron in/ on raw agricultural commodities are now considered reassessed as safe under section 408( q) of the FFDCA. FQPA requires that EPA consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity." The reason for consideration of other substances is due to the possibility that lowlevel exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect, as would a higher level of exposure to any of the other substances individually. EPA did not perform a cumulative risk assessment as part of this reregistration review of Tebuthiuron, because the Agency has not determined if there are any other chemical substances that have a mechanism of toxicity common with that of Tebuthiuron. If EPA identifies other substances that share a common mechanism of toxicity with Tebuthiuron, then a cumulative risk assessment will be conducted that includes Tebuthiuron once the final framework EPA will use for conducting cumulative risk assessments is available. The Agency's human health findings for the pesticide Tebuthiuron, were discussed in a closure conference call, and are summarized in the attached chemical overview of the risk assessments. These risk assessments and other documents pertaining to the Tebuthiuron tolerance reassessment decision are listed at the end of this document and are available on the Internet at http:// www. epa. gov/ pesticides/ reregistration/ status. htm and the public docket for viewing. Tolerances for residues of tebuthiuron are related to the consumption of secondary residues in meat and milk from livestock fed tebuthiuron­ treated grass forage and hay. The registered uses of tebuthiuron are classified in 40 CFR§ 180.390. The 40 CFR tolerance expression under 40 CFR§ 180.390 must be modified as follows: CFR§ 180.390 Tebuthiuron; tolerances for residues (a) Tolerances are established for the combined residues of the herbicide tebuthiuron (N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl­ N, N'­ dimethylurea) and its metabolites N­[ 5­( 2­ hydroxy­ 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N, N'dimethylurea –[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea, and N 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N'­ hydroxymethyl­ N­ methylurea in or on the following agricultural commodities: Grass, hay Grass, forage (b) Tolerances are established for the combined residues of the herbicide tebuthiuron (N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl­ N, N'­ dimethylurea) and its metabolites N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea, –[ 5­ (1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl] urea, 2­ dimethylethyl­ 5­ amino­ 1, 3, 4thiadiazole and N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N'­ hydroxymethylN methylurea in or on the following raw agricultural commodities: Cattle, fat Cattle, mbyp Cattle, meat Goats, fat Goats, mbyp Goats, fat Horses, fat Horses, mbyp Horses, meat Sheep, fat Sheep, mbyp Sheep, meat (c) A tolerance is established for the combined residues of the herbicide tebuthiuron (N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl­ N, N'­ dimethylurea) and its metabolites N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea, N­[ 5 2­ hydroxy­ 1, 1­ dimethylethyl)­ 1, 3, 4­ thiadiazol­ 2­ yl]­ N­ methylurea, N­[ 5­( 1, 1dimethylethyl 1, 3, 4­ thiadiazol­ 2­ yl] urea, N­[ 5­( 1, 1­ dimethylethyl)­ 1, 3, 4thiadiazol 2­ yl]­ N'­ hydroxymethyl­ N­ dimethylurea, and N­[ 5­( 2­ hydroxy­ 1, 1dimethylethyl 1, 3, 4­ thiadiazol­ 2­ yl]­ N'­ hydroxymethyl­ N­ methylurea in or on the following raw agricultural commodity: Milk The Codex Commission has established that there are no maximum residue limits (MRLs) for residues of tebuthiuron in/ on various raw agricultural and processed commodities. Therefore, issues of compatibility with respect to U. S. tolerances and Codex MRLs do not exist. Tebuthiuron Tolerances Commodity Current Tolerance (ppm) Reassessed Tolerance (ppm) Tolerance Reassessment Cattle, Fat 2 1 Lowered Cattle, MBYP 2 5 Raised Cattle, Meat 2 1 Lowered Goats, Fat 2 1 Lowered Goats, MBYP 2 5 Raised Goats, Meat 2 1 Lowered Grasses, Forage 20 10 Lowered Grasses, Hay 20 10 Lowered Horses, Fat 2 1 Lowered Horses, MBYP 2 5 Raised Horses, Meat 2 1 Lowered Milk 0. 3 0. 8 Raised Sheep, Fat 2 1 Lowered Sheep, MBYP 2 5 Raised Sheep, Meat 2 1 Lowered A generic Data Call­ In (DCI) that outlines further data requirements for this chemical will be prepared and mailed to you in the near future. If you have questions on this document, please contact the Chemical Review Manager, Wilhelmena Livingston, at (703) 308­ 8025. Lois A. Rossi, Director Special Review and Reregistration Attachments: TRED for Tebuthiuron Addendum to TRED Drinking Water Assessment for Tebuthiuron Product Chemistry Chapter for the TRED Residue Chemistry Chapter for the TRED Acute and Chronic Dietary Exposure Assessment for the TRED Toxicology Chapter for the TRED Third Report of the HIARC Committee Report of the FQPA Safety Factor Committee The Outcome of the HED MARC Meeting

epa

2024-06-07T20:31:42.671291

regulations

EPA-HQ-OPP-2002-0159-0002

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: February 7, 2002 SUBJECT: Chronic and Cancer Dietary Exposure Assessments for the Tolerance Reassessment Decision Document (TRED) for Pronamide; PC code [101701]; DP Barcode [D280422]. FROM: Dave Soderberg, Chemist Jose Morales, Chemist Steve Knizner, Branch Chief RRB3, Health Effects Division (HED) (7509C) THROUGH: Catherine Eiden, Branch Senior Scientist RRB3, Health Effects Division (7509C) And Christina Swartz, Chemist David Hrdy, Biologist Dietary Exposure Science Advisory Council (DESAC) Health Effects Division (7509C) And Chemistry Science Advisory Council (Chem SAC) Health Effects Division (7509C) TO: Gary Bangs, Industrial Hygienist RRB3 Health Effects Division (7509C) And Cecelia R. Watson, Chemical Review Manager Special Review and Reregistration Division (7508C) 1 cPAD = chronic Population Adjusted Dose = Chronic RfD FQPA Safety Factor 1 EPA Reviewers: Dave Soderberg, Jose Morales, Steve Knizner; Date: 17 Jan, 2002 STUDY TYPE: Chronic and Cancer Dietary Exposure Assessments for the Tolerance Reassessment Decision Document (TRED) for Pronamide SYNONYMS: Propyzamide [3, 5 dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide] RESIDUE OF CONCERN: The nature of the residue in plants and animals is adequately understood. The residues of concern are pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety. Executive Summary A chronic and cancer dietary exposure assessment was requested to support the Tolerance Reassessment Eligibility Document (TRED) for Pronamide. In response, a refined tier 3 chronic/ cancer dietary exposure assessment was conducted for all supported food uses (i. e, all currently registered and proposed uses). Although tolerance level residues were used for some newly registered crops, the assessment was based primarily upon residue monitoring data for fruits and vegetables and upon calculation of anticipated residues for meat, milk, poultry and eggs, and is the most refined to date for pronamide. We note that these data consisted almost entirely of non­ detectable residues. Estimates of percent crop treated (% CT) generated by the Biological and Economic Assessment Division (BEAD) were used to further refine this assessment. This assessment showed that the chronic risk estimates are below the Agency's level of concern (< 100% cPAD 1 ) for the general U. S. population and for all population subgroups. The chronic dietary exposure estimates for the two most highly exposed population subgroups, children 1­ 6 and seniors, are both estimated at 0.000005 mg/ kg/ day (< 1% cPAD). The cancer dietary risk estimate is 1.06 x 10 ­7 for the U. S. population, and is below the level that HED generally considers to be of concern (1.0 x 10 ­6 ). I. Introduction This memorandum provides the results of the dietary exposure assessment for the general U. S. population and various population subgroups to residues of pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety. Risk estimates were generated for chronic longterm and cancer dietary exposure using the most recent version of the Dietary Exposure Evaluation Model (DEEM™, Version 7.75), and using toxicological doses and endpoints 2 selected by the HED Hazard Identification Assessment Review Committee (HIARC). The committee concluded that toxicological effects were not expected after a single dietary dose and so did not select an acute dietary endpoint for pronamide. This assessment is the first dietary exposure analysis that has been conducted for pronamide under the Food Quality Protection Act (FQPA). A previous dietary assessment was a Dietary Risk Evaluation System (DRES) analysis reported by M. Metzger, Feb 19, 1994. For a general introduction to dietary exposure assessments references are available on the EPA/ pesticides web site. See, for instance: "Available Information on Assessing Exposure from Pesticides, A User's Guide", 6/ 21/ 2000, web link: http:// www. epa. gov/ fedrgstr/ EPA­ PEST/ 2000/ July/ Day­ 12/ 6061. pdf ; or see HED SOP 99.6, 8/ 20/ 99. II. Toxicological Information On November 6, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) evaluated the recommendations of the HED toxicologist for pronamide with regard to the acute and chronic Reference Doses (RfDs), and with regard to the toxicological endpoint selection for occupational/ residential exposure assessments. The potential for increased susceptibility of infants and children from exposure to pronamide was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. On December 3, 2001, the FQPA Safety Factor Committee met to evaluate both the hazard and exposure databases for pronamide. The Safety Factor Committee recommended that the 10x FQPA Safety Factor for pronamide be reduced to 3x. A summary of the doses and endpoints relevant to dietary exposure assessment is presented in Table 1. Table 1. Summary of Toxicological Doses and Endpoints for Pronamide for Use in Dietary Exposure Assessment EXPOSURE SCENARIO DOSE (MG/ KG/ DAY) ENDPOINT STUDY Acute Dietary females (13­ 50) and general population including infants and children No appropriate endpoint was available to quantitate risk to the general population from a singledose administration of pronamide. The developmental effect, abortion, was not considered to occur after a single dose in this instance because they were observed in rabbits during the post­ dosing phase of the study (days 22­ 24). Therefore, no endpoint was chosen to quantitate risk to females 13­ 50 from a single­ dose administration of pronamide. Chronic Dietary (all populations) NOAEL = 8.46 Increased relative (to body) liver weight and non­ neoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat UF = 100 FQPA SF = 3 Chronic RfD = 0.08 mg/ kg/ day Chronic PAD = 0.03mg/ kg/ day 3 Cancer Q1* = 2.59 x 10 ­ 2 (mg/ kg/ day) ­1 Group B2 chemical ­ "Probable human carcinogen" based on thyroid follicular cell adenomas (males and females) and benign interstitial cell tumors (males) in rats and hepatocellular carcinomas in male mice. Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat III. Residue Information Pronamide/ propyzamide [3, 5 dichloro­ n­( 1,1­ dimethyl­ 2­ propynyl) benzamide] tolerances are established under 40 CFR §180.317( a), (b), and (c). The tolerance expression, listed in (a) and (c), is in terms of "the combined residues of the herbicide propyzamide and its metabolites (containing the 3,5­ dichlorobenzoyl moiety and calculated as 3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide)." The tolerance expression, listed in (b), is in terms of the parent only. Pronamide tolerances listed in 40 CFR §180.317( a) range from 0.02 ppm (for certain animal commodities) to 10.0 ppm (for a non­ grass animal feeds group). The time­ limited tolerances listed in 40 CFR §180.317( b), with an expiration date of 12/ 31/ 01, are for Section 18 emergency exemptions for pronamide uses on cranberries (0.05 ppm) and grasses (forage 1.0 ppm and hay 0.5 ppm). The tolerances listed in 40 CFR §180.317( c) are for regional registrations of pronamide on dried (winter) peas (0.05 ppm) and rhubarb (0.1 ppm). Adequate enforcement methods are available for the determination of residues in/ on plant and animal commodities. Updates to the tolerances that are used in this document are taken from proposed reassessments of tolerances reported in the residue chemistry chapter of the TRED (J. Morales, in process). Pronamide is a systemic herbicide. Residues are translocated into the plant through the roots. Pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety are the residues of concern. Although pronamide is a large part of the total residue of interest, significant amounts of metabolites containing the 3,5­ dichlorobenzoyl moiety may also be present. The residues measured in field trials include these metabolites by incorporation of a hydrolysis step; however, results of monitoring by the U. S. Department of Agriculture, Agricultural Marketing Service's Pesticide Data Program (PDP) analyses are also used in this assessment for some crops, and analyses performed by PDP measured only the parent compound. Therefore, all PDP results are multiplied by a factor of 2 to assure that residues of the 3,5­ dichlorobenzoyl containing metabolites are conservatively accounted for in this assessment. [The factor of 2 comes from a report on a confined rotational crop study (L. Cheng, D197436, 5 May, 1994) that showed residues of the 3,5­ dichlorobenzoyl containing metabolites to be present in roughly equal amounts to the parent up to 97 days after treatment.] Because all PDP results, but one, are non­ detects, which are ordinarily valued at ½ of the method limit of detection (LOD), this means that the non­ detects in the PDP data for this assessment are valued at the LOD to account for the metabolites. Percent Crop Treated and Processing Information: 4 The percent crop treated (% CT) dataset from OPP's Biological and Economic Assessment Division (BEAD) is provided in Attachment 1. This report was last updated on September 26, 2001. No processing information was used in this assessment. DEEM™ default processing factors were used wherever they existed for processed food derived from the relevant crops. However, because residue data were available in the PDP database for grape juice, pear juice and apple juice, these PDP data were used directly, i. e, without DEEM default processing factors, for grape juice and grape wine, and for pear juice and apple juice. Factors for the juice concentrates were estimated from the ratio of the DEEM default factors for juice/ juice concentrate. Residue Estimates: Crops Apples ­ In the year 2000, PDP analyzed 184 samples of fresh apples and detected no residues of pronamide with an average LOD of 0.005 ppm. This result is also supported by multi­ year FDA testing for pronamide in apples with no detectable residues. The anticipated residue estimate (AR) for apples is 0.005 ppm. BEAD reported that 1% of the apple crop is treated with pronamide. For apples and all other crops, except lettuce, the percent crop treated value is applied as adjustment factor 2 in the DEEM TM program. Apple Juice ­ In 1998, PDP tested 619 samples of apple juice for pronamide and detected no residues. The average LOD was 0.013 ppm. The absence of residues in apple juice is supported by the absence of residues in apples. Therefore 0.013 ppm was used as the AR for apple juice. Because 1% of the apple crop was reported to be treated with pronamide, this was applied as adjustment factor 2. Since direct monitoring data were available, no processing factor was used for apple juice and the ratio of DEEM default processing factors of 3.9/ 1.3 = 3.0 was used for apple juice concentrate. Apricot ­ A previous AR memo (L. Cheng, 12/ 15/ 93, No DP Barcode) recommended an AR of 0.005 ppm (½ LOD) for stone fruits based upon the then available FDA data. Because FDA methods are capable of measuring parent only, and to assure that residues of 3,5­ dichlorobenzoyl containing metabolites are also included, an AR of 0.01 ppm, rather than the previously proposed 0.005 ppm, should be used. FDA has since tested the following numbers of stone fruit samples for pronamide between 1993 ­ 1999 with the same lower limit of reported results. Table 2. Number of Stone Fruit samples Tested by FDA in recent Years. No Residues of Pronamide were detected in these samples. 5 year/ crop 1993 1994 1995 1996 1997 1998 1999 apricots2828288 2 8 18 cherries 80 43 47 15 46 29 68 nectarines35454 2 6 6 4 peaches 116 189 117 75 105 114 77 plums 3 14 4 2 ­ ­ None of these samples contained any detectable residues of pronamide. As noted below, under the specific crops, in the year 2000 PDP tested cherries, nectarines and peaches for pronamide and all were non­ detects. A weighted average LOD from these various samples is 0.009 ppm. An AR of 0.01 ppm will therefore be translated to apricots. As noted under the peaches topic, cherries and plums were reported by BEAD to be treated at a rate of less than 1% of the crop. Thus, a value of 1 % crop treated was translated to all stone fruits. Artichoke ­ A previous AR memo (L. Cheng, 12/ 15/ 93, No DP Barcode) recommended an AR of 0.005 ppm based upon ½ of the lower limit reported in field trials (which also include testing for metabolites). BEAD reported that 21% of artichokes are treated with pronamide. Blackberries ­ A previous AR memo (L. Cheng, 12/ 15/ 93, No DP Barcode) recommended an AR of 0.01 ppm for blackberries, blueberries, boysenberries and raspberries based upon field trials. BEAD reported that 6% of blackberries are treated with pronamide. Blueberries ­ A previous AR memo (L. Cheng, 12/ 15/ 93, No DP Barcode) recommended an AR of 0.01 ppm for blackberries, blueberries, boysenberries and raspberries based upon field trials. BEAD reported that <1% of blackberries are treated with pronamide. HED practice is to default to 1% crop treated when BEAD reports less than 1% of the crop is treated. Boysenberries ­ A previous AR memo (L. Cheng, 12/ 15/ 93, No DP Barcode) recommended an AR of 0.01 ppm for blackberries, blueberries, boysenberries and raspberries based upon field trials. BEAD reported that 6% of blackberries are treated with pronamide, and this value was translated to boysenberries. Cherries ­ In the year 2000, PDP tested 275 samples of cherries for pronamide and detected no residues with an average LOD of 0.0106 ppm. This result is supported by multi­ year testing by FDA for pronamide in cherries and other stone fruits, as described above. Thus, the AR for cherries is 0.011 ppm. BEAD has reported that less than 1% of cherries are treated with pronamide, which is rounded up to 1% by HED. 6 Cranberries ­ The tolerance of 0.05 ppm was used for cranberries. No information was available on the percentage of the crop treated so it was assumed that 100% of cranberries are treated with pronamide. Endive ­ The tolerance of 1 ppm was used for endive. BEAD reported that 31% of the endive crop is treated with pronamide. Grapes: In the year 2000, PDP tested 741 grape samples for pronamide and detected no residues with an average LOD of 0.013. This result is supported by multi­ year testing by FDA for pronamide in grapes with no detections of pronamide. This value is the AR. BEAD has reported that <1% of grapes are treated with pronamide. Grape Juice ­ In 1998­ 1999, PDP analyzed 1007 samples of grape juice and found no residues of pronamide. This result is supported by the findings of no detectable residues in grapes. The average LOD of these analyses is 0.013 ppm. Therefore an AR of 0.013 was used for grape juice, grape juice concentrate and wine. BEAD reported that 1% of the grape crop is treated with pronamide. Since direct analyses were used, the DEEM processing factor was removed for grape juice, and was replaced by the ratio of the DEEM factors for grape juice concentrate/ grape juice (3.6/ 1.2 = 3.0) for grape juice concentrate. Lettuce: In 1999 ­ 2000, PDP analyzed 925 samples of fresh lettuce for pronamide (parent only). One sample contained a detectable residue at 0.012 ppm (evaluated here as 0.024 ppm to include metabolites). The average LOD for this data set is 0.0148 ppm. The average LOD, rather than ½ LOD, is used as a conservative estimate of the non­ detect level for all pronamide residues containing the dichlorobenzene ring because PDP analyzed only for parent pronamide. Lettuce is 36% crop treated in the assessment. The AR, including % crop treated, is 0.0053 ppm. (% CT cannot be applied separately for lettuce, because that would incorrectly change the one detectable residue. Nectarines ­ In the year 2000, PDP analyzed 345 nectarines for pronamide and detected no residues with an average LOD of 0.003 ppm. This finding is supported by multi­ year testing of various stone fruits by FDA with no detectable residues, as described above. As explained for peaches, the estimate of 1% crop treated is translated to nectarines. Peaches ­ In the year 2000, PDP tested 536 five­ pound composite samples of peaches for pronamide and detected no residues with an average LOD of 0.012 ppm. In the same year PDP tested 532 individual peaches for pronamide and detected no residues with an average LOD of 0.012 ppm. This finding is also supported by multi­ year testing of various stone fruits by FDA with no detectable residues, as described above. BEAD reported less than 1% crop treated for cherries and plums, but did not report usage for other stone fruits. Therefore, 1% crop treated is used for all stone fruits. Pears ­ In 1998 ­ 1999, PDP analyzed 1007 fresh pears for pronamide (parent only). None of the samples contained detectable residues. This finding is supported by the absence of residues in 7 PDP testing of apples and also by multi­ year testing by FDA with no detectable residues. The average LOD for this data set is 0.011 ppm. This value is used as the AR. This same value is used for pear juice and other processed pear commodities. PDP also analyzed canned pears in this time period, and also found no detects in these products. The value of 1% crop treated was translated from apples. Dried Peas ­ The tolerance of 0.05 ppm was used for dried peas. BEAD reported that considerably less than 1% of peas are treated with pronamide. Dried peas were presumed to be subsumed within this value, and since the reported value was below 0.1% crop treated for all peas, it was reasonable to use 1% crop treated for dried peas. Plums ­ As discussed under apricots, an AR of 0.01 ppm and 1% crop treated is also used for plums. Radicchio ­ The tolerance of 2 ppm was used for radicchio. No information was available on the percent of radicchio treated with pronamide, therefore, 100% of the crop was assumed to be treated. Raspberries ­ A previous AR memo (L. Cheng, 12/ 15/ 93, No DP Barcode) recommended an AR of 0.01 ppm for blackberries, blueberries, boysenberries and raspberries based upon field trials. BEAD reported that 5% of raspberries are treated with pronamide. Rhubarb ­ A previous AR memo (L. Cheng, 12/ 15/ 93, No DP Barcode) recommended an AR of 0.039 ppm for rhubarb based upon field trials. BEAD did not report what percent of rhubarb is treated with pronamide. In such cases HED practice is to default to 100% crop treated. Animal Products Chronic Anticipated Residues ­ Meat/ Milk/ Poultry/ Eggs Feedstuffs Anticipated residues for meat and milk were calculated using a dairy cattle feeding study and field trial data for residues of pronamide in/ on alfalfa, plus percent of crop treated information (A. Halverson, 9/ 26/ 01). The field trial data used to calculate the AR for alfalfa hay and meal were presented in a previous memo (L. Cheng, 12/ 17/ 93). Briefly, alfalfa seed, hay and meal were the major feed items for cattle and poultry. An anticipated residue (4.8 ppm) in alfalfa hay was calculated based on field data obtained from trials conducted in CA, ID, MN, WA (West of the Mississippi River), MS, NJ, NY, and PA (East of the Mississippi River). Alfalfa seed and meal were assumed to contain similar levels of pronamide residues. Because chronic ARs were being calculated, the alfalfa anticipated residue level for dietary burden calculations was adjusted by the percent of crop treated data. The estimated maximum percent crop treated from BEAD for alfalfa is 0.2% and the average is 0.1%. These estimates are far below the usual HED default of 1%, so HED considered using these actual estimates to avoid overestimating pronamide residues in the large consumption items: meat, milk, poultry and eggs. To assure this would be correct, HED consulted BEAD about the expected reliability of these 8 estimated values. For safety, BEAD recommended using a more conservative estimate of 0.5% (electronic communication, A. Halverson to D. Soderberg, 6 February 2002), and the ARs were calculated using this value of 0.5%. Meat and Fat Two groups of cattle were fed alfalfa hay containing 20 or 40 ppm field­ aged pronamide residues for three weeks. Residues in tissues are listed in Table 3. Table 3. Pronamide Residues in Meat and Fat. Sample Dose Level (ppm) Residues (ppm) Number of Samples Average Residue (ppm) after feeding at 20 ppm Kidney 20 40 0.05­ 0.31 0.66­ 1.18 2 2 0.18 Liver 20 40 0.23­ 0.55 0.92­ 1.48 2 2 0.39 Diaphragm muscle 20 40 <0.01­ 0.02 0.05­ 0.06 2 2 0.015 Front leg muscle 20 40 <0.01­ 0.02 0.03­ 0.05 2 2 0.015 Hind leg muscle 20 40 <0.01­ 0.02 0.03­ 0.06 2 2 0.015 Mesentery fat 20 40 0.02­ 0.08 0.21­ 0.48 2 2 0.05 Thoracic fat 20 40 <0.01­ 0.09 0.18­ 0.34 2 2 0.05 Kidney fat 20 40 0.02­ 0.10 0.25­ 0.47 2 2 0.06 Assuming 40% alfalfa hay (89% dry matter) and 10% alfalfa meal (89% dry matter) in the cattle diet, with an AR in both of 4.8 ppm and 0.5% crop treated, the anticipated dietary burden is 4.8 x 0.50/ 0.89 x 0.005 = 0.013 ppm. Using the results obtained from the 20 ppm feeding level, the following ARs are estimated: muscle, 0.015/ 20 x .013 = 1 x 10 ­5 ppm; fat, 4 x 10 ­5 ppm; liver, 2.5 x 10 ­4 ppm; and kidney, 1.2 x 10 ­4 ppm. Milk Rohm and Haas has submitted a feeding study in which 12 lactating Holstein and Guernsey cows were fed alfalfa hay containing pronamide residues at 3 dosage levels for varying 9 periods of time. The dosage levels were 1.8 ppm for 16­ 30 days; 7.5 ppm for 16­ 30 days; or 0.7 ppm for 21 days followed by 3.5 ppm for 16­ 30 days. Milk was collected twice daily and pooled for residue analysis. Results are summarized in Table 4. Table 4. Pronamide Residues in Milk. Sample Feeding Level, ppm Residues, ppm Number of Samples Range Average Milk 0.7 <0.005 <0.005 33 1.8 <0.005­ 0.007 <0.005 37 3.5 <0.005­ 0.01 0.005 38 7.5 0. 005­ 0.015 0.011 37 A dairy cattle diet of 50 percent alfalfa hay (89% dry matter) for which an anticipated residue of 4.8 ppm had been calculated, in conjunction with 0.2% crop treated, gives an anticipated dietary burden of 0.013 ppm. Based on the average residue in the feeding trial being non­ detectable at the 1.8 ppm feeding level and extrapolating from one­ half the limit of detection (½ LOD = 0.0025 ppm), anticipated residues in milk are 1.8 x 10 ­5 ppm. Poultry and eggs Hens in three groups of 15 animals were fed diets containing 0.22, 0.51, or 1.82 ppm pronamide residues for a period of up to seven weeks. Combined residues of pronamide and its metabolites were <0.01 ppm in all eggs from the 0.22 and 0.51 ppm feeding groups (94 eggs/ group). Eggs (7 samples) in the 1.82 ppm feeding group contained <0.01 ppm residues for the first five days of dosing, after which residues in 68 subsequent samples contained <0.01­ 0.022 ppm. Most samples contained residues at 0.01­ 0.016 ppm, and residues remained fairly stable over the duration of the experiment. Combined residues in gizzard, heart, muscle, skin, fat, and liver were <0.01 ppm in hens dosed at 0.22 ppm. At the 0.51 ppm dose level, 0.01 ppm residues were found in samples of fat and gizzard (6 samples), and liver. In hens dosed at 1.82 ppm, combined residues were 0.01­ 0.03 ppm in gizzard, <0.01 ppm in heart, <0.01 ppm (0.007, 0.008 ppm) in light meat, <0.01 ppm (0.007 ppm) in dark meat, <0.01­ 0.03 ppm in fat, and 0.02­ 0.04 ppm in liver. The expected dietary intake of pronamide by poultry is based on a diet of 20% alfalfa seed and 5% alfalfa meal, correcting for 0.5% crop treated, resulting in an anticipated dietary burden of 0.006 ppm. Based on the results from the 0.22 ppm feeding group (all non­ detectable residues) and using one­ half the limit of detection (½ LOD = 0.005 ppm), the AR for all poultry commodities is 1.4 x 10 ­4 ppm. Table 5. Data and Residue Estimates Used in Dietary Analyses 10 Crop Food Forms Included Source of Data Processing Factor Percent Crop Treated Anticipated Residue (ppm) Apples All PDP DEEM Default 1% 0. 005 Apple Juice All PDP 1% 0. 013 Apricots All translated from other stone fruits DEEM Default 1% 0. 01 Artichokes All previous AR memofield trials DEEM Default 21% 0.005 Blackberries All previous AR memofield trials DEEM Default 6% 0. 01 Blueberries All previous AR memofield trials DEEM Default 1% 0. 01 Boysenberries All previous AR memofield trials DEEM Default 6% 0. 01 Cherries All PDP DEEM Default 1% 0. 011 Cranberries All tolerance DEEM Default 100% 0.05 Endive All tolerance DEEM Default 31% 1.0 Grapes Fresh Grapes, Raisins and Leaves PDP DEEM Default 1% 0. 013 Grape Juice Juice, Concentrate and Wine PDP 1% 0. 013 Lettuce All PDP DEEM Default 0 0.0053 (includes % CT) Nectarines All PDP DEEM Default 1% 0. 003 Peaches All PDP DEEM Default 1% 0. 012 Pears All PDP DEEM Default 1% 0. 011 Peas (Dried) All tolerance DEEM Default 1% 0. 05 Plums All translated from other stone fruits DEEM Default 1% 0. 01 Prunes All translated from other stone fruits DEEM Default 1% 0. 01 Radicchio All tolerance DEEM Default 100% 2.0 Raspberries All previous AR memofield trials DEEM Default 5% 0. 01 Rhubarb All previous AR memofield trials DEEM Default 100% 0.039 Crop Food Forms Included Source of Data Processing Factor Percent Crop Treated Anticipated Residue (ppm) 11 Beef Muscle All calculated ARs DEEM Default N/ A 0.00001 Byproducts All calculated ARs DEEM Default N/ A 0.00012 Liver All calculated ARs DEEM Default N/ A 0.00025 Kidney All calculated ARs DEEM default N/ A 0.00012 Beef Fat All calculated ARs DEEM Default N/ A 0.00004 Other Organ Meat All calculated ARs DEEM Default N/ A 0.00012 Chicken Muscle All calculated ARs DEEM Default N/ A 0.00014 Byproducts All calculated ARs DEEM Default N/ A 0.00014 Liver All calculated ARs DEEM Default N/ A 0.00014 Fat All calculated ARs DEEM Default N/ A 0.00014 Other Organ Meat All calculated ARs DEEM Default N/ A 0.00014 Eggs All calculated ARs DEEM Default N/ A 0.00014 Goat Muscle All calculated ARs DEEM Default N/ A 0.00001 Byproducts All calculated ARs DEEM Default N/ A 0.00012 Liver All calculated ARs DEEM Default N/ A 0.00025 Kidney All calculated ARs DEEM default N/ A 0.00012 Fat All calculated ARs DEEM Default N/ A 0.00004 Other Organ Meat All calculated ARs DEEM Default N/ A 0.00012 Hog Muscle All calculated ARs DEEM Default N/ A 0.00001 Byproducts All calculated ARs DEEM Default N/ A 0.00012 Liver All calculated ARs DEEM Default N/ A 0.00025 Kidney All calculated ARs DEEM default N/ A 0.00012 Fat All calculated ARs DEEM Default N/ A 0.00004 Other Organ Meat All calculated ARs DEEM Default N/ A 0.00012 Horse Meat All calculated ARs DEEM Default N/ A 0.00001 Milk All calculated ARs DEEM Default N/ A 0.000018 Poultry Muscle All calculated ARs DEEM Default N/ A 0.000055 Crop Food Forms Included Source of Data Processing Factor Percent Crop Treated Anticipated Residue (ppm) 12 Byproducts All calculated ARs DEEM Default N/ A 0.000055 Liver All calculated ARs DEEM Default N/ A 0.000055 Fat All calculated ARs DEEM Default N/ A 0.000055 Other Organ Meat All calculated ARs DEEM Default N/ A 0.000055 Sheep Muscle All calculated ARs DEEM Default N/ A 0.00001 Byproducts All calculated ARs DEEM Default N/ A 0.00012 Liver All calculated ARs DEEM Default N/ A 0.00025 Kidney All calculated ARs DEEM default N/ A 0.00012 Fat All calculated ARs DEEM Default N/ A 0.00004 Other Organ Meat All calculated ARs DEEM Default N/ A 0.00012 Turkey Muscle All calculated ARs DEEM Default N/ A 0.000055 Byproducts All calculated ARs DEEM Default N/ A 0.000055 Liver All calculated ARs DEEM Default N/ A 0.000055 Fat All calculated ARs DEEM Default N/ A 0.000055 Other Organ Meat All calculated ARs DEEM Default N/ A 0.000055 Veal Muscle All calculated ARs DEEM Default N/ A 0.00001 Byproducts All calculated ARs DEEM Default N/ A 0.00012 Liver All calculated ARs DEEM Default N/ A 0.00025 Kidney All calculated ARs DEEM default N/ A 0.00012 Fat All calculated ARs DEEM Default N/ A 0.00004 Other Organ Meat All calculated ARs DEEM Default N/ A 0.00012 * Ordinarily, in this assessment, the ARs for the fruit and vegetable crops are based entirely upon LODs and the percent crop treated is entered into the DEEM program separately from the AR, as adjustment factor 2. However, this was not possible for lettuce, because lettuce has one sample with detected residues of pronamide. Therefore, for lettuce the AR includes the 36% crop treated and adjustment factor 2 is set to a value of 1. IV. DEEM™ Program and Consumption Information 13 The chronic and cancer dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model (DEEM™) software Version 7.75, which incorporates consumption data from USDA's Continuing Surveys of Food Intake by Individuals (CSFII), 1989­ 1992. The 1989­ 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive days, and therefore represent more than 30,000 unique "person days" of data. Foods "as consumed" (e. g., apple pie) are linked to raw agricultural commodities, and their food forms (e. g., apples­ cooked/ canned or wheat­ flour), by proprietary recipe translation files internal to the DEEM software. For chronic and cancer exposure and risk assessment, an estimate of the residue level in each food or food­ form (e. g., orange or orange­ juice) on the commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms on the commodity residue list to arrive at the total estimated exposure. Exposure estimates are expressed in mg/ kg body weight/ day and as a percent of the cPAD. This procedure is performed for each population subgroup. HED notes that there is a degree of uncertainty in estimating exposures for certain population subgroups that may not be sufficiently represented in the consumption surveys (e. g, nursing and non­ nursing infants or Hispanic females). Therefore, risks estimated for these population subgroups are not reported explicitly but are included within larger representative populations (e. g., all infants or females, 13­ 50 years). V. Results and Discussion A refined, tier 3, chronic and cancer dietary exposure assessment for pronamide was performed. The analysis was based primarily upon residue monitoring data for fruits and vegetables and upon calculated ARs for meat, milk, poultry and eggs. Field trial data and tolerance level residues were used for some minor crops. This assessment is the most refined to date for pronamide. Results for chronic exposure are shown in Table 6 and in Attachment 2. Results for cancer exposure are shown in Table 7 and Attachment 3. All results for all appropriate population subgroups are below HED's levels of concern. Table 6. Results of Chronic Dietary Exposure Analysis 14 Population Subgroup cPAD (mg/ kg/ day) Exposure (mg/ kg/ day) % cPAD U. S. Population (total) 0. 03 mg/ kg/ day 0. 000004 <1% All Infants (< 1 year) 0. 03 mg/ kg/ day 0. 000002 <1% Children 1­ 6 years 0. 03 mg/ kg/ day 0. 000005 <1% Children 7­ 12 years 0. 03 mg/ kg/ day 0. 000004 <1% Females 13­ 50 0.03 mg/ kg/ day 0. 000004 <1% Males 13­ 19 0.03 mg/ kg/ day 0. 000003 <1% Males 20+ years 0. 03 mg/ kg/ day 0. 000004 <1% Seniors 55+ 0.03 mg/ kg/ day 0. 000005 <1% Table 7. Results of Cancer Dietary Exposure Analysis Population Subgroup Exposure (mg/ kg/ day) Anticipated Cancer Risk U. S. Population (total) 0. 000004 1.06 X 10 ­7 VI. Uncertainties Because the estimated exposure is well below the chronic and cancer levels of concern, any uncertainties are unlikely to cause the exposure to exceed a level of concern. However, there are some conservative assumptions that may have introduced some uncertainties into this assessment. Tolerance level residues and 100 % CT were assumed for cranberries and radicchio. The LOD was used instead of ½LOD for the non­ detects in the PDP data. For the animal product ARs the maximum percent crop treated was assumed instead of the average percent crop treated. Default DEEM processing factors were used for most processed foods. VII. Conclusions A tier 3 chronic and cancer dietary risk assessment was conducted for all supported pronamide food uses. Chronic dietary risk estimates are provided for the general U. S. population and appropriate population subgroups. This assessment concludes that the chronic exposure estimates are below HED's level of concern (< 100% cPAD) for the general U. S. population and all population subgroups. The chronic dietary exposure estimate for both of the two highest population subgroups, children 1­ 6 years and seniors 55+ years, is 0.000005 mg/ kg/ day (< 1% of the cPAD) . The cancer dietary risk estimate associated with the use of pronamide for the U. S. population is 1.06 x10 ­7 , and is therefore below the level (1.0 x 10 ­6 ) that generally is of concern to HED. VIII. List of Attachments 15 Attachment 1: Quantitative Usage Analysis Attachment 2: Results of Chronic Dietary Exposure Analysis Attachment 3: Results of Cancer Dietary Exposure Analysis Attachment 4: Residue Input File cc: RRB3RF; D. Soderberg; S. Knizner; C. Eiden; C. Swartz; D. Hrdy; M. Sahafeyen. 16 Attachment 1. Quantitative Usage Analysis for Pronamide/ Propyzamide Case Number: 82 PC Code: 101701 Date: September 26, 2001 Analyst: Alan Halvorson Based on available pesticide usage information for 1991 through 2000, total annual domestic usage of herbicide pronamide (propyzamide) is approximately 225 thousand pounds active ingredient (a. i.). In terms of pounds a. i., total usage is allocated mainly to head lettuce (29%), other lettuce (19%), seed crops (13%), fallowland (11%), hay other than alfalfa (8%), horticulture (3%) and alfalfa (3%). Sites with 5% or more of acreage treated include lettuce other than head lettuce (49%), head lettuce (36%), California endive/ escarole (31%), artichokes (21%), blackberries (6%) and raspberries (5%). Rates per application and rates per year are each generally less than 2 pounds a. i. per acre for agricultural sites. States with significant usage in terms of pounds a. i. include Arizona, California, Oregon and Washington. Pronamide/ Propyzamide Case #: 0082 AI #: 101701 EPA QUANTITATIVE USAGE ANALYSIS Analyst: Alan Halvorson 9­ 26­ 01 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Acres Acres Treated (000) % Crop Treated Lb AI Appl'd (000) Avg Applic Rates/ Acre States of Most Usage (000) ­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­ (% of total lb ai Site Grown Est Est Est lb ai/ # appl/ lb ai/ used by these states) Avg Max Avg Max Avg Max year year appl ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Alfalfa 23,724 14.2 42.5 0.1% 0.2% 6.3 18.9 0.45 1.0 0.45 OR KS CA WA 100% Apples 513.9 2.9 8.8 1% 2% 4.1 12.3 1.41 1.0 1.41 OR WA NY 100% Apricots ­ 0* 0* 0* 0* 0* 0* ­ ­ ­ Artichokes 9.7 2.0 2.9 21% 30% 3.1 4.5 1.55 1.0 1.55 CA 100% Berries 175.9 2.1 4.2 1% 2% 2.2 4.3 1.03 1.0 1.03 OR WA NY 100% ­ Blackberries 5.3 0.3 0.5 6% 9% 0.3 0.4 0.79 1.0 0.79 OR 100% ­ Blueberries 59.1 0.1 0.2 0.1% 0.4% 0.1 0.2 0.97 1.0 0.97 OR NY 100% ­ Raspberries 13.9 0.7 1.1 5% 8% 0.9 1.5 1.38 1.0 1.38 OR WA 100% Cherries 117.6 0.2 0.6 0.2% 0.5% 0.2 0.6 1.00 1.0 1.00 MI OR 100% Clover, CA ­ 0.9 1.8 ­ ­ 0.9 1.8 1.01 1.0 1.01 Cole Crops 305.7 1.0 3.1 0.3% 1.0% 0.9 2.6 0.84 1.0 0.84 CA 100% Cucumbers, Process 71.5 0.3 1.0 0.4% 1.3% 0.3 0.9 0.94 1.2 0.78 NC 100% Endive/ Escarole, CA 3.3 1.0 1.3 31% 40% 0.9 1.1 0.87 1.0 0.87 Fallowland 19,334 96.1 192.2 0.5% 1.0% 24.0 48.0 0.25 1.0 0.25 WA ID 100% Grapes 942.7 0.2 0.7 0.02% 0.07% 0.4 1.2 1.87 1.0 1.87 PA NC 100% Hay, Other(*) 34,597 17.9 53.6 0.1% 0.2% 17.0 50.9 0.95 1.0 0.95 OR 100% Leafy Veget, Oth(**) 73.4 0.05 0.14 0.1% 0.2% 0.05 0.14 1.00 1.0 1.00 CA 100% ­ Celery 27.5 0.04 0.12 0.1% 0.4% 0.04 0.11 0.92 1.0 0.92 CA 100% Lettuce, Head 206.8 75.4 94.3 36% 46% 65.5 91.4 0.87 1.1 0.76 CA AZ 99% Lettuce, Other 84.8 41.6 55.1 49% 65% 41.5 60.0 1.00 1.2 0.81 CA 76% Nectarines ­ 0* 0* 0* 0* 0* 0* ­ ­ ­ Peaches 171.0 0.3 0.9 0.2% 0.5% 0.3 0.9 1.00 1.0 1.00 WA 100% 17 Pears 70.9 2.3 5.4 3% 8% 4.1 10.0 1.76 1.0 1.76 OR 100% ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Acres Acres Treated (000) % Crop Treated Lb AI Appl'd (000) Avg Applic Rates/ Acre States of Most Usage (000) ­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­ (% of total lb ai Site Grown Est Est Est lb ai/ # appl/ lb ai/ used by these states) Avg Max Avg Max Avg Max year year appl ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Peas, Green 270.6 0.4 1.2 0.1% 0.4% 0.4 1.3 1.09 1.0 1.09 MN 100% Peppers 68.1 0.2 0.6 0.3% 0.8% ­ ­ ­ 1.0 ­ Plums/ Prunes ­ 0* 0* 0* 0* 0* 0* ­ ­ ­ Rhubarb ­ ­ ­ ­ ­ ­ ­ ­ ­ ­ Roots/ Tubers(#) 235.8 3.3 6.5 1% 3% 2.9 5.8 0.89 1.0 0.89 CA 100% Seed Crops 1,382.7 42.2 63.3 3% 5% 28.1 42.2 0.67 1.0 0.67 OR 98% Sugar Beets 1,454.4 4.5 13.5 0.3% 0.9% 3.6 10.8 0.80 1.0 0.80 OR 100% Woodland 60,478 5.0 25.2 0.01% 0.04% 0.6 2.8 0.11 1.0 0.11 NC 100% Golf Courses ­ ­ ­ ­ ­ 5.1 10.3 ­ ­ ­ CA FL OK SC GA AL 93% Horticultural ­ ­ ­ ­ ­ 5.9 11.9 ­ ­ ­ FL North­ Central 100% Landscape Maint, CA ­ ­ ­ ­ ­ 1.5 3.1 ­ ­ ­ Lawn Care Operators ­ ­ ­ ­ ­ 0.4 0.8 ­ ­ ­ Ornamental Turf, CA ­ ­ ­ ­ ­ 1.0 2.1 ­ ­ ­ Rights­ of­ Way, CA ­ ­ ­ ­ ­ 0.1 0.2 ­ ­ ­ Turf Farms ­ ­ ­ ­ ­ 1.9 3.8 ­ ­ ­ Total 223.4 314.1 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ (*) Other than alfalfa (**) Other than lettuce (#) Beets, carrots, horseradish, parsnips, radish, rutabagas, sweet potatoes, turnips and yams. NOTES ON TABLE DATA ­­­­­­­­­­­­­­­­­­ ­ A dash(­) indicates that information is not readily available or is not applicable. ­ A "0*" indicates that available EPA sources show no observed usage for this site, which implies that there is little or no usage. ­ Allocation of usage among states includes only states covered in corresponding data sources. ­ Calculations of the above numbers may not appear to agree with each other because they are displayed as rounded. ­ Reported usage estimates above may include usage due to Section 18s, misuse, errors, etc. ­ Usage data cover 1992 ­ 2000 for agriculture and 1991 ­ 1999 for non­ agriculture. CROP/ SITE GROUPS AND DEFINITIONS ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­ Sites that reference California give usage only for California, not for the total U. S. ­ Sub­ categories under a crop group are not exhaustive. DATA SOURCES ­­­­­­­­­­­ ­ CA EPA, Summary of Pesticide Use Report Data, 1997, 1998 & 1999. ­ Garber & Hudson, Pest Management in the United States Greenhouse and Nursery Industry, 1993 data. ­ NCFAP, National Use Pesticide Database, circa 1992 & circa 1997. 18 ­ US EPA, proprietary data, 1991 ­ 1994 & 1996 ­ 2000. ­ USDA/ NASS, Agricultural Chemical Usage ­ Fruits Summary, 1993 & 1997. ­ Vegetables Summary, 1996, 1998 & 2000 19 Attachment 2. Results of Chronic Dietary Exposure Analysis U. S. Environmental Protection Agency Ver. 7.73 DEEM Chronic analysis for PRONAMIDE (1989­ 92 data) Residue file name: D:\ pronamidefeb6b. RS7 Adjustment factor #2 used. Analysis Date 02­ 07­ 2002/ 08: 47: 49 Residue file dated: 02­ 06­ 2002/ 17: 53: 38/ 8 Reference dose (RfD, Chronic) = .03 mg/ kg bw/ day COMMENT 1: contains PDP data from 2000 =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Percent of Subgroup body wt/ day Rfd ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­­­ U. S. Population (total) 0.000004 0.0% U. S. Population (spring season) 0.000005 0.0% U. S. Population (summer season) 0.000003 0.0% U. S. Population (autumn season) 0.000004 0.0% U. S. Population (winter season) 0.000005 0.0% Northeast region 0.000005 0.0% Midwest region 0.000003 0.0% Southern region 0.000003 0.0% Western region 0.000006 0.0% Hispanics 0.000005 0.0% Non­ hispanic whites 0.000004 0.0% Non­ hispanic blacks 0.000002 0.0% Non­ hisp/ non­ white/ non­ black 0.000005 0.0% All infants (< 1 year) 0.000002 0.0% 20 Nursing infants 0.000001 0.0% Non­ nursing infants 0.000003 0.0% Children 1­ 6 yrs 0.000005 0.0% Children 7­ 12 yrs 0.000004 0.0% Females 13­ 19 (not preg or nursing) 0.000002 0.0% Females 20+ (not preg or nursing) 0.000004 0.0% Females 13­ 50 yrs 0.000004 0.0% Females 13+ (preg/ not nursing) 0.000003 0.0% Females 13+ (nursing) 0.000004 0.0% Males 13­ 19 yrs 0.000003 0.0% Males 20+ yrs 0.000004 0.0% Seniors 55+ 0.000005 0.0% Pacific Region 0.000007 0.0% ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 21 Attachment 3. Results of Cancer Dietary Exposure Analysis U. S. Environmental Protection Agency Ver. 7.73 DEEM Chronic analysis for PRONAMIDE (1989­ 92 data) Residue file name: D:\ pronamidefeb6b. RS7 Adjustment factor #2 used. Analysis Date 02­ 07­ 2002/ 08: 48: 48 Residue file dated: 02­ 06­ 2002/ 17: 53: 38/ 8 Q* = 0.0259 COMMENT 1: contains PDP data from 2000 =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Lifetime risk Subgroup body wt/ day (Q*= .0259) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­ U. S. Population (total) 0.000004 1.06E­ 07 22 Attachment 4: Residue Input File U. S. Environmental Protection Agency Ver. 7.73 DEEM Chronic analysis for PRONAMIDE 1989­ 92 data Residue file: D:\ pronamidefeb6b. RS7 Adjust. #2 used Analysis Date 02­ 07­ 2002 Residue file dated: 02­ 06­ 2002/ 17: 53: 38/ 8 Reference dose (RfD) = 0.03 mg/ kg bw/ day Comment: contains PDP data from 2000 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Food Crop RESIDUE Adj. Factors Comment Code Grp Food Name (ppm) #1 #2 ­­­­ ­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ 1 13A Blackberries 0.010000 1.000 0.060 AR mem Full comment: AR memo ­ field trials 2 13A Boysenberries 0.010000 1.000 0.060 AR mem Full comment: AR memo ­ field trials 5 13A Raspberries 0.010000 1.000 0.050 AR mem Full comment: AR memo ­ field trials 7 13B Blueberries 0.010000 1.000 0.010 AR mem Full comment: AR memo ­ field trials 8 O Cranberries 0.050000 1.000 1.000 tolera Full comment: tolerance 9 O Cranberries­ juice 0.050000 1.100 1.000 tolera Full comment: tolerance 13 O Grapes 0.013000 1.000 0.010 PDP 14 O Grapes­ raisins 0.013000 4.300 0.010 PDP 15 O Grapes­ juice 0.013000 1.000 0.010 PDP 52 11 Apples 0.005000 1.000 0.010 PDP 53 11 Apples­ dried 0.005000 8.000 0.010 PDP 54 11 Apples­ juice/ cider 0.013000 1.000 0.010 PDP 56 11 Pears 0.011000 1.000 0.010 PDP 57 11 Pears­ dried 0.011000 6.250 0.010 PDP 59 12 Apricots 0.010000 1.000 0.010 other 23 Full comment: other stone fruits 60 12 Apricots­ dried 0.010000 6.000 0.010 other Full comment: other stone fruits 61 12 Cherries 0.011000 1.000 0.010 PDP 62 12 Cherries­ dried 0.011000 4.000 0.010 PDP 63 12 Cherries­ juice 0.011000 1.500 0.010 PDP 64 12 Nectarines 0.003000 1.000 0.010 PDP 65 12 Peaches 0.012000 1.000 0.010 PDP 66 12 Peaches­ dried 0.012000 7.000 0.010 PDP 67 12 Plums (damsons) 0.010000 1.000 0.010 other Full comment: other stone fruits 68 12 Plums­ prunes (dried) 0.010000 5.000 0.010 other Full comment: other stone fruits 69 12 Plums/ prune­ juice 0.010000 1.400 0.010 other Full comment: other stone fruits 176 4A Lettuce­ leafy varieties 0.005300 1.000 1.000 PDP 178 4A Endive­ curley and escarole 1.000000 1.000 0.310 tolera Full comment: tolerance 181 O Artichokes­ globe 0.005000 1.000 0.210 AR mem Full comment: AR memo ­ field trials ­ 1/ 2 LOD 182 4A Lettuce­ unspecified 0.005300 1.000 1.000 PDP 185 4B Rhubarb 0.039000 1.000 1.000 AR mem Full comment: AR memo ­ field trial average 192 4A Lettuce­ head varieties 0.005300 1.000 1.000 PDP 195 O Grapes­ leaves 0.013000 1.000 0.010 PDP 203 1CD Artichokes­ jerusalem 0.005000 1.000 0.210 AR mem Full comment: AR memo ­ field trials ­ 1/ 2 LOD 240 6C Peas (garden)­ dry 0.050000 1.000 0.010 tolera Full comment: tolerance 315 O Grapes­ wine and sherry 0.013000 1.000 0.010 PDP 318 D Milk­ nonfat solids 0.000018 1.000 1.000 AR 319 D Milk­ fat solids 0.000018 1.000 1.000 AR 320 D Milk sugar (lactose) 0.000018 1.000 1.000 AR 24 321 M Beef­ meat byproducts 0.000120 1.000 1.000 AR 322 M Beef­ other organ meats 0.000120 1.000 1.000 AR 323 M Beef­ dried 0.000010 1.920 1.000 AR 324 M Beef­ fat w/ o bones 0.000040 1.000 1.000 AR 325 M Beef­ kidney 0.000120 1.000 1.000 AR 326 M Beef­ liver 0.000250 1.000 1.000 AR 327 M Beef­ lean (fat/ free) w/ o bones 0.000010 1.000 1.000 AR 328 M Goat­ meat byproducts 0.000120 1.000 1.000 AR 329 M Goat­ other organ meats 0.000120 1.000 1.000 AR 330 M Goat­ fat w/ o bone 0.000040 1.000 1.000 AR 331 M Goat­ kidney 0.000120 1.000 1.000 AR 332 M Goat­ liver 0.000250 1.000 1.000 AR 333 M Goat­ lean (fat/ free) w/ o bone 0.000010 1.000 1.000 AR 334 M Horsemeat 0.000010 1.000 1.000 AR 336 M Sheep­ meat byproducts 0.000120 1.000 1.000 AR 337 M Sheep­ other organ meats 0.000120 1.000 1.000 AR 338 M Sheep­ fat w/ o bone 0.000040 1.000 1.000 AR 339 M Sheep­ kidney 0.000120 1.000 1.000 AR 340 M Sheep­ liver 0.000250 1.000 1.000 AR 341 M Sheep­ lean (fat free) w/ o bone 0.000010 1.000 1.000 AR 342 M Pork­ meat byproducts 0.000120 1.000 1.000 AR 343 M Pork­ other organ meats 0.000120 1.000 1.000 AR 344 M Pork­ fat w/ o bone 0.000040 1.000 1.000 AR 345 M Pork­ kidney 0.000120 1.000 1.000 AR 346 M Pork­ liver 0.000250 1.000 1.000 AR 347 M Pork­ lean (fat free) w/ o bone 0.000010 1.000 1.000 AR 355 P Turkey­ byproducts 0.000140 1.000 1.000 AR 356 P Turkey­ giblets (liver) 0.000140 1.000 1.000 AR 357 P Turkey­­ fat w/ o bones 0.000140 1.000 1.000 AR 358 P Turkey­ lean/ fat free w/ o bones 0.000140 1.000 1.000 AR 360 P Poultry­ other­ lean (fat free) w/ 0.000140 1.000 1.000 AR 361 P Poultry­ other­ giblets( liver) 0.000140 1.000 1.000 AR 362 P Poultry­ other­ fat w/ o bones 0.000140 1.000 1.000 AR 25 363 P Eggs­ whole 0.000140 1.000 1.000 AR 364 P Eggs­ white only 0.000140 1.000 1.000 AR 365 P Eggs­ yolk only 0.000140 1.000 1.000 AR 366 P Chicken­ byproducts 0.000140 1.000 1.000 AR 367 P Chicken­ giblets( liver) 0.000140 1.000 1.000 AR 368 P Chicken­ fat w/ o bones 0.000140 1.000 1.000 AR 369 P Chicken­ lean/ fat free w/ o bones 0.000140 1.000 1.000 AR 377 11 Apples­ juice­ concentrate 0.013000 3.000 0.010 PDP 380 13A Blackberries­ juice 0.010000 1.000 0.060 AR mem Full comment: AR memo ­ field trials 385 P Chicken­ giblets (excl. liver) 0.000140 1.000 1.000 AR 389 O Cranberries­ juice­ concentrate 0.050000 3.300 1.000 tolera Full comment: tolerance 392 O Grapes­ juice­ concentrate 0.013000 3.000 0.010 PDP 398 D Milk­ based water 0.000018 1.000 1.000 AR 402 12 Peaches­ juice 0.012000 1.000 0.010 PDP 404 11 Pears­ juice 0.011000 1.000 0.010 PDP 410 12 Apricot juice 0.010000 1.000 0.010 other Full comment: other stone fruits 424 M Veal­ fat w/ o bones 0.000040 1.000 1.000 AR 425 M Veal­ lean (fat free) w/ o bones 0.000010 1.000 1.000 AR 426 M Veal­ kidney 0.000120 1.000 1.000 AR 427 M Veal­ liver 0.000250 1.000 1.000 AR 428 M Veal­ other organ meats 0.000120 1.000 1.000 AR 429 M Veal­ dried 0.000010 1.920 1.000 AR 430 M Veal­ meat byproducts 0.000120 1.000 1.000 AR 449 P Turkey­ other organ meats 0.000140 1.000 1.000 AR 492 O Radicchio 2.000000 1.000 1.000 tolera Full comment: tolerance

epa

2024-06-07T20:31:42.681845

regulations

EPA-HQ-OPP-2002-0159-0003

Supporting & Related Material

1 Drinking Water Assessment PronamideTRED. wpd UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES PC Code: 101701 DP Barcode: D274842 MEMORANDUM May 16, 2001 SUBJECT: Drinking Water Assessment to Support TRED for Propyzamide (Pronamide) FROM: Lucy Shanaman, Chemist Environmental Risk Branch IV Environmental Fate and Effects Division THROUGH: Betsy Behl, Chief Environmental Risk Branch IV Environmental Fate and Effects Division R. David Jones, Senior Agronomist Environmental Risk Branch IV Environmental Fate and Effects Division TO: Susan Lewis, Branch Chief Reregistration Branch I Special Review Reregistration Division This memo presents the Tier I Drinking Water Assessment for propyzamide calculated using FIRST (surface water) and SCIGROW (groundwater) for use in the human health risk assessment. For surface water, the acute (peak) value is 390 ppb, and the chronic (average annual) value is 122 ppb. The groundwater screening concentration is 3.0 ppb. These concentrations were predicted from recommended use information for ornamental herbaceous plants, and represent upper­ bound estimates of the concentrations that might be found in surface water and groundwater due to the use of pronamide/ propyzamine on registered crops. Should the results of this assessment indicate a need for further refinement, please contact us as soon as possible so that we may schedule a Tier II assessment. 2 Drinking Water Assessment PronamideTRED. wpd Background Information on FIRST: As indicated in the User's Manual, `FIRST' is a first tier screening model designed as a coarse screen to estimate the pesticide concentrations found in an `Index Reservoir' located in Shipman, Illinois for use in environmental risk assessments for drinking water. As such, it provides high­ end values on the concentrations due to the use of a pesticide in drinking water that might be found derived from surface water. Pesticide concentration values estimated using this scenario should be exceeded only rarely in the source water at the intake pipe of a community water supply (CWS) systems in the United States. This first level tier is designed as a coarse screen and estimates concentrations from only a few basic chemical parameters and pesticide label application information. The program considers reductions in dissolved concentration: (1) due to the percentage of the watershed which is cropped, (2) due to adsorption of pesticide to field soil and to reservoir bottom sediment, (3) due to incorporation of the pesticide at the time of application, (4) due to degradation in soil before washoff to the reservoir, and (5) due to degradation of the pesticide within the water body. Reservoir water concentrations may be increased due to deposition of spray drift into the feeding stream or directly into the reservoir itself. The program does not consider the impact of water treatment processes. The `FIRST' program is designed to mimic a more complex simulation such as using the linked PRZM and EXAMS models, but requires less time and effort to complete. If a risk assessment performed using `FIRST' output does not exceed the level of concern, then one can be reasonably confident that the acute risk will not be exceeded. However, because `FIRST' can substantially overestimate true drinking water concentrations, it will be necessary to refine the `FIRST' estimates if the level of concern is exceeded. Background Information on SCIGROW: SCIGROW provides a groundwater screening exposure value to be used in determining the potential risk to human health from drinking water contaminated with the pesticide. Since the SCIGROW concentrations are likely to be approached in only a very small percentage of drinking water sources, i. e., highly vulnerable aquifers, it is not appropriate to use SCIGROW concentrations for national or regional exposure estimates. SCIGROW estimates likely groundwater concentrations if the pesticide is used at the maximum allowable rate in areas where groundwater is exceptionally vulnerable to contamination. In most cases, a large majority of the use area will have groundwater that is less vulnerable to contamination than the areas used to drive the SCIGROW estimate. 3 Drinking Water Assessment PronamideTRED. wpd Modeling Inputs and Results Table 1 and Table 2 summarize the general input values used in the model runs for FIRST and SCIGROW, respectively for pronamide (propyzamide), applied four times by low pressure ground spray, at a rate of two pounds per acre to ornamental herbaceous plants. FIRST predicted surface water acute peak concentration is 390 ppb. Chronic (average annual) concentration is 122 ppb. SCIGROW predicted groundwater concentration is 3.0 ppb. Modeling results for low pressure ground spray application to ornamental herbaceous plants appear in Table 3. FIRST and SCIGROW output files appear at the end of this document. Appendix I summarizes (1) the yearly application rates for individual crops as application rate and number of applications per year (pounds/ acre) for (2) specific methods of application, along with the (3) FIRST and (4) SCIGROW output values for all registered uses. Table 1. Input Parameters for FIRST Chemical propyzamide PC Code 101701 Water Solubility (25 °C) 15 mg/ L Hydrolysis Half­ Life (pH7) stable Aerobic Soil Metabolism Half­ Life 1176 days (n= 1; use 3 x reported half­ life) Aerobic Aquatic Metabolism Half­ Life 2352 days (no reported value; use 2 x aerobic soil metabolism value) Photolysis Half­ Life 41 days Organic Carbon Adsorption Coefficient (Koc) 504 L/ kg (slope of plot, adsorption Kd versus % organic carbon Application Method low pressure ground spray Application Rate 2 lbs. a. i./ acre Application Frequency 4 per year Interval Between Applications 21 days 4 Drinking Water Assessment PronamideTRED. wpd Table 2. Input Parameters for SCIGROW Chemical propyzamide PC Code 101701 Organic Carbon Adsorption Coefficient (Koc) 701 L/ kg Aerobic Soil Metabolism Half­ Life 392 days Application Rate 2 lbs. a. i./ acre Application Frequency 4 per year Table 3. Modeling Results Based on Low Pressure Ground Spray Application of Propyzamide to Ornamental Herbaceous Plants Model Concentration FIRST Peak Day (Acute) 390 ppb FIRST Annual Average (Chronic) 122 ppb SCIGROW Ground Water Value 3. 0 ppb 5 Drinking Water Assessment PronamideTRED. wpd RUN No. 9 FOR Pronamide on ornamental herbaceous plants (8 lb/ Acre, ground spray) INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RATE (#/ AC) No. APPS & SOIL SOLUBIL APPL TYPE %CROPPED INCORP ONE( MULT) INTERVAL Koc (PPM ) (% DRIFT) AREA (IN) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 2.000( 7.854) 4 21 504.0 15.0 GROUND( 6.4) 87.0 .0 FIELD AND RESERVOIR HALFLIFE VALUES (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED (FIELD) RAIN/ RUNOFF (RESERVOIR) (RES.­ EFF) (RESER.) (RESER.) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 1176.00 2 N/ A 41.00­ 5084.00 ****** 1608.06 UNTREATED WATER CONC (MICROGRAMS/ LITER (PPB)) Ver 1.0 MAY 1, 2001 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ PEAK DAY (ACUTE) ANNUAL AVERAGE (CHRONIC) CONCENTRATION CONCENTRATION ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 390.164 139.657 (Multiply by 0.87 to correct error in program) RUN No. 9 FOR Proamide on ornamental herbaceous plants (8 lb/ Acre, ground spray) INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APPL (#/ AC) APPL. URATE SOIL SOIL AEROBIC RATE NO. (#/ AC/ YR) KOC METABOLISM (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 2.000 4 8.000 701.0 392.0 GROUND­ WATER SCREENING CONCENTRATIONS IN PPB ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 3.014783 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ A= 387.000 B= 706.000 C= 2.588 D= 2.849 RILP= 2.979 F= ­. 424 G= .377 URATE= 8.000 GWSC= 3.014783 6 Drinking Water Assessment PronamideTRED. wpd APPENDIX I Modeling Results for use on Registered Crops CROP APPLICATION RATE PER YEAR (pounds / acre) FREQUENCY (number of uses / interval between use, in days ) FIRST DRINKING WATER VALUES (ppb) SCIGROW GROUND WATER VALUES (ppb) APPLICATION METHOD Peak Day Annual Average C fallow 0. 51 NA 25.96 8.29 0.192192 aircraft C endive C lettuce 2.04 NA 103.85 33.17 0.768770 aircraft C Christmas tree 3.06 NA 155.78 49.76 1.153154 aircraft C artichoke 4.08 2 / 21 206.46 65.95 1.537539 aircraft C lettuce 6.12 NA 311.56 99.52 2.306309 aircraft C fallow 0. 51 NA 25.33 7.89 0.192192 low pressure ground sprayer C ornamental sod farm (turf) C peas (filled) 1.53 NA 76.00 23.66 0.576577 low pressure ground sprayer C alfalfa C blueberry C chicory C clover C crown vetch C endive C grass for seed C lettuce C ornamental shade trees C ornamental lawns and turf C ornamental woody shrubs / vines C rhubarb C sainfoin C trefoil 2.04 NA 101.33 31.55 0.768770 low pressure ground sprayer C blackberry C boysenberry C Christmas tree C raspberry (black, red) 3.06 NA 151.99 47.33 1.153154 low pressure ground sprayer 7 Drinking Water Assessment PronamideTRED. wpd C lettuce 6.12 NA 303.98 94.66 2.306309 low pressure ground sprayer C ornamental herbaceous plants 8 2 / 4 390.16 121.50 3.014783 low pressure ground sprayer C sugar beet 1.02 NA 50.66 15.77 0.384385 sprayer C golf course turf C recreational areas 1.5 NA 75.50 23.20 0.565272 sprayer C apricot C apple C artichoke, C cherry C grapes C nectarine C peach C pear C plum C prune 4.08 NA 202.65 63.10 1.537539 sprayer C alfalfa C chicory C endive C lettuce 2.04 NA 101.33 31.55 0.768770 soil incorporation equipment

epa

2024-06-07T20:31:42.697596

regulations

EPA-HQ-OPP-2002-0159-0004

Supporting & Related Material

1 EPA Pesticides in Ground Water Database, A Compilation Of Monitoring Studies: 1971­ 7991 National Summary; Office of Pesticide Programs, Environmental Fate and Effects Division; Environmental Fate and Ground Water Branch, Jacoby H.; Pesticide Monitoring Program Section, Hoheisel C, Karrie J, Lees S, Davies­ Hilliard L, Hannon P, Bringham R; Ground Water Technology Section, Behl E, Wells D, Waldman E. 2 J. D. Blomquist, J. M. Davis, J. L. Cowles, J. A. Hetrick, R. D. Jones, and N. B. Birchfield. 2001. Pesticides in Selected Water­ Supply Reservoirs and Finished Drinking Water, 1 Final Water Assessment PronamideTIER2.wpd UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES PC Code: 101701 DP Barcodes: D281443, D281445 MEMORANDUM June 5, 2002 SUBJECT: Tier II Drinking Water Assessment to Support TRED for Pronamide (Propyzamide) FROM: Lucy Shanaman, Chemist Environmental Risk Branch IV Environmental Fate and Effects Division THROUGH: RDavid Jones, Senior Scientist Environmental Risk Branch IV Environmental Fate and Effects Division Betsy Behl, Chief Environmental Risk Branch IV Environmental Fate and Effects Division TO: Robert McNally, PM 60 Cecelia Watson, PM team reviewer Special Review Branch Special Review Reregistration Division This memo presents the Tier II Drinking Water Assessment for pronamide (propyzamine) in surface water, calculated using PRZM/ EXAMS, and a Tier I Drinking Water Assessment in groundwater using SCIGROW, for use in the human health risk assessment. Pronamide detections have been found in monitoring data from both the USGS, NAWQA database, the EPA Pesticides in Ground Water Database 1 , and the pilot reservoir monitoring program 2 . Tier 1 and Tier 2 modeling 1999­ 2000: Summary of Results from a Pilot Monitoring Program. Open­ file Report 01­ 456. Baltimore, MD. 2 Final Water Assessment PronamideTIER2.wpd results of the most current drinking water exposures for use of pronamide on registered crops follows: 1. SURFACE WATER (output tables in Appendix I) EFED's PRZM/ EXAMS model results (input parameters in table 1) for use of pronamide on registered crops (application rates of between 1.5 ­ 4.0 lb/ acre; Table 2) for drinking water derived from surface sources: 10.3 ug/ L (ppb)* for acute exposure from application to pears in Oregon (one in ten year peak value) 4.45 ug/ L (ppb)* for non­ cancer chronic exposure from application to alfalfa in California (one in ten year annual mean value) 4.30 ug/ L (ppb)* for cancer exposure from application to alfalfa in California (overall mean annual value from 36 years) * Reported values adjusted for percent crop area by multiplying by a factor of 0.86, as dictated by EFED policy. 2. GROUND WATER (output in Appendix II) EFED's SCI­ GROW model screening level results for pronamide groundwater screening concentration for an application to all crops at a rate of 4.0 lbs. of active ingredient per acre: 1.1 ug/ L (ppb) (for both acute and chronic exposures) Monitoring Data Pronamide detections have been found in monitoring data from the USGS, NAWQA database, EPA Pesticides in Ground Water Database, and the Pilot Reservoir Monitoring Program. The USGS, NAWQA national database indicates that, out of almost 14 thousand samples, pronamide is detected in surface water in < 3% of the samples. The maximum recorded value is 0.365 ppb. Between 1984 and 1990, a total of 432 wells were sampled for the EPA Pesticides in Ground Water Database. No detections of pronamide were recorded for tested locations in California, Mississippi, or Oregon. A total of 12 sites were chosen for the Pilot Reservoir Monitoring Program to represent locations that are particularly vulnerable to pesticide contamination. Only one reservoir out of the twelve, located in Oklahoma, recorded positive 3 http:// ca. water. usgs. gov/ pnsp/ use92/ pronmid. html 3 Final Water Assessment PronamideTIER2.wpd detections for pronamide of up to 0.044 ppb in 83% (34 of 41) of the raw water samples, and up to 0.012 ppb in 42 % (8 of 19) of the finished water samples. It is worth noting that only a cursory review of the monitoring data has been presented here. It can not be determined if this monitoring data is representative of pronamide use nation wide, based on this level of analysis. In none of these studies, were sites selected based on pronamide use patterns. A more extensive evaluation of the monitoring data could reveal what percentage of the samples reported were collected within a vulnerable time frame, and from locations where pronamide was actually being used. The pesticide use map below, taken from the USGS, NAWQA program web site 3 , shows historical regional scale patterns in use intensity within the United States. The map is based on state­ level estimates of pesticide use rates compiled by the National Center for Food and Agricultural Policy (NCFAP) for 1991, 1992, 1993 and 1995, and on county­ based crop acreage data obtained from the 1992 Census of Agriculture, and indicates that the major current agricultural uses are for lettuce, alfalfa, grass and pears. The map depicts that the heaviest historical agricultural uses are in California, the Pacific Northwest, and in smaller scattered pockets use sites. It is interesting to note that the only site within the Pilot Reservoir Monitoring Program reporting proanamide detections was in Oklahoma, where the above map indicates that proanamide does not have extensive agricultural use. USGS, NAWQA Pesticide National Synthesis Project 4 soils and scenario data for the standard scenarios is located at: F:\ USER\ SHARE\ Models\ Aquatic Exposure\ PRZMEXAMS\ Scenarios\ STD_ SCEN\ Standard Scenario Documentation 4 Final Water Assessment PronamideTIER2.wpd Models Used The Tier 2 Estimated Environmental Concentrations (EEC's) for the major registered crop uses were calculated using two models: PRZM version 3.12 (Carsel et al., 1997), dated May 7, 1998 to simulate the transport of the pesticide off the field, and EXAMS 2.97.5 (Burns, 1997), dated June 13, 1997, to simulate the fate of the chemicals in the water body. Both models were launched from a shell (pe3) recently developed within EFED, and adopted for use on February 27, 2002. SCIGROW (version 2.1; May 1, 2001) provides a Tier 1, groundwater screening exposure value to be used in determining the potential risk to human health from drinking water contaminated with the pesticide. While use of this version is provisional, it is expected to produce more accurate estimated values for compounds with longer half lives. In most cases, a large majority of the use area will have groundwater that is less vulnerable to contamination than the areas used to drive the SCIGROW estimate. Scenarios Several standard scenarios were chosen to model estimated environmental concentrations in surface water resulting from the proposed crop uses of pronamide, based on particularly vulnerable crop sites for registered uses. Meteorological data files were adjusted to reflect irrigation amounts required for wetting­ in of pronamide, as per label recommendation, by including the required additional water in with the recorded precipitation for each application date. Four standard, index reservoir scenarios were chosen as surrogates for estimating environmental concentrations in sites more vulnerable to the offsite movement of pesticide than most sites planted with their respective crops. The standard Oregon apples scenario was used to represent application of pronamide to northwestern pear orchards. The apple scenario is an orchard in Marion County, Oregon, MLRA A2. The soil at the site is Cornelius silt loam, a fine­ silty, mixed, superactive, mesic Mollic Fragixeralfs. Data for the Cornelius silt loan was taken from the USDA National Cooperative Soil Survey, Official Series Description 4 . Weather data was taken from wether station W24232, at Salem, Oregon. The weather data file is part of the PIRANHA shell, and is used to represent the weather for MLRA A2. The standard California alfalfa scenario was used to represent application of pronamide to alfalfa crops, in general. The alfalfa scenario is a field in the central valley of California, MLRA 17. The soil at the site is Sacramento clay, very­ fine, smectitic, thermic Cumulic Vertic Endoaquolls. Data for the Sacramento clay was taken from the USDA National Cooperative Soil Survey, Official 5 soils and scenario data for the standard scenarios is located at: F:\ USER\ SHARE\ Models\ Aquatic Exposure\ PRZMEXAMS\ Scenarios\ STD_ SCEN\ Standard Scenario Documentation 6 soils and scenario data for the standard scenarios is located at: F:\ USER\ SHARE\ Models\ Aquatic Exposure\ PRZMEXAMS\ Scenarios\ STD_ SCEN\ Standard Scenario Documentation 7 soils and scenario data for the standard scenarios is located at: F:\ USER\ SHARE\ Models\ Aquatic Exposure\ PRZMEXAMS\ Scenarios\ STD_ SCEN\ Standard Scenario Documentation 5 Final Water Assessment PronamideTIER2.wpd Series Description 5 . Weather data was taken from weather station W23155, at Bakersfield, California. The weather data file is part of the PIRANHA shell, and is used to represent the weather for MLRA 17. The standard Oregon seed grass scenario was chosen to represent application of pronamide to both field and seed grass sites. The seed grass scenario is a field in Portland, Oregon in MLRA 2. The soil at the site is Dayton silt loam, a fine, smectitic, mesic Vertic Albaqualfs. Data for the Dayton silt loam was taken from the USDA National Cooperative Soil Survey, Official Series Description 6 . Weather data was taken from wether station W24232, at Salem, Oregon. The weather data file is part of the PIRANHA shell, and is used to represent the weather for MLRA 2. The standard Florida cabbage scenario was chosen to represent application of pronamide to east coast lettuce crops. The Florida cabbage scenario is a field in Tampa, Florida in MLRA 156B. The soil at the site is Riviera sand,, loamy, siliceous, active, hyperthermic Arenic Glossaqualfs. Data for the Riviera sand was taken from the USDA National Cooperative Soil Survey, Official Series Description 7 . Weather data was taken from weather station W12844, at West Palm Beach, Florida. The weather data file is part of the PIRANHA shell, and is used to represent the weather for MLRA 156B. The configuration of the water body represented by these standard scenario sites are a 172.8 hectare watershed draining into a 5.26 hectare lake, 2.74 m deep. The scenario known as the index reservoir, was developed to represent a watershed that was more vulnerable than most watersheds to pesticide contamination. It represents a real drinking water reservoir in Illinois, Shipman City Lake. The geometry of the index reservoir and its watersher are used with local weather and soils to represent vulnerable watersheds for different crops in different regions of the country. A detailed description of the index reservoir found in the guidance for using the index reservoir (U. S. Environmental Protection Agency, 2000). 8 http:// www. epa. gov/ oppefed1/ models/ water/ index. htm 6 Final Water Assessment PronamideTIER2.wpd Modeling Inputs and Results Table 1 and Table 2 summarize the general input values used in the model runs for PRZM/ EXAMS and SCIGROW, respectively for pronamide, applied annually by ground spray, at rates between 1.5 and 4.0 pounds per acre applied to registered crops. Surface water modeling results appear in Table 3. PRZM/ EXAMS and SCIGROW output files have been appended to this document. Table 1. Input Parameters for PRZM/ EXAMS (pe3 shell input) Chemical pronamide Water Solubility (25 °C) 15 mg/ L Hydrolysis Half­ Life (pH7; MRID 00107980) stable Aerobic Soil Metabolism Half­ Life (MRID 41568901) 1176 days Aerobic Aquatic Metabolism Half­ Life 2352 days Photolysis Half­ Life (MRID 404203­ 01, 40320601) 41 days Organic Carbon Adsorption Coefficient (Koc; MRID 40211103, 40211104) 656 L/ kg Application Method ground spray, wetted­ in Application Rate 1.5 to 4.0 lb/ acre (one annual application) The PRZM/ EXAMS input parameters for metabolism half­ lives were selected in accordance with US EPA OPP EFED water model parameter selection guidelines, Guidance for Selecting Input Parameters in Modeling the Environmental Fate and Transport of Pesticides, Version II, February 28, 2002 8 . Only one submitted metabolism half­ life of 392 days was available for aerobic soil metabolism. That value was multiplied by three, as per guidance instructions. The resulting value of 1176 days was used for the aerobic metabolism half­ life for modeling. In the absence of anaerobic metabolism data, that value was multiplied by two, as outlined in the guidelines, to generate an anaerobic metabolism half­ life of 2352 days. The organic carbon adsorption coefficient (Koc) value of 656 was calculated, from submitted data, as the slope of the plot of the adsorption Kd value versus percent organic carbon of the specific soils. Submitted data included several test soils with either high or low percent organic matter values, and a wide variance in resulting values. While this is not the method recommended in the input guidance for calculating the absorption coefficient, this overall Koc value better predicts the mobility of pronamide in the environment. Weather data was adjusted to reflect the additional water needed for the recommended practice of "wetting­ in" the pesticide, by adjusting the recorded precipitation amount on the annual application date to include the required additional water. Application methods and rates for specific crops were obtained from submitted labels. 9 http:// www. epa. gov/ oppefed1/ models/ water/ index. htm 7 Final Water Assessment PronamideTIER2.wpd Table 2. Input Parameters for SCIGROW Chemical pronamide Organic Carbon Adsorption Coefficient (Koc) 701 L/ kg Aerobic Soil Metabolism Half­ Life 392 days Annual Application Rates 2 ­ 4 lbs. a. i./ acre The SCIGROW input parameters were selected in accordance with US EPA OPP EFED water model parameter selection guidelines, Guidance for Selecting Input Parameters in Modeling the Environmental Fate and Transport of Pesticides, Version II, February 28, 2002 9 . Application rates were obtained from submitted labels. Table 3. Modeling Results for Use on Representative Crops CROP Annual Application Rate (pounds / acre) Application Method Application Date PRZM/ EXAMS Values (ppb)* Acute Exposure (one in 10 year peak value) Non­ Cancer Chronic Exposure (one in 10 year annual mean value) 36 Year Average (overall mean annual value for 36 years) C Lettuce in FL 1.5 ground sprayer / wetted­ in 2" October 20 3.69 0.53 0.54 C Seed Grass in OR 1.5 ground sprayer / wetted­ in 1" September 15 4.19 1.94 1.86 C Pears in OR 4.0 ground sprayer / wetted­ in 1" November 21 10.3 4. 05 3. 92 C Alfalfa in CA 2.0 ground sprayer / wetted­ in 1" January 7 7. 13 4. 45 4. 30 * Reported values adjusted for percent crop area by multiplying by a factor of 0.86, as dictated by EFED policy. 8 Final Water Assessment PronamideTIER2.wpd Associated files for PRZM/ EXAMS modeling of Proanamide located on the F­ drive at F:\ USER\ LSHANAMA\ 101701PRONAMIDE\ : Caalfalfa. pzr Caalfalfa. out Caalfalf. zts Fllettuce. pzr Fllettuce. out Fllettuc. zts Ororchard. pzr Ororchard. out Ororchar. zts Orseedgrass. pzr Orseedgrass. out Orseedgr. zts MET156c1. MET MET17alf. MET MET2ap1. MET MET2gs1. MET setstfloEXAM. wpd 9 Final Water Assessment PronamideTIER2.wpd APPENDIX I OUTPUT TABLES OF DRINKING WATER MODELING RESULTS PRZM/ EXAMS Results for Pronamide Use on Florida Lettuce WATER COLUMN DISSOLVED CONCENTRATION (PPB) YEAR PEAK 96 HOUR 21 DAY 60 DAY 90 DAY YEARLY ­­­­ ­­­­ ­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ ­­­­­ 1948 4.204 4.039 3.426 2.438 1.785 0.4442 1949 4.223 4.057 3.444 2.455 1.802 0.5995 1950 4.231 4.066 3.452 2.463 1.81 0.6101 1951 4.236 4.07 3.456 2.467 1.814 0.6154 1952 4.238 4.072 3.458 2.469 1.816 0.6166 1953 4.239 4.073 3.459 2.47 1.817 0.6196 1954 4.239 4.074 3.46 2.47 1.818 0.6203 1955 4.24 4.074 3.46 2.471 1.818 0.6207 1956 4.24 4.074 3.46 2.471 1.818 0.6193 1957 4.24 4.074 3.46 2.471 1.818 0.621 1958 4.24 4.074 3.46 2.471 1.818 0.6211 1959 4.24 4.074 3.46 2.471 1.818 0.6211 1960 4.24 4.074 3.46 2.471 1.818 0.6195 1961 4.24 4.074 3.46 2.471 1.818 0.6211 1962 4.24 4.074 3.461 2.471 1.818 0.6211 1963 4.24 4.074 3.461 2.471 1.818 0.6211 1964 4.24 4.074 3.46 2.471 1.818 0.6195 1965 4.24 4.074 3.46 2.471 1.818 0.6211 1966 4.24 4.074 3.461 2.471 1.818 0.6211 1967 4.24 4.074 3.461 2.471 1.818 0.6211 1968 4.24 4.074 3.46 2.471 1.818 0.6195 1969 4.24 4.074 3.46 2.471 1.818 0.6211 1970 4.24 4.074 3.461 2.471 1.818 0.6211 1971 4.24 4.074 3.461 2.471 1.818 0.6211 1972 4.24 4.074 3.46 2.471 1.818 0.6195 1973 4.24 4.074 3.46 2.471 1.818 0.6211 1974 4.24 4.074 3.461 2.471 1.818 0.6211 1975 4.24 4.074 3.461 2.471 1.818 0.6211 1976 4.24 4.074 3.46 2.471 1.818 0.6195 1977 4.24 4.074 3.46 2.471 1.818 0.6211 1978 4.24 4.074 3.461 2.471 1.818 0.6211 1979 4.24 4.074 3.461 2.471 1.818 0.6211 1980 4.24 4.074 3.46 2.471 1.818 0.6195 1981 4.24 4.074 3.46 2.471 1.818 0.6211 1982 4.24 4.074 3.461 2.471 1.818 0.6211 1983 4.24 4.074 3.461 2.471 1.818 0.6211 Upper Tenth 4.240* 4.074 3.461 2.471 1.818 0.6211* Percentile MEAN OF ANNUAL VALUES = 0.615* *Indicates drinking water assessment endpoints BEFORE correction for percent cropped area, as pre EFED policy. 10 Final Water Assessment PronamideTIER2.wpd PRZM/ EXAMS Results for Pronamide Use on Oregon Pears WATER COLUMN DISSOLVED CONCENTRATION (PPB) YEAR PEAK 96 HOUR 21 DAY 60 DAY 90 DAY YEARLY ­­­­ ­­­­ ­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ 1948 10.47 10.31 9.668 6.136 4.091 1.021 1949 11.4 11.23 10.54 7.012 5.887 3.905 1950 11.65 11.48 10.79 7.258 6.532 4.322 1951 11.78 11.61 10.91 7.389 6.752 4.493 1952 11.84 11.67 10.98 7.509 6.869 4.577 1953 11.89 11.72 11.02 7.573 6.932 4.638 1954 11.91 11.74 11.05 7.614 6.973 4.67 1955 11.93 11.76 11.06 7.637 6.995 4.687 1956 11.93 11.76 11.06 7.649 7.007 4.688 1957 11.94 11.77 11.07 7.653 7.011 4.701 1958 11.94 11.77 11.08 7.66 7.017 4.706 1959 11.94 11.77 11.08 7.663 7.02 4.708 1960 11.94 11.77 11.07 7.664 7.022 4.699 1961 11.94 11.77 11.08 7.661 7.0 19.707 1962 11.94 11.77 11.08 7.665 7.022 4.709 1963 11.94 11.77 11.08 7.665 7.023 4.71 1964 11.94 11.77 11.07 7.666 7.023 4.7 1965 11.94 11.77 11.08 7.662 7.03 4.708 1966 11.94 11.77 11.08 7.665 7.023 4.71 1967 11.94 11.77 11.08 7.666 7.023 4.71 1968 11.94 11.77 11.07 7.666 7.023 4.701 1969 11.94 11.77 11.08 7.662 7.02 4.708 1970 11.94 11.77 11.08 7.665 7.023 4.71 1971 11.94 11.77 11.08 7.666 7.023 4.71 1972 11.94 11.77 11.07 7.666 7.023 4.701 1973 11.94 11.77 11.08 7.662 7.02 4.708 1974 11.94 11.77 11.08 7.665 7.023 4.71 1975 11.94 11.77 11.08 7.666 7.023 4.71 1976 11.94 11.77 11.07 7.666 7.023 4.701 1977 11.94 11.77 11.08 7.662 7.02 4.708 1978 11.94 11.77 11.08 7.665 7.023 4.71 1979 11.94 11.77 11.08 7.666 7.023 4.71 1980 11.94 11.77 11.07 7.666 7.023 4.701 1981 11.94 11.77 11.08 7.662 7.02 4.708 1982 11.94 11.77 11.08 7.665 7.023 4.71 1983 11.94 11.77 11.08 7.666 7.023 4.71 Upper Tenth 11.94* 11.77 11.08 7.666 7.023 4.71* Percentile MEAN OF ANNUAL VALUES = 4.558* *Indicates drinking water assessment endpoints BEFORE correction for percent cropped area, as pre EFED policy. 11 Final Water Assessment PronamideTIER2.wpd PRZM/ EXAMS Results for Pronamide Use on Oregon Seedgrass WATER COLUMN DISSOLVED CONCENTRATION (PPB) YEAR PEAK 96 HOUR 21 DAY 60 DAY 90 DAY YEARLY ­­­­ ­­­­ ­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ 1948 3.971 3.92 3.715 3.302 3.028 0.8523 1949 4.51 4.454 4.229 3.774 3.473 1.779 1950 4.674 4.618 4.389 3.928 3.622 1.994 1951 4.758 4.701 4.472 4.008 3.7 2.093 1952 4.804 4.747 4.517 4.052 3.743 2.145 1953 4.835 4.778 4.548 4.081 3.772 2.181 1954 4.852 4.795 4.565 4.098 3.788 2.201 1955 4.862 4.806 4.575 4.108 3.798 2.213 1956 4.865 4.808 4.578 4.111 3.801 2.216 1957 4.871 4.814 4.584 4.116 3.806 2.223 1958 4.874 4.817 4.586 4.118 3.808 2.226 1959 4.875 4.818 4.587 4.12 3.81 2.228 1960 4.873 4.816 4.585 4.118 3.808 2.224 1961 4.876 4.819 4.588 4.12 3.81 2.228 1962 4.877 4.82 4.589 4.121 3.811 2.229 1963 4.877 4.82 4.589 4.121 3.811 2.229 1964 4.874 4.817 4.586 4.119 3.809 2.225 1965 4.876 4.82 4.589 4.121 3.811 2.229 1966 4.877 4.82 4.589 4.121 3.811 2.229 1967 4.877 4.82 4.589 4.122 3.811 2.23 1968 4.874 4.817 4.586 4.119 3.809 2.225 1969 4.877 4.82 4.589 4.121 3.811 2.229 1970 4.877 4.82 4.589 4.121 3.811 2.23 1971 4.877 4.82 4.589 4.122 3.811 2.23 1972 4.874 4.817 4.586 4.119 3.809 2.225 1973 4.877 4.82 4.589 4.121 3.811 2.229 1974 4.877 4.82 4.589 4.121 3.811 2.23 1975 4.877 4.82 4.589 4.122 3.811 2.23 1976 4.874 4.817 4.586 4.119 3.809 2.225 1977 4.877 4.82 4.589 4.121 3.811 2.229 1978 4.877 4.82 4.589 4.121 3.811 2.23 1979 4.877 4.82 4.589 4.122 3.811 2.23 1980 4.874 4.817 4.586 4.119 3.809 2.225 1981 4.877 4.82 4.589 4.121 3.811 2.229 1982 4.877 4.82 4.589 4.121 3.811 2.23 1983 4.877 4.82 4.589 4.122 3.811 2.23 Upper Tenth 4.877* 4.82 4.589 4.122 3.811 2.23* Percentile MEAN OF ANNUAL VALUES = 2.162* *Indicates drinking water assessment endpoints BEFORE correction for percent cropped area, as pre EFED policy. 12 Final Water Assessment PronamideTIER2.wpd PRZM/ EXAMS Results for Pronamide Use on California Alfalfa WATER COLUMN DISSOLVED CONCENTRATION (PPB) YEAR PEAK 96 HOUR 21 DAY 60 DAY 90 DAY YEARLY ­­­­ ­­­­ ­­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ ­­­­­­ 1948 5.236 5.217 5.135 4.842 4.58 2.873 1949 6.66 6.638 6.549 6.205 5.892 3.843 1950 7.277 7.257 7.169 6.816 6.487 4.324 1951 7.632 7.611 7.527 7.171 6.835 4.616 1952 7.858 7.838 7.755 7.398 7.059 4.799 1953 7.999 7.98 7.899 7.541 7.2 4.925 1954 8.102 8.083 8.003 7.644 7.301 5.01 1955 8.168 8.149 8.07 7.71 7.366 5.066 1956 8.212 8.193 8.114 7.754 7.409 5.096 1957 8.234 8.215 8.136 7.777 7.432 5.122 1958 8.257 8.238 8.16 7.8 7.455 5.141 1959 8.271 8.252 8.174 7.814 7.468 5.152 1960 8.28 8.261 8.183 7.823 7.477 5.154 1961 8.279 8.26 8.182 7.823 7.477 5.16 1962 8.287 8.269 8.19 7.831 7.484 5.166 1963 8.291 8.272 8.194 7.834 7.488 5.169 1964 8.293 8.275 8.196 7.836 7.49 5.165 1965 8.288 8.269 8.191 7.831 7.485 5.168 1966 8.293 8.274 8.196 7.836 7.49 5.171 1967 8.295 8.276 8.198 7.838 7.492 5.172 1968 8.296 8.277 8.199 7.839 7.493 5.167 1969 8.289 8.271 8.193 7.833 7.487 5.169 1970 8.294 8.276 8.197 7.838 7.491 5.172 1971 8.296 8.277 8.199 7.839 7.492 5.173 1972 8.296 8.278 8.199 7.84 7.493 5.167 1973 8.29 8.271 8.193 7.833 7.487 5.169 1974 8.295 8.276 8.197 7.838 7.491 5.172 1975 8.296 8.277 8.199 7.839 7.493 5.173 1976 8.296 8.278 8.199 7.84 7.493 5.168 1977 8.29 8.271 8.193 7.833 7.487 5.169 1978 8.295 8.276 8.198 7.838 7.491 5.172 1979 8.296 8.277 8.199 7.839 7.493 5.173 1980 8.296 8.278 8.199 7.84 7.493 5.168 1981 8.29 8.271 8.193 7.834 7.487 5.169 1982 8.295 8.276 8.198 7.838 7.491 5.172 1983 8.296 8.277 8.199 7.839 7.493 5.173 Upper Tenth 8.296* 8.2773 8.199 7.8393 7.493 5.173* Percentile MEAN OF ANNUAL VALUES = 5.001* *Indicates drinking water assessment endpoints BEFORE correction for percent cropped area, as pre EFED policy. 13 Final Water Assessment PronamideTIER2.wpd APPENDIX II SCIGROW Ground Water Results for Pronamide SCIGROW VERSION 2.1 MAY 1, 2001 RUN No. 1 FOR pronamide ** INPUT VALUES ** ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APP RATE APPS/ TOTAL/ SOIL AEROBIC SOIL METAB (LBS/ AC) YEAR SEASON KOC HALFLIFE (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 4.000 1 4.000 701.0 392.00 GROUND­ WATER SCREENING CONCENTRATION (IN PPB) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 1.0966 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ SCIGROW VERSION 2.1 MAY 1, 2001 RUN No. 2 FOR proanamide ** INPUT VALUES ** ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APP RATE APPS/ TOTAL/ SOIL AEROBIC SOIL METAB (LBS/ AC) YEAR SEASON KOC HALFLIFE (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 2.000 1 2.000 701.0 392.00 GROUND­ WATER SCREENING CONCENTRATION (IN PPB) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .5483 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

epa

2024-06-07T20:31:42.701449

regulations

EPA-HQ-OPP-2002-0159-0005

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: May 23, 2002 Memorandum SUBJECT: Addendum to EPA March 8, 2002: Pronamide. Tolerance Reassesment Eligibility Decision (TRED). FROM: Gary Bangs, Risk Assessor Reregistration Branch 3 Health Effects Division (7509C) THROUGH: Steve Knizner, Chief Reregistration Branch 3 Health Effects Division (7509C) TO: Cecelia Watson, Chemical Review Manager Special Review and Reregistration Division (7508C) PC Code: Pronamide 101701. DPBarcode: D282842 PURPOSE: Pronamide Revised Aggregate Risk Estimates After Application of Labeling Changes to Eliminate Use on Residential Turf 2 Pronamide Revised Aggregate Risk Estimates After Application of Labeling Changes to Eliminate Use on Residential Turf Cancellation of the single label allowing application of pronamide to home lawns and recreational turf will make children's oral non­ dietary exposures unlikely. However, since the registrant wants to retain use on golf courses and athletic fields, the potential for low and highcontact exposures for adults still exists. Based on the use pattern of pronamide (the elimination of selected grasses from golf course and professional playing field turf) it is anticipated that children would rarely be exposed to pronamide residues. Labels should strongly encourage watering­ in to reduce residues, and management practices to restrict entry until the pronamide product is watered into the turf. Given these proposed restrictions on the use of pronamide on turf, the high­ contact dermal exposure scenario is not considered likely and would result in an overestimate of player exposure. Short­ term Aggregate Risk Estimates The short­ term food, water, and low­ contact dermal (golfing) pronamide exposures were aggregated in the Risk Assessment, and the estimated environmental concentrations (EECs) modeled using Sci­ Grow and PRZM­ EXAMS did not exceed the drinking water level of concern (DWLOC) . Therefore, risk estimates for all pathways of exposure are not of concern for pronamide in the short­ term when pronamide use is restricted per the label changes cited above. Chronic Aggregate Risk Estimates The chronic risk estimates would remain the same for all populations as stated in the Risk Assessment, as there are no anticipated long­ term non­ dietary exposure scenarios for pronamide. All aggregate food and water estimates do not exceed the level of concern. Cancer Risk Estimates Aggregate cancer risk estimates will be reduced by restricting non­ agricultural uses to turf for sod and seed, ornamental landscaping, industrial sites, professional athletic fields, and golf courses. Golfing is believed to be a representative scenario for likely exposures to the public. The cancer risk estimate for golfing a single day per year is about the same as the dietary cancer risk estimate, or 1 x 10 ­7 . When both dietary and non­ dietary risk are added, the cancer risk estimate is 2.2 x 10 ­7 . The DWLOC for the aggregated dietary and golfing cancer risks is 1.06 ppb. Without golf course exposure (i. e., no recreational turf uses at all), the cancer DWLOC of 1.2 ppb is based on dietary exposure alone. The Tier 2 PRZM­ EXAMS 37­ year mean EECs are 0.535­ 4.35 ppb. This modeling was based on the maximum label rates for pronamide, whereas typical rates for many crops are 25%­ 50% less. No targeted water monitoring data were available, but USGS water monitoring data showed maximum pronamide levels of 0.82 ppb in ground water and 0.365 ppb in surface water. Further refinement of drinking water modeling estimates and/ or targeted monitoring of water sources in high pronamide use areas would provide more confidence in the risk assessment. 3 Risk Characterization The cancer risk estimate for playing on treated turf used the turf residues averaged over 14 days, which is how long pronamide takes to dissipate to negligible levels. A single day's exposure was used, based on the national average rate of golfing of 18 times per year, or about every 2 weeks. The residential/ recreational exposure estimates are based on a default dermal absorption value of 100%, therefore, a dermal absorption study would help to reduce these risk estimates. Additional label language encouraging prompt watering­ in of the product would help to reduce available residues (as shown in the submitted turf residue study) and thereby also reduce risks.

epa

2024-06-07T20:31:42.706238

regulations

EPA-HQ-OPP-2002-0159-0006

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: March 7, 2002 Memorandum SUBJECT: Pronamide: Residential Risk Assessment and Recommendations for the Tolerance Reassessment Eligibility Decision (TRED) Document. FROM: Barry O'Keefe, Biologist Reregistration Branch 3 Health Effects Division (7509C) THROUGH: Catherine Eiden, Senior Scientist Reregistration Branch 3 Health Effects Division (7509C) TO: Gary Bangs, Risk Assessor Reregistration Branch 3 Health Effects Division (7509C) PC Code: 101701 DP Barcode: D275538 Pronamide study MRID: 44952501 This is a preliminary exposure and risk assessment. The assessment is limited to registered residential uses of pronamide. Pronamide is a restricted use pesticide, and therefore requires professional applicators. HED has determined that there is a potential for exposure in occupational settings from handling pronamide products during the application process (i. e., mixer/ loader, applicator and mixer/ loader/ applicator) and from entering previously treated areas. As a result, risk assessments would normally have been completed for occupational handler and postapplication scenarios. The occupational handler and postapplication risk assessment was previously performed as part of the pronamide reregistration eligibility decision (RED) document completed in May, 1994. However, for pronamide the occupational handler and postapplication scenarios will not be assessed now, since this assessment is only for a tolerance reassessment eligibility decision (TRED) document. Additionally, the determination of the status of the Agency's occupational exposure data base for regulatory purposes was not performed. When an occupational risk assessment is performed data gaps may be identified, and additional data and/ or studies may be required. No residential exposure data and/ or specific studies are required at this time. 2 TABLE OF CONTENTS EXECUTIVE SUMMARY...................................................... 3 1. BACKGROUND ....................................................... 10 1. 1 Purpose......................................................... 10 1.2 Criteria for Conducting Exposure Assessments ......................... 10 1.3 Summary of Toxicity Concerns Relating to Residential Exposures .......... 10 1. 4 Incident Reports.................................................. 12 1. 5 Summary of Use Patterns and Formulations ............................ 13 2.0 RESIDENTIAL AND OTHER NON­ OCCUPATIONAL EXPOSURES AND RISKS ..................................................................... 17 2.1 Methods of Estimating Non Cancer Risks And Calculating Exposures ............. 17 2.2 Residential Handler Exposures and Risks .................................... 19 2.2.1 Residential­ Handler Exposure Scenarios, Data, and Assumptions ........... 19 2.3 Non­ Occupational Postapplication Exposure and Risk Estimates ................. 19 2.3.1 Postapplication Exposure Scenarios, Data, and Assumptions ............... 19 2.3.2 Postapplication Exposure and Non­ Cancer Risk Estimates ................ 25 2.3.3 Postapplication Cancer Risk Estimates ................................ 26 2.3.4 Summary of Postapplication Risks, Data Gaps, and Confidence in Exposure and Risk Estimates ................................................... 27 2.4 RESIDENTIAL AND NON­ OCCUPATIONAL RISK CHARACTERIZATION .... 28 2.4.1 Residential Handler Risk Characterization ............................. 28 2.4.2 Non­ Occupational Postapplication Risk Characterization ................. 28 References .................................................................. 29 Appendix Pronamide Exposure and Risk Estimates ­ Tables 4 through 7 .................... 30 Table 4. Summary of Postapplication Turf Transferable Residue Study .................. 31 Table 5. Pronamide Residential Postapplication Activities on Treated Turf: Dermal Exposure and Non­ Cancer Risk Estimates ........................................... 32 Table 6. Pronamide Postapplication Dermal Cancer Risk Estimates for Activities on Treated Turf ................................................................. 33 Table 7. Residential Oral Nondietary Short­ Term Postapplication Risks to Children from "Hand­ to­ Mouth" and Ingestion Exposure When Reentering Treated Lawns ........ 34 3 EXECUTIVE SUMMARY Background: Use Pronamide is a restricted use, selective pre and postemergent herbicide used to control grasses and broadleaf weeds. It is applied as a liquid spray, which is packaged in water soluble pouches and then mixed in water before application. It is a soil active systemic herbicide with uptake by susceptible weeds occurring through the roots. Therefore, to be effective, pronamide is applied to the soil and transported by water into the root zone where it is taken up by plants. Pronamide is applied in the late Fall and/ or late Winter, only by certified pesticide applicators and professional lawn care operators (LCOs). Pronamide is registered for use in agricultural, ornamental, and residential settings. There are two manufacturers of pronamide end­ use products with only two active section 3 registrations. There are also nine active 24C registrations. Major food/ feed crops include: stone fruits (apricot, cherry, nectarine, peach, plum, prune), pome fruits (apple, pear), grapes, artichokes, berries (blackberry, blueberry, boysenberry, red raspberry, black raspberry), leafy greens (lettuce, endive, radicchio), winter peas, chicory, rhubarb, sugarbeets, and forages (alfalfa, clover, birdsfoot trefoil, crown vetch, sainfoin). Non­ agricultural uses include woody ornamentals, ornamental warm season grasses grown for turf (i. e. bermudagrass, Zoysiagrass, St. Augustine, and Centipedegrass) or seed (bermudagrass), residential/ recreational turf (bermudagrass lawns, playing fields, and golf courses), Christmas trees, grasses grown for seed, rangeland, and fallow land. There is a potential for exposure from commercial applications to agricultural and residential/ recreational areas. Therefore, normally both occupational and residential exposure assessments would be conducted. However, since this is a Tolerance Reassessment Eligibility Decision (TRED) document, only a residential postapplication exposure assessment was conducted; i. e. for residential/ recreational turf uses. Hazard Profile As reported by the Hazard Identification Assessment Review Committee (HIARC) 2 , for shortterm (1­ 30 days) incidental oral exposures an adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. This dose is derived from the no observed adverse effect level (NOAEL) from a chronic toxicity/ carcinogenicity study in rats, where the effects are increased liver weight and non­ neoplastic histologic changes in liver, thyroid, and ovaries observed at the lowest observed adverse effect level (LOAEL) of 42.6 mg/ kg/ day. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. Although this study is of the appropriate route (oral) and duration (13 days), the NOAEL (5 mg/ kg/ day) in this study is lower than the NOAEL (8.46 mg/ kg/ day) established in the chronic toxicity/ carcinogenicity study in the rat. The apparent disparity between these NOAELs is driven by the doses of pronamide selected for testing in these studies. The HIARC concluded that using a more realistic NOAEL of 8.46 mg/ kg/ day, rather than 5 mg/ kg/ day, would provide a sufficiently 4 protective dose for risk assessment. The NOAEL of 3 mg/ kg/ day established in the special thyroid study conducted in male rats was also considered. However this dose was not selected because the wide gap between the NOAEL (3 mg/ kg/ day) and the LOAEL (67 mg/ kg/ day) in this study resulted in the 3 mg/ kg/ day dose (NOAEL) being artificially low. In addition, the LOAEL of 67 mg/ kg/ day is comparable to the LOAEL (56 mg/ kg/ day) established in the chronic toxicity/ carcinogenicity study conducted in rats. For short­ term (1­ 30 days) dermal exposures the same oral dose and endpoint was selected for risk assessment, i. e. 8.46 mg/ kg/ day. A dermal absorption factor is needed, since the endpoint is based on a study using oral dosing. A default dermal absorption factor of 100% relative to oral absorption was chosen by the HIARC, since the dermal absorption study sent to the Agency was classified as unacceptable (i. e. unable to verify amount applied and poor recovery data) and no dermal toxicity studies were submitted. In accordance with the Agency's Proposed Guidelines for Carcinogen Risk Assessment (September 30, 1992), the HED Carcinogenicity Peer Review Committee (CPRC) classified pronamide as a Group B2 chemical) probable human carcinogen with inadequate evidence in humans). This decision was based on the finding of two types of tumors in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas), and one type of tumor in the mouse (hepatocellular adenomas and carcinomas). A linear, low dose approach (Q1 * ) is used for human risk characterization. The most potent unit risk Q1 * , based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2.59 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents [converted from animal to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor]. Therefore, the Hazard Identification Assessment Review Committee (HIARC) recommended that a cancer risk assessment be conducted for pronamide (November 6, 2001). In a memo dated December 19, 2001, the FQPA Safety Factor Committee recommended that the FQPA safety factor be reduced to 3x. The FQPA Committee determined that the safety factor is necessary when assessing the risk posed by pronamide because of evidence of endocrine effects. The FQPA safety factor is required for all population subgroups when assessing residential exposures of all durations. Residential Exposure Estimates Background When the pronamide RED document was completed in May, 1994, the Agency did not have the data to make a reregistration decision on pronamide for use on residential lawns. An estimate of risk was not feasible because of numerous uncertainties in potential exposure levels, especially for children. In the 1994 RED document, regulatory decisions concerning postapplication reentry to residential lawns were postponed until after the submittal and review of studies 5 required to support the residential lawn use; i. e. foliar dislodgeable dissipation (old guideline 132­ 1( a) or new guideline 875.2100) and dermal passive dosimetry (old guideline 133­ 3 or new guideline 875.2400). In the interim since 1994, a turf transferrable residue (TTR) study was submitted, reviewed, and found acceptable and useful for some aspects of risk assessment. The study provided the required residue dissipation data. The methodology used to determine turf transferability (i. e. the modified California roller method) does not match the Agency's current methodology (i. e. Jazzercise and the California roller method) used to determine the dermal transfer coefficient on turf. Note, that the Outdoor Residential Exposure Task Force (ORETF) is currently funding a study which is intended to provide concurrent TTR and transfer coefficient data for a surrogate chemical. The requirement for a dermal passive dosimetry study remains outstanding. However, the Agency can perform an adequate risk assessment to estimate risk on residential lawns by using dissipation data from the TTR study in conjunction with the transferability assumptions and equations found in the Agency's residential SOPs. Short­ Term Exposure Scenarios A review of incident data sources found that relatively few incidents of pronamide poisonings were reported. 1 There are only two Poison Center reports, no incident reports in OPPs Incident Data System and only two reports from the California Pesticide Illness Surveillance Program. In sum, recommendations based on the few incidents reported are unlikely. All pronamide end use products are labeled as restricted use pesticides. Therefore, residents are restricted from handling or applying pronamide products. Consequently, only residential/ recreational postapplication exposures to the general population are anticipated and are evaluated in this assessment. Adults and children are potentially exposed to pronamide residues after application of pronamide products by professional lawn care operators (LCOs) in residential/ recreational settings. Applications are made to lawns, playing fields, and golf courses. After application to turf, short­ term dermal exposures are anticipated for adults and children. Incidental oral exposure is also expected to occur for small children and is combined with their dermal exposures, where applicable (i. e., playing on turf). Residential exposures have been estimated based on label application frequency and timing, and the persistence of pronamide. Most assumptions for risk estimation were based on the Residential SOPs (see section 2.0). Residents are assumed to play or work on treated lawns, or play golf within the first 24 hours of spraying. Restrictions on early re­ entry are impractical and unenforceable for residents. Therefore, short­ term risks from residential postapplication dermal and incidental oral exposures are anticipated and were estimated for pronamide. No intermediate­ or long­ term exposure scenarios (i. e. > 30 days) are anticipated, since turf residues dissipate rapidly to below the limit of quantification by day 14 following application (pronamide TTR study). The short­, intermediate­, and long­ term endpoints are the same. Postapplication exposures via the inhalation route are not anticipated, since pronamide is applied as a liquid, and is a mobile systemic herbicide, which when watered in (as directed on the label) quickly moves into soil, where it is rapidly absorbed into vegetation. Additionally, the uses and primary exposures are 6 outdoors, allowing for significant dilution. The scenarios assessed for the purpose of determining risk estimates included adults and children (toddlers) performing high­ contact play or work activities on treated lawns, and adults mowing lawns or golfing. Small children (toddlers) were also assessed for incidental oral exposure from ingestion of soil, object­ to­ mouth activity (turfgrass mouthing), and hand­ to­ mouth activity while playing on treated lawns. Some of these exposures were combined, where it was deemed reasonably likely that activities would co­ occur. Residential risk estimates utilized data from a submitted turf transferable residue (TTR) study, as well as the EPA's original and revised Draft SOPs for Residential Exposure Assessment. 3, 5 For pronamide short­ term non­ occupational risks, HED has established a level of concern for MOEs < 300. Wherever available, reported usage data are used in this process to define values such as application rates and application frequency. Only one end use product label can be used in a residential setting. This residential label (EPA Reg. No. 8660­ 85) indicates a maximum application rate of 1.5 lb ai/ acre for pre­ emergence applications by lawn care operators (LCOs) to lawns, playing fields, and golf courses as a single application. The maximum application rate for post­ emergence applications is 1.0 lb ai/ acre. The label indicates that typical application rates for pre­ and post­ emergence applications are at 0.5 to 1.0 lb ai/ acre, with the maximum rate being used in areas of heavy growth weeds. This residential label does not specify or restrict the number of applications allowed per year to turf. However, the agricultural label (EPA Reg. No. 707­ 159) allows only one application per year to grasses grown for turf or seed. For both labels, applications to turf are only made in the late Fall or late Winter. For residential turf, it is reasonable to assume that typically only one application is made, and potentially only two applications would be made in any year. If two applications were made, one would probably be made in late Fall, followed by another application in late Winter. Therefore, HED assumed one application per year to estimate short­ term exposures. Results from environmental fate studies indicate that pronamide is very persistent in soil and water with half­ lifes of many months. Additionally, rotational crop studies show accumulation in several crop types at one, six and twelve months after application. Results from a recent turf transferable residue study on turf using pronamide (i. e. MRID 44952501) indicate that the halflife of turf transferrable (TTR) residues was slightly less than two days. The residential label (EPA Reg. No. 8660­ 85) instructs applicators to lightly irrigate within a day of application if no rain occurs. Such irrigation occurred at 24 hours after application in the TTR study. Since the compound is soluble in water, and therefore mobile, it is likely the irrigation dissolves the compound and transports it from the turf into the soil. Study data showed that residues dissipate to below the level of quantification by day 14 following application. Therefore, only short­ term (i. e., one day to one month) exposures would be anticipated, since most of the pesticide should move into the soil, and any remaining foliar residues should dissipate within a month. While residues in soil could persist for greater than 30 days, it is unlikely that children will play on or contact soil for greater than 30 consecutive days during the late Fall or late Winter months. The HED always completes short­ term risk assessments using maximum application rates for 7 each scenario because what is possible under the label (the legal means of controlling pesticide use) must be evaluated for complete stewardship in order to ensure the HED has no risk concern for the specific use. Cancer Exposure Scenario The low­ dose extrapolation model used to estimate the Q1 * assumes that any exposure at any time may increase the risk of cancer. Therefore, HED conducted an exposure assessment for cancer based on residential exposures to pronamide. The same residential exposure scenarios assumed under the short­ term exposure assessment were used as the basis of the exposure scenario for cancer. Based on the pesticide label, a typical residential/ recreational lawn application rate of 1.0 lb/ acre, with an application frequency of once per year, was assumed for the residential cancer risk assessment. Pronamide is applied in the dormant season, which reduces the number of contact days expected. A single exposure is deemed more likely, but up to 14 days exposure could occur based on the residue dissipation pattern. The 14­ day average turf residues from the TTR study (MRID 44952501) were used (i. e. 0.07913 F g/ cm 2 , when adjusted to a typical application rate of 1.0 lb ai/ acre); since residues in the TTR study dissipated to the level of quantitation by 14 days after application. The average residue, and an exposure frequency of one day per year, or 50 days in a lifetime, was assumed for high contact activities (e. g. playing and working on lawns and turf) and low contact activities (e. g. mowing or golfing). Residential Postapplication Short­ Term Risk Estimates The level of concern (LOC) for residential risks for short­ term dermal and incidental oral exposures is set by the HED at a margin of exposure (MOE) < 300. Turf transferrable residue (TTR) data from the pronamide TTR study provided by the registrant were used quantitatively in this risk assessment. Risk estimates based on residue data from the TTR study for short­ term dermal contact with treated turf during high contact lawn activities on day zero following application (DAT 0) exceed HED's level of concern, i. e. result in MOEs < 300 for adults (MOE = 71) and children (MOE = 42). However, using DAT 2 residue data from the TTR study yielded MOEs that do not exceed the level of concern (MOEs $ 300) for adults (MOE = 890) and children (MOE = 530) during high contact lawn activities. Note that the test plots were irrigated immediately after the DAT 1 samples were taken, i. e. 24 hours after application of pronamide, as specified on the label. The data show that watering­ in the pronamide product clearly alleviates these risk concerns. Risk estimates for short­ term dermal contact with residues on treated turf during the low contact activities of grass mowing or golfing on the day of treatment (DAT 0) do not exceed the level of concern (MOEs $ 300) for adults (MOEs 2100 and 1000, respectively) (See Table 5.) HED also assessed short­ term risks to small children from incidental oral ingestion of pronamide residues following application to residential lawns (see Table 7). The risk calculations for small 8 children's non­ dietary ingestion of pronamide on treated turf indicate that risks do not exceed the level of concern (i. e. MOEs $ 300) for incidental hand­ to­ mouth activity (MOE = 380), incidental ingestion of soil (MOE = 113,000), and incidental object to mouth activity (MOE = 1500). The small children's combined oral hand­ to­ mouth scenarios (MOE = 300) also do not exceed the level of concern. When risks from dermal exposures from pronamide to small children are combined with risks from incidental oral exposures, the combined short­ term risk estimates exceed the level of concern (MOEs < 300), with an MOE at 37. However, the likelihood of all incidental oral exposures co­ occurring with dermal exposures is low. Residential Postapplication Cancer Risk Estimates The HED endeavors to reduce estimated cancer risks for the general population to less than one in one million (10 ­6 ). Estimated adult cancer risks were calculated using the same residential exposure scenarios as described above; i. e. performing high­ contact play or work activities on treated lawns, mowing lawns or golfing. An adult mowing a treated lawn has a cancer risk of 5.73 x 10 ­8 . The adult golfer cancer risk is estimated at 1.15 x 10 ­7 . An adult performing dermal high contact activities on turf has a cancer risk of 8.36 x 10 ­7 . In order to exceed the cancer risk (1.0 x 10 ­6 ), exposure frequencies of 17.5, 8.7 and 1.2 days per year would be needed for the activities of mowing, golfing and high contact work, respectively. Summary of Risk Concerns, Exposure Assumptions, and Confidence in Estimates The exposure estimates generated for the residential/ recreational turf uses used the HED SOPs that are based on some upper­ percentile assumptions (i. e., duration of exposure and maximum application rate for short­ term assessments) and are considered to be representative of high end exposures. The uncertainties associated with this assessment stem from the use of assumptions regarding the transfer of pronamide residues. The exposure estimates are believed to be reasonably high­ end estimates, since the maximum application rate is used, a 100% dermal absorption factor is assumed, and exposures are assumed to occur on the day of treatment. The translation of a dose based on a chronic effect for the purpose of short­ term risk estimation also contributes to a high­ end exposure estimate. However, dermal exposure estimates are not considered overly conservative, since turf transferrable residue (TTR) data from a pronamide TTR field study was used; specifically 0.289 µg/ cm 2 , which is the average residue observed on day zero after application, and represents 1.65% of the pronamide applied (i. e. the transfer efficiency). The study was acceptable and met the OPPTS guidelines, so the level of confidence is fairly high. There is less confidence in the oral risk estimates, which are solely based on the HED SOPs. HED assumes that the general public's exposure may not be mitigated by use of personal protective gear. Therefore, only administrative controls (e. g., formulation changes or use rate reductions) are feasible methods of risk reduction. Mitigating circumstances for residential exposure to pronamide residues may include the watering­ in of the product to turf immediately after application, instead of within 24 hours after application, as the label currently recommends. Pronamide product was watered­ in for the TTR study (MRID 44952501). This instruction, 9 however, does not prevent contact with treated turf prior to watering­ in. HED recommends that the residential turf label (EPA Reg. No. 8660­ 85) be changed to specify only one application per year and to required the product to be watered­ in to turf immediately after application. The exposure scenarios and risk estimates are summarized below. Summary of Postapplication Exposure Scenarios and Risk Estimates Exposure Scenario Route of Exposure Population Short­ Term MOE using DAT 0 TTR Data from Turf Study a Short­ Term MOE using DAT 2 TTR Data from Turf Study a Short­ Term MOE using HED Residential SOPs a Cancer Risk Estimate b High Contact Activities ­ Playing or Working on Lawns or Turf Dermal Adult 71 890 N/ A 8. 36E­ 07 Toddler 42 530 N/ A N/ A Low Contact Activity ­ Mowing Dermal Adult 2100 26,000 N/ A 5. 73E­ 08 Low Contact Activity ­ Golf Course Reentry Dermal Adult 1000 13,000 N/ A 1. 15E­ 08 Incidental Hand­ toMouth Activity (Finger Licking) Oral Toddler N/ A N/ A 380 N/ A Incidental Object­ toMouth Activity (Turfgrass Mouthing) Oral Toddler N/ A N/ A 1500 N/ A Incidental Ingestion of Soil Oral Toddler N/ A N/ A 113,000 N/ A Combined Postapplication Exposures Incidental Oral NonDietary Oral Toddler N/ A N/ A 300 N/ A Dermal & Incidental Oral Oral & Dermal Toddler N/ A N/ A 37 N/ A a Short­ term Margin of Exposure. MOEs that are < 300 are of concern for short­ term exposures and are shown in bold. N/ A = Not Applicable. b The HED endeavors to reduce estimated cancer risks for the general population to less than one in one million (10 ­6 ). N/ A = Not Applicable. 10 Pronamide: Residential Exposure/ Risk Characterization 1. BACKGROUND 1.1 Purpose This document is intended to support the development of the Pronamide Tolerance Reassessment Eligibility Decision (TRED) document and includes the results of HED's review of the potential human health effects associated with non­ dietary exposure to pronamide. This is a preliminary exposure and risk assessment. HED has determined that there is a potential for exposure in occupational settings from handling pronamide products during the application process (i. e., mixer/ loader, applicator and mixer/ loader/ applicator) and from entering previously treated areas. As a result, risk assessments would normally have been completed for occupational handler and postapplication scenarios. However, for pronamide the occupational handler and postapplication scenarios will not be assessed, since the assessment is only for a TRED document. The assessment is limited to registered non­ occupational postapplication (residential and recreational) uses of pronamide, i. e. residential/ recreational turf only. Pronamide is a restricted use pesticide, and therefore requires professional applicators. 1.2 Criteria for Conducting Exposure Assessments A residential exposure assessment is required for an active ingredient (ai) if (1) certain toxicological criteria are triggered and (2) there is potential exposure to handlers, such as mixers, loaders and applicators during use or to persons entering treated sites after application is complete. Pronamide meets the criteria, because of the potential for postapplication residential exposure to residues on turf. Therefore, a residential risk assessment/ characterization was completed for this chemical. Non­ occupational (residential/ public) handler exposures are not expected, since all pronamide products are labeled as restricted use pesticides. Postapplication exposures to pronamide residues are anticipated to be short­ term (one to 30 days) in duration for residential scenarios, since pronamide specific data show that turf transferrable residues decline to less than the limit of quantification by day 14 after application (see Table 4.). 1.3 Summary of Toxicity Concerns Relating to Residential Exposures Toxicological Endpoints The toxicological endpoints (effects), the doses and the uncertainty factors that were used to complete this assessment are summarized in Table 1 below in order to provide a quick reference to the residential post­ application exposure assessments (based on the November 1, 2001, HIARC Report). 11 Table 1. Toxicological Endpoints for Assessing Residential Risks for Pronamide. Exposure Scenario Study Dose Absorption Endpoint UF & FQPA/ Target MOE Short­ term Dermal & Inhalation Chronic Toxicity/ Carcinogenicity in Rats Oral NOAEL 8.46 mg/ kg/ day 100% of oral Increased liver weight & nonneoplastic histologic changes in liver, thyroid & ovaries 300 Intermediateterm Dermal & Inhalation 300 Long­ term Dermal & Inhalation 300 Short­ term Incidental Oral Ingestion N/ A 300 Intermediateterm Incidental Oral Ingestion N/ A 300 Lifetime Cancer Risk [All Populations] Chronic Toxicity/ Carcinogenicity in Rats & Carcinogenicity in Mice Q1 * = 0.0259 (mg/ kg/ day) ­1 N/ A Benign testicular interstitial cell tumors & uncommon thyroid follicular cell adenomas in rats; Hepatocellular carcinoma in mouse N/ A Acute, Short­ term, Intermediate­ term, and Long­ term Endpoints: Pronamide is classified as category III for acute dermal and inhalation toxicity and primary eye irritation, category IV for acute oral toxicity and for primary skin irritation. Pronamide is not a skin sensitizer. For short­ term (1­ 30 days) incidental oral exposures an adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. This dose is derived from the no observed adverse effect level (NOAEL) from a chronic toxicity/ carcinogenicity study in rats, where the effects are increased liver weight and non­ neoplastic histologic changes in liver, thyroid, and ovaries observed at the lowest observed adverse effect level (LOAEL) of 42.6 mg/ kg/ day. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. Although this study is of the appropriate route (oral) and duration (13 days), the NOAEL (5 mg/ kg/ day) in this study is lower than the NOAEL (8.46 mg/ kg/ day) established in the chronic 12 toxicity/ carcinogenicity study in the rat. The apparent disparity between these NOAELs is driven by the doses of pronamide selected for testing in these studies. The HIARC concluded that using a more realistic NOAEL of 8.46 mg/ kg/ day, rather than 5 mg/ kg/ day, would provide a sufficiently protective dose for risk assessment. The NOAEL of 3 mg/ kg/ day established in the special thyroid study conducted in male rats was also considered. However this dose was not selected because the wide gap between the NOAEL (3 mg/ kg/ day) and the LOAEL (67 mg/ kg/ day) in this study resulted in the 3 mg/ kg/ day dose (NOAEL) being artificially low. In addition, the LOAEL of 67 mg/ kg/ day is comparable to the LOAEL (56 mg/ kg/ day) established in the chronic toxicity /carcinogenicity study conducted in rats. For short­ term (1­ 30 days) dermal exposures the same oral dose and endpoint was selected for risk assessment, i. e. 8.46 mg/ kg/ day. A dermal absorption factor is needed, since the endpoint is based on a study using oral dosing. A default dermal absorption factor of 100% relative to oral absorption was chosen by the HIARC, since the dermal absorption study sent to the Agency was classified as unacceptable and no dermal toxicity studies were submitted. Uncertainty Factor (UF): The short­ term dermal and oral incidental endpoints have a 10x UF for intra­ species variability and a 10x UF for inter­ species extrapolation. In a memo dated December 19, 2001, the FQPA Safety Factor Committee recommended that the FQPA safety factor be reduced to 3x. The FQPA Committee determined that the safety factor is necessary when assessing the risk posed by pronamide because of evidence of endocrine effects. The FQPA safety factor is required for all population subgroups when assessing residential exposures of all durations. Total uncertainty factor applied to short­ term residential exposures is 300x. Carcinogenicity: In accordance with the Agency's Proposed Guidelines for Carcinogen Risk Assessment (September 30, 1992), the HED Carcinogenicity Peer Review Committee (CPRC) classified pronamide as a Group B2 chemical (probable human carcinogen with inadequate evidence in humans). This decision was based on the finding of two types of tumors in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas), and one type of tumor in the mouse (hepatocellular carcinomas). A linear, low dose approach (Q1 * ) is used for human risk characterization. The most potent unit risk Q1 * , based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2.59 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents [converted from animal to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor]. Therefore, the Hazard Identification Assessment Review Committee (HIARC) recommended that a cancer risk assessment be conducted for pronamide (November 6, 2001). 1.4 Incident Reports A review of incident data sources was conducted for pronamide on August 10, 2001 by J. Blondell. 1 Only one exposure incident to pronamide was reported to Poison Control Centers from 1993 through 1998. Cases involving exposures to multiple products were excluded. No cases were reported among children under six years of age or among older children and adults 13 exposed at their workplace. There was one non­ occupationally exposed case among older children and adults which was not reported to have symptoms related to their exposure and was not seen in a health care facility. Detailed descriptions of two cases submitted to the California Pesticide Illness Surveillance Program (1982­ 1999) were reviewed. In the first case, a worker applied pronamide product on the ground for ten days and reported malaise, anorexia, fatigue, dizziness, nausea, and vomiting. In the second case, one of two workers moved an irrigation pipe in a field and later reported dizziness, vomiting, and weakness. Both cases were categorized as `possible', meaning the pronamide exposure was a possible cause of the reported symptoms. On the list of the top 200 chemicals for which the National Pesticide Telecommunications Network (NPTN) received calls from 1984­ 1991, inclusively, pronamide was not reported to be involved in human incidents. In summation, very few illness cases have been reported due to pronamide and none have been confirmed. No recommendations can be made on the very limited incident data available for this pesticide. 1.5 Summary of Use Patterns and Formulations Pronamide products are described in this section. Additionally, available information that describes the manner in which pronamide products are applied is provided in this section (e. g. use categories/ sites, application methods and application rates). i. End­ Use Products Pronamide was manufactured by Rohm & Haas, but has been recently sold to Dow AgroSciences. One additional registrant, Pursell Incorporated, maintains a registration on one end use product. Based on a review (7/ 25/ 01) of the Office of Pesticide Programs­ Reference Files System (REFS) these two registrants supported 13 registrations of four products containing the active ingredient pronamide, including one technical product, one formulation intermediate, two section 3 registration end use products, and nine section 24( c) state registration labels. All end­ use products are wettable powders packaged in water soluble pouches. Table 2: Active Labels for Pronamide. Formulation Percent Active Ingredient EPA Registration Number Technical 92% 707­ 113 Formulation Intermediate 51% 707­ 98 Wettable Powder 51% 707­ 159; CO99001000 14 Wettable Powder 50% 8660­ 85; AZ79003600; CA86006500; FL91000700; ID91001600; OR90000400; OR99000700; OR99000800; WA91004300 ii. Mode of Action and Targets Controlled Pronamide (3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide) is a selective pre­ and postemergent herbicide used to control grasses and broadleaf weeds. It is a systemic herbicide with uptake by susceptible weeds occurring through the roots. Therefore, to be effective, pronamide is applied to the soil and transported by water into the root zone. Applications are made in the late Fall and/ or late Winter. iii. Registered Use Categories Based on available pesticide usage information for 1991 through 2000 supplied from the Biological and Economic Analysis Division (BEAD) Quantitative Usage Analysis (QUA) for Pronamide, dated September 26, 2001, total annual domestic usage of pronamide is approximately 225,000 pounds active ingredient (a. i.). In terms of pounds a. i., total usage is allocated mainly to head lettuce (29%), other lettuce (19%), seed crops (13%), fallowland (11%), hay other than alfalfa (8%), horticulture (3%) and alfalfa (3%). Sites with 5% or more of acreage treated include lettuce other than head lettuce (49%), head lettuce (36%), California endive/ escarole (31%), artichokes (21%), blackberries (6%) and raspberries (5%). Rates per application and rates per year are each generally less than 2 pounds a. i. per acre for agricultural sites. States with significant usage in terms of pounds a. i. include Arizona, California, Oregon and Washington. There is one label used exclusively for occupational use on commercial sites, i. e. EPA Reg. No. 707­ 159. Use sites on this label include stone fruits, pome fruits, grapes, artichokes, berries, forages, leafy greens, winter peas, Christmas trees, ornamentals, turf, rangeland, and fallow land. Another label is used exclusively by commercial applicators on residential/ recreational bermudagrass turf, i. e. EPA Reg. No. 8660­ 85. Use sites on this label include bermudagrass lawns, playing fields, and golf courses. There are several active 24C state labels. However, for risk assessment purposes the use sites and use patterns on these 24C labels are covered by EPA Reg. No. 707­ 159. iv. Application Parameters Application parameters are generally defined by the physical nature of the use site, the physical nature of the formulation (e. g., form and packaging), by the equipment required to deliver the chemical to the use site, and by the application rate required to achieve an efficacious dose, along with seasonal limits to applications. Table 3 contains the crops, application types and rates for pronamide. 15 Table 3: Use Parameters for Pronamide EPA Reg. No. Formulation Restrictions/ Limitations, etc. Use Sites Max App Rate in lb a. i./ A Max. # of Apps per Crop Cycle or Year Min Interval (Days) Reentry Interval (Hours) App Timing App Method Type App Equipment 707­ 159 51% W (3 x 1 lb water soluble pouches) Restricted Use Pesticide. Do not apply this product through any type of irrigation system. Hand­ spray applications may be made only to ornamentals & nursery stock of ornamentals. Apple, Apricot, Artichoke Globes (CA only), Cherry, Grape, Nectarine, Peach, Pear, Plum, Prune. Blackberry, Boysenberry, Raspberry (Black & Red). Alfalfa, Blueberry, Chicory, Christmas Trees, Clover, Birdsfoot Treefoil, Crown Vetch, Endive (Escarole), Lettuce, Radicchio, Rhubarb (OR & WA only), Sainfoin, Woody Ornamentals, Nursery Stock of Ornamentals. Grasses (Ornamental) Grown for Seed or Turf, Winter Peas (ID, OR & WA only). Conservation Reserve Program (CRP) Established Grass Stands, CRP Fallow land, Fallow land. 4.08 3.06 2.04 1.53 0.51 1 (Fruits); 2 Arti choke) 1 1 1 1 NS NS NS NS NS 24 24 24 24 24 Preemergence & early post emergence control of winter annual & perennial grasses & chickweed & preemergence control only of certain other grasses. Treatments mainly in fall, and some in winter. Fruits by band treatment & directed spray. Berries by band treatment & broadcast. Forages by broadcast & soil incorporation. Leafy greens by band treatment, low volume spray, broadcast & soil incorporation. Turf & Grasses by broadcast, band treatments & directed sprays. Fruits, berries, forages, chicory, artichoke, fallow land & ornamentals by low pressure ground sprayer. Alfalfa, chicory, endive & lettuce by soil incorporation. Artichoke, Christmas trees, endive, fallow land & lettuce by aircraft. Ornamentals by hand held sprayer. 8660­ 85 50% W (6 x 8 oz water soluble pouches) Restricted Use Pesticide. Not for use on turf being grown for sale or other commercial use as sod, or for commercial seed production or for research purposes. Bermudagrass Lawns, Playing Fields, & Golf Courses (Not recommended on greens.). 1. 5NS NS NS Preemergence & early post emergence control of Poa annua in the fall or late winter. Broadcast Sprayer OR90000 400 50% W Same as EPA Reg. No. 707­ 159 Sugarbeets 1. 02NS NS NS Fall & E arly Winter Broadcast Sprayer EPA Reg. No. Formulation Restrictions/ Limitations, etc. Use Sites Max App Rate in lb a. i./ A Max. # of Apps per Crop Cycle or Year Min Interval (Days) Reentry Interval (Hours) App Timing App Method Type App Equipment 16 CO99001 000 50% W Same as EPA Reg. No. 707­ 159 Alfalfa 2. 04 NS NS 24 Fall, Winter, Spring Broadcast & soil incorporated. Ground, low pressure ground sprayer, soil incorporated. ID910016 00 50% W Same as EPA Reg. No. 707­ 159 Blackberries & Raspberries 3.06 1 NS 24 Fall & Winter Band treatment & broadcast Low pressure ground sprayer. WA9100 4300 50% W Same as EPA Reg. No. 707­ 159 Christmas Tree Plantations 2.04 NS NS 24 Fall Band treatment & broadcast Aircraft & low pressure ground sprayer. AZ79003 600 50% W Same as EPA Reg. No. 707­ 159 Lettuce & Endive (Escarole) 2.04 1 for Lettuce NS for Endive NS 24 Fall & Winter Band treatment, low volume spray, broadcast & soil incorporation. Aircraft, low pressure ground sprayer, & soil incorporation. CA86006 500 50% W Same as EPA Reg. No. 707­ 159 Lettuce 1.53 1 NS 24 Fall & Winter Band treatment, low volume spray, broadcast & soil incorporation. Aircraft, low pressure ground sprayer, & soil incorporation. OR99000 700 50% W Same as EPA Reg. No. 707­ 159 Grasses grown for Seed 0.3825 1 NS 24 Fall & Winter Broadcast Ground & low pressure ground sprayer. OR99000 800 50% W Same as EPA Reg. No. 707­ 159 Grasses grown for Seed 0.255 1 NS 24 Fall & Winter Broadcast Ground & low pressure ground sprayer. FL91000 700 50% W Same as EPA Reg. No. 707­ 159 Gladiolus 2. 0 4 NS 24 Preemergence Ground spray Low pressure ground sprayer. ID910016 00 50% W Same as EPA Reg. No. 707­ 159 Raspberry (Red & Black) 3. 06 1 NS 24 Fall & Winter Band treatment & broadcast Sprayer ai = active ingredient; NS = Not Specified WP = Wettable Powder 17 2.0 RESIDENTIAL AND OTHER NON­ OCCUPATIONAL EXPOSURES AND RISKS This assessment for pronamide reflects the HED's current approaches for completing residential exposure assessments based on the guidance provided in the Draft: Series 875­ Occupational and Residential Exposure Test Guidelines, Group B­ Postapplication Exposure Monitoring Test Guidelines, the Draft: Standard Operating Procedures (SOPs) for Residential Exposure Assessment, the Overview of Issues Related to the Standard Operating Procedures for Residential Exposure Assessment presented at the September 1999 meeting of the FIFRA Scientific Advisory Panel (SAP), and the Revised SOPs (February 2001) for Residential Exposure Assessment 6,5, 3 . The HED is, however, currently in the process of revising its guidance for completing these types of assessments. Modifications to this assessment shall be incorporated as updated guidance becomes available. This will include expanding the scope of the residential exposure assessments by developing guidance for characterizing exposures from other sources not already addressed, such as from spray drift; residential residue track­ in; exposures to farm worker children; and exposures to children in schools. 2.1 Methods of Estimating Non Cancer Risks And Calculating Exposures The exposures that were calculated below represent the amount of pronamide that can be deposited on the surface of the skin after application, or that can be attributed to the mouthing behaviors of children after contact with treated turf. The HED calculates dose levels using the following formula: Where: Daily Dose = the amount as absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/ kg body weight/ day); Daily Exposure = the amount of dermal (on the skin), or nondietary ingestion (from mouthing behaviors of children) exposure (mg pesticide active ingredient/ day); Absorption Factor = a measure of the flux or amount of chemical that crosses a biological boundary (% of the total available); and Body Weight = body weight determined to represent the population of interest in a risk assessment (kg). For pronamide, the average body weight for adults used in all residential exposure assessments is 70 kg, which represents the general population. Although the short­ term dermal endpoint is from a developmental study, the effect is clinical signs and liver toxicity, not developmental 18 toxicity. The average body weight used in all assessments for 1­ 6 year old children is 15 kg, based on the SOPs for Residential Exposure Assessment. A 100% dermal absorption factor is applied to the oral NOAEL used for dermal risk estimates (i. e. dermal and oral absorption are equivalent), since the dermal absorption study sent to the Agency was classified as unacceptable and no dermal toxicity studies were submitted. For oral exposures for children, the oral NOAEL of 8.46 mg/ kg/ day for general population is used. HED expresses non cancer risk estimates for residential exposures to pesticides as a Margin of Exposure (MOE). The NOAEL and the combined uncertainty factors that apply to all pronamide risk estimates are listed in Section 1.3, Table 1. The non­ occupational short­ term target MOE is 300. MOEs were calculated using the following formula: Where: MOE = margin of exposure or ratio of endpoint of concern to the chemical exposure; Absorbed Daily Dose = the absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/ kg body weight/ day); and NOAEL = the highest dose level in a toxicity study where no observed adverse effects occur (mg pesticide active ingredient/ kg body weight/ day). In order for the Agency to make more informed risk management decisions, MOEs can be added together in order to look at the combined exposures that occur for an individual if the toxic effect for each route of exposure (e. g., to the skin and being ingested) is the same. For example, combining dermal and oral non­ dietary ingestion MOEs for children is of interest because these exposures can occur at the same time. The equation the HED uses to add MOEs together is presented below: MOE total = 1/(( 1/ MOE a) + (1/ MOE b) +.... (1/ MOE n)) Where: MOE a, MOE b, and MOE n represent MOEs for each exposure route of concern Children's dermal high­ contact exposures to pronamide on treated lawns were combined with hand to mouth exposure, as these events are likely to coincide. 19 2.2 Residential Handler Exposures and Risks 2.2.1 Residential­ Handler Exposure Scenarios, Data, and Assumptions All pronamide end use products are labeled as restricted use pesticides. Therefore, residents are restricted from handling pronamide products. 2.3 Non­ Occupational Postapplication Exposure and Risk Estimates When the pronamide RED document was completed in May, 1994, the Agency did not have the data to make a reregistration decision on pronamide for use on residential lawns. An estimate of risk was not feasible because of numerous uncertainties in potential exposure levels, especially for children. In the 1994 RED document, regulatory decisions concerning postapplication reentry to residential lawns were postponed until after the submittal and review of studies required to support the residential lawn use; i. e. foliar dislodgeable dissipation (old guideline 132­ 1( a) or new guideline 875.2100) and dermal passive dosimetry (old guideline 133­ 3 or new guideline 875.2400). In the interim since 1994, a turf transferrable residue (TTR) study was submitted, reviewed, and found acceptable and useful for some aspects of risk assessment. The study provided the required residue dissipation data. The methodology used to determine turf transferability (i. e. the modified California roller method) does not match the Agency's current methodology (i. e. Jazzercise and the California roller method) used to determine the dermal transfer coefficient on turf. Note, that the Outdoor Residential Exposure Task Force (ORETF) is currently funding a study which is intended to provide con current TTR and transfer coefficient data for a surrogate chemical. The requirement for a dermal passive dosimetry study remains outstanding. However, the Agency can perform an adequate risk assessment to estimate risk on residential lawns by using dissipation data from the TTR study in conjunction with the transferability assumptions and equations found in the Agency's residential SOPs. 2.3.1 Postapplication Exposure Scenarios, Data, and Assumptions Adults and children, are potentially exposed to pronamide residues after application of pronamide products in residential settings. After application to turf, short­ term dermal exposures are anticipated for adults and children. Incidental oral exposure is also expected to occur for small children and is combined with their dermal exposures, where applicable (i. e., playing on turf). Representative, range­ finding activities include working and playing on turf, mowing, golfing, and incidental ingestion by children. Therefore, the pronamide post­ application exposure/ risk assessment contains exposure scenarios in each category. The physical, behavioral, and physiological differences between adults and children are continuously being studied by the Agency and many others, and the current standard assumptions set forth by the HED and the Science Advisory Panel (SAP) are contained in the aforementioned Residential SOPs. The SOPs were updated, in February, 2001, to reflect the latest research findings and refined assessment strategies since the presentation to the SAP in September 1999. 20 Wherever available, reported usage data are used in this process to define values such as application rates and application frequency. Only one end use product label can be used in a residential setting. This residential label (EPA Reg. No. 8660­ 85) indicates a maximum application rate of 1.5 lb ai/ acre for pre­ emergence applications by lawn care operators (LCOs) to lawns, playing fields, and golf courses as a single application. The maximum application rate for post­ emergence applications is 1.0 lb ai/ acre. The label indicates that typical application rates for pre­ and post­ emergence applications are at 0.5 to 1.0 lb ai/ acre, with the maximum rate being used in areas of heavy growth weeds. This residential label does not specify or restrict the number of applications allowed per year to turf. However, the agricultural label (EPA Reg. No. 707­ 159) allows only one application per year to grasses grown for turf or seed. For both labels, applications to turf are only made in the late Fall or late Winter. Therefore, for residential turf, it is reasonable to assume that typically only one application is made, and potentially only two applications would be made in any year. If two applications were made, one would probably be made in late Fall, followed by another application in late Winter. Results from environmental fate studies indicate that pronamide is very persistent in soil and water with half­ lifes of many months. Additionally, rotational crop studies show accumulation in several crop types at one, six and twelve months after application. However, results from a recent turf transferable residue (TTR) study on turf using pronamide (i. e. MRID 44952501) indicate that the half­ life of turf transferrable residues was slightly less than two days. Also, the residential label (EPA Reg. No. 8660­ 85) instructs applicators to lightly irrigate within a day of application if no rain occurs. Such irrigation occurred at 24 hours after application in the TTR study. Study data showed that residues dissipate to below the level of quantification by day 14 following application. Therefore, only short­ term (i. e., one day to one month) exposures would be anticipated, since most of the pesticide should move into the soil, and any remaining foliar residues should dissipate within a month. While residues in soil could persist for greater than 30 days, it is unlikely that children will play on or contact soil for greater than 30 consecutive days during the late Fall or late Winter months. MRID 44952501 (Determination of Turf Transferrable Residue on Turf Treated with Kerb® 50W Herbicide): Turf transferable residues (TTR) were monitored using the Modified California Roller sampling methodology for the typical end­ use product (EPA Reg. No. 707­ 159), a wettable powder formulation containing 50 % active ingredient (ai). The product was applied at one geographically representative site in North Carolina (NC) with three replicated subplots. A single application by ground sprayer was applied prior to monitoring. The product was applied once at the label specified maximum application rate of 1.5 lb ai per acre (lb a. i./ A). The application was made on September 23, 1998, which agrees with the label specified application time period of Fall or late Winter. Also, the treated plot was irrigated 24 hours after the application (DAT 1; but after samples were taken) with 0.9 inches of water to move the ai into the root zone. The product label specifies that if a rain event does not occur within one day after application, that the site should be lightly irrigated. Rain occurred prior to the application of the pronamide and then again on DAT 7 (0.25 inches) and DAT 11 (0.23 inches). Control samples were taken prior to application for background analyses and for fortification purposes. After application triplicate samples were collected at day zero (0) as soon as the spray dried; at 21 6, 12 and 24 hours (0.25, 0.5 and 1) and 2, 4, 7, 10 and 14 days after application treatment (DAT) of the test substance. Samples were stored in a freezer for 15 to 37 days prior to analysis. Six replicate field fortification samples at each of two levels (50 and 10,000 µg) were prepared at sampling times DAT 0 and DAT 14. Fortification samples were handled and stored the same as treated samples. The results of the TTR data (mean and coefficient of variation) are presented in Table 4. Observed residue values exhibited a wide range of variability (i. e. 6 to137%). Field fortification recoveries averaged 85.8% (standard deviation 6.9%), indicating that pronamide was relatively stable in the sampling media during the handling and storage periods. Versar corrected these TTR data to the nearest fortification recovery. These data had only minor deficiencies; such as a limited number of controls, a relatively high variance, and only one site was tested; although three sites are required in the guidelines. Since bermudagrass is a regionally selective use site, the employment of only one test site is acceptable. The dissipation rate derived from these data was relatively rapid with an estimated pronamide half­ life of 1.8 days in turf. Also, the data show that the average pronamide residues found immediately after application (DAT 0) was approximately one percent of the target application. The maximum average pronamide residue found shortly after application (DAT 0.5) was approximately 2.6% of the applied pronamide (i. e. the transfer efficiency), and the overall average residue observed on day zero after application (i. e. DAT 0, DAT 0.25 & DAT 0.5) was approximately 1.65% of the applied pronamide. By comparison, the Agency's SOP uses a transfer efficiency (percent of application rate) of 5%. These TTR data were found to be acceptable for use quantitatively in the postapplication exposure assessment. The HED used the mean observed residue data from DAT 0 through DAT 0.5 from this study to estimate short­ term non­ occupational exposures, since the percent transferred was greater than one percent. However, the predicted TTR data are most suitable for longer term exposures. The HED always completes short­ term risk assessments using maximum application rates for each scenario, because what is possible under the label (the legal means of controlling pesticide use) must be evaluated for complete stewardship in order to ensure the HED has no concern for the specific use. As a result of home lawn uses, the HED has concerns for potential postapplication exposures to both adults and children. Anticipated routes of postapplication exposure include dermal exposure to adults and children (toddlers), and incidental oral exposure to children (toddlers). Postapplication exposures via the inhalation route are not anticipated, since pronamide is applied as a liquid, and is a mobile systemic herbicide, which when watered in (as directed on the label) quickly moves into soil, where it is rapidly absorbed into vegetation. Additionally, the uses and primary exposures are outdoors, allowing for significant dilution. Also, the vapor pressure of pronamide is 8.5E­ 5 mm Hg at 25 0 C. In order to adequately consider the risks to children, the guidance from the HED's updated Residential SOPs (2/ 01) was used to address the exposures of children contacting recently 22 treated turf. The SOPs for turf use a high contact activity based on the use of Jazzercise® to represent the exposures of an actively playing child or active adult. Lower­ contact activities, such as walking, mowing, or golfing, for example, use transfer coefficients based on mowing and golfing studies. The HED believes that pronamide exposures can occur over a single day or up to a few weeks at a time. This is supported by the length of time that residues took to decline in the pronamide turf TTR study. The HED classifies these as short­ term exposures (one day to one month). No intermediate­ term (one to six months) or long­ term (six months or more) residential exposures are anticipated with the use of pronamide, due to the product's use pattern, and since turf residues dissipate rapidly to below the limit of quantification by day 14 following application (pronamide TTR study), and the short­, intermediate­, and long­ term endpoints are the same. These classifications are the basis for selecting toxicological endpoints for chemicals and are generally included in each risk assessment. Route­ specific (i. e., dermal and incidental oral) pronamide exposures were combined where appropriate (i. e. small children). Restricted entry intervals are not considered a practical regulatory tool for reducing exposures and risks in the residential environment (i. e., for the general population). Although LCOs may inform residents to stay off treated turf, or signs may be posted, there is no practical way to restrict access by humans or pets. Therefore, for chemicals used in the residential environment or any other areas where the general population can be exposed, the HED currently considers the risks associated with a chemical on the day they are applied. Exposure Scenarios and Assumptions: The activities that were selected as the basis for the risk assessment are represented by the following assumptions and transfer coefficients for short­ term endpoints: ° Adults involved in a low exposure activity on turf such as golfing (4 hours a day), mowing (2 hours per day), or other light work activities (2 hours per day), with a transfer coefficient = 500 cm 2 /hour; ° Adults involved in a high exposure activity on turf such as heavy yard work, gardening or laying sod for 2 hours per day, with a transfer coefficient = 14,500 cm 2 /hour; ° Small children involved in a high exposure activity for 2 hours per day, with a transfer coefficient = 5,200 cm 2 /hour (based on the recommended revisions to the SOPs for residential exposure assessments (2/ 2001)); Small children's exposure levels were calculated for the residential exposure assessment and for the purposes of completing an aggregate risk assessment that also considers exposure from dietary intake of food and water (for all age groups). Dermal exposure values for adults and children on the day of treatment were calculated based on the following equation (see Residential SOP 2.2: Postapplication dermal potential dose from pesticide residues on turf): 23 DE( t) (mg/ day) = (TTR( t) (µg/ cm 2 ) x TC (cm 2 /hr) x Hr/ Day)/ 1000 (µg/ mg) Where: DE = Dermal exposure at time (t) attributable for activity in a previously treated area (mg/ day); TTR = Turf Transferable Residue (TTR) data (from MRID # 44952501, i. e. mean observed residue value of 0.289 µg/ cm 2 from day zero after application (DAT 0) through DAT 0.5); TC = Transfer Coefficient (cm 2 /hr); and Hr = Exposure duration in hours. The HED's Residential SOP contains guidance for considering children's exposure to treated turf. The dermal calculations, as noted above, were completed based on the guidance provided in the document. All nondietary exposures were also calculated using guidance from this document. Specifically, the kinds of nondietary ingestion exposures that were considered in this assessment include the following: ° Dose from hand­ to­ mouth activity calculated using SOP 2.3.2: Postapplication dose among small children from incidental nondietary ingestion of pesticide residues on residential lawns from hand­ to­ mouth transfer; ° Dose from mouthing treated turf calculated using SOP 2.3.3: Postapplication dose among small children from the ingestion of pesticide treated turfgrass; and ° Dose from incidental ingestion of soil calculated using SOP 2.3.4: Postapplication dose among small children from the ingestion of soil in pesticide treated areas. Hand­ to­ Mouth Transfer (Mouthing) The following demonstrates the method used to calculate exposures that are attributable to a child touching treated turf and then putting their hands in their mouth (SOP 2.3.2): PDR = (AR * F­ DR * CF * SA * EXT * Freq * Hr * (1 mg/ 1000 µg) where: PDR = potential dose rate (mg/ day) AR = application rate (lb ai/ A) F­ DR = fraction of dislodgeable residue from turf for hand­ to­ mouth behavior with wet hands (5%) CF = conversion factor to convert lb ai/ A to µg/ cm 2 (11.2) SA = surface area of 1 to 3 fingers (20 cm 2 ); EXT = extraction rate by saliva (50%) Freq = frequency of hand­ to­ mouth events (20 events/ hour); and Hr = exposure duration (2 hours) 24 The surface area for 1­ 3 fingers used (20 cm 2 ) is the median surface area for a small child (age 3 years) as updated in 12/ 99. The frequency of hand­ to­ mouth events is 20 events per hour as updated in 12/ 99. The fraction of residue dislodgeable from wet hands is five percent and the extraction rate by saliva is fifty percent as updated in 12/ 99. The time spent outdoors (2 hours/ day) is also a recommended value from the U. S. EPA Exposure Factors Handbook. This model for hand­ to­ mouth dose is based on the premise that a child puts 2­ 3 fingers in their mouth, five percent of the residues on the hands are transferred from the hands to the mouth, fifty percent of the residues is extracted by saliva and that all of the residues available on the treated turf transfer to the child's hand each time they exhibit this behavior. Object­ to­ Mouth The following illustrates the approach used to calculate exposures that are attributable to a child mouthing treated turf (SOP 2.3.3): PDR = (AR * F­ DR * CF * IgR * (1 mg/ 1000µg) where: PDR = potential dose rate (mg/ day); AR = application rate F­ DR = fraction of residue dislodgeable from turf (20%) CF = conversion factor to convert lb ai/ A to µg/ cm 2 (11.2) IgR = ingestion rate for mouthing of grass per day (25 cm 2 /day) The ingestion rate used (25 cm 2 /day) assumes that a child will grab a handful of turf, mouth it and remove twenty percent pronamide residues, and then remove it from their mouth as described in the Residential SOPs. The surface area of 25 cm 2 /day is thought to approximate a handful of turf that is mouthed. Incidental Soil Ingestion The following is the formula used to estimate exposure from incidental ingestion of soil treated with pronamide (SOP 2.3.4): PDR = (AR * (1­ D) t * IgR * CF1 * CF2 * CF3 * CF4) where: PDR = potential dose rate (mg/ kg/ day) AR = application rate (lb ai/ A) (1­ D) = fraction or residue retained on uppermost 1 cm of soil, assumed to be 100 percent based on soil incorporation into top 1 cm of soil after application (1.0/ cm) t = postapplication day on which exposure is being assessed, assumed to be day 0 IgR = ingestion rate of soil (100 mg/ day) CF1 = weight unit conversion factor to convert the lbs ai in the 25 application rate to µg for the soil residue value (4.54 x 10 8 µg/ lb) CF2 = area unit conversion factor to convert the surface area units (ft 2 ) in the application rate to cm 2 for the SR value (2.47 x 10 ­8 acre/ cm 2 if the application rate is per acre) CF3 = volume to weight unit conversion factor to convert the volume units (cm 3 ) to weight units for the SR value (0.67 cm 3 /g soil) 7 CF4 = weight unit conversion factor to convert the µg of residues on the soil to grams to provide units of mg/ day (1E­ 6 g/ µg) The estimated exposure from ingestion of soil from an area treated with pesticide is a minor contributor to the total incidental oral dose. The following specific assumptions and factors were used to complete the exposure assessment: ° These assessments were based on the guidance provided in the Residential SOPs and the Recommended Revisions to the SOPs for Residential Exposure Assessments (2/ 22/ 01). ° To assess short­ term dermal exposures, the TTR value (0.289 µg/ cm 2 ) was used for turf on the day of application (DAT 0 through DAT 0.5) from the turf transferrable residue study (MRID 44952501); ° Calculations for short­ term exposures are based on the maximum application rate (1.5 lb ai/ acre) for residential turf; ° Due to a lack of scenario­ specific exposure data, HED has calculated exposure values for adults using surrogate dermal transfer coefficients that represent activities such as mowing, golfing, and yardwork. 2.3.2 Postapplication Exposure and Non­ Cancer Risk Estimates The results of the residential post­ application exposure and risk estimates are presented in Tables 5­ 7 in Appendix A. The dermal non­ cancer risk estimates for adults and children exposed to pronamide while doing activities on turf are shown in Table 5. The dermal cancer risk estimates for adults exposed to pronamide while doing activities on turf are shown in Table 6. The oral nondietary non­ cancer risk estimates for small children from hand­ to­ mouth and ingestion exposure while playing on pronamide­ treated turf are contained in Table 7. For pronamide short­ term non­ occupational risks, the HED has established a level of concern for MOEs < 300. Risk estimates for short­ term dermal contact with treated turf during high contact lawn activities on day zero following application (DAT 0) exceed HED's estimated level of concern, using residue data from the TTR study, i. e. result in MOEs < 300 for adults (MOE = 71) and children (MOE = 42). However, using DAT 2 residue data from the TTR study yielded MOEs that do not exceed the level of concern (MOEs $ 300) for adults (MOE = 890) and children (MOE = 530) during high contact lawn activities. Note that the test plots were irrigated immediately after the DAT 1 samples were taken, i. e. 24 hours after application of pronamide, as specified on the label. The data show that watering­ in the pronamide product clearly alleviates these risk 26 concerns. Risk estimates for adults for short­ term dermal contact with residues on treated turf during the low contact activities of grass mowing (MOE = 2100) or golfing (MOE = 1000) on the day of treatment do not exceed the level of concern (MOEs $ 300); see Table 5. HED also assessed short­ term risks to small children from incidental oral ingestion of pronamide residues following application to residential lawns (see Table 7). The level of concern for residential risks is set by the HED at a MOE < 300. The risk calculations for small children's non­ dietary ingestion of pronamide on treated turf indicate that risks do not exceed the level of concern (i. e. MOEs $ 300) for hand­ to­ mouth finger licking (MOE = 380), incidental ingestion of soil (MOE = 113,000), and incidental object to mouth (MOE = 1500). The small children's combined oral hand­ to­ mouth scenarios (MOE = 300) also do not exceed the level of concern. When risks from dermal exposures from pronamide to small children are combined with risks from incidental oral exposures, the combined short­ term risk estimates exceed the level of concern (MOEs < 300), with an MOE at 37. However, the likelihood of all incidental oral exposures co­ occurring with dermal exposures is low. 2.3.3 Postapplication Cancer Risk Estimates The HED endeavors to reduce estimated cancer risks for the general population to less than one in one million (10 ­6 ). Estimated adult cancer risks were calculated using the same residential exposure scenarios as described in section 2.3.1. The lifetime average daily dose (LADD) must be calculated by first determining the dermal exposure (DE) from foliar contact (see formula above in Section 2.3.1); i. e. DE( t) (mg/ day) = (TTR( t) (µg/ cm 2 ) x TC (cm 2 /hr) x hr/ day)/ 1000 (µg/ mg). Then, the dermal exposure is converted to absorbed daily dose multiplied by the frequency of exposure in days per year, as follows: LADD (mg/ kg/ day) = DE/ 70 kg (mg/ kg/ day) x absorption factor (100%) x (exposure frequency/ 365 days per year) x (50 years residential duration/ 70 year lifetime) and the cancer risk = LADD (mg/ kg/ day) x Q1 * (mg/ kg/ day) ­1 Based on the pesticide label, a typical residential/ recreational lawn application rate of 1.0 lb/ acre, with an application frequency of once per year, was assumed for the residential cancer risk assessment. Pronamide is applied in the dormant season, which reduces the number of contact days expected. A single exposure is deemed more likely, but up to 14 days exposure could occur based on the residue dissipation pattern. The 14­ day average turf residues from the TTR study (MRID 44952501) were used (i. e. 0.07913 F g/ cm 2 , when adjusted to a typical application rate of 1.0 lb ai/ acre); since residues in the TTR study dissipated to the level of quantitation by 14 days after application. The average residue, and an exposure frequency of one day per year, or 50 days in a lifetime, was assumed for high contact activities (e. g. playing and working on lawns and turf) and low contact activities (e. g. mowing or golfing). An adult mowing a treated lawn one day each year has a cancer risk of 5.7 x 10 ­8 . The average golfer plays 18 times per year, so one day's exposure is possible if pronamide is applied once per year 27 on average. These assumptions are not meant to imply that exposures will occur for only one day. The adult golfer cancer risk is estimated at 1.2 x 10 ­7 . An adult performing dermal high contact activities on turf during the 2 week period of residue dissipation has a cancer risk of 8.4 x 10 ­7 . The HED endeavors to reduce estimated cancer risks for the general population to less than one in one million (10 ­6 ). In order to exceed the cancer risk (1.0 x 10 ­6 ), exposure frequencies of 17.5, 8.7 and 1.2 days per year would be needed for the activities of mowing, golfing and high contact work, respectively. 2.3.4 Summary of Postapplication Risks, Data Gaps, and Confidence in Exposure and Risk Estimates Residential exposures are anticipated as a result of professional lawn care operator application. Risk estimates were performed for potential contact with lawn or soil treated with pronamide, using data from a turf transferable residue study submitted for pronamide, and using HED's Draft SOPs for Residential Exposure Assessment. These estimates are considered conservative, but appropriate, since the study data and risk estimates were generated at the maximum application rate. The Residential SOPs are considered to be upper bound scenarios for determining risk estimates. The adult and children's transfer coefficients are based on the Jazzercise protocol and an upper percentile exposure duration value. Where study data were used with the SOP formulae, these risk estimates were better refined, and hence, less conservative. Therefore, the exposure estimates related to turf skin contact (which were based on study data) are more refined than the estimates of incidental ingestion. For postapplication residential exposures, the scenarios with short­ term risk estimates that exceed HED's level of concern (MOEs < 300) are the high contact dermal exposure activities (adults & toddlers) of working or playing on lawns. The scenarios with risks estimates that do not exceed HED's level of concern (MOEs $ 300) are as follows: 1) the low contact dermal exposure activities of mowing lawns (adults) and golfing (adults) on treated turf; and 2) the incidental oral exposure activities by toddlers of ingesting soil, hand­ to­ mouth (finger licking), and object to mouth (turfgrass mouthing) while playing on lawns. Combining risk estimates for exposure scenarios that are likely to occur together resulted in risk estimates of greater concern. For example, it is possible that the same child could receive dermal exposures from performing high contact activities on a lawn, while at the same time receive incidental oral exposures from hand­ to­ mouth, object­ to­ mouth and/ or soil ingestion. Combining the postapplication turf short­ term risk estimates for the incidental oral nondietary exposures to small children resulted in a risk estimate (MOE = 302) that does not exceed HED's level of concern (MOE < 300). However, combining the postapplication turf dermal and incidental oral risk estimates for small children resulted in an MOE (MOE = 37) that exceeds HED's level of concern (MOEs < 300); primarily due to the dermal exposure. However, the likelihood of all incidental oral exposures co­ occurring with dermal exposures is low. 28 2.4 RESIDENTIAL AND NON­ OCCUPATIONAL RISK CHARACTERIZATION 2.4.1 Residential Handler Risk Characterization All pronamide end use products are labeled as restricted use pesticides. Therefore, residents are restricted from handling pronamide products. 2.4.2 Non­ Occupational Postapplication Risk Characterization The short­ term residential exposures to treated lawns were based upon exposure to transferable residues at the earliest possible opportunity (i. e. residues at day zero after application), the maximum application rate, and a 100% dermal absorption. While these are high­ end scenarios, they are not worst­ case, because the time of exposure is short (i. e. 2 to 4 hours) and risk estimates are based on behavioral data, actual field residue data supplied by the registrant, and are generated using HED SOPs. The translation of a dose based on a chronic effect for the purpose of short­ term risk estimation also contributes to a high­ end exposure estimate. Mitigating circumstances for residential exposure to pronamide residues may include the watering­ in of the product to turf immediately after application, instead of within 24 hours after application, as the label currently recommends. Pronamide product was watered­ in for the TTR study (MRID 44952501). This instruction, however, does not prevent contact with treated turf prior to watering­ in. HED recommends that the residential turf label (EPA Reg. No. 8660­ 85) be changed to specify only one application per year, and require the product to be watered into turf immediately after application. 29 References 1. Blondell, J. Review of Pronamide Incident Reports, DP Barcode D276935. EPA. August 10, 2001. 2. Hazard Identification Assessment Review Committee (HIARC) Meeting on Pronamide. November 1, 2001. 3. Recommended Revisions to the Standard Operating Procedures (SOPs) for Residential Exposure Assessments. EPA, HED Exposure SAC, February 22, 2001. 4. Outdoor Residential Exposure Task Force. Response to the Outdoor Residential Exposure Data Call in Dated: March 3, 1995. ORETF. November 12, 1999. 5. Draft SOPs for Residential Exposure Assessments. EPA. December 18, 1997. 6. [Draft] OPPTS Series 875­ Occupational and Residential Test Guidelines: Group BPostapplication Exposure Monitoring Test Guidelines. EPA. February 1998 version. 7. Martin, D.; Determination of Transferrable Turf Residues on Turf Treated with Pronamide (Kerb® 50W Herbicide). Rohm and Haas Company; 06/ 30/ 99; EPA MRID 44952501. 30 Appendix Pronamide Exposure and Risk Estimates Tables 4 through 7 31 Table 4. Summary of Postapplication Turf Transferable Residue Study MRID 44952501 TTR on Turf Treated with Pronamide (50% Wettable Powder in Water Soluble Pouches) Study Application Rate: 1.5 lb ai/ acre Slope = ­0.387; Intercept = ­1.86; R 2 = 0.79 DAT (days) Mean Observed TTR (µg/ cm 2 ) (CV) Predicted TTR (µg/ cm 2 ) 0 0.161 (10.8) 0.155 0.25 0.252 (8.3) ­­ 0.5 0.453 (18.0) ­­ Average of DAT 0­ 0.5 0.289 ­­ 1 0.154 (7.24) 0.105 2 0.023 (48.0) 0.072 4 0.016 (12.8) 0.033 7 0.004 (6.2) 0.010 10 0.002 (38.2) 0.003 14 0.003 (137) 0.0007 Average of DAT 0­ 14 0.1187 0.032 32 Table 5. Pronamide Residential Postapplication Activities on Treated Turf: Dermal Exposure and Non­ Cancer Risk Estimates Short­ term Risk Estimates at DAT 0 using TTR Data from Turf Study Short­ term Risk Estimates at DAT 2 using TTR Data from Turf Study Activity Transfer Coefficient (cm 2 /hr) (a) TTR µg/ cm 2 DAT 0 (b) Dermal Dose (mg/ kg/ day) (c) MOE (d) TTR µg/ cm 2 DAT 2 (b) Dermal Dose (mg/ kg/ day) (c) MOE (d) high contact lawn activities: adults 14,500 0.2886 0.1196 71 0.023 0.00953 890 high contact lawn activities: toddler 5,200 0.2886 0.2001 42 0.023 0.0159 530 mowing turf: adults 500 0.2886 0.00413 2100 0.023 0.000329 26,000 golf course reentry: adult 500 0.2886 0.00825 1000 0.023 0.000657 13,000 a Transfer coefficients from the Residential SOP's (02/ 01). b TTR Source: MRID # 44952501 turf transferable residue study ­ see Table 4 for raw data and regression statistics. Mean observed residue values from DAT 0 through DAT 0.5 were used for the DAT 0 short­ term assessments. Mean observed residue values from DAT 2 were used for the DAT 2 short­ term assessments. c Dermal Dose = TTR (µg/ cm 2 ) x TC (cm 2 /hr) x conversion factor (1 mg/ 1,000 µg) x exposure time (2 hrs/ day playing & mowing; 4 hrs golfing) x Dermal Absorption Factor (100%/ 100)/ body weight (70 kg adult or 15 kg child 1­ 6 yrs). Short­ term MOEs were calculated using DAT 0 or DAT 2 values. d MOE = NOAEL (8. 46 mg/ kg/ day; based on an oral study) / dermal dose; Note: Target MOE is 300 or greater; numbers are rounded to two significant figures. Note: TTR = turf transferable residue DAT = days after treatment MOEs in bold exceed HEDs level of concern (i. e. MOEs < 300). 33 Table 6. Pronamide Postapplication Dermal Cancer Risk Estimates for Activities on Treated Turf Activity Typical Application Rate (lb ai/ acre) (a) Days of Exposure per Year (b) 14­ day avg TTR, adjusted for "typical" rate (µg/ cm 2 ) (c) Transfer Coefficient (cm2/ hr) (d) Absorbed Dermal Daily Dose (mg/ kg/ day) (e) LADD (mg/ kg/ day) (f) Cancer Risk (g) Days of Exposure per Year to Exceed 1.0E­ 06 High­ contact activities 1.0 1 0.07913 7300 1.65E­ 02 3.23E­ 05 8.36E­ 07 1.2 Mowing 1.0 1 0.07913 500 1.13E­ 03 2.21E­ 06 5.73E­ 08 17.5 Golfing 1.0 1 0.07913 500 2.26E­ 03 4.42E­ 06 1.15E­ 07 8.7 a Typical (not maximum) application rates were used to adjust TTR study residue data; rate confirmed per label and registrants' comments. b Average or typical days per year for cancer risk estimates, based upon a single annual application and a fairly rapid foliar dissipation rate (half life of 1.8 days, from TTR study, i. e. MRID # 44952501). c TTR source: MRID # 44952501 turf transferable residue study ­ see Table 4 for raw data and regression statistics. Mean observed residue values for DAT 0 through DAT 14 were used for the assessment. The study was conducted in NC using a maximum application rate of 1.5 lb ai/ acre. When assessing activities involving a different application rate than what was used in the study, the TTR values are adjusted proportionately to reflect the different application rate. For example, for the "typical" application rate of 1.0 lb ai/ acre : normalized (adjusted) TTR = Turf study TTR x 1.0 lb ai/ A assessed rate / 1.5 lb ai/ A study rate; 0.1187 µg/ cm 2 x 1.0 lb ai/ A assessed rate / 1.5 lb ai/ A study rate = 0.07913 µg/ cm 2 . d Transfer coefficient from the updated Residential SOP's (02/ 01). e Absorbed daily dose = Average day 0­ 14 TTR (µg/ cm 2 ) x intermediate­ term transfer coefficient (cm 2 /hr) x mg/ 1,000 µg x exposure duration (2 hrs/ day for playing/ gardening/ mowing; 4 hrs/ day to play golf) x dermal absorption factor (100%) / body weight (70 kg adult). f LADD = absorbed daily dose (mg/ kg/ day) x days of exposure/ year x 50 years of expected exposure/ (365 days/ year x 70 year lifetime); g Cancer Risk = LADD x Q 1 * , where Q 1 * = 2.59 x 10 ­2 (mg/ kg/ day) ­1 TTR used for cancer risk estimate = 0­ 14 DAT average residue normalized for typical application rate. TTR = turf transferable residue DAT = days after treatment 34 Table 7. Residential Oral Nondietary Short­ Term Postapplication Risks to Children from "Hand­ to­ Mouth" and Ingestion Exposure When Reentering Treated Lawns Type of Exposure Short­ term Oral Dose a (mg/ kg/ day) Short­ term MOE b (1) Hand to Mouth Activity (Finger licking) 0.0224 380 (2) Incidental Object to Mouth (Turfgrass Mouthing) 0.0056 1500 (3) Incidental Ingestion of Soil 7.51E­ 5 113,000 Combined Oral Nondietary c 0.028 300 Combined Oral and Dermal d ­­­ 37 a Application rate for the short­ term estimates represents maximum label rate from current EPA registered label: EPA Reg. No. 8660­ 85 wettable powder product formulation, max rate is 1.5 lb ai/ acre. Incidental oral doses were calculated using formulas presented in the Residential SOPs (updated 1999­ 2000). Short­­ term doses were calculated using the following formulas: (1) Hand­ to­ mouth oral dose to children on the day of treatment (mg/ kg/ day) = [application rate (lb ai/ acre) x fraction of residue dislodgeable from potentially wet hands (5%) x 11.2 (conversion factor to convert lb ai/ acre to µg/ cm 2 )] x median surface area for 1­ 3 fingers (20 cm 2 /event) x hand­ to­ mouth rate (20 events/ hour) x exposure time (2 hr/ day) x 0.001 mg/ : g] x 50% extraction by saliva / bw (15 kg child 1­ 6 yrs). This formula is based on proposed changes to the December 1999 Residential SOPs. (2) Turf mouthing oral dose to child on the day of treatment (mg/ kg/ day) = [application rate (lb ai/ acre) x fraction of residue dislodgeable for transfer to mouth (20%) x 11.2 (conversion factor to convert lb ai/ acre to µg/ cm 2 ) x ingestion rate of grass (25 cm 2 /day) x 0.001 mg/ : g] / bw (15 kg child 1­ 6 yrs). (3) Soil ingestion oral dose to child on the day of treatment (mg/ kg/ day) = [( application rate (lb ai/ acre) x fraction of residue retained on uppermost 1 cm of soil (100% or 1.0/ cm) x 4.54e+ 08 µg/ lb conversion factor x 2.47e­ 08 acre/ cm 2 conversion factor x 0.67 cm 3 /g soil conversion factor) x 100 mg/ day ingestion rate x 1.0e­ 06 g/ µg conversion factor] / bw (15 kg; child 1­ 6 yrs). Short term dose based residue on the soil on day of application. b Short­ term MOE = NOAEL (8.46 mg/ kg/ day) / Oral Dose (mg/ kg/ day). NOAEL from a non­ developmental toxicity study in rabbits; target MOE of 100. Numbers are rounded to two significant figures. c Combined MOEs = NOAEL / [sum of incidental oral doses], with a target MOE of 100. d Combined Dermal + Incidental Oral MOEs = 1/ [1/ MOEdermal + 1/ MOEoral ]; see Table 5 for dermal MOE for high­ contact short­ term activity for toddlers on turf (MOE = 42). MOEs in bold exceed HEDs level of concern (i. e. MOEs < 300).

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Supporting & Related Material

TXR NO. 0050361 December 19, 2001 MEMORANDUM SUBJECT: PRONAMIDE­ Report of the FQPA Safety Factor Committee FROM: Carol Christensen, Acting Executive Secretary FQPA Safety Factor Committee Health Effects Division (7509C) THROUGH: Ed Zager, Chair FQPA Safety Factor Committee Health Effects Division (7509C) TO: Jose Morales, Risk Assessor Reregistration Branch III Health Effects Division (7509C) PC Code: 101701 The FQPA Safety Factor Committee evaluated the available hazard and exposure data for pronamide on December 3 rd , 2001 and made the recommendation for the FQPA safety factor to be used in human health risk assessments (as required by Food Quality Protection Act of August 3, 1996). The committee concluded that the FQPA safety factor could be reduced (3x) in assessing the risk posed by this chemical. 2 I. HAZARD ASSESSMENT (Memorandum: Michelle Centra to Carol Christensen, dated November 26, 2001) A. Adequacy of the Toxicology Database The toxicology data base for pronamide is adequate for FQPA assessment. The toxicology data base for pronamide was reviewed by the Hazard Identification Assessment Review Committee (HIARC) on November 6 th , 2001. Prenatal developmental toxicity studies in the rabbit and a two­ generation reproduction study are available with pronamide. However, the submitted prenatal developmental toxicity study in rats was evaluated and classified as unacceptable­ guideline (not upgradeable). Neither a LOAEL nor a definitive NOAEL was established in this study, and, no toxicities were observed in the maternal animals and their fetuses. B. Determination of Susceptibility The results of the available developmental toxicity study in rabbits and two­ generation reproduction study in rats indicated no susceptibility to the fetuses of rabbits or to the offspring of rats following pre­ and/ or postnatal exposure to pronamide. Fetal/ offspring effects in both the rat and rabbit were observed at either the same or higher dose levels which produced maternal/ parental toxicity. C. Requirement of a Developmental Neurotoxicity Study The HIARC determined that a developmental neurotoxicity study in rats is not required. However, endocrine effects (thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus) were identified in the majority of studies conducted across species. Since thyroid hormone disruptions are known to be associated with adverse effects on neurological development, a special study designed to assess thyroid function in adult animals and their offspring will be required. II. EXPOSURE ASSESSMENTS A. Dietary Food Exposure Considerations (Memorandum: Jose Morales to Carol Christensen on November 27, 2001) Pronamide [3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide] is a selective, systemic, pre­ and post­ emergence herbicide registered for the control of grasses and broadleaf weeds in several food and feed crops as well as woody ornamentals, Christmas trees, nursery stocks, lawns, turfs, and fallow land. The application rates range from 0.2 lbs ai/ A to 4.0 lbs ai/ A and can be applied 1 to 2 times per season. There are no Codex MRLs established or proposed for residues of pronamide in or on foods. Tolerances range from 0.05­ 10 ppm. Pronamide is a systemic herbicide. The qualitative nature of the residue in plants and 3 animals is adequately understood. The terminal residues of concern are pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety. Monitoring data are available from the Pesticide Data Program (PDP) for the years 1998 and 1999. There were only 2 instances of detectable residues. Percent of crop treated data are also available. The HED Dietary Exposure Evaluation Model (DEEM) will be used to assess the risk from dietary exposure to pronamide residues in food. The DEEM analysis will be refined (Tier II) using anticipated residues and percent of crop treated data. The Committee recognizes that further refinement to the dietary food exposure analyses may be required as the risk assessment is developed. Therefore, provided the final dietary food exposure assessment includes the metabolites of toxicological concern does not underestimate the potential risk for infants and children, the safety factor recommendations of this Committee stand. B. Dietary Drinking Water Exposure Considerations (Correspondence: Lucy Shanaman to Carol Christensen on November 27, 2001) The environmental fate data base for the parent compound (pronamide, also known as propyzamide) is complete. Pronamide is relatively mobile and persistent in the environment, and therefore could possibly move to surface and groundwater. Only the parent compound pronamide is assessed in the drinking water exposure analysis. Laboratory studies indicate that leaching appears to be the major route of dissipation for pronamide. The FIRST and SCI­ GROW models will be used to estimate environmental concentrations (EEC's) of pronamide in surface water and groundwater. These models are considered Tier I. The ornamental application scenario is used to assess water exposure because application rate and frequency associated with this use is expected to result in the highest modeled EECs. Monitoring data were not used in this assessment directly. However, available data do indicate that the values estimated through modeling are conservative. The FQPA Safety Factor Committee recognizes that further refinement to the dietary drinking water exposure analyses may be required as the risk assessment is developed. Therefore, provided the final dietary water exposure assessment does not underestimate the potential risk for infants and children, the safety factor recommendations of this Committee stand. 4 C. Residential Exposure Considerations (Correspondence: Barry O'Keefe to Carol Christensen on November 27, 2001) Use of pronamide in the residential environment is by certified applicators only. Postapplication dermal and incidental oral exposures to children and infants are possible from exposure to lawns and turf treated with pronamide. Typical application rates are 0.5 to 1.0 lbs ai/ acre. Applications to turf are only made in the late Fall or late Winter. Therefore, for residential turf, it is reasonable to assume that typically one or two applications are made per year. If two applications were made, one would probably be made in late Fall, followed by another application in late Winter. Both a registrant submitted turf transferable residue (TTR) study and the EPA's original and revised Draft SOPs for Residential Exposure Assessment were used to assess postapplication dermal exposure to adults and children as well as incidental oral exposure of toddlers. A 100% dermal absorption factor was assumed. Incident data are available, and report only a few exposures. 5 II SAFETY FACTOR RECOMMENDATION AND RATIONALE A. Recommendation of the Factor The Committee recommended that the FQPA safety factor be reduced to 3x. B. Rationale for Reducing the FQPA Safety Factor The FQPA Committee determined that the safety factor is necessary when assessing the risk posed by pronamide because: 1. There is evidence of endocrine effects (thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus) identified in the majority of studies conducted across species. A special study designed to assess thyroid function in adult animals and their offspring will be required. However, the Committee concluded that the safety factor could be reduced for pronamide because: 1. The toxicological database is adequate for FQPA assessment; and, 2. There is no indication of quantitative or qualitative increased susceptibility of rabbits to in utero exposure or to rats following pre/ postnatal exposure. Also, in the available, unacceptable rat study, no increased susceptibility was seen even though the animals could have tolerated higher doses. 3. A developmental neurotoxicity study is not required; and, 4. The dietary (food and drinking water) and residential exposure assessments will not underestimate the potential exposures for infants and children. C. Application of the Safety Factor ­ Population Subgroups/ Risk Assessment Scenarios: All population subgroups: The 3x FQPA Safety factor will be applied when assessing chronic dietary and short­ term residential exposure scenarios because of evidence of endocrine effects.

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EPA-HQ-OPP-2002-0159-0008

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES August 10, 2001 MEMORANDUM SUBJECT: Review of Pronamide Incident Reports DP Barcode D276937, Chemical #101701 FROM: Jerome Blondell, Ph. D., Health Statistician Chemistry and Exposure Branch 1 Health Effects Division (7509C) Monica F. Spann, M. P. H., Environmental Health Scientist Chemistry and Exposure Branch 1 Health Effects Division (7509C) THRU: Francis B. Suhre, Senior Scientist Chemistry and Exposure Branch 1 Health Effects Division (7509C) TO: Gary Bangs, Industrial Hygienist Reregistration Branch 3 Health Effects Division (7509C) BACKGROUND The following data bases have been consulted for the poisoning incident data on the active ingredient Pronamide (PC Code: 101701): 1) OPP Incident Data System (IDS) ­ reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. Reports submitted to the Incident Data System represent anecdotal reports or allegations only, unless otherwise stated. Typically no conclusions can be drawn implicating the pesticide as a cause of any of the reported health effects. Nevertheless, sometimes with enough cases and/ or enough documentation risk mitigation measures may be suggested. 2 2) Poison Control Centers ­ as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1998 for all pesticides. Most of the national Poison Control Centers (PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System which obtains data from about 65­ 70 centers at hospitals and universities. PCCs provide telephone consultation for individuals and health care providers on suspected poisonings, involving drugs, household products, pesticides, etc. 3) California Department of Pesticide Regulation ­ California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required, by statute, to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides. The majority of the incidents involve workers. Information on exposure (worker activity), type of illness (systemic, eye, skin, eye/ skin and respiratory), likelihood of a causal relationship, and number of days off work and in the hospital are provided. 4) National Pesticide Telecommunications Network (NPTN) ­ NPTN is a toll­ free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984­ 1991, inclusive has been prepared. The total number of calls was tabulated for the categories human incidents, animal incidents, calls for information, and others. PRONAMIDE REVIEW I. Incident Data System There were no reported cases of incidents related to pronamide in the Incident Data System where it alone was responsible for an incident. II. Poison Control Center Data ­ 1993 through 1998 Results for the years 1993 through 1998 were acquired for 1 exposure to pronamide reported to Poison Control Centers. Cases involving exposures to multiple products are excluded. No cases were reported among children under six years of age or among older children and adults exposed at their workplace. This was too few cases to warrant detailed analysis. There was 1 nonoccupationally exposed case among older children and adults which was not reported to have symptoms related to their exposure and was not seen in a health care facility. One should be cautious about drawing conclusions from such a small number of cases 3 III. California Data ­ 1982 through 1999 Detailed descriptions of 2 cases submitted to the California Pesticide Illness Surveillance Program (1982­ 1999) were reviewed. In the first case, a worker applied the product on the ground for ten days and reported malaise, anorexia, fatigue, dizziness, nausea, and vomiting. In the second case, one of two workers moved an irrigation pipe in a field and later reported dizziness, vomiting, and weakness. Both cases were categorized as `possible', meaning the exposure was a possible cause of the reported symptoms. IV. National Pesticide Telecommunications Network On the list of the top 200 chemicals for which NPTN received calls from 1984­ 1991 inclusively, pronamide was not reported to be involved in human incidents. VI. Conclusions Very few illness cases have been reported due to pronamide and none have been confirmed. VII. Recommendations No recommendations can be made on the very limited incident data available for this pesticide. cc: Correspondence Pronamide file (chemical no. 101701) Lori Montford, SRRD ­ (7508C)

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EPA-HQ-OPP-2002-0159-0009

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION PESTICIDES AND TOXIC SUBSTANCES TXR NO. 0050364 MEMORANDUM DATE: December 10, 2001 SUBJECT: Pronamide (Propyzamide): Report of the Hazard Identification Assessment Review Committee (HIARC) Meeting for the Herbicide, Pronamide. FROM: Michelle M. Centra, Pharmacologist Reregistration Branch III Health Effects Division (7509C) THRU: Jess Rowland, Co­ Chair and Elizabeth Doyle, Co­ Chair Hazard Identification Assessment Review Committee Health Effects Division (7509C) TO: Jose Morales, Chemist/ Risk Assessor Reregistration Branch III Health Effects Division (7509C) PC Code: 101701 On November 6, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for PRONAMIDE with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to PRONAMIDE was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. The conclusions drawn at this meeting are presented in this report. 2 Committee Members in Attendance Members present were: Jess Rowland, Elizabeth Doyle, William Burnam, Pamela Hurley, David Nixon, Paula Deschamp, Susan Makris, John Liccione, and Brenda Tarplee. Member( s) in absentia: Ayaad Assaad, Jonathan Chen, and Elizabeth Mendez. Data evaluation prepared by: Michelle M. Centra, Reregistration Branch III. Also in attendance were: Jose Morales (HED), Barry O'Keefe (HED), Steve Knizner (HED), Virginia Fornillo (HED), Lucy Shanaman (EFED), Kevin Crofton (NHEERL/ ORD), Michael McDavit (SRRD), and Cecelia Watson (SRRD). Data Evaluation / Report Presentation _______________________ Michelle M. Centra Pharmacologist 3 Cl Cl O C CH 3 N H CH CH 3 1. INTRODUCTION Pronamide [3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide], trade name Kerb ® , is a selective, systemic, pre­ and post­ emergence herbicide which inhibits root and shoot growth from seedlings and is used to control a wide range of annual and perennial grasses as well as certain broadleaf weeds. Pronamide is produced and formulated for use as a 50­ W wettable powder in water soluble pouches (Kerb ® , EPA Reg. No. 707­ 159) by Rohm and Hass Co., Springhouse, Pennsylvania and may be applied to various food/ feed using ground spray equipment, by soil incorporation, or by aircraft. It is registered for use in/ on several food and feed crops (alfalfa, apples, globe artichokes, birdsfoot trefoil, blackberries, blueberries, cherries, clover, crown vetch, endive, grapes, lettuce, nectarines, peaches, pears, plums, prunes, raspberries, and sainfoin). Pronamide is also registered for terrestrial non­ domestic, non­ food use on woody ornamentals (azalea, holly, juniper, pine, rhododendron, and yew), Christmas trees, nursery stocks (forsythia, holly, juniper, pine, rhododendron, and yew) and for domestic outdoor uses on lawns, turfs, and fallow land to control bermudagrass, centipedegrass, St. Augustinegrass, and zoysiagrass. Technical pronamide [also known as propyzamide] is a white crystalline solid with a melting point of 155­ 156 0 C and a specific gravity of 0.48 g/ cc. Pronamide is soluble in water (15 ppm at 25 0 C); in dimethyl sulfoxide and dimethyl formamide at 33 ppm; in mesityl oxide, isophorone, methyl ethyl ketone, and cyclohexanone at 20 ppm; in methanol, isopropanol, and chlorobenzene at 12­ 15 ppm; in butyl cellosolve, xylene, acetonitrile, and kerosene at 10 ppm; and in nitrobenzene and ethylene dichloride at 5 ppm. The chemical structure of pronamide is shown below: Empirical Formula: C12H11NOCl2 Molecular Weight: 256.13 CAS Registry Number: 23950­ 58­ 5 On November 6, 2001, the HIARC met to evaluate the available toxicology data base, re­ assess the existing chronic RfD, select the toxicological endpoints for occupational and residential exposure risk assessments, and assess the potential susceptibility of infants and children from exposure as required by the FQPA for the pronamide tolerance reassessment eligibility decision (TRED). 4 2 HAZARD IDENTIFICATION 2.1 Acute Reference Dose (RfD) No appropriate endpoint was available to quantitate risk to the general population from a single­ dose administration of pronamide. The developmental effect, abortions, were not considered to occur after a single dose in this instance because they were observed in rabbits during the postdosing phase of the study (days 22­ 24). Therefore, no endpoint was chosen to quantitate risk to females 13­ 50 from a single­ dose administration of pronamide. 2.2 Chronic Reference Dose (RfD) Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: In a chronic oral (dietary) toxicity/ carcinogenicity study (MRID# 41714001 and 41714002), Crl: CD( BR) VAF/ Plus Rats (Supplier: Charles River Laboratories, Inc., Kingston, NY) received either 0, 25, 100, or 400 ppm for the first 2 weeks then 0, 35, 140, or 560 ppm for the next 3 weeks and then 0, 40, 200, or 1000 ppm thereafter (equal to 0, 1.73, 8.46, and 42.59 mg/ kg/ day for males and 0, 2.13, 10.69, and 55.09 mg/ kg/ day for females, respectively) Kerb ® Technical (Purity: 96.4%; Batch No. 2­ 5002) in the diet. Animals were observed twice daily for moribundity, mortality and toxic signs. Body weights and food consumption were recorded weekly for 14 weeks and then biweekly thereafter, food efficiency was calculated at 26 and 53 weeks. Ophthalmological examinations were conducted on all animals prior to study initiation and in the control and high dose animals at sacrifice at 6, 12, and 24 months. Blood was collected from 10 animals/ sex/ dose group in the satellite groups at 6 and 12 months and from 10 animals/ sex/ dose group at 24 months for hematological and clinical chemistry studies. Urine was collected form 10 animals/ sex/ dose group at 5 months and due to the small amount of urine collected, it was repeated at 6 months. At 11 months in the satellite group and 23 months in the main study, urine was collected from 10 animals/ sex/ dose group in the control and high dose groups and prior to sacrifice at 24 months, urine was collected from the low and mid dose groups. Animals were sacrificed as specified at 6, 12, and 24 months and received a complete gross examination, organs were weighed as required and required tissues were collected and fixed for histopathological examination. At 1000 ppm (55.09 mg/ kg/ day), mean body weights and body weight gains were decreased in female rats. Increased incidences of non­ neoplastic lesions were observed in the liver, thyroid, and ovaries of high­ dose (1000 ppm) rats. In the liver, centrilobular hypertrophy was observed in males and females at 12 months (65% in males; 95% in females) and 24 months (20% in males; 48% in females). Hypertrophy was accompanied by eosinophilic cell alteration at 24months (positive trend in both sexes; pair­ wise comparison in high­ dose/ controls for males and females). The histologic liver changes were accompanied by increases in relative (to body) weight in the high­ dose groups of both sexes. In the thyroid, follicular cell hypertrophy was observed (positive trend in males and in females) at 12 months but not at 24 months. The increased incidence observed at 1000 ppm was only significant (pair­ wise comparison in high­ dose/ controls) in females. At 24 months, follicular cell hyperplasia was observed in females (positive trend) but the increased incidence observed at 5 1000 ppm was not statistically significant. In the ovaries, sertoliform tubular hyperplasia (positive trend) was observed in females at 24 months and the increase in incidence observed at 1000 ppm was significant by pair­ wise comparison. No toxicologic effects were observed at 25 ppm or 200 ppm treated male and female rats. The Systemic Toxicity NOAEL was 200 ppm (8.46 mg/ kg/ day for males; 10.69 mg/ kg/ day for females) and the Systemic Toxicity LOAEL was 1000 ppm (42.59 mg/ kg/ day for males; 55.09 mg/ kg/ day for females) based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries. At 1000 ppm, in the 24­ month phase, both male and female rats had increased rates of thyroid follicular cell adenomas, and male rats had an increased incidence of benign testicular interstitial cell tumors. Thyroid tumors were not observed until weeks 53 and 82 for males and females, respectively, and testicular tumors were not observed until week 67. The increase in thyroid tumor rate was statistically significant by pair­ wise comparison (p < 0.01) only in males, but there was a positive trend (p < 0.01) for both sexes. Both high dose male and female tumor rates (21% and 10%, respectively) exceeded the historical control range which was 0­ 14.8% (mean 5%) for males and 0­ 9.5% (mean 2%) for females (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 13 studies conducted between 1985 and 1990). There were no significant differences in thyroid follicular cell carcinoma rates between groups. There was increasing trends and/ or rates in combined thyroid follicular cell adenomas and carcinomas (trend p < 0.01 in males, p < 0.05 in females; pair­ wise comparison of high dose males/ controls, p < 0.05) which were a reflection of the treatment­ related changes in thyroid follicular cell adenoma rates. The increase in testicular interstitial cell benign tumor rate was statistically significant by pair­ wise comparison (p < 0.05) and there was a positive trend (p < 0.01). In high dose males, the tumor rate (27%) exceeded the historical range of 4.8­ 18.2% with a mean value of 5.6% (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 11 studies conducted between 1985 and 1990). In the 12­ month phase, thyroid follicular cell and testicular interstitial cell neoplasia were not observed in any group. Benign pituitary adenomas of the pars distalis were observed in every dose group during both the 12­ and 24­ month phases, but the tumor rates were statistically comparable among all groups. The respective tumor rates for the 0, 40, 200, and 1000 ppm dose groups were 1/ 19, 0/ 19, 0/ 20, and 3/ 20 in males and 0/ 20, 2/ 20, 1/ 19, and 3/ 20 in females in the 12­ month phase and 31/ 60, 33/ 60, 35/ 60, and 34/ 60 in males and 49/ 60, 49/ 60, 49/ 60, and 54/ 60 in females in the 24­ month phase. Under the conditions of this study, the dosing was considered adequate for assessing carcinogenic potential of Pronamide, based on body weight gain depressions (p < 0.05) of $ 10% observed at 1000 ppm (weeks 0­ 26 in males; weeks 0­ 52 in females), increased relative liver weight in both sexes and the non­ neoplastic histological changes in the liver, thyroid and ovaries. The statistical evaluation of mortality indicates no significant incremental changes with increasing doses of pronamide in either male or female rats. CLASSIFICATION: This study is classified as Acceptable­ Guideline and satisfies the guideline requirements (OPPTS 870.4300; § 85­ 3) for a chronic oral (dietary) toxicity/ carcinogenicity study in rodents. 6 Dose and Endpoint for Establishing RfD: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day. Uncertainty Factor( s): Uncertainty factor of 100 was applied to account for intraspecies extrapolation (10x) and interspecies variability (10x). Comments about Study/ Endpoint/ Uncertainty Factor( s): The current RfD (0.08 mg/ kg/ day) for pronamide is based on the NOAEL of 8.46 mg/ kg/ day established in the two­ year chronic toxicity/ carcinogenicity study in rats (MRID 41714001, 41714002) and an uncertainty factor of 100 (10x for intraspecies extrapolation and 10x for interspecies variation). The LOAEL of 42.59 mg/ kg/ day was based on increased relative liver weight and non­ neoplastic histologic changes in the liver, thyroid, and ovaries. Since the long­ term feeding/ carcinogenicity study in rats is appropriate for the route and duration of exposure and the dose/ endpoint established in this study is the most protective dose (NOAEL = 8.46 mg/ kg/ day) for the target effects of concern (organ toxicities in the liver, thyroid, and ovaries) in the available pronamide toxicity data base, it will remain as the study selected for the chronic RfD. 2.3 Occupational/ Residential Exposure 2.3.1 Short­ Term (1­ 30 Days) Incidental Oral Exposure Study Selected: Developmental Toxicity in Rabbits Guideline #: 870.3700 MRID No.: 00148065, 00148064 Executive Summary: In a prenatal developmental toxicity study (MRID# 00148065, 00148064), pregnant six month old New Zealand white rabbits received Pronamide as an aqueous suspension in 0.5% methyl cellulose by gavage from gestation days 7 through 19, inclusive, at dose levels of 0, 5, 20, or 80 mg/ kg/ day. Each animal was examined once daily for signs of toxicity and mortality. Body weights were recorded on gestation days 0, 4, 7, 11, 15, 20, 25, and 29. All surviving rabbits were weighed and sacrificed on gestation day 29, the numbers or corpora lutea, implantation sites, live and dead fetuses and embyronic deaths were recorded, in addition the maternal livers, gall bladders and kidneys (with ureters) were removed and process for microscopic examination. All live fetuses were weighed and examined for external abnormalities. The fetuses were then sacrificed, internally sexed and the viscera was examined for anomalies. The brain was examined by mid­ coronal incision and the heart by a modified Staples technique. The fetuses were then fixed and cleared and stained in Alizarin red S for skeletal examinations. Maternal toxicity was noted at the mid dose as soiled anal area, anorexia, and punctate vacuolation of hepatocytes. The high dose group was also associated with abortions, late resorptions, and 1 death as well as additional histopathology in the liver (hepatocellular necrosis eosinophilia, swelling of hepatocytes, pigmentation of Kupffer cells, etc). The Maternal Toxicity NOAEL is 5 mg/ kg/ day and Chronic RfD = 8.46 mg/ kg/ day (NOAEL) = 0.08 mg/ kg/ day 100 (UF) 7 the Maternal Toxicity LOAEL is 20 mg/ kg/ day based on clinical signs of toxicity and liver effects. Developmental Toxicity was seen at the high dose as abortions. The Developmental Toxicity NOAEL is 20 mg/ kg/ day and the Developmental Toxicity LOAEL is 80 mg/ kg/ day based on abortions. CLASSIFICATION: This study is classified as Acceptable­ Guideline and satisfies the guideline requirements for a prenatal developmental toxicity study in rabbits (OPPTS 870.3700; OPP §83­ 3b). Dose and Endpoint for Risk Assessment: An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. Comments about Study/ Endpoint: Although the developmental toxicity study in rabbits selected for short­ term incidental exposure is of the appropriate route (oral) and duration (13 days), the NOAEL (5 mg/ kg/ day) in this study is lower than the NOAEL (8.46 mg/ kg/ day) established in the chronic toxicity/ carcinogenicity study in the rat. The apparent disparity between these NOAELs is driven by the the doses of pronamide selected for testing in these studies. The HIARC concluded that using a more realistic NOAEL of 8.46 mg/ kg/ day rather than 5 mg/ kg/ day would provide a sufficiently protective dose for risk assessment. The NOAEL of 3 mg/ kg/ day established in the special thyroid study conducted in male rats was also considered. However this dose was not selected because the wide gap between the NOAEL (3 mg/ kg/ day) and the LOAEL (67 mg/ kg/ day) in this study resulted in the 3 mg/ kg/ day dose (NOAEL) being artificially low. In addition, the LOAEL of 67 mg/ kg/ day is comparable to the LOAEL (56 mg/ kg/ day) established in the chronic toxicity /carcinogenicity study conducted in rats. 2.3.2 Intermediate­ Term (1­ 6 Months) Incidental Oral Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day. Comments about Study/ Endpoint: The NOAEL of 12.3 mg/ kg/ day established in the 90­ day subchronic toxicity study in rats was considered for risk assessment. However, the severity of the toxicities (increased absolute and relative liver weights and hepatocellular hypertrophy) observed in this study were determined to be minimal. Since this NOAEL (12.3 mg/ kg/ day) is numerically close to the NOAEL of 8.46 mg/ kg/ day established in the 8 long­ term toxicity study conducted in rats and the organ toxicities (liver, thyroid, and ovaries) observed in the 24 month study occurred as early as 6 months and continued to study termination, the HIARC determined that the chronic feeding/ carcinogenicity study in rats is an appropriate study for the (1­ 6 months) intermediate­ term exposure duration. Therefore, the selection of a NOAEL of 8.46 mg/ kg/ day for the intermediate­ term incidental oral exposure scenario is adequately protective of the population of concern (infants and children). 2.3.3 Dermal Absorption Percentage (%) Dermal Absorption: 100% dermal absorption (default value). Comments about Dermal Absorption: A dermal absorption study submitted to the Agency was classified as unacceptable because 1) the actual dose applied to the skin was not determined and 2) there were discrepancies in recovery for the 50W formulation doses (78% and 122% of nominal doses). In addition, there were no dermal toxicity studies submitted which could be used for comparison to oral toxicity studies. A 100% dermal absorption default value was determined for risk assessment purposes due to the limitations of the available pronamide toxicity data base (absence of dermal toxicity studies as well as an unacceptable dermal absorption study). 2.3.4 Short­ Term (1 ­ 30 Days) Dermal Exposure Study Selected: Developmental Toxicity in Rabbits Guideline#: 870.3700 MRID No.: 00148065, 00148064 Executive Summary: See Short­ Term (1­ 30 days) Incidental Oral Exposure, Section 2.3.1 Dose and Endpoint for Risk Assessment: An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. Comments about Study/ Endpoint: See Short­ Term (1­ 30 days) Incidental Oral Exposure, Section 2.3.1. Since there were no dermal toxicity studies submitted, it is appropriate to select an endpoint from an oral study of the appropriate duration of exposure. A dermal absorption factor of 100% should be applied for this risk assessment. 2.3.5 Intermediate­ Term (1­ 6 Months) Dermal Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 9 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day. Comments about Study/ Endpoint: See Intermediate­ Term (1­ 6 months) Incidental Oral Exposure, Section 2.3.2. Since no dermal toxicity studies were submitted, it is appropriate to select an oral endpoint from a study of the appropriate duration of exposure. A dermal absorption factor of 100% should be applied for this risk assessment. 2.3.6 Long­ Term (> 6 Months) Dermal Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day. Comments about Study/ Endpoint: Since no dermal toxicity studies were submitted, the selected endpoint is from an oral study of the appropriate duration of exposure. A dermal absorption factor of 100% should be applied for this risk assessment. 2.3.7 Short­ Term (1 ­ 30 Days) Inhalation Exposure Study Selected: Developmental Toxicity in Rabbits Guideline #: 870.3700 MRID No.: 00148065, 00148064 Executive Summary: See Short­ Term (1­ 30 days) Incidental Oral Exposure, Section 2.3.1 Dose and Endpoint for Risk Assessment: An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. Comments about Study/ Endpoint: See Short­ Term (1­ 30 days) Incidental Oral Exposure, Section 2.3.1. With the exception of an acute oral inhalation toxicity study conducted with the 50W Kerb formulation, no other inhalation toxicity studies were submitted. Therefore, an oral end point was selected from a study of the appropriate duration of exposure. An inhalation absorption factor of 100% should be applied for this risk assessment. 10 2.3.8 Intermediate­ Term (1­ 6 Months) Inhalation Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day. Comments about Study/ Endpoint: See Intermediate­ term (1­ 6 months) Incidental Oral Exposure, Section 2.3.2. With the exception of an acute oral inhalation toxicity study conducted with the 50W Kerb formulation, no other inhalation toxicity studies were submitted. Therefore, an oral end point was selected from a oral study of the appropriate duration of exposure. An inhalation absorption factor of 100% should be applied for this risk assessment. 2.3.9 Long­ Term (> 6 Months) Inhalation Exposure Study Selected: Chronic Toxicity/ Carcinogenicity in Rats Guideline #: 870.4300 MRID No.: 41714001, 41714002 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Dose and Endpoint for Risk Assessment: A NOAEL of 8.46 mg/ kg/ day based on based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.59 mg/ kg/ day. Comments about Study/ Endpoint: With the exception of an acute oral inhalation toxicity study conducted with the 50W Kerb formulation, no other inhalation toxicity studies were submitted. Therefore, an oral end point was selected from a oral study of the appropriate duration of exposure. An inhalation absorption factor of 100% should be applied for this risk assessment. 2.3.10 Margins of Exposure for Occupational/ Residential Risk Assessments A MOE of 100 is required for short­, intermediate­, and long­ term occupational risk assessments for both dermal and inhalation routes of exposure. This includes 10x for interspecies extrapolation and 10x for intraspecies variation. The acceptable MOEs for residential exposure will be determined by the FQPA SF committee. 11 2.4 Recommendation for Aggregate Exposure Risk Assessments For short­ term exposure, incidental oral, dermal, and inhalation routes can be aggregated because of the use of oral equivalents and a common endpoint (clinical signs of toxicity and liver effects). For intermediate­ term and long­ term exposure, incidental oral, dermal and inhalation routes can be aggregated because of oral equivalents and a common endpoint (increased relative liver weight and non­ neoplastic histologic changes in the liver, thyroid, and ovaries). 3 CLASSIFICATION OF CARCINOGENIC POTENTIAL 3.1 Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No.: 00417140, 00417141 Executive Summary: See Chronic Reference Dose (RfD), Section 2.2 Discussion of Tumor Data: Statistical analysis of tumor rates was based on the Cochran­ Armitage Trend Test and Fisher's Exact Test for pair­ wise comparison of controls and each treated group since there was no significant statistical evidence of differential mortality with increasing doses of Pronamide. At 1000 ppm, in the 24­ month phase, both male and female rats had increased rates of thyroid follicular cell adenomas, and male rats had an increased incidence of benign testicular interstitial cell tumors. Thyroid tumors were not observed until weeks 53 and 82 for males and females, respectively, and testicular tumors were not observed until week 67. The increase in thyroid tumor rate was statistically significant by pair­ wise comparison (p < 0.01) only in males, but there was a positive trend (p < 0.01) for both sexes. Both high dose male and female tumor rates (21% and 10%, respectively) exceeded the historical control range which was 0­ 14.8% (mean 5%) for males and 0­ 9.5% (mean 2%) for females (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 13 studies conducted between 1985 and 1990). There were no significant differences in thyroid follicular cell carcinoma rates between groups. There were increasing trends and/ or rates in combined thyroid follicular cell adenomas and carcinomas (trend p < 0.01 in males, p < 0.05 in females; pair­ wise comparison of high dose males/ controls, p < 0.05) which were a reflection of the treatment­ related changes in thyroid follicular cell adenoma rates. The increase in testicular interstitial cell benign tumor rate was statistically significant by pair­ wise comparison (p < 0.05) and there was a positive trend (p < 0.01). In high dose males, the tumor rate (27%) exceeded the historical range of 4.8­ 18.2% with a mean value of 5.6% (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 11 studies conducted between 1985 and 1990). In the 12­ month phase, thyroid follicular cell and testicular interstitial cell neoplasia were not observed in any group. Benign pituitary adenomas of the pars distalis were observed in every dose group during both the 12­ and 24­ month phases, but the tumor rates were statistically comparable among all groups. The respective tumor rates for the 0, 40, 200, and 1000 ppm dose groups were 1/ 19, 0/ 19, 0/ 20, and 3/ 20 in males and 0/ 20, 2/ 20, 1/ 19, and 3/ 20 in females in the 12­ month phase and 31/ 60, 33/ 60, 35/ 60, and 34/ 60 in males and 49/ 60, 49/ 60, 49/ 60, and 54/ 60 in females in the 24­ month phase. 12 Adequacy of the Dose Levels Tested: The dosing was considered to be adequate for assessing carcinogenic potential of Pronamide, based on body weight gain depressions (p < 0.05) of $ 10% observed at 1000 ppm (weeks 0­ 26 in males; weeks 0­ 52 in females). Feed consumption was also depressed (p < 0.05) at 1000 ppm in males during weeks 1­ 13 (7%), 1­ 26 (7%), and 1­ 52 (5%). Survival rate was comparable between groups. The statistical evaluation of mortality indicates no significant incremental changes with increasing doses of Pronamide in either male or female rats. 3.2 Carcinogenicity Studies in Mice Carcinogenicity Study in Male and Female Mice, 1974 MRID No.: 00107968, 00066794 Executive Summary: In a carcinogenicity study (MRID# 00107968), pronamide (97 % a. i.) was administered to male and female B6C3F1 mice (125/ sex/ dose) in the diet at dose levels of 0 (control) 1000, or 2000 ppm for 18 months. This corresponds approximately to 0, 150, and 300 mg/ kg/ day. Mice (25/ sex/ dose) were sacrificed at the end of a 30­ week treatment period (interim sacrifice); the remaining mice were sacrificed at the end of the 18­ month treatment period. The study design also included, for comparison, mice treated with known hepatocarcinogens, including 4­ 6 mg/ kg/ day diethylnitrosamine (DEN) and 2­ acetamidofluorene (AAF). There were no apparent treatment­ related effects on survival. At the end of the 18­ month study, survival rates were comparable between groups with no gender differences (rates greater than 90%). Significant decreases in mean body weights were observed in females treated with 2000 ppm (the high dose) during the study. Mean body weight gains were reduced in the low­ dose (1000 ppm) females (50­ 78 weeks), the high­ dose females (0­ 30 weeks; 50­ 78 weeks) and the high­ dose males ( 50­ 78 weeks). At interim sacrifice, absolute and relative liver weights were significantly increased in the low­ dose and high­ dose females, and in the high­ dose males. At terminal sacrifice, relative liver weights were significantly increased in the low­ and high­ dose males and females. A dose­ related increase in the incidence of hepatocellular carcinomas (respective rates at 0, 1000, and 2000 ppm were 7/ 100, 18/ 99, and 24/ 99) was observed in male mice sacrificed at 18 months. The hepatocellular carcinomas were characterized as non­ metastisizing. Pronamide did not significantly induce hepatocellular carcinomas in female mice compared to controls (respective rates at 0, 1000, and 2000 ppm were 0/ 100, 1/ 100, and 2/ 100) at 18 months. Some of the high­ dose males exhibited cholestasis in hepatocytes and/ or Kupffer's cells. The LOAEL is 1000 ppm (150 mg/ kg/ day) based on decreased body weight gain in treated females and increased relative (to body weight) liver weights in both sexes. A NOAEL was not established. Under the conditions of this study, there was evidence of a treatment­ related increase in tumor incidence in the livers of male mice when compared to controls. Dosing is considered adequate to assess the carcinogenic potential of pronamide based on body weight gain depressions in treated females and increases in relative (to body) weight of the liver at $ 1000 ppm in both sexes. Although this study would not normally meet the guideline requirement for a carcinogenicity study (83­ 2b) in this species (i. e., study deficiencies included lack of dietary analyses and food consumption to ensure homogeneity, stability, and concentration of test material in the diet, and to 13 assess potential palatability problems with the diet), confidence in the reported tumor data is enhanced by the findings of a subsequent 1982 special carcinogenicity study in male mice (MRID# 001114114) that confirm the tumor findings. Moreover, if reviewed in conjunction with the 1982 special carcinogenicity study in male mice, the present study is adequate to assess the carcinogenic potential of pronamide in mice, and can be used for regulatory and risk assessment purposes. Discussion of Tumor Data: A dose­ related increase in the incidence of hepatocellular carcinomas was observed in male mice sacrificed at termination (18 months). The increases in tumor rates observed at 1000 and 2000 ppm were both statistically significant by pair­ wise comparison with controls (p < 0.01). Pronamide did not induce hepatocellular carcinomas in female mice (rates at termination were 0/ 100 in controls; 1/ 100 at 1000 ppm; 2/ 100 at 2000 ppm). Survival rates of all groups were comparable ( $ 90%). Adequacy of the Dose Levels Tested: The dosing was considered to be adequate for assessing the carcinogenic potential of Pronamide, based on body weight gain depressions in high dose females (16.5% decrease, weeks 2­ 78, p < 0.05), and increasers in relative body weight of the liver at $ 1000 ppm in both sexes [23% at 1000 ppm and 41% at 2000 ppm, p < 0.05 (males); 14% at 1000 ppm and 36% at 2000 ppm, p < 0.05 (females)]. Carcinogenicity Study in Male Mice, 1982 MRID No.: 00114114, 00151822 Executive Summary: In a special carcinogenicity study (MRID# 0011411), pronamide (93.8­ 99% a. i.) was administered to male B6C3F1 mice (63/ group) in the diet at dose levels of 0 (control group1 and control group 2), 20, 100, 500, or 2500 ppm for 24 months. This corresponds to 0, 3, 15, 75, and 375 mg/ kg/ day. The two matched control groups received untreated diet. Additional groups were assigned to interim sacrifices at 6 months (42 mice at 0 ppm; 42 mice at 2500 ppm) and at 15 and 18 months (42/ group including control groups 1 and 2, and 20, 100, 500, and 2500 ppm groups). Survival rats were greater than 93% for all groups. Both the 500 ppm and 2500 ppm males exhibited gross findings of increased incidences of liver nodules/ masses and enlarged livers at the 24­ month interval. Non­ neoplastic hepatic effects observed in males treated with the high dose (2500 ppm) for 24 months, included increased incidences of liver enlargement, liver nodules/ masses, hypertrophy, parenchymal necrosis, and cholestasis. Administration of pronamide also resulted in decreased body weights. The results of the special study confirmed that long­ term exposure of male mice to pronamide was associated with an increased incidence of hepatocellular carcinomas (respective rates at 0, 0, 20, 100, 500, or 2500 ppm at the 24­ month sacrifice were 5/ 63, 5/ 63, 9/ 63, 12/ 63, 18/ 63, and 14/ 61). Additionally, hepatocellular adenomas were observed (respective rates at 0, 0, 20, 100, 500, or 2500 ppm at the 24­ month sacrifice were 4/ 63, 6/ 63, 6/ 63, 7/ 63, 8/ 63, and 28/ 61). The incidence of adenoma and carcinoma was significantly increased in the 500 ppm and 2500 ppm males when compared to controls. There was an apparent progression from benign to malignant tumors. This special study confirmed the carcinogenic effect of pronamide in male mice. The LOAEL is 500 ppm (75 mg/ kg/ day) based on gross findings (increased incidences of hepatic nodules/ masses and hepatic enlargement) observed after 24 months of treatment. The NOAEL is 100 ppm (15 mg/ kg/ day). 14 Under the conditions of this study, there was evidence of a treatment­ related increase in tumor incidence in the liver of male mice when compared to controls. Dosing is considered adequate to assess the carcinogenic potential of pronamide based on liver effects (non­ neoplastic lesions and increased weight). This special carcinogenicity study in the male mice is classified as Acceptable­ Nonguideline. The data confirmed the results of a previously conducted carcinogenicity study in mice (1974, MRID# 00107968). When reviewed in conjunction with the 1974 carcinogenicity study, these two studies fulfill the guideline requirement for a carcinogenicity study [870.4200 (§ 83­ 2b)] in mice and can be used for regulatory and risk assessment purposes. Discussion of Tumor Data: This study confirmed the results of the MCV 1974 study; long term (24 months) exposure of male mice to Pronamide was associated with an increased incidence of hepatocellular carcinomas. A positive trend (p < 0.05) in incidences of hepatocellular carcinomas was observed in mice sacrificed at 24 months, and the increased tumor rates observed at $ 100 ppm were statistically significant (p < 0.05 at 100 ppm; p < 0.01 at 500 and 2500 ppm). Hepatocellular adenomas were not observed in pair­ wise differences at 2500 ppm (p < 0.01) in mice sacrificed at 24 months in this study. There also appeared to be a progression from benign to malignant tumors. Survival rates were excellent for all groups ( $ 93%). Adequacy of the Dose Levels Tested: The dosing was considered to be adequate for assessing the carcinogenic potential of Pronamide, based on decreased body weight (30%, months 6­ 24) and increased liver weight (30­ 40% absolute weight increase; 100% relative body weight increase) in the high dose group. 3.3 Classification of Carcinogenic Potential In accordance with the Agency's Proposed Guideline for Carcinogen Risk Assessment (April, 1996), the HED Carcinogenicity Peer Review Committee (CPRC) classified Pronamide as a Group B2 chemical, probable human carcinogen with inadequate evidence in humans (Memorandum: N. B. Thoa and E. Rinde, May 26, 1993). This decision was based on the finding of two types of tumors in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas), and one type of tumor in the mouse (hepatocellular carcinomas). A linear, low dose approach (Q1*) is used for human risk characterization. The most potent unit risk Q1*, based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2.59 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents [converted from animal to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor] (Memorandum: L. Brunsman, October 26, 2001, TXR# 0050181). 4 MUTAGENICITY With the exception of one gene mutation toxicology study, the remaining five mutagenicity studies were reviewed and found to be acceptable for regulatory purposes (The acceptable studies statisfy the 1991 mutagencity guideline requirements). The results from these studies indicate that pronamide was not mutagenic in Salmonella typhimurium, Escherichia coli or in cultured Chinese hamster lung cells and did not produce a genotoxic response in Bacillus subtiltis or in cultured primary rat hepatocytes. There was also no evidence of clastogenicity in cultured Chinese hamster ovary cells and pronamide administration did not result in the induction of micronucleated polychromatic erythrocytes in bone marrow of mice. Overall, the data suggest that pronamide is negative for mutagenicity in vitro and in vivo. 15 Gene Mutation in Salmonella typhimurium/ mammalian microsome mutagenicity assay; OPPTS 870.5100 [§ 84­ 2]. In a microbial reverse gene mutation assay (MRID No. 40090601) Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 were exposed to four doses of propyzamide as RH­ 315 (purity not specified) ranging from 1­ 500 : g/ plate in both the presence and the absence of S9 activation. The S9 fractions were derived from Aroclor 1254­ induced C57BL/ 6 x C3H/ Anf male and female mouse livers and the test material was delivered to the test system in an unspecified solvent. Cytotoxicity was reported at levels >500 µg/ plate with or without the two S9 fractions (male and female S9 fractions were processed separately) but no data were presented. Strains TA1535, TA1538, TA98 and TA100 responded in the expected manner to the solvent and the appropriate positive controls. However, the spontaneous revertant colony counts of strain TA1537 +/­ S9 were outside of the expected range and this strain failed to respond to the positive control, activated by either the S9 fraction derived from male or female mouse livers. There was no evidence that RH­ 315 induced a mutagenic effect in any strain at any dose without or without the S9 homogenates. However, the study is not valid because neither the test material purity nor the solvent were reported, the claim of cytotoxicity was not supported, the number of replicates at each experimental concentration was not listed and strain TA1537 performed poorly. This study is classified as Unacceptable and does not satisfy the guideline requirements for a bacterial gene mutation assay (84­ 2). Gene Mutation in Salmonella typhimurium and Escherichia coli/ mammalian microsome mutagenicity assay/ Bacillus subtiltis DNA damage/ repair assay; OPPTS 870.5100/ 5500 [§ 84­ 2]. In a series of microbial assays (MRID No. 40090602), propyzamide as KERB® (93.7% a. i.) in dimethyl sulfoxide (DMSO) was tested for the ability to induce reverse gene mutations in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 and in Escherichia coli WP2 hcr at 10 to 5000 : g/ plate in both the presence and the absence of S9 activation. DNA damage/ repair was assessed in Bacillus subtilis H17 (rec + ) and M45 (rec ­ ) at 20 to 2000 : g/ disc with and without S9 activation. The S9 fractions were derived from Aroclor 1254­ induced Sprague Dawley rat livers. No cytotoxicity was seen up to the limit dose (5000 µg/ plate) with or without S9 activation in either the S. typhimurium or the E. coli strains or up to a dose approaching the limit of solubility in the B. subtilis strains. All strains responded in the expected manner to the solvent and the appropriate positive controls. There was also no evidence that KERB® induced a genotoxic effect in any strain at any dose without or without the S9 homogenate. This study is classified as Acceptable and satisfies the guideline requirements for a bacterial gene mutation assay and a bacterial DNA damage/ repair assay (84­ 2). Gene Mutation/ in vitro mammalian cell assay in Chinese hamster lung (CHL) cells; OPPTS 870.5300 [§ 84­ 2]. In independently performed in vitro mammalian cell gene mutation assays (MRID No. 40211106), cultures of Chinese hamster lung (CHL) fibroblasts were exposed for 3 hours to concentrations of of 2.5 to 40 : g/ mL propyzamide as KERB® Technical (96.3%) in the presence and absence of S9 activation. Treated cell cultures were allowed three expression times (48, 96 and 168 hours) with or without S9 activation. The S9 homogenate was derived from rat livers induced with phenobarbitone and $ naphthoflavone and the test material was delivered to the test system in dimethyl sulfoxide (DMSO). KERB® Technical was slightly cytotoxic at 40 : g/ mL+/­ S9; higher levels were insoluble. Cells responded as expected to the solvent and positive controls. There was, however, no evidence that KERB® Technical was mutagenic at any dose under any assay condition. This study is classified as Acceptable and satisfies the guideline requirement for a gene mutation in cultured mammalian cell assay (§ 84­ 2). Cytogenetics/ in vitro mammalian cell assay in Chinese hamster ovary (CHO) cells; OPPTS 870.5375 [§ 84­ 2]. In a mammalian cell cytogenetic assay (MRID No. 40211108), cultured Chinese hamster ovary (CHO) cells were exposed continuously to propyzamide as KERB technical (94.2%) at seven doses ranging from 16 25­ 400 : g/ mL in the absence of metabolic activation for 14 and 24 hours. Cells were also exposed to S9­ activated doses of 25­ 400 : g/ mL for 2 hours and harvested following a 12­ and 22­ hour recovery period. The S9 homogenate was derived from Aroclor 1254­ induced Sprague Dawley rat livers and the test material was delivered to the test system in dimethyl sulfoxide. Doses $ 250 : g/ mL were insoluble; cytotoxicity was not seen at any concentration. The positive controls induced the expected clastogenic responses with or without S9 activation. There was, however, no evidence that KERB technical induced a clastogenic response either in the presence or the absence of S9 activation. This study is classified as Acceptable and satisfies the guideline requirement for an in vitro mammalian cell cytogenetic assay (§ 84­ 2). Cytogenetics/ in vivo mammalian bone marrow chromosomal aberration test in mice; OPPTS 870.5385 [§ 84­ 2]. In an in vivo cytogenetic assay (MRID No. 40211105), groups of 10 male B6C3F1 mice received single doses of 480, 1940 or 4940 mg/ kg propyzamide as KERB® technical (96.8%) once daily for 1 day or for 5 consecutive days and were sacrificed 6, 12 or 24 hours postdosing (acute exposure) or 6 hours postdosing (subacute exposure). The highest assayed dose was determined based on the estimated oral LD50 >5 g/ kg in male B6C3F1 mice. The test material was delivered to the animals in 0.5% methyl cellulose. At the appropriate sacrifice intervals (6, 24 and 48 hrs postdosing with 4940 mg/ kg ­acute exposure or 6 hrs after the 5­ day administration of 1940 mg/ kg/ day), bone marrow cells were harvested and were examined for the incidence of structural chromosome aberrations. Unscheduled deaths occurred as follows: 7% in the acute high dose group, 10% in the subacute intermediate dose group and 60% in the subacute high dose group (Days 2 or 3). Other signs of compound toxicity observed in the surviving animals included signs of central nervous system depression [i. e., lethergy and ataxia ­­ Day 1 (high and mid dose –acute regimen); lethergy, ataxia, reduced spontaneous motor activity, loss of righting reflex, catalepsy and abdominal breathing [Day 1 and/ or Day 2 (high and mid dose –subacute regimen)]. The positive control induced the expected significant increase in the frequency of cells with aberrant chromosomes. There was, however, no evidence that KERB® technical induced a clastogenic effect at the selected dose or sacrifice times. The study is classified as Acceptable and satisfies the requirements for FIFRA Test Guideline 84­ 2 for in vivo cytogenetic mutagenicity data. Other Mutagenic Mechanisms/ in vitro unscheduled DNA synthesis in mammalian cells in culture; OPPTS 870.5550 [§ 84­ 2]. In an in vitro unscheduled DNA synthesis (UDS) assay (MRID No. 40211107), primary rat hepatocytes were exposed to propyzamide as KERB® technical (94.2%) at 9 doses ranging from 0.1­ 500 µg/ mL. Hepatocytes, harvested 19 hours after treatment with 1, 5, 10, 25 or 50 µg/ mL were scored for net nuclear grains/ nucleus. The test material was delivered to the test system in dimethyl sulfoxide. Cytotoxicity (< 50% cell survival) was seen at $ 100 µg/ mL and cells treated with these doses were not scored. The positive control induced the expected marked increases in UDS. There was, however, no evidence that KERB® technical induced a genotoxic response. This study is classified as Acceptable and satisfies the guideline requirement for a UDS assay (84­ 2). 5 FQPA CONSIDERATIONS 5.1 Adequacy of the Data Base The following pronamide toxicity studies are available and adequate for evaluation of FQPA: ­­ Developmental Toxicity Study in Rabbits ­­ Two­ Generation Reproduction Study There is a data gap for a developmental toxicity study in rats. A definitive NOAEL as well as a LOAEL were not established in this study; no toxicities were observed in the maternal animals and 17 their fetuses. Therefore, the rat developmental toxicity study is classified as unacceptable­ guideline (not upgradeable) and can not be used for endpoint selection. 5.2 Neurotoxicity Data Mammalian neurotoxicity studies for Pronamide have not been conducted. However, since this chemical is not an organophosphate and there is no evidence of neurotoxicity seen in any of the existing studies, neurotoxicity studies (e. g., an acute delayed neurotoxicity study in the hen, a neurotoxicity screening battery or a developmental neurotoxicity study) were not required. 5.3 Developmental Toxicity Developmental Rat In a prenatal developmental toxicity study (MRID# 40334501), pregnant Crl: CD ® BR rats (Charles River Breeding Laboratories, Montreal Quebec) received KERB ® Herbicide (94.2% a. i.; Lot 4859) as an aqueous suspension in 0.5% methyl cellulose by gavage from gestation days 6 through 15 inclusive at dose levels of 0, 5, 20, 80 or 160 mg/ kg/ day. Each animal was examined once daily for signs of toxicity and mortality. Body weights were recorded on gestation days 0, 6, 8, 10, 13, 16, and 20. All surviving rats were sacrificed on gestation day 20, the thoracic and abdominal cavities were examined for gross pathologic changes. The gravid uterus was weighed and the the numbers of corpora lutea, implantation sites, and resorptions were recorded. The number of fetuses were counted and their locations in the uterus were recorded. All fetuses were weighed and examined for external abnormalities. Half of the fetuses were then fixed and cleared and stained in Alizarin red S for skeletal examinations and the other half were examined for visceral anomalies. No Maternal Toxicity was noted at the dose levels tested. The Maternal Toxicity NOAEL is equal to or greater than 160 mg/ kg/ day and the Maternal Toxicity LOAEL is greater than 160 mg/ kg/ day. No Developmental Toxicity was noted at the dose levels tested. The Developmental Toxicity NOAEL is equal to or greater than 160 mg/ kg/ day and the Developmental Toxicity LOAEL is greater than 160 mg/ kg/ day. CLASSIFICATION: This study is classified as Unacceptable­ Guideline (not upgradeable). It does not satisfy the guideline requirements for a prenatal developmental toxicity study in rats (OPPTS 870.3700; OPP §83­ 3a) because there were no maternal or fetal toxicities observed at any dose tested (a LOAEL was not established). In addition, the highest dose tested may not be the definitive NOAEL. Developmental Rabbit See Short­ Term Incidental Oral Exposure (Section 2.3.1) for executive summary. 18 5.4 Reproductive Toxicity Reproduction Rat In a 2 generation reproduction study (MRID# 41540301), Pronamide (93.1% a. i.; Lot Number WHC1742 was administered to Crl: CD® BR Rats (Charles River Labs, Kingston, N. Y.) in the diet at dose levels of 0, 40, 200 or 1500 ppm (equal to 3.1, 16.0 and 120.7 mg/ kg/ day for females and 3.6, 18.0 and 130.1 mg/ kg/ day for males for the 40, 200 and 1500 ppm dose groups, respectively) through 2 generations (one mating period per generation). All animals were observed daily for clinical signs of toxicity and twice daily for mortality/ moribundity. Individual body weights and food consumption were recorded weekly during the premating period and females body weights were recorded on gestation days 0, 7, 14, and 21 and on lactation days 0, 7, 14, and 21. Reproductive parameters were recorded including number of females paired, mated, pregnant, duration of gestation, number of females with live litters, and sex ratio/ litter. The litter observations included number of pups born alive or dead, sex, gross abnormalities and the pus were examined twice daily for mortality/ moribundity and were weighed and examined for behavior and appearance on lactation days 0, 4, 7, 14, and 21. All animals found dead, sacrificed early and at termination were subject to a complete necropsy, this included all pups found dead before weaning, those not selected for breeding and all F2 weanling at study termination. No treatment­ related mortalities and/ or clinical signs were observed in either parental (Pl and P2) generations. There were parental systemic effects at the high dose based on decreases in body weight and feed consumption in both sexes and increased incidences of histopathology of the liver (centrilobular hepatocytes hypertrophy; both sexes), adrenal gland (zona glomerulosa cellular hypertrophy; both sexes), thyroid gland (follicular cell hypertrophy; females), and anterior pituitary gland (cellular hypertrophy; males) in both P1 and P2 generations, and increased incidences of uterine gross pathology (black foci/ serosal surface) in P2 females. The Parental Systemic Toxicity NOAEL was 200 ppm (16.0 mg/ kg/ day for females and 18.0 mg/ kg/ day for males) and the Parental Systemic LOAEL was 1500 ppm (120.7 mg/ kg/ day for females and 130.1 mg/ kg/ day for males), based on decreases in body weight and feed consumption in both sexes and increased incidences of histopathology of the liver, adrenal gland, thyroid gland, and anterior pituitary gland in both P1 and P2 generations, and increased incidences of uterine gross pathology in P2 females. There were no reproductive effects in either the P1 or P2 generations, including the females' mating, fertility, and gestation indexes, the number of pups born dead or alive/ litter and sex ratio per litter. The Reproductive Toxicity NOAEL is equal to or greater than 1500 ppm and the Reproductive Toxicity LOAEL is greater than 1500 ppm. There were no effects on F1/ F2 litter parameters including the number of live pups/ litter on lactation days 0, 4, 7, 14, or 21 and the viability and lactation indexes. Combined (male + female) F1/ F2 pups body weight/ litter at birth and/ or during the lactation period were unaffected by the low­ or mid­ dose, but was significantly reduced by the high dose (F1 at birth and during the entire lactation period; F2 during lactation days 14 and 21). There were no treatment­ related filial abnormal necropsy findings. The Developmental/ Offspring Toxicity NOAEL was 200 ppm and the Developmental/ Offspring Toxicity LOAEL was 1500 ppm, based on decreases in combined male/ female pup weight/ litter. 19 Classification: This study is classified as Acceptable­ Guideline and satisfies the guideline requirements for a 2­ generation reproductive toxicity study in rats (OPPTS 870.3800; OPP §83­ 4). 5.5 Additional Information from Literature Sources (if available) There is no additional toxicity information from literature sources for the herbicide, pronamide. 5.6 Determination of Susceptibility There was no quantitative or qualitative evidence of increased susceptibility in the fetuses or the offspring of rats or rabbits following pre­ and/ or postnatal exposure to pronamide. In the prenatal developmental toxicity study in rabbits and the multigeneration reproduction study in rats, any observed toxicity to the fetuses or offspring occurred at equivalent or higher doses than did toxicity to parental animals. Evidence for susceptibility could not be ascertained in the developmental toxicity study conducted in rats because there were no maternal or fetal toxicities observed at any dose tested (a LOAEL was not established). In addition, the highest dose tested may not be the definitive NOAEL. The HIARC determined that this study is a data gap. Although this study failed to demonstrate maternal and/ or developmental toxicities, it can be used in the weight­ of­ evidence evaluation for determining the FQPA safety factor since the highest dose tested in this rat developmental toxicity study exceeded the highest doses tested in both the rabbit developmental toxicity study (80 mg/ kg/ day) and the rat multigeneration reproduction study (120.7 mg/ kg/ day in males; 130.1 mg/ kg/ day in females). 5.7 Determination of the Need for Developmental Neurotoxicity Study 5.7.1 Evidence that suggest requiring a Developmental Neurotoxicity study: ­­ The results of several toxicity studies conducted in both the rat and dog demonstrated evidence of endocrine organ toxicity (thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus) following exposure to pronamide. ­­ Pronamide is listed as a potential endocrine disruptor on EPA's Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) list. 5.7.2 Evidence that do not support the need for a Developmental Neurotoxicity study – There was no evidence of increased susceptibility to rabbit fetuses in the developmental toxicity study or to rat offspring in the multigeneration reproduction study following pronamide exposure. – There was no evidence of neurotoxicity in any of the available mammalian toxicity studies conducted with pronamide. The HIARC recommended that a developmental neurotoxicity study in the rat not be required. A comparative study designed to assess thyroid function in adult animals and their offspring as well as potential central nervous system effects in the young will be required due to endocrine toxicities 20 observed in several organ systems (thyroid, testes, ovaries, adrenal glands, pituitary gland and thymus) of the rat and/ or dog. Since the data obtained from these toxicity studies (a special endocrine/ thyroid study in addition to the required guideline studies) are suggestive of a potential hormonal mechanism for thyroid toxicity and considering that it is thyroid hormone which is essential for growth, brain development and nervous system maturation, a comparative thyroid assay rather than a developmental neurotoxicity study, would provide a more complete characterization of endocrine disruption (precursor effects in the thyroid) associated with exposure to pronamide. The Registrant is advised to consult the Agency with regard to the submission of a thyroid assay protocol prior to the initiation of this special study. 6 HAZARD CHARACTERIZATION Pronamide technical has a low order of acute toxicity via the oral, dermal, and inhalation routes of exposure (Toxicity Category III or IV), produces mild irritation to the eyes and skin (Toxicity Category IV), and is not a dermal sensitizer. Pronamide appears to be a liver toxicant. Adverse liver­ related effects (increases in liver weight and/ or liver­ related serum enzymes and/ or histopathology) were consistently observed in every animal species studied, including the rat (subchronic, chronic, and 2­ generation reproduction studies), mouse (carcinogenicity studies), rabbit (developmental study), and dog (subchronic and chronic studies). Other target organs included the thyroid in rats (increase in weight and/ or histopathology observed in the chronic toxicity/ carcinogenicity and the 2­ generation reproduction studies as well as a subchronic, special 13­ week thyroid function study), the testes in rats (histopathology in the chronic toxicity/ carcinogenicity study) and the kidneys, adrenal glands thymus, heart, testes, and brain in dogs (increase in organ weights in the chronic toxicity study), and the pituitary in rats (histopathology observed in the subchronic and 2­ generation reproduction studies). Many chemicals belonging to the class of organochlorine chemicals are known to produce disruption of the endocrine system. Pronamide belongs to this class of chemicals. There was no quantitative or qualitative evidence of increased susceptibility in the fetuses or the offspring of rats or rabbits following pre­ and/ or postnatal exposure to pronamide. In the prenatal developmental toxicity study in rabbits and the multigeneration reproduction study in rats, any observed toxicity to the fetuses or offspring occurred at equivalent or higher doses than did toxicity to parental animals. Although the highest dose of pronamide tested in the rat developmental toxicity study exceeded the highest doses tested in both the rabbit developmental toxicity study and the rat multigeneration reproduction study without demonstrating toxicities, it failed to assess the potential increased susceptability to infants and children as required by the Food Quality Protection Act (FQPA) of 1996. The Carcinogenicity Peer Review Committee (CPRC) classified Pronamide as a group B2 ­ probable human carcinogen with inadequate evidence in humans. This decision was based on the finding of two types of tumors in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas), and one type of tumor in the mouse (hepatocellular carcinomas). A linear, low dose approach (Q1*) is used for human risk characterization. The most potent unit risk Q1*, based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2.59 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents [converted from animal to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor]. Although endocrine effects have been observed in several toxicity studies, the data provided in two special studies conducted to explore pronamide's effect on hormonal balance in support of a threshold mechanism for the induction of thyroid and testicular neoplasms, are incomplete. Based on the CPRC's weight of the evidence evaluation of this data base, it was determined that even if a hormonal mechanism could be demonstrated for tumors in the rat, the mouse liver tumors can not be discounted (the Q1* is based on the 21 incidence of liver tumors in mice). Therefore, a mechanistic approach to risk assessment for the active ingredient pronamide is not plausible. Results of mutagenicity studies with an acceptable classification (forward and reverse gene mutation, in vivo and in vitro cytogenetic/ structural chromosome aberration and unscheduled DNA synthesis assays) indicate that pronamide is not a mutagenic agent. Mammalian neurotoxicity studies for Pronamide have not been conducted. However, since this chemical is not an organophosphate and there is no evidence of neurotoxicity seen in any of the existing studies, neurotoxicity studies (e. g., an acute delayed neurotoxicity study in the hen, a neurotoxicity screening battery or a developmental neurotoxicity study) were not required. Pronamide is rapidly absorbed and completely and rapidly eliminated; the radioactivity administered was recovered (93­ 103%) in the urine (40­ 61%), feces (40­ 60%) and tissues and carcass (0.08­ 2.43%). No bioaccumulation was apparent and tissues with the highest radioactivity content were, in decreasing order, the fat, adrenals, bone marrow, thyroids, liver kidney, and plasma. The elimination of radioactivity from the plasma of low dose rats was biphasic [rapid phase = 12.6 hrs (males) and 12.7 hrs (females); slow phase = 36.6 hrs (males) and 45.3 (females)] and that of the high dose rats was monophasic [t½ = 24.1 hrs (males) and 24.8 hrs (females)]. Very little unchanged pronamide was recovered in the urine and no significant difference in urinary metabolite profile was observed between the doses or the sexes. The two major urinary metabolites were SS47­ 70 (3.0­ 5.9%) of the dose and metabolite 10 (12.7­ 18.9%). In the urine, 27 metabolites were found and none exceeded 3.3% of the dose, whereas, almost all of the unknowns were less than 1% of the dose. There is no acceptable dermal absorption study in the pronamide data base. In addition, there were no dermal toxicity studies submitted which could be used for comparison to oral toxicity studies. Therefore, a 100% (default value) dermal absorption factor was determined for risk assessment purposes. 7 DATA GAPS Developmental Toxicity Study in Rats 21­ Day Dermal Toxicity Study 28­ Day Inhalation Toxicity Study Dermal Penetration Study A Comparative Thyroid Rat Assay in Adult Animals and Offspring 22 8 ACUTE TOXICITY Acute Toxicity of Pronamide (Propyzamide) Guideline Number Study Type MRID# Results Toxicity Category 870.1100 (§ 81­ 1) Acute Oral ­ Rat, > 92.0% a. i. 00085505 LD50 (males and females) > 5000 mg/ kg IV 870.1100 (§ 81­ 1) Acute Oral (Limit test) Rat 95.7% a. i. 43583901 LD50 (males and females) > 5000 mg/ kg IV 870.1200 (§ 81­ 2) Acute Dermal (Limit Test) ­ Rabbit, 95.7% a. i. 43583902 LD50 (males and females) > 2000 mg/ kg III 870.1300 (§ 81­ 3) Acute Inhalation ­ Rat, 95.7% a. i. 44034201 LC50 > 2.1 mg/ L (4 hour exposure) III 870.2400 (§ 81­ 4) Primary Eye Irritation Rabbit 95.7% a. i. 43583904 Mild occular irritant IV 870.2500 (§ 81­ 5) Primary Dermal Irritation ­ Rabbit, 95.7% a. i. 43583903 Slight dermal irritant IV 870.2600 (§ 81­ 6) Dermal Sensitization Guinea pig, > 92.0% a. i. 00062605 Not a sensitizer N/ A 23 9 SUMMARY OF TOXICOLOGY ENDPOINT SELECTION The doses and toxicological endpoints selected for various exposure scenarios are summarized below EXPOSURE SCENARIO DOSE (MG/ KG/ DAY) ENDPOINT STUDY Acute Dietary females (13­ 50) and general population including infants and children No appropriate endpoint was available to quantitate risk to the general population from a single­ dose administration of pronamide. The developmental effect, abortions, were not considered to occur after a single dose in this instance because they were observed in rabbits during the post­ dosing phase of the study (days 22­ 24). Therefore, no endpoint was chosen to quantitate risk to females 13­ 50 from a single­ dose administration of pronamide. Chronic Dietary (all populations) NOAEL = 8.46 Increased relative (to body) liver weight and nonneoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat UF = 100 Chronic RfD = 0.08 mg/ kg/ day Cancer Q1* = 2.59 x 10 ­ 2 (mg/ kg/ day) ­1 Group B2 chemical ­ "Probable human carcinogen" based on thyroid follicular cell adenomas (males and females) and benign interstitial cell tumors (males) in rats and hepatocellular carcinomas in male mice. Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat Incidental Oral, Short­ Term NOAEL = 8.46* Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes). Developmental Toxicity Study ­ Rabbit Incidental Oral, Intermediate­ Term NOAEL = 8.46 Increased relative (to body) liver weight and nonneoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat Dermal, Short­ Term a NOAEL = 8.46* Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes). Developmental Toxicity Study ­ Rabbit Dermal, Intermediateand long­ Term a NOAEL = 8.46 Increased relative (to body) liver weight and nonneoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat Inhalation, Short­ Term a NOAEL = 8.46* Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation hepatocytes). Developmental Toxicity Study ­ Rabbit Inhalation, Intermediateand Long­ Term a NOAEL = 8.46 Increased relative (to body) liver weight and nonneoplastic histologic changes in the liver, thyroid, and ovaries. Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat a Since an oral endpoint was selected, a dermal absorption factor of 100% (default value) and an inhalation absorption factor of 100% (default value) should be used in route­ to­ route extrapolation. * An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits.

epa

2024-06-07T20:31:42.729533

regulations

EPA-HQ-OPP-2002-0159-0010

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES, ANDTOXIC SUBSTANCES March 8, 2002 MEMORANDUM SUBJECT: Pronamide. Tolerance Reassessment Eligibility Decision (TRED). Chemical ID No. 101701. DP Barcode No. D275194. FROM: Gary Bangs, Risk Assessor Michelle Centra, Pharmacologist Jose Morales, Chemist Barry O'Keefe, Biologist David Soderberg, Chemist Reregistration Branch 3 Health Effects Division (7509C) THRU: Catherine Eiden, Branch Senior Scientist Reregistration Branch 3 Health Effects Division (7509C) TO: Cecelia Watson, Chemical Review Manager Michael McDavit, Acting Branch Chief Reregistration Branch II Special Review and Reregistration Division (7508W) This memorandum and attachments constitute the Tolerance Reassessment Eligibility Decision (TRED) for pronamide and updates the Health Effects Division (HED) Chapter of the Reregistration Eligibility Decision Document (RED) for pronamide (August 24, 1993) taking into consideration requirements of the 1996 Food Quality Protection Act (FQPA). The Agency RED for pronamide was issued in May 1994. A Tolerance Reassessment Eligibility Decision (TRED) document is required because EPA completed the RED for pronamide before passage of the FQPA. This document only discusses the human health risk assessment required for reassessment of pesticide residue tolerances and does not revise the occupational risk assessment conducted in the 1993 HED human health risk assessment document. Therefore, data submitted for assessment of occupational exposure have been used only for non­ dietary (i. e., residential) risk assessment under FQPA. Cumulative risk assessment considering risks from other pesticides which have a common mechanism of toxicity is also not addressed in this document. NOTE: Only the Rohm and Haas 94.6% technical and 51% wettable powder formulation are subject to the tolerance reassessment. Rohm and Haas sold this product to Dow Agro Sciences (Letter sent to J. Tompkins in RD, 9/ 21/ 01). In addition, Earth Care, Division of United Industries Corp., (previously Pursell Industries) has requested voluntary cancellation of the product GREEN UP KERB 50W, EPA Reg. No. 8660­ 85, which is the only label which contains a residential turf use. However, as of the time of this TRED, the product is registered and a postapplication residential exposure and risk assessment have been included in this document. Cancellation of the GREEN UP label (8660­ 85) would eliminate all uses that result in potential public or residential exposure. Attachments: C Hazard Identification Assessment Review Committee (HIARC) report (M. Centra, December 10, 2001) C Report of the FQPA Safety Factor Committee (C. Christensen, December 19, 2001) C Toxicology Chapter of the Tolerance Reassessment Eligibility Decision (TRED) (M. Centra, March 7, 2002) C Report of the Mechanism of Toxicity Assessment Review Committee (MTARC) (M. Centra, January 21, 2001) C Review of Pronamide Incident Reports ( J. Blondell & M.. Spann, August 12, 2001) C Chronic and Cancer Dietary Exposure Assessments (D. Soderberg, et al., February 7, 2002) C Pronamide Residue Chemistry chapter (J. Morales, February 28, 2002) C Residential Risk Assessment, (B. O'Keefe, March 7, 2002) C Drinking Water Assessment to Support TRED for Propyzamide (Pronamide) (L. Shanaman, May 16, 2001) TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY ....................................................... 1 2.0 PHYSICAL CHEMICAL PROPERTIES CHARACTERIZATION ..................... 9 3.0 HAZARD CHARACTERIZATION ................................................ 9 3.1 Hazard Profile ............................................................ 9 3.2 FQPA Considerations ..................................................... 19 3.3 Hazard Endpoint Selection ................................................ 20 3.4 Endocrine Disruption ..................................................... 24 4. 0 EXPOSURE ASSESSMENT .................................................. 25 4.1 Summary of Registered Uses ............................................... 25 4.2 Dietary Exposure and Risk Assessment ....................................... 26 4.2.1 Residues in Food .................................................. 26 4.3 Dietary Exposure from Water Sources ....................................... 29 4.3.1. Environmental Fate .............................................. 29 4.3.2 Drinking Water Exposure Estimates ................................. 29 4.4 Residential Exposure ...................................................... 30 4.4.1 Residential/ Recreational Postapplication Exposure and Risk ............ 30 4.4.2 Spray Drift ..................................................... 35 5.0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION ........... 35 5.1 Acute Risk ............................................................... 36 5.2 Short­ Term Risk ......................................................... 36 5.2.1 Aggregate Short­ Term Risk Assessment .............................. 36 5.2.2 Short­ Term DWLOC Calculations ................................. 36 5.3 Intermediate­ Term Risk ................................................... 37 5.4 Chronic Risk ............................................................ 37 5.5 Cancer Risk Estimates ..................................................... 39 5.5.1 Cancer Aggregate Risk Assessment ................................. 39 5.5.2 Cancer DWLOC Calculations ..................................... 39 6.0 CUMULATIVE EXPOSURE TO SUBSTANCES WITH A COMMON MECHANISM OF TOXICITY................................................................. 41 7. 0 INCIDENT DATA........................................................... 42 8.0 TOLERANCE REASSESSMENT RECOMMENDATIONS ........................... 42 8.1 Tolerance Reassessment Recommendation .................................... 42 9.0 DATA NEEDS ................................................................. 44 1 1.0 EXECUTIVE SUMMARY Purpose A Tolerance Reassessment Eligibility Decision (TRED) document is required for pronamide (propyzamide). EPA completed the 1994 RED for pronamide before passage of the 1996 Food Quality Protection Act (FQPA). Consequently, pronamide is herein reassessed in accordance with the FQPA. This document only discusses the human health risk assessment required for reassessment of pesticide residue tolerances. Potential drinking water and residential exposure is also considered in order to estimate the potential aggregate risk. Cumulative risk assessment considering risks from other pesticides which have a common mechanism of toxicity is not addressed in this document. Uses: Pronamide [3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide] is a selective, systemic, preand post­ emergence herbicide registered for the control of grasses and broadleaf weeds in several food and feed crops as well as woody ornamentals, Christmas trees, nursery stocks, turf, and fallow land. Pronamide is a restricted use herbicide applied as a liquid spray, which is packaged in water soluble pouches and then mixed in water before application. It is a soil active systemic herbicide with uptake by susceptible weeds occurring through the roots. Application rates range from 0.5 to 6 lbs active ingredient (ai) per acre per application, with one to four applications per year, but no more than 8 lbs ai per acre per year. Only the Rohm and Haas 94.6% technical and 51% wettable powder formulation are subject to the tolerance reassessment. Rohm and Haas sold this product to Dow Agro Sciences (Letter sent to J. Tompkins in RD, 9/ 21/ 01). In addition, Earth Care, Division of United Industries Corp., (previously Pursell Industries) has requested voluntary cancellation of the product GREEN UP KERB 50W, EPA Reg. No. 8660­ 85 (letter to C. Watkins, B. Metzger, 1/ 14/ 02), which is the only label containing a residential/ recreational turf use. Cancellation of the GREEN UP label (8660­ 85) would eliminate all uses that result in potential public or residential exposure. Hazard Assessment Pronamide technical has a low order of acute toxicity via the oral, dermal, and inhalation routes of exposure (Toxicity Category III or IV), produces mild irritation to the eyes and skin (Toxicity Category IV), and is not a dermal sensitizer. The active ingredient pronamide appears to be a liver toxicant. Adverse liver­ related effects (increases in liver weight and/ or liver­ related serum enzymes and/ or histopathology) were consistently observed in every animal species studied, including the rat (subchronic, chronic, and multi­ generation reproduction studies), mouse (carcinogenicity studies), rabbit (developmental toxicity study), and dog (subchronic and chronic studies). Other target organs included the thyroid in rats (increase in weight and/ or histopathology observed in the chronic toxicity/ carcinogenicity and the multi­ generation reproduction studies as well as a subchronic, special 13­ week thyroid function study), the testes in rats (histopathology in the chronic toxicity/ carcinogenicity study) and the kidneys, adrenal glands, thymus, heart, testes, and brain in dogs (increase in organ weights in the chronic toxicity study), and the pituitary in rats (histopathology observed in the subchronic and multi­ generation reproduction studies). There was no quantitative or qualitative evidence of increased susceptibility in the fetuses or the 2 offspring of rats or rabbits following pre­ and/ or postnatal exposure to pronamide. In the prenatal developmental toxicity study in rabbits and the multigeneration reproduction study in rats, any observed toxicity to the fetuses or offspring occurred at equivalent or higher doses than did toxicity to parental animals. In the rat developmental toxicity study, the highest dose of pronamide tested exceeded the doses tested in both the rabbit developmental toxicity study and the rat multigeneration reproduction study without demonstrating toxicities in either maternal animals or fetuses. Since this study failed to provide evidence concerning the potential increased susceptibility to infants and children (a LOAEL was not be established) as required by the Food Quality Protection Act (FQPA) of 1996, a repeat developmental toxicity study in the rat is required to fulfill the OPPTS harmonized test guideline 870.3700. Results of the battery of mutagenicity studies (forward and reverse gene mutation, in vivo and in vitro cytogenetic/ structural chromosome aberration and unscheduled DNA synthesis assays) indicate that pronamide is not a mutagenic agent. However, the Carcinogenicity Peer Review Committee (CPRC) classified Pronamide as a group B2 ­ probable human carcinogen (with inadequate evidence in humans) based on the finding of two tumor types in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas) and one tumor type in the mouse (hepatocellular carcinomas). A linear, low dose approach (Q1*) is used for human risk characterization. The most potent unit risk Q1*, based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2.59 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents [converted from animals to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor]. Pronamide has been identified by the Agency's Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) as a potential endocrine disruptor. Evidence of endocrine effects from several guideline toxicity studies as well as two special studies submitted to the Agency by the Registrant include, in part,: (i) histopathology of the thyroid gland, pituitary gland, adrenal glands, testes and ovaries, (ii) changes in hormone levels; decreased T4 and increased TSH, LH and FSH, and (iii) the induction of enzymes such as cytochrome­ P450 and ­B5, and NADPH­ cytochrome­ c­ reductase in addition to those enzymes involved in the oxidation of testosterone. Mammalian neurotoxicity studies for pronamide have not been conducted. However, since pronamide does not belong to a class of chemicals known to exhibit neurotoxicity, and there is no evidence of neurotoxicity seen in any of the existing studies, neurotoxicity studies (e. g., an acute delayed neurotoxicity study in the hen, a neurotoxicity screening battery or a developmental neurotoxicity study) are not required. Pronamide is rapidly absorbed and completely and rapidly eliminated equally in the urine (40­ 61%) and feces (40­ 60%) within 7 days post­ dosing. No bioaccumulation was apparent and very little unchanged pronamide was recovered in the urine. All of the fecal metabolites were unidentified and comprised less than 1% of the dose whereas two major urinary metabolites have been identified and quantified; 2­( 3,5­ dichlorophenyl)­ 4,4­ dimethyl­ 5­ carboxyoxazoline (metabolite SS47­ 70, 3.0­ 5.9% of the administered dose) and N­ carboxymethyl­ 3,5­ dichlorobenzamide (metabolite 10, 12.7­ 18.9% of the administered dose). There is no acceptable dermal absorption study in the pronamide data base. In addition, there were no dermal toxicity studies submitted which could be used for comparison to oral toxicity studies. Therefore, a 100% (default value) dermal absorption factor was determined for risk assessment 3 purposes. A FQPA safety factor is required for all population subgroups when assessing dietary and residential exposure scenarios because of the evidence of endocrine effects in the pronamide data base. However, the FQPA safety factor was reduced to 3x because: (i) the toxicological database is adequate for FQPA assessment (ii) there is no indication of quantitative or qualitative increased susceptibility of rabbits to in utero exposure or to rats following pre/ post­ natal exposure. Also, in the available, unacceptable rat study, no increased susceptibility was seen even though the animals could have tolerated higher doses (iii) a developmental neurotoxicity study is not required and (iv) the dietary (food and drinking water) and residential exposure assessments will not underestimate the potential exposures for infants and children. Toxicological endpoints were established for all relevant exposure scenarios. Acute dietary exposure for females 13­ 50 years of age or for the general population is not assessed since there was no appropriate endpoint attributable to a single dose available in the pronamide data base. Two toxicological studies determined all toxicological endpoint doses used in the risk assessment: a prenatal developmental toxicity study in the rabbit and a chronic toxicity/ carcinogenicity in the rat. A discussion of the dose­ response relationships for chronic dietary endpoints as well as residential exposure endpoints follows the presentation of the summary of toxicological endpoint selection (See Table 3, Section 3.3 of the text). A chronic reference dose (cRfD) of 0.08 mg/ kg/ day was determined on the basis of the two­ year chronic toxicity/ carcinogenicity study in rats and the application of an uncertainty factor of 100 (10x for interspecies extrapolation and 10x for intra­ species variation). The NOAEL in this study was 8.46 mg/ kg/ day and the LOAEL was 42.59 mg/ kg/ day based upon increased relative liver weight and the non­ neoplastic histologic changes in the liver (centrilobular hypertrophy and hepatocellular eosinophilic alteration in males and females), thyroid (follicular cell hypertrophy in males and females) and ovaries (sertoliform tubular hyperplasia in females). The 3x FQPA safety factor was applied to the chronic dietary risk assessment because there is evidence of endocrine effects (thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus) identified in the majority of subchronic/ chronic studies conducted across species. The cPAD is the cRfD adjusted for the FQPA safety factor. Therefore, the cPAD is 0.027 mg/ kg/ day. Dietary risk estimates which are less than 100% of the cPAD do not exceed HED's level of concern. For risk assessments based on short­ term (1­ 30 days) incidental oral, dermal and inhalation exposures, an adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and the clinical signs (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. Although selection of this study for short­ term exposure scenarios is appropriate for the route (oral) and duration (13 days), the NOAEL of 5 mg/ kg/ day is lower than the NOAEL (8.46 mg/ kg/ day) established in the chronic toxicity/ carcinogenicity study in the rat. The apparent disparity between these NOAELs is driven by the doses of pronamide selected for testing in these studies. The Hazard Identification Assessment Review Committee (HIARC) concluded that using a more realistic NOAEL of 8.46 mg/ kg/ day rather than 5 mg/ kg/ day would provide a sufficiently protective dose for risk assessment. The 3x FQPA safety factor was also applied to these risk assessments because of the evidence of endocrine effects in the pronamide toxicity data base. Due to the lack of appropriate dermal or inhalation endpoints, absorption factors of 4 100% (default value) were used with the oral endpoints. Intermediate­ and long­ term toxicity endpoints were also selected, however only short­ term oral, dermal or inhalation exposures to pronamide are anticipated, based on its' use pattern. Exposure and Risk Assessment There is a potential for dietary (food and drinking water) exposure from commercial applications of pronamide in agriculture and for postapplication dermal and incidental oral exposures from residential/ recreational uses (lawns and turf). If the label allowing residential/ recreational turf uses is canceled, the nondietary exposures will be eliminated. The occupational exposure was assessed in the 1993 HED RED chapter. However, because this is a tolerance reassessment document, only nonoccupational dietary and residential postapplication exposures to pronamide are considered in this document. Short­ term, chronic and cancer exposures were assessed for pronamide residues in food and water. A review of incident data sources found that relatively few incidents of pronamide poisonings were reported. There are only two Poison Center reports, no incident reports in OPP's Incident Data System and only two reports from the California Pesticide Illness Surveillance Program. Dietary The dietary risk assessment for chronic exposures to pronamide shows that chronic dietary exposure to pronamide is not a significant exposure pathway. As stated previously, an acute toxicity endpoint was not selected, therefore an acute exposure assessment was not conducted. Refined tier 3 chronic and cancer dietary exposure assessments were conducted for all supported food uses (i. e., all currently registered and proposed uses). Pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety are the residues of concern and are included in the assessment. Although tolerance level residues were used for four registered crops (dried peas, endives, radicchio, and cranberries), the assessment was based primarily upon residue monitoring data for fruits and vegetables and upon calculation of anticipated residues for meat, milk, poultry and eggs, and is the most refined assessment to date for pronamide. These data are based mostly upon non­ detectable residues. Estimates of percent crop treated (% CT) generated by the Biological and Economic Analysis Division (BEAD) were used to further refine the dietary exposure assessment. Estimates were generated for chronic (long­ term) and cancer dietary exposure using the most recent version of the Dietary Exposure Evaluation Model (DEEM™, Version 7.75). This assessment showed that the chronic dietary risk estimates are below the Agency's level of concern (< 100% of the cPAD) for the U. S. population and for all population subgroups. The chronic dietary exposure estimates for the two most highly exposed population subgroups, children (1­ 6) and seniors (55+), are both estimated at 0.000005 mg/ kg/ day (< 1% cPAD). The cancer dietary risk estimate is 1.06 x 10 ­7 for the U. S. population, and is below the level that the Agency generally considers to be of concern (1.0 x 10 ­6 or one in one million). Residential Postapplication Exposure Based on the application frequency and rate of residue dissipation, only short­ term residential 5 postapplication exposures to pronamide are anticipated after lawn and turf treatments. A margin of exposure (MOE) of 300 (10x for interspecies extrapolation, 10x for interspecies variation and a 3x FQPA safety factor) is required for short­ term incidental oral, dermal and inhalation risk assessments. Therefore, short­ term residential risk estimates with a MOE > 300 do not exceed the level of concern. The risk assessment for short­ term residential postapplication exposure indicates that dermal exposures to pronamide are a significant pathway of exposure. All pronamide end use products are labeled as restricted use pesticides. Therefore, consumers are restricted from handling or applying pronamide products. Consequently, only residential/ recreational postapplication exposures to the general population are anticipated and are evaluated in this assessment. Adults and children are potentially exposed to pronamide residues via the dermal route after application of pronamide products by professional lawn care operators (LCOs) in residential/ recreational settings. Inhalation exposure to pronamide is not anticipated after application due to the low vapor pressure of the active ingredient and outdoor air dilution. Incidental oral exposure is expected to occur for small children and is combined with their dermal exposures, where applicable (i. e., playing on turf). Residential exposures were estimated based on label application frequency and the persistence of pronamide. Most assumptions for risk estimation were based on the Agency's Residential SOPs. Residents are assumed to play or work on treated lawns or recreational turf within the first 24 hours of spraying. Only short­ term risks from residential postapplication dermal and incidental oral exposures are anticipated since turf residues dissipate below the limit of quantitation by day 14 following application (based on the submitted pronamide turf transferable residue (TTR) study). Risk estimates based on residue data from the TTR study for short­ term dermal exposures to treated turf during high contact lawn activities on day zero following application (DAT 0) exceed HED's level of concern, i. e. result in MOEs < 300 for adults (MOE = 71) and children (MOE = 42). After the turf was watered, residues declined sufficiently that all risk estimates were below the level of concern for adults (MOE = 890) and children (MOE = 530). However, label language regarding immediate watering­ in after application to turf is neither required nor enforceable for consumers. Risk estimates for short­ term dermal contact with residues on treated turf during the low contact activities of grass mowing or golfing on the day of treatment do not exceed the level of concern for adults (MOEs 2100 and 1000, respectively). Postapplication cancer risk was estimated using 14­ day average residues and only a single day's activity, based on a single dormant season application. The estimated cancer risk from one day per year of high­ contact (e. g., playing on lawn) postapplication dermal exposure to pronamide treated turf was 8.4 x 10 ­7 and did not exceed the Agency's level of concern of 1 x 10 ­6 . Other, lower contact activities (e. g., golfing) could be conducted for several days without exceeding the level of concern. The risk estimates for small children's incidental ingestion of pronamide from treated turf indicate that risks do not exceed the level of concern (i. e. MOEs > 300) for hand­ to­ mouth (MOE = 380), ingestion of soil (MOE = 113,000), and object to mouth (MOE = 1500) scenarios. The small children's combined oral hand­ to­ mouth incidental ingestion scenarios (MOE = 300) also do not exceed the level of concern. When risks from dermal exposures to pronamide by small children are combined with risks from incidental oral exposures, the combined short­ term risk estimates exceed the level of concern (MOEs < 300), with a MOE of 37. There is significant uncertainty involved in predicting co­ occurrence of exposures by different routes and in adding these scenarios, as well as the degree of conservatism generated in the combined risk estimate. 6 Drinking Water Risk assessment for short­ term and chronic exposure to pronamide indicates that drinking water is not a significant exposure pathway, but may be of some potential concern for cancer. Risk estimates for exposure to pronamide in drinking water are assessed by comparing drinking water levels of comparison (DWLOCs) to the estimated environmental concentrations (EECs) of pronamide in surface water and groundwater. In the case of pronamide, there are monitoring data available for surface and ground water. The monitoring database used in the risk assessment is considered to be of good quality (US Geological Survey), but the data are not specific to pronamide use areas. Therefore they are cited for comparison, rather than verification of modeling estimates. A Tier I Drinking Water Assessment for pronamide was calculated (L. Shanaman, May 16, 2001) using the SCIGROW model to provide groundwater EECs. The Tier I groundwater concentration estimates were predicted from application of pronamide at maximum label rate, and represent upper­ bound estimates of the concentrations that might be found in shallow groundwater at vulnerable sites due to the use of pronamide/ propyzamine. The resulting modeled groundwater screening concentration is 3.0 ppb, which does not exceed the DWLOC for short­ term exposure for the most sensitive populations (females >55 years ) of 560 ppb. The Tier II PRZM­ EXAMS model (L. Shanaman, in progress, 2002) was used to predict EECs for pronamide in surface water, i. e., 90 th percentile average annual concentration values for use in chronic exposure assessments, and 36­ year mean concentration values for use in "cancer" exposure assessments. Maximum label application rates were used for major use crops. Chronic exposure values ranged from 1.5 to 6.4 ppb, which are lower than the chronic DWLOC of 300 ppb for the most sensitive populations, infants and children. Conservative inputs were used for the environmental (soil and water metabolism) assumptions, i. e., 2­ 3x uncertainty factors were applied to soil and water half­ lives used in the PRZMEXAMS assessment. The Tier II cancer risk assessment for exposure to pronamide in water indicates that drinking water may be a significant exposure pathway. The the refined Tier II modeling result is greater than the aggregate cancer DWLOC estimate of <0.1 ppb and therefore exceeds the cancer level of concern of 1 x 10 ­6 . The estimated DWLOC for cancer based on dietary exposures only (food + water) is 1.2 ppb, which is below some of the drinking water concentrations estimated by EFED and above others (0.535 ­ 4.3 ppb for surface water and 3 ppb for groundwater) and therefore is of concern for some scenarios. Surface and ground water monitoring data are available for pronamide from routine USGS sampling, and are being analyzed to determine if they provide support for the modeling estimates. Aggregate Exposure Aggregate risk assessments were conducted for short­ term and chronic exposures, and for cancer. All of the aggregate risk estimates are considered high­ end, or conservative, due to the compounding of conservative assumptions in individual exposure route estimates. Aggregate risk estimates for acute exposures were not conducted as no acute endpoint was selected from the toxicity database. Because there are no intermediate­ term or chronic non­ dietary exposures to pronamide, the chronic aggregate risk assessment only considers exposures from dietary (via food and drinking water) consumption. HED has no concerns for aggregate chronic exposures to pronamide residues in food and drinking water. 7 Estimated drinking water exposures using Tier 2 modeling and actual sampling data for surface water and groundwater result in equivocal cancer risk estimates of approximately 1 to 3 x 10 ­6 , independent of dietary and residential exposures to pronamide. Therefore, HED has some concerns for the potential exposures from surface and groundwater sources under the cancer asessment, particulary for the scenario assessed surface water for alfalfa in California. Aggregated exposures from food, water, and residential uses result in cancer risk estimates that further exceed HED's level of concern for cancer. The short­ term aggregate risk assessment conducted for pronamide considered ingestion of food and drinking water, combined with postapplication dermal and incidental oral exposures. Because the risk estimates for high­ contact dermal exposures for both children and adults alone are of concern, a shortterm aggregate exposure assessment was not conducted for those populations and scenarios, as they would only further exceed the HED's level of concern. Risk estimates are in excess of the level of concern (MOE < 300) for short­ term dermal exposures to pronamide residues on turf for adults (MOE = 71) and children (MOE = 42) engaged in high­ contact activities, such as playing on treated turf immediately after pronamide application. However, as the risk estimate for short­ term exposures of adults golfing does not exceed HED's level of concern, HED included this short­ term residential exposure with food and drinking water exposure in a short­ term aggregate risk assessment. The aggregate risk estimate for food and golfing exposure was a MOE of 1050, and there was still enough room to add the estimated drinking water exposure without exceeding the HED DWLOC. This short­ term aggregate risk estimate including adults engaged in lowcontact activities on turf may be useful in risk management decisions. HED notes that all of the residential scenarios with risk estimates of concern, including the aggregate cancer risk estimate are considered high­ end estimates based on standard HED assumptions and a 100% dermal absorption factor. Data Gaps Most pertinent product chemistry data requirements are satisfied for the Rohm and Haas 94.6% T/ TGAI, and 51% FI. Some additional physical chemistry and processing information are required. There is confidence in the overall scientific quality of the available toxicity data, but several data gaps were identified: a developmental toxicity study in rats, a 21­ day dermal toxicity study, 28­ day inhalation toxicity study, a dermal penetration study and a comparative thyroid rat assay in adult animals and offspring. Some label amendments and data submissions are required, including additional residue data for use on grasses, dried winter peas (outstanding), the vines and hay of winter peas, grass forage, and hay. The registrant is required to improve the analytical method for animal residue data; and to submit bridging independent laboratory validation data. Additional confirmatory storage stability data for the regulated pronamide metabolites on alfalfa, apples, grapes, lettuce, and peaches or plums are required. 8 Cl Cl O N H CH 3 CH 3 CH 2.0 PHYSICAL CHEMICAL PROPERTIES CHARACTERIZATION The chemical name for pronamide is [3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide]. The chemical structure is Empirical Formula: C12H11NOCl2 Molecular Weight: 256.13 CAS Registry No.: 23950­ 58­ 5 PC Code: 101701 Technical pronamide is a white crystalline solid with a melting point of 155­ 156 °C, specific gravity of 0.48 g/ cc, octanol/ water partition coefficient (log POW) of 3.05­ 3.27, and vapor pressure of 8.50 x 10 ­5 torr at 25 °C. Because of its' low vapor pressure, pronamide is not expected to present an inhalation exposure risk when used outdoors. There are no toxicologically significant impurities in the manufacturing process. 3.0 HAZARD CHARACTERIZATION The active ingredient pronamide appears to be a liver toxicant. Adverse liver­ related effects (increases in liver weight and/ or liver­ related serum enzymes and/ or histopathology) were consistently observed in every animal species studied. Other target organs included the thyroid, testes and pituitary in rats, and the kidneys, adrenal glands, thymus, heart, testes, and brain in dogs. 3.1 Hazard Profile Acute Toxicity The acute toxicity data base for pronamide technical is considered complete. No additional studies are required at this time. Pronamide technical has a low order of acute toxicity via the oral, dermal, and inhalation routes of exposure (Toxicity Category III or IV), produces mild irritation to the eyes and skin (Toxicity Category IV), and is not a dermal sensitizer. The acute toxicity data for pronamide is summarized below in Table 1. 9 Table 1. Acute Toxicity of Pronamide (Propyzamide) Guideline Number Study Type MRID Number Results Toxicity Category 870.1100 (§ 81­ 1) Acute Oral ­ Rat, > 92.0% a. i. 00085505 LD50 (males and females) is greater than 5000 mg/ kg IV 870.1100 (§ 81­ 1) Acute Oral (Limit test) Rat 95.7% a. i. 43583901 LD50 (males and females) is greater than 5000 mg/ kg IV 870.1200 (§ 81­ 2) Acute Dermal (Limit Test) ­ Rabbit, 95.7% a. i. 43583902 LD50 (males and females) is greater than 2000 mg/ kg III 870.1300 (§ 81­ 3) Acute Inhalation ­ Rat, 95.7% a. i. 44034201 LC50 is greater than 2.1 mg/ L following a 4 hour exposure III 870.2400 (§ 81­ 4) Primary Eye Irritation Rabbit 95.7% a. i. 43583904 Mild occular irritant IV 870.2500(§ 81­ 5) Primary Dermal Irritation ­ Rabbit, 95.7% a. i. 43583903 Slight dermal irritant IV 870.2600 (§ 81­ 6) Dermal Sensitization Guinea pig, > 92.0% a. i. 00062605 Not a sensitizer N/ A Subchronic Toxicity The data base for subchronic toxicity is considered incomplete. The HIARC identified two subchronic toxicity study data gaps and recommended the following studies be conducted in order fulfill the requirements cited for a food/ feed use chemical (40 CFR 158.340): 1) a 21­ day dermal toxicity study (guideline 870.3200; old 82­ 2); and 2) a 28­ day inhalation toxicity study (non­ guideline) However, the pronamide subchronic data base does contain two acceptable studies conducted in the rat that can be used for regulatory purposes; a 4­ week oral toxicity study (non­ guideline) and a 13­ week oral toxicity study (guideline). In the non­ guideline, 4­ week study, systemic toxicities were noted in males treated with 37.24 or 74.05 mg/ kg/ day pronamide and in females treated with 43.65 or 87.65 mg/ kg/ day pronamide. These toxicities were limited to the liver and included increases in absolute and relative (to body) liver weights (males: both doses; females: high­ dose) and a positive trend in the increased incidence of centrilobular hypertrophy (males). When pronamide was administered in the diet for 13 consecutive weeks, male rats treated with 60.0 mg/ kg/ day and females rats treated with 74.6 mg/ kg/ day presented with the following systemic toxicities in one or both sexes: decreased body weight, body weight gain and food consumption, increased blood cholesterol levels, increased relative (to body) liver weights and incidence of hepatic centrilobular hypertrophy. At the highest dose tested (254.0 mg/ kg/ day for males and 289.2 mg/ kg/ day in females), many of these toxicities were observed in both 10 sexes and showed an increase in incidence and/ or severity. The following additional changes were also observed in high­ dose animals: clinical signs (brown and/ or yellow staining of the anogenital area (males), increased enzyme activity (SGOT and alkaline phosphatase) in males, triglyceride blood levels (females), increased absolute liver weights (males and females), and increased incidences of thyroid follicular cell hypertrophy (males and females) sexes and anterior pituitary cellular hypertrophy (males). After 4 weeks of recovery, most of the adverse effects observed at the high­ dose were partially or completely reversed with the exception of the increase in incidence of pituitary cellular hypertrophy (males only). Reproductive & Developmental Toxicity There was no quantitative or qualitative evidence of increased susceptibility in the fetuses or the offspring of rats or rabbits following pre­ and/ or postnatal exposure to pronamide. Fetal/ offspring effects in both of these species were observed at either the same or higher dose levels which produced maternal/ parental toxicity. In the developmental toxicity study in rabbits, abortions were observed at a higher dose level (80 mg/ kg/ day) compared to the dose (20 mg/ kg/ day) at which maternal toxicity (soiled anal area, anorexia and punctate vacuolation of hepatocytes) was observed. Also, no evidence of increased susceptibility was demonstrated in the two­ generation reproduction study in rats. Offspring toxicity (decreased combined male/ female pup weight/ litter) was observed at the same dose that caused parental toxicity (decreased body weight and food consumption in both sexes, increased incidences of histopathology of the liver, adrenal gland, thyroid gland, and anterior pituitary gland in both P1 and P2 generations, and increased incidences of uterine gross pathology in P2 females). Parental and offspring toxicities were observed at the same LOAEL of 1500 ppm (130.1 mg/ kg/ day for males and 120.7 mg/ kg/ day for females). Evidence for susceptibility could not be ascertained in the developmental toxicity study conducted in rats. No toxicities were observed in either maternal animals or fetuses at any dose tested (5­ 160 mg/ kg/ day); a LOAEL could not be established in the rat developmental toxicity study. Since this study failed to provide evidence concerning the potential increased susceptibility to infants and children as required by the Food Quality Protection Act (FQPA) of 1996, a repeat developmental toxicity study in the rat is required to fulfill the OPPTS harmonized test guideline 870.3700. Chronic Toxicity: Following chronic exposure (mid­ dose and/ or high­ dose groups; 33.1 mg/ kg/ day and/ or 67.7 mg/ kg/ day) in dogs, systemic toxicities presented as decreased body weights, body weight gains, food consumption, serum albumin, platelet counts, increased enzyme activity (alkaline phosphatase, alanine aminotransferase, and gamma glutamyltransferase), increased absolute and/ or relative weights of the thyroid, liver, heart, testes, adrenal glands, kidneys and thymus, and histopathology of the liver (hepatocytic hypertrophy, hyperplasia and granular brown pigmentation/ mononuclear infiltration of Kupffer cells) and kidneys (granular brown pigment in the epithelial cells of the proximal convoluted tubules). In rats, the toxicities observed included decreased body weight/ body weight gain, increased liver weight and histopathology of the liver (hypertrophy accompanied by eosinophilic cell alteration), thyroid (follicular cell hypertrophy and hyperplasia), and ovaries (sertoliform tubular hyperplasia) at 42.59 mg/ kg/ day (LOAEL). In the carcinogenicity study conducted in mice, systemic toxicities observed at the LOAEL of 75 mg/ kg/ day were limited to decreased body weight/ body weight gain, increased liver weight and histopathology of the liver (hypertrophy, nodules/ masses, parenchymal necrosis, and cholestasis). Under the conditions of this study, there was evidence of a treatment­ related increase in tumor incidence in the liver of male mice when compared to controls. Dosing is considered adequate to assess the carcinogenic potential of 11 pronamide based on liver effects (non­ neoplastic lesions and increased weight). Mutagenicity: With the exception of one gene mutation assay, the remaining five mutagenicity studies were determined to be acceptable for regulatory purposes (The acceptable studies satisfy the 1991 mutagenicity guideline requirements). The results from these studies indicate that pronamide was not mutagenic in Salmonella typhimurium, Escherichia coli or in cultured Chinese hamster lung cells and did not produce a genotoxic response in Bacillus subtiltis or in cultured primary rat hepatocytes. There was also no evidence of clastogenicity in cultured Chinese hamster ovary cells and pronamide administration did not result in the induction of micronucleated polychromatic erythrocytes in bone marrow of mice. Overall, the data suggest that pronamide is negative for mutagenicity in vitro and in vivo. Carcinogenicity: The Carcinogenicity Peer Review Committee (CPRC) classified Pronamide as a group B2 ­ probable human carcinogen with inadequate evidence in humans (Memorandum: E. Rinde, May 26, 1993). This decision was based on the finding of two types of tumors in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas), and one type of tumor in the mouse (hepatocellular carcinomas). A linear, low dose approach (Q1*) is used for human risk characterization and the tumor incidence data used in this calculation is derived from the 1982 mouse carcinogenicity study (MRID 00114114, 00151822). The most potent unit risk Q1*, based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2.59 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents [converted from animal to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor] (Memorandum: L. Brunsman, October 26, 2001). Neurotoxicity: Mammalian neurotoxicity studies for pronamide have not been conducted. However, since pronamide does not belong to a class of chemicals known to exhibit neurotoxicity, and there is no evidence of neurotoxicity seen in any of the existing studies, neurotoxicity studies (e. g., an acute delayed neurotoxicity study in the hen, a neurotoxicity screening battery or a developmental neurotoxicity study) were not required. Metabolism: Pronamide is rapidly absorbed from the gastrointestinal tract and extensively and rapidly metabolized; 93­ 103% the radioactivity administered was recovered . It is excreted (7 days post­ dosing) equally in both the urine (40­ 61%) and the feces (40­ 60%). No bioaccumulation was apparent; radioactivity recovered in all tissues were consistently highest at the first sampling time (8 hours postdose then gradually declined to insignificant levels 7 days after dosing. The elimination of radioactivity from the plasma of low dose rats was biphasic [rapid phase = 12.6 hrs (males) and 12.7 hrs (females); slow phase = 36.6 hrs (males) and 45.3 hrs (females)] and that of the high dose rats was monophasic [t½ = 24.1 hrs (males) and 24.8 hrs (females)]. Tissues with the highest radioactivity contents were, in decreasing order, the fat, adrenals, bone marrow, thyroids, liver, kidney, and plasma. Very little unchanged pronamide was recovered in the urine and no significant difference in the urinary metabolite profile was observed between the doses or the sexes. Approximately 27 unidentified metabolites were found in the urine and none exceeded 3.3% of the dose whereas all of the fecal metabolites were unidentified and comprised less than 1% of the dose. Two major urinary metabolites have been identified and quantified; 2­( 3,5­ dichlorophenyl)­ 4,4­ dimethyl­ 5­ carboxyoxazoline (metabolite SS47­ 70, 3.0­ 5.9% of the administered dose) and N­ carboxymethyl­ 3,5­ dichlorobenzamide (metabolite 10, 12.7­ 18.9% of the administered dose). Dermal Absorption/ Toxicity: No dermal penetration study conducted with pronamide technical is available in the toxicity data base. A dermal penetration study conducted with the Kerb 50W and 3.3F 12 pronamide formulations was submitted, however, this study was classified as unacceptable­ guideline (the actual doses applied to the skin were not determined and there were discrepancies in the percent radioactive recovery). In addition, there were no dermal toxicity studies submitted which could be used for comparison to oral toxicity studies. Therefore, a 100% (default value) dermal absorption factor was determined for risk assessment purposes. A repeat dermal penetration study in the rat is required to fulfill the OPPTS harmonized test guideline 870.7600. Endocrine Effects: Pronamide is an organochlorine herbicide which has been identified by the Agency's Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) as a potential endocrine disruptor. Evidence of endocrine effects from several guideline toxicity studies as well as two special studies submitted to the Agency by the Registrant include, in part: (i) histopathology of the thyroid gland, pituitary gland, adrenal glands, testes and ovaries, (ii) changes in hormone levels; decreased T4 and increased TSH, LH and FSH, and (iii) the induction of enzymes such as cytochrome­ P450 and ­B5, and NADPH­ cytochrome­ c­ reductase in addition to those enzymes involved in the oxidation of testosterone. Two special studies were conducted by the Registrant to evaluate pronamide's effect on hormonal balance in support of a threshold mechanism for the induction of thyroid and testicular neoplasms. Although the results of these special endocrine studies are suggestive of a pronamide­ induced thyroid and testicular neoplastic effect via disruption of the pituitary­ thyroid and pituitary­ testis hormonal balance, these data are far from conclusive. Based on the absence of any additional information as well as the Mechanism of Toxicity Assessment Review Committee's (MTARC) evaluation of the existing pronamide toxicology data base (Memorandum: M. Centra, January 21, 2001) and the Agency's previous hazard characterization of this active ingredient (Memorandum: N. Thoa, May 26, 1993), it was determined that the postulated threshold mechanism for the induction of thyroid and testicular neoplasms is not supported by the available data. Therefore, HED has recommended that additional studies be conducted with pronamide to determine its mechanism of endocrine toxicity. One such study, a comparative assay in the rat that is designed to assess thyroid function in adult animals and their offspring as well as potential central nervous system effects in the young, is required because of the endocrine toxicities observed in various organ systems (thyroid gland, testes, ovaries, adrenal glands, pituitary gland) of rats and/ or dogs. The toxicity study profile is summarized in Table 2. TABLE 2. Subchronic, Chronic and Other Toxicity Profiles for Pronamide (Propyzamide Guideline No./ Study Type MRID No. (year)/ Classification/ Doses Results 870.3100 (§ 82­ 1a) 4­ Week Oral Toxicity Rat MRID 42669402 (6/ 18/ 87)/ Acceptable­ Nonguideline ppm = 0, 500, or 1000 mg/ kg/ day (males) = 0, 37.24, or 74.05 mg/ kg/ day (females) = 0, 43.65, or 87.65 NOAEL = less than 500 ppm (37.24 mg/ kg/ day for males; 43.65 mg/ kg/ day for females) LOAEL = less than or equal to 1000 ppm (74.05 mg/ kg/ day for males; 87.65 mg/ kg/ day for females) based upon increased absolute and relative (to body) liver weights in males and females and a positive trend in increased incidence of liver centrilobular hypertrophy in males. TABLE 2. Subchronic, Chronic and Other Toxicity Profiles for Pronamide (Propyzamide Guideline No./ Study Type MRID No. (year)/ Classification/ Doses Results 13 870.3100 (§ 82­ 1a) 90­ Day Oral Toxicity Rat MRID 42669403 (11/ 2/ 67)/ Acceptable­ Guideline ppm = 0, 40, 200, 1000, or 4000 mg/ kg/ day (males) = 0, 2.5, 12.3, 60.0, or 254.0 mg/ kg/ day (females) = 0, 3.1, 15.0, 74.6, or 289.2 NOAEL (males and females) = 200 ppm (12.3 mg/ kg/ day in males; 15.0 mg/ kg/ day in females) LOAEL = 1000 ppm (60.0 mg/ kg/ day in males; 74.6 mg/ kg/ day in females) based upon increased relative liver weights and increased incidence of centrilobular hypertrophy of the liver in both sexes, decreased body weight, body weight gain and food consumption in females and increased blood cholesterol levels in males. 870.3700 (§ 83­ 3a) Developmental Toxicity ­ Rat MRID 40334501 (7/ 10/ 87)/ Unacceptable­ Guideline (not upgradeable) mg/ kg/ day = 0, 5, 20, 80, or 160 Maternal Toxicity NOAEL = greater than or equal to 160 mg/ kg/ day LOAEL = greater than 160 mg/ kg/ day (highest dose tested; LOAEL not established) Developmental Toxicity NOAEL = greater than or equal to 160 mg/ kg/ day LOAEL = greater than 160 mg/ kg/ day (highest dose tested; LOAEL not established) 870.3700 (§ 83­ 3b) Developmental Toxicity ­ Rabbit MRID 00148065, 00148064 (6/ 4/ 85 )/ Acceptable­ Guideline mg/ kg/ day = 0, 5, 20, or 80 Maternal Toxicity NOAEL = 5 mg/ kg/ day LOAEL = 20 mg/ kg/ day based upon clinical signs of toxicity (soiled anal area, anorexia and punctate vacuolation of hepatocytes) and liver effects (hepatocellular necrosis, eosinophilia, swelling of hepatocytes, pigmentation of Kupffer cells). Developmental Toxicity NOAEL = 20 mg/ kg/ day LOAEL = 80 mg/ kg/ day based upon abortions. 870.3800 (§ 83­ 4) Multigeneration Reproductive Toxicity ­ Rat MRID 41540301 (1968)/ Acceptable­ guideline ppm = 0, 40, 200, or 1500 mg/ kg/ day (males) = 0, 3.1, 16.0, or 120.7 mg/ kg/ day (females) = 0, 3.6, 18.0, or 130.1 Parental/ Systemic Toxicity NOAEL = 200 ppm (16.0 mg/ kg/ day for females and 18.0 mg/ kg/ day for males) LOAEL = 1500 ppm (120.7 mg/ kg/ day for females and 130.1 mg/ kg/ day for males) based upon decreases in body weight and feed consumption in both sexes and increased incidences of histology of the liver (centrilobular hepatocyte hypertrophy; both sexes), adrenal glands (zona glomerulosa cellular hypertrophy; both sexes), thyroid gland (follicular cell hypertrophy; females), and anterior pituitary gland (cellular hypertrophy; males) in both P1 and P2 generations, and increased incidences of uterine gross pathology (black foci/ serosal surface) in P2 females. Reproductive Toxicity NOAEL = greater than or equal to 1500 ppm LOAEL = greater than 1500 ppm; not established TABLE 2. Subchronic, Chronic and Other Toxicity Profiles for Pronamide (Propyzamide Guideline No./ Study Type MRID No. (year)/ Classification/ Doses Results 14 870.4100 (§ 83­ 1b) Chronic Toxicity ­ Dog MRID 41807601,41807602, 4213030 (8/ 5/ 68)/ Acceptable­ Guideline ppm = 0, 300, 875, or 1750 mg/ kg/ day (males) = 0, 11.9, 33.1, or 67.7 mg/ kg/ day (females) = 0, 11.9, 36.1, or 69.0 NOAEL (males, females) = 300 ppm (11.9 mg/ kg/ day) LOAEL = 875 ppm (33.1 mg/ kg/ day in males; 36.1 mg/ kg/ day in females) based upon increased serum alkaline phosphatase (males), increased thyroid and liver weights (females), and increased incidence in liver histopathology (males and females; increased incidence of hepatocyte hypertrophy, granular pigmentation, mononuclear infiltration, and granular brown pigmentation in Kupffer cells). 870.4300 (§ 83­ 1/ 2a/ 5) Combined Chronic Toxicity/ Carcinogenicity ­Rat MRID 41714001, 41714002 (10/ 1/ 90)/ Acceptable­ Guideline ppm = 0, 40, 200, or 1000 mg/ kg/ day (males) = 0, 1.73, 8.46, or 42.59 mg/ kg/ day (females) = 0, 2.13, 10.69, or 55.09 NOAEL (males and females) = 200 ppm (8.46 mg/ kg/ day in males; 1069 mg/ kg/ day in females) LOAEL = 1000 ppm (42.59 mg/ kg/ day in males; 55.09 mg/ kg/ day in females) based upon increased relative liver weight and the non­ neoplastic histologic changes in the liver (centrilobular hypertrophy and hepatocellular eosinophilic alteration in males and females), thyroid (follicular cell hypertrophy in males and females) and ovaries (sertoliform tubular hyperplasia in females). Rats fed diets containing 1000 ppm pronamide showed an increased incidence of thyroid follicular cell adenomas in male and female rats and benign testicular interstitial cell tumors in male rats. There was no progression of tumors to carcinomas. Under the conditions of this study, the dosing was considered to be adequate based upon decreased body weight gain and the non­ neoplastic histologic changes in the liver. TABLE 2. Subchronic, Chronic and Other Toxicity Profiles for Pronamide (Propyzamide Guideline No./ Study Type MRID No. (year)/ Classification/ Doses Results 15 870.4200 (§ 83­ 2b) Carcinogenicity ­Mouse MRID 00107968 (1974)/ Although this study would not normally meet the guideline requirement for a carcinogenicity study (870.4300) in this species (i. e., study deficiencies included lack of dietary analyses and food consumption to ensure homogeneity, stability, and concentration of test material in the diet, and to assess potential palatability problems with the diet), confidence in the reported tumor data is enhanced by the findings of a subsequent 1982 special carcinogenicity study in male mice (MRID 00114114) that confirm the tumor findings. If reviewed in conjunction with the 1982 study, the present study is adequate to assess the carcinogenic potential of pronamide in mice and it can be used for regulatory and risk assessment purposes. ppm = 0, 1000, or 2000 mg/ kg/ day = 0, 150, or 300 NOAEL (males, females) = not established LOAEL = 1000 ppm (150 mg/ kg/ day) based upon decreases in body weight gain in high­ dose females and increases in relative (to body) weight of the liver in both sexes. Male and female B6C3F1 mice fed diets containing pronamide for 18 months showed a dose related increase in the incidence of hepatocellular carcinomas in male mice. Pronamide did not induce hepatocellular carcinomas in female mice. Under the conditions of this study, the dosing was considered to be adequate based upon decreases in body weight gain in high­ dose females and increases in relative (to body) weight of the liver in both sexes at doses greater than or equal to 1000 ppm. 870.4300 (§ 83­ 1/ 2a/ 5) Carcinogenicity ­Mouse (Males ) MRID 00114114, 00151822 (1982)/ This special carcinogenicity study in the male mouse is classified as AcceptableNonguideline The data confirmed the results of a previously conducted carcinogenicity study in mice (1974, MRID 00107968). When reviewed in conjunction with the 1974 carcinogenicity study, these two studies fulfill the guideline requirement for a carcinogenicity study [870.4200 (§ 83­ 2b)] in mice and can be used for regulatory and risk assessment purposes. ppm = 0, 20, 100, 500, or 2500 mg/ kg/ day = 0, 3, 15, 75, or 375 NOAEL (males) = 100 ppm (15 mg/ kg/ day) LOAEL = 500 ppm (75 mg/ kg/ day) based upon gross findings (increased incidences of hepatic nodules/ masses and hepatic enlargement) observed after 24 months of treatment. 870.5100 (§ 84­ 2) Gene Mutation/ In vitro mammalian cell assay in Chinese hamster ovary [CHO] cells MRID 40090601 (2/ 10/ 87)/ Unacceptable­ Guideline Fg/ plate = 1, 10, 100 and 500 Negative. Pronamide did not induce a mutagenic or genotoxic effect in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 at concentrations of 1, 10, 100 and 500 Fg/ plate ± S9 activation. TABLE 2. Subchronic, Chronic and Other Toxicity Profiles for Pronamide (Propyzamide Guideline No./ Study Type MRID No. (year)/ Classification/ Doses Results 16 870.5100 (§ 84­ 2) Gene Mutation in Salmonella typhimurium, Bacillus subtilis and Escherichia coli MRID 40090602 (8/ 10/ 78)/ Acceptable­ Guideline Escherichia. coli Fg/ plate = 10 ­ 5000 Bacillus subtilis Fg/ disk = 20 ­ 2000 Negative. Pronamide did not induce a mutagenic or genotoxic effect in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 or WP2 hcr of Escherichia coli at concentrations of 10­ 5000 Fg/ plate ± S9 activation. Pronamide did not induce DNA damage in Bacillus subtilis at concentrations of 20­ 2000 Fg/ disk. 870.5300 (§ 84­ 2) Gene Mutation/ In vitro mammalian cell assay in Chinese hamster V79 cells MRID 40211106 (10/ 29/ 84)/ Acceptable­ Guideline Fg/ ml = 2.5, 5, 10, 20 and 40 Negative. Pronamide did not induce a mutagenic effect in Chinese hamster V79 cells at [noncytotoxic] concentrations of 2.5, 5, 10, 20 and 40 Fg/ ml ± S9 activation following a 48, 96 or 168 hour incubation period. 870.5300 (§ 84­ 2) Gene Mutation/ In vitro mammalian cell assay in Chinese hamster ovary [CHO] cells MRID 40211108 (2/ 10/ 87)/ Acceptable­ Guideline Fg/ ml = 25, 50, 75, 100 and 150 Negative. Pronamide did not induce a mutagenic effect in Chinese hamster ovary cells at [noncytotoxic] concentrations of 25, 50, 75, 100 and 150 Fg/ ml ± S9 activation. 870.5385 (§ 84­ 2) Cytogenetics/ In vivo cytogenetics bone marrow assay in mice MRID 40211105 (10/ 31/ 84)/ Acceptable­ Guideline g/ kg = 0, 0.48, 1.94 or 4.94 Negative. Pronamide did not induce any structural chromosomal aberrations in bone marrow cells of male mice given doses of 0, 0.48, 1.94 or 4.94 g/ kg in either acute or subacute dosing regimens. 870.5900 (§ 84­ 2) Other Mutagenic Mechanisms/ In vitro Unscheduled DNA Synthesis in primary rat hepatocytes MRID 40211107 (2/ 11/ 87)/ Acceptable­ Guideline g/ ml = 1, 5, 10, 25 or 50 Negative. There was no evidence that Pronamide caused unscheduled DNA synthesis in primary rat hepatocytes at concentrations of 1, 5, 10, 25 or 50 g/ ml. TABLE 2. Subchronic, Chronic and Other Toxicity Profiles for Pronamide (Propyzamide Guideline No./ Study Type MRID No. (year)/ Classification/ Doses Results 17 870.7485 (§ 85­ 1) Metabolism and Phamacokinetics­ Rat MRID 41801801, 41929901 (2/ 21/ 91, 6/ 25/ 91)/ AcceptableGuideline single oral dose (2 or 100 mg/ kg) or multiple low doses (20 ppm a. i. in the diet for 14 days) followed by a low dose (2 mg/ kg) 14 Cpronamide Pronamide is rapidly absorbed and completely and rapidly eliminated. Over a 7 day period, most of the radioactivity administered was recovered (93­ 103%) in the urine (40­ 61%) and feces (40­ 60%). Only 0.08­ 0.21 and 0.83­ 2.43 percent of the administered dose were recovered in tissues and carcasses, respectively. No bioaccumulation was apparent; radioactivity recovered in all tissues were consistently highest at the first sampling time (8 hours post­ dose) then gradually declined to insignificant levels 7 days after dosing. Tissues with the highest radioactivity contents were, in decreasing order, the fat, adrenals, bone marrow, thyroids, liver, kidney, and plasma. Very little unchanged pronamide was recovered in urine. Of the twenty metabolites found, only thirteen (constituting 51.1% of the total radioactivity in urine) were clearly identified. The feces was not examined for metabolites. However, when these data (MRID 41801801, 41929901) are reviewed in conjunction with the characterization of the urinary and fecal metabolites of pronamide (MRID 42858001), the guideline requirement for a metabolism and pharmacokinetics study [OPPTS 870.7485 (§ 85­ 1)] is satisfied. 870.7485 (§ 85­ 1) Metabolism and Pharmacokinetics ­ Rat MRID 42858001 (7/ 15/ 93)/ Acceptable­ Guideline single oral dose (2 or 100 mg/ kg) or multiple low doses (20 ppm a. i. in the diet for 14 days) followed by a low dose (2 mg/ kg) 14 Cpronamide Urinary and fecal metabolites of pronamide were identified in male and female rats. No significant difference in urinary metabolite profile was observed between sex or dose. The major urinary metabolites were: 2­( 3,5­ dichlorophenyl)­ 4,4­ dimethyl­ 5­ carboxyoxazoline (metabolite SS47­ 70, 3.0­ 5.9% of the administered dose) and N­ carboxymethyl­ 3,5­ dichlorobenzamide (metabolite 10, 12.7­ 18.9% of the administered dose). In the urine, approximately 27 unidentified metabolites were found and none exceeded 3.3% of the dose. In contrast, significant differences in the fecal metabolite profile was observed between doses. Fecal excretion of parent ranged from 9.2­ 10.9% of the dose for the low dose and low repeated dose groups and 37.4­ 40.9% for the high dose group. In the feces, almost all of the unidentified metabolites are under 1% of the dose. The metabolic pathway( s) of the test compound have been postulated in rats. This study adequately describes the characterization of urinary and fecal metabolites of pronamide in rats following lowand high­ dose oral and repeated oral exposure. When these data (MRID 42858001) are reviewed in conjunction with previous metabolism studies (MRID 41801801, 41929901), the guideline requirement for a metabolism and pharmacokinetics study [OPPTS 870.7485 (§ 85­ 1)] is satisfied. TABLE 2. Subchronic, Chronic and Other Toxicity Profiles for Pronamide (Propyzamide Guideline No./ Study Type MRID No. (year)/ Classification/ Doses Results 18 870.7600 (§ 85­ 3) Dermal Penetration Rats Kerb 50W and 3.3F ­ formulations only MRID 40256701, 41117201 (4/ 14/ 87, 1/ 27/ 89) UnacceptableGuideline (not upgradeable) 0.08 and 4.4 mg/ cm 2 The dermal absorption rates per 6 hours were 19% and 17% for 50W and 15.1% and 5.4% for 3.3F. However, these data are based on a normalization of numerical values rather than the actual results obtained from the study. The actual doses applied to the skin were not determined and there were discrepancies in recovery for the 50W doses (78% and 122% of nominal doses). A default dermal absorption factor of 100% is used in this risk assessment. Non ­Guideline Thyroid Function and Hepatic Clearance of Thyroxine in Male Rats. This non­ guideline study was submitted to the Agency as an addendum to the chronic toxicity/ carcinogenicity study in rats (MRID 41714001, 41714002) MRID 42093401 (10/ 9/ 91)/ Acceptable­ Nonguideline ppm = 0, 40, 1000, or 4000 mg/ kg/ day = 0, 3, 67 or 279 Systemic and Thyroid Toxicity NOAEL = 40 ppm (3 mg/ kg/ day) LOAEL = 1000 ppm (67 mg/ kg/ day) based upon decreases in body weight and food consumption, increases in absolute and/ or relative weight of the liver and thyroid, an increase in serum TSH (at 4 weeks but not at 13 weeks), a decrease in serum T4, and an increase in incidences of thyroid and pituitary hypertrophy/ hyperplasia. Non­ Guideline Effects of Endocrine Regulation of the Testis in Rats Pilot Study MRID 42139601 (12/ 6/ 91)/ Acceptable­ Nonguideline ppm = 0, 40, 1000, or 4000 In the 13 week study, Pronamide treatment (4000 ppm) resulted in decreased body weight (weeks 1­ 13) and food consumption (weeks 1­ 8), increased serum LH and FSH (respective increases at 4 and 13 weeks were 60% and 58% for FSH, and 100% and 77% for LH), increased absolute and relative (to body) liver weight, increased microsomal protein content, increased oxidation of testosterone, increased activity of cytochrome­ P450 and ­B5, and NADPH­ cyochrome­ creductase increased gross pathology of the liver (enlarged/ dark), increased relative (to body) testicular weight, and increased testicular interstitial cell hyperplasia. In the 4­ week study, alterations in clinical chemistry parameters were noted only at 4000 ppm as increases in sreum LH and FSH. These effects were comparable with increases observed after 13 weeks. 3.2 FQPA Considerations On December 3, 2001, the FQPA Safety Factor Committee evaluated the hazard (See Section 5.0, Hazard Characterization and Dose Response Assessment Summary), endocrine (See Section 9.0, Endocrine Disruption) and exposure data for pronamide and made the recommendation for the FQPA safety factor to be used in human health risk assessments as required by Food Quality Protection Act of August 3, 1996. (Memorandum: C. Christensen, December 19, 2001). 19 Based on these available data, the FQPA SF Committee determined that the safety factor is necessary when assessing the risk posed by pronamide because: 1. There is evidence of endocrine effects (thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus) identified in the majority of studies conducted across species. A special study designed to assess thyroid function in adult animals and their offspring will be required. However, the Committee concluded that the FQPA safety factor could be reduced to 3x in assessing the risk posed by exposure to pronamide because: 1. The toxicological database is adequate for FQPA assessment; and, 2. There is no indication of quantitative or qualitative increased susceptibility of rabbits to in utero exposure or to rats following pre/ post­ natal exposure. Also, in the available, unacceptable rat study, no increased susceptibility was seen even though the animals could have tolerated higher doses. 3. A developmental neurotoxicity study is not required; and, 4. The dietary (food and drinking water) and residential exposure assessments will not underestimate the potential exposures for infants and children. The 3x FQPA safety factor for pronamide is applicable to all population subgroups when assessing dietary and residential exposure scenarios because of evidence of endocrine effects. The FQPA safety factor was not applied to the acute dietary endpoint because no appropriate endpoint was available to quantitate risk to either the general population or to females13­ 50 years of age from a single­ dose administration of pronamide. A MOE of 300 (10x for interspecies extrapolation, 10x for interspecies variation and a 3x FQPA safety factor) is required for short­ term, intermediate­ and long­ term incidental oral, dermal, and inhalation risk assessments. Therefore, short­ term, intermediate to long­ term risk estimates with a MOE $ 300 do not exceed the HED level of concern. 3.3 Hazard Endpoint Selection The strengths and weaknesses of the pronamide toxicology database were considered during the process of toxicity endpoint and dose selection. 20 Table 3. Summary of Toxicological Dose and Endpoints for Pronamide for Use in Human Risk Assessment 1 Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary females 13­ 50 years of age and the general population including infants and children No appropriate acute dietary endpoints were available to quantify risk to females 13­ 50 years of age or to the general population from a single­ dose administration of pronamide. The adverse effect observed in the rabbit developmental toxicity study, abortions, were not considered to occur after a single dose because they were observed in rabbits during the postdosing phase of the study (days 22­ 24). Therefore, no acute dietary endpoints were selected which represented toxicities from a single­ dose exposure. Chronic Dietary all populations NOAEL = 8.46 mg/ kg/ day UF = 100 Chronic RfD = 0.08 mg/ kg/ day FQPA SF = 3 cPAD = chronic RfD FQPA SF = 0.027 mg/ kg/ day Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat LOAEL = 42.59 mg/ kg/ day based on increased relative (to body) liver weight and non­ neoplastic histological changes in the liver, thyroid, and ovaries. Short­ Term Oral (1­ 30 days) (Residential) oral study NOAEL = 8.46 mg/ kg/ day LOC for MOE = 300 (Residential, includes the FQPA SF) Developmental Toxicity Study ­ Rabbit LOAEL = 20 mg/ kg/ day based on Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes). Intermediate­ Term Oral (1 ­ 6 months) (Residential) oral study NOAEL = 8.46 mg/ kg/ day LOC for MOE = 300 (Residential, includes the FQPA SF) Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat LOAEL = 42.59 mg/ kg/ day based on increased relative (to body) liver weight and non­ neoplastic histological changes in the liver, thyroid, and ovaries. Short­ Term Dermal (1­ 30 days) (Occupational/ Resi dential) oral study NOAEL = 8.46 mg/ kg/ day dermal absorption rate $ = 100% LOC for MOE = 300 (Residential, includes the FQPA SF) Developmental Toxicity Study ­ Rabbit LOAEL = 20 mg/ kg/ day based on Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes). IntermediateTerm Dermal (1­ 6 months) (Occupational/ Resi dential) oral study NOAEL = 8.46 mg/ kg/ day dermal absorption rate $ = 100% LOC for MOE = 300 (Residential, includes the FQPA SF) Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat LOAEL = 42.59 mg/ kg/ day based on increased relative (to body) liver weight and non­ neoplastic histological changes in the liver, thyroid, and ovaries. Long­ Term Dermal (6 months lifetime (Occupational/ Resi dential) oral study NOAEL = 8.46 mg/ kg/ day dermal absorption rate $ = 100% LOC for MOE = 300 (Residential, includes the FQPA SF) Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat LOAEL = 42.59 mg/ kg/ day based on increased relative (to body) liver weight and non­ neoplastic histological changes in the liver, thyroid, and ovaries. Table 3. Summary of Toxicological Dose and Endpoints for Pronamide for Use in Human Risk Assessment 1 Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects 21 Short­ Term Inhalation (1­ 30 days) (Occupational/ Resi dential) oral study NOAEL = 8.46 mg/ kg/ day inhalation absorption rate $ = 100% LOC for MOE = 300 (Residential, includes the FQPA SF) Developmental Toxicity Study ­ Rabbit LOAEL = 20 mg/ kg/ day based on Clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes). IntermediateTerm Inhalation (1­ 6 months) (Occupational/ Resi dential) oral study NOAEL = 8.46 mg/ kg/ day inhalation absorption rate $ = 100% LOC for MOE = 300 (Residential, includes the FQPA SF) Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat LOAEL = 42.59 mg/ kg/ day based on increased relative (to body) liver weight and non­ neoplastic histological changes in the liver, thyroid, and ovaries. Long­ Term Inhalation (6 months ­ lifetime) (Occupational/ Resi dential) oral study NOAEL = 8.46 mg/ kg/ day inhalation absorption rate $ = 100% LOC for MOE = 300 (Residential, includes the FQPA SF) Combined Chronic Toxicity/ Carcinogenicity Study ­ Rat LOAEL = 42.59 mg/ kg/ day based on increased relative (to body) liver weight and nonneoplastic histological changes in the liver, thyroid, and ovaries. Cancer (oral, dermal, inhalation) Group B2 ­ "Probable human carcinogen" Q1* = 2.59 x 10 ­ 2 (mg/ kg/ day) ­1 Cancer classification based on thyroid follicular cell adenomas (males and females) and benign interstitial cell tumors (males) in rats and hepatocellular carcinomas in mice (males). 1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic), RfD = reference dose, LOC = level of concern, MOE = margin of exposure, Q1* = the low­ dose linear extrapolation value used to express the risk to the human population for development of cancer following exposure to pesticide residues. " An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. $ Since an oral endpoint was selected, a dermal absorption factor of 100% (default value) and an inhalation absorption factor of 100% (default value) should be used in route­ to­ route extrapolation. Acute Dietary Risk Assessment: No appropriate acute dietary endpoints were available to quantify risk to females 13­ 50 years of age or to the general population from a single­ dose administration of pronamide. The adverse effect observed in the rabbit developmental toxicity study, abortions, were not considered to occur after a single dose because they were observed in rabbits during the postdosing phase of the study (days 22­ 24). Therefore, no acute dietary endpoints were selected which represented toxicities from a single­ dose exposure. Chronic Dietary Risk Assessment: A chronic reference dose (cRfD) of 0.08 mg/ kg/ day was determined on the basis of the two­ year chronic toxicity/ carcinogenicity study in rats and the application of an uncertainty factor of 100 (10x for inter­ species extrapolation and 10x for intra­ species variation). The 22 NOAEL in this study was 8.46 mg/ kg/ day and the LOAEL was 42.59 mg/ kg/ day based upon increased relative liver weight and the non­ neoplastic histologic changes in the liver (centrilobular hypertrophy and hepatocellular eosinophilic alteration in males and females), thyroid (follicular cell hypertrophy in males and females) and ovaries (sertoliform tubular hyperplasia in females). The 3x FQPA safety factor was applied for chronic dietary risk assessment because there is evidence of endocrine effects (thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus) identified in the majority of subchronic/ chronic studies conducted across species. The chronic population adjusted dose is the cRfD adjusted for the FQPA safety factor. Therefore, the chronic population adjusted dose (cPAD) is 0.027 mg/ kg/ day. Short­ Term Incidental Oral, Dermal and Inhalation Exposure Risk Assessments: An adjusted dose of 8.46 mg/ kg/ day was established for use in this risk assessment. This dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and the clinical signs (soiled anal area and anorexia) and liver effects (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. Although selection of this study for short­ term exposure scenarios is appropriate for the route (oral) and duration (13 days), the NOAEL of 5 mg/ kg/ day is lower than the NOAEL (8.46 mg/ kg/ day) established in the chronic toxicity/ carcinogenicity study in the rat. The apparent disparity between these NOAELs is driven by the doses of pronamide selected for testing in these studies. The HIARC concluded that using a more realistic NOAEL of 8.46 mg/ kg/ day rather than 5 mg/ kg/ day would provide a sufficiently protective dose for risk assessment. The 3x FQPA safety factor was also applied to these risk assessments because of the evidence of endocrine effects in the pronamide toxicity data base. Intermediate­ Term Incidental Oral, Dermal and Inhalation Exposure Risk Assessments: A NOAEL of 8.46 mg/ kg/ day was selected from the combined chronic toxicity/ carcinogenicity study conducted in the rat. This NOAEL is based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries which were observed at the LOAEL of 42.59 mg/ kg/ day. The HIARC determined that this study is appropriate for the (1­ 6 months) intermediate­ term exposure duration because (i) the organ toxicities (liver, thyroid, and ovaries) observed in the 24 month study occurred as early as 6 months and continued to study termination and (2) this NOAEL (8.46 mg/ kg/ day) is numerically close to the NOAEL of 12.3 mg/ kg/ day established in the 90­ day subchronic toxicity study conducted in the rat. Although the 90­ day subchronic study in rats demonstrated liver toxicities (increased absolute and relative liver weights and hepatocellular hypertrophy) at a LOAEL of 60 mg/ kg/ day, these effects were considered minimal. Therefore the developmental NOAEL 12.3 mg/ kg/ day is not recommended for this exposure scenario. The 3x FQPA safety factor is applicable because of the evidence of endocrine effects in the pronamide toxicity data base. Long­ Term Dermal and Inhalation Exposure Risk Assessments: The NOAEL of 8.46 mg/ kg/ day was also selected from the combined chronic toxicity/ carcinogenicity study in rats and is considered appropriate for these exposure scenarios. This NOAEL is based on increased relative liver weight and the non­ neoplastic histological changes in the liver, thyroid, and ovaries which were observed at the LOAEL of 42.59 mg/ kg/ day. The 3x FQPA safety factor is applicable because of the evidence of endocrine effects in the pronamide toxicity data base. Dermal and Inhalation Absorption: Since no dermal or inhalation toxicity studies were submitted, the selected endpoint is from an oral study of the appropriate duration of exposure and a 100% (default) absorption factor was applied to dermal and inhalation exposure routes. 23 Aggregating doses: For short­ term exposure, incidental oral, dermal, and inhalation routes can be aggregated because of the use of oral equivalents and a common endpoint (clinical signs of toxicity and liver effects). For intermediate­ term and long­ term exposure, incidental oral, dermal and inhalation routes can be aggregated because of oral equivalents and a common endpoint (increased relative liver weight and non­ neoplastic histologic changes in the liver, thyroid, and ovaries). 3.4 Endocrine Disruption Many chemicals belonging to the class of organochlorine chemicals are known to produce disruption of the endocrine system. Pronamide is an organochlorine herbicide which has been identified by the Agency's Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) as a potential endocrine disruptor. Evidence of endocrine effects from several guideline toxicity studies as well as two special studies submitted to the Agency by the Registrant include, in part: (i) histopathology of the thyroid gland, pituitary gland, adrenal glands, testes and ovaries, (ii) changes in hormone levels; decreased T4 and increased TSH, LH and FSH, and (iii) the induction of enzymes such as cytochromeP450 and ­B5, and NADPH­ cytochrome­ c­ reductase in addition to those enzymes involved in the oxidation of testosterone. On October 23, 2001, the Mechanism of Toxicity Assessment Review Committee (MTARC) reviewed the available toxicology data submitted in support of a proposed threshold mechanism for the induction of thyroid and testicular neoplasms resulting from exposure to pronamide. Although the results of these special endocrine studies conducted by the Registrant are suggestive of a pronamide­ induced thyroid and testicular neoplastic effect via disruption of the pituitary­ thyroid and pituitary­ testis hormonal balance, these data are far from conclusive. Based on the Committee's (MTARC) evaluation of the existing pronamide toxicology data base (Memorandum: M. Centra, January 21, 2001) and in the absence of any additional information, it was determined that the postulated threshold mechanism for the induction of thyroid and testicular neoplasms is not supported by the available data. Therefore, HED has recommended that additional studies be conducted with pronamide to determine its mechanism of endocrine toxicity. One such study, a comparative assay in the rat that is designed to assess thyroid function in adult animals and their offspring as well as potential central nervous system effects in the young, is required by the Agency because of the endocrine toxicities observed in various organ systems (thyroid gland, testes, ovaries, adrenal glands, pituitary gland) of rats and/ or dogs. The Agency is required under the Federal Food, Drug and Cosmetic Act (FFDCA), as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific bases for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). 24 When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, pronamide may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption. 4.0 EXPOSURE ASSESSMENT 4.1 Summary of Registered Uses Pronamide [3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide], or propyzamide, is a selective, systemic, pre­ and post­ emergence herbicide registered for use in agricultural, ornamental, and residential settings. There are two manufacturers of pronamide end­ use products with only two active section 3 registrations. There are also nine active Section 24C registrations. Approximately 225,000 lb of active ingredient are used domestically each year. Major food/ feed crops include: stone fruits (apricot, cherry, nectarine, peach, plum, prune), pome fruits (apple, pear), grapes, artichokes, berries (blackberry, blueberry, boysenberry, red raspberry, black raspberry), leafy greens (lettuce, endive, radicchio), winter peas, chicory, rhubarb, sugarbeets, and forages (alfalfa, clover, birdsfoot trefoil, crown vetch, sainfoin). Non­ agricultural uses include woody ornamentals, ornamental warm season grasses grown for turf (i. e. bermudagrass, zoysiagrass, St. Augustine, and centipedegrass) or seed (bermudagrass), residential/ recreational turf (bermudagrass lawns, playing fields, and golf courses), Christmas trees, grasses grown for seed, rangeland, and fallow land. In terms of pounds a. i., total usage is allocated mainly to head lettuce (29%), other lettuce (19%), seed crops (13%), fallowland (11%), hay other than alfalfa (8%), horticulture (3%) and alfalfa (3%). Rates per application and rates per year are each generally less than 2 pounds a. i. per acre for agricultural sites (based on the economic analysis by A. Holverson, September 26, 2001). Pronamide label rates range from 2 to 8 lbs ai per acre per year at 0.5 to 6 lbs ai per acre per application, with from one to four applications per year. Pronamide is formulated as a wettable powder and may be applied by ground or aerial spray, depending on the crop. States with significant usage in terms of pounds a. i. include Arizona, California, Oregon and Washington. Pre­ harvest intervals, where specified, are generally long, ranging from 25 to 180 days. There are several active Section 24C state labels. For risk assessment purposes the use sites and use patterns on these 24C labels are covered by EPA Reg. No. 707­ 159. 4.2 Dietary Exposure and Risk Assessment 4.2.1 Residues in Food Background Pronamide/ propyzamide [3, 5 dichloro­ n­( 1,1­ dimethyl­ 2­ propynyl) benzamide] tolerances are established under 40 CFR §180.317( a), (b), and (c). The tolerance expression, listed in (a) and (c), is in terms of "the combined residues of the herbicide propyzamide and its metabolites (containing the 3,5­ dichlorobenzoyl moiety and calculated as 3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide)." The 25 tolerance expression, listed in (b), is in terms of the parent only. Pronamide tolerances listed in 40 CFR §180.317( a) range from 0.02 ppm (for certain animal commodities) to 10.0 ppm (for a non­ grass animal feeds group). The time­ limited tolerances listed in 40 CFR §180.317( b), with an expiration date of 12/ 31/ 01, are for Section 18 emergency exemptions for pronamide uses on cranberries (0.05 ppm) and grasses (forage 1.0 ppm and hay 0.5 ppm). The tolerances listed in 40 CFR §180.317( c) are for regional registrations of pronamide on dried (winter) peas (0.05 ppm) and rhubarb (0.1 ppm). Residue Profile The qualitative nature of the residue in plants is adequately understood. The 4/ 16/ 93 Residue Chapter reported that studies with alfalfa and lettuce indicate that pronamide is readily absorbed by plants through the root system, translocated upward, and distributed into the entire plant. The degree of translocation from leaf absorption is not appreciable. Metabolism primarily occurs via conjugation to (malonyl) glucose. No evidence of fragmentation or loss of the chloro substituent of the aromatic ring was observed. The terminal residues of concern are pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety. For purposes of reregistration, no additional plant metabolism studies are required; however, because the available metabolism studies were only conducted on alfalfa and lettuce, the Agency may require additional metabolism studies in the future should the registrants seek for additional uses on other crop groups. The qualitative nature of the residue in animals is adequately understood. The 4/ 16/ 93 Residue Chapter reported studies involving lactating goats and laying hens indicate that the primary route of elimination is by excretion (urine and feces). Minimal residues were distributed to goat and poultry muscle. The major metabolites in the eggs, liver, and fat of poultry are pronamide and 3,5­ dichlorobenzoic acid. The major metabolites in the milk, fat, muscle, and liver of goats are pronamide, 3,5­ dichlorobenzoic acid, and compounds containing the 3,5­ dichlorobenzoyl moiety. The metabolic pathway involves modification of the aliphatic portion of pronamide. The terminal residues of concern are pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety. An adequate residue analytical method is available for plant and animal tolerance enforcement, a GLC/ ECD method listed in the Pesticide Analytical Manual (PAM) Volume II. Designated as Method I, it converts residues of pronamide and its metabolites to methyl 3,5­ dichlorobenzoate. The data­ collection method used in the analysis of samples, collected from a recently reviewed field rotational crop study, was a GLC/ ECD method entitled "An Improved Analytical Method for the Determination of Kerb Residues in Crops and Soil." The method was adequately validated by the registrant and is deemed adequate for data­ gathering purposes. This method should be validated by EPA in order to support the established and proposed tolerances for pronamide. Since the 1993 dietary chapter was published, the registrant has submitted independent laboratory validation for a revised animal method (TR 34­ 91­ 68). However, prior to Agency validation of Method TR 34­ 91­ 68, the registrant is required to further optimize/ improve the method to yield acceptable recoveries at higher fortification levels. Then, following method improvement, the registrant is required to submit bridging ILV data. Multiresidue method testing data for pronamide and a metabolite containing the 3,5­ dichlorobenzoyl moiety are also available (MRID434932­ 03); these data have been forwarded to FDA. 26 Plant product residue storage stability data were submitted but provided only indirect evidence that the precursors to the 3,5 dichlorobenzoyl moiety, are most likely stable. Additional confirmatory storage stability data for the regulated pronamide metabolites on alfalfa, apples, grapes, lettuce, and peaches or plums are required. Likewise, animal product storage stability data were submitted, but an analysis of metabolites containing the 3,5­ dichlorobenzoyl moiety was not included in the study. Additional confirmatory storage stability data for the regulated pronamide metabolites on milk are required. 4.2.2 Acute Dietary Risk from Food Sources As there was no toxicological endpoint selected for acute exposure, an acute dietary risk assessment was not performed. 4.2.3 Chronic and Cancer Dietary Risk from Food Sources A refined tier 3, chronic and cancer dietary exposure assessment has been performed for pronamide. The analysis is based primarily upon residue monitoring data for fruits and vegetables from the U. S. Department of Agriculture (USDA), Agricultural Marketing Service's Pesticide Data Program (PDP) and FDA data. Tolerance level residues were used for four registered crops (dried peas, endives, radicchio, and cranberries), and anticipated residues were calculated for meat, milk, poultry and eggs. The percent crop treated (% CT) data from OPP's Biological and Economic Assessment Division (BEAD) (September 26, 2001) were used to further refine the dietary exposure assessment. Pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety are the residues of concern and should be included in the assessment. The residues measured in field trials include the other metabolites by incorporation of a hydrolysis step. However, the PDP analyses measured only the parent compound; therefore, the method limit of detection (LOD) was used instead of 1/ 2 the LOD to account for metabolites of concern for the treated portion of those crops. No processing information was used in this assessment. DEEM™ default processing factors were used wherever they existed for processed food derived from the relevant crops. However, because residue data were available in the PDP database for grape juice, pear juice and apple juice, these PDP data were used directly, i. e. without DEEM default processing factors, for grape juice and grape wine, and for pear juice and apple juice. Factors for the juice concentrates were estimated from the ratio of the DEEM default factors for juice/ juice concentrate. The dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model (DEEM™) software Version 7.75, which incorporates consumption data from USDA's Continuing Surveys of Food Intake by Individuals (CSFII), 1989­ 1992. The 1989­ 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive days, and therefore represent more than 30,000 unique "person days" of data. Foods "as consumed" (e. g., apple pie) are linked to raw agricultural commodities and their food forms (e. g., apples­ cooked/ canned or wheat­ flour) by recipe translation files internal to the DEEM software. HED notes that there is a degree of uncertainty in extrapolating exposures for certain population subgroups from the general U. S. population which may not be sufficiently represented in the consumption surveys, (e. g., nursing and non­ nursing infants or Hispanic females). Therefore, risks estimated for these population subgroups are not reported explicitly but are included within larger 27 representative populations having sufficient numbers of survey respondents (e. g., all infants or females, 13­ 50 years). For chronic and cancer exposure and risk assessment, an estimate of the residue level in each food or food­ form (e. g., orange or orange­ juice) on the commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms on the commodity residue list to arrive at the total estimated exposure. Exposure estimates are expressed in mg/ kg body weight/ day and as a percent of the cPAD. This procedure is performed for each population subgroup. A summary of the pronamide chronic dietary risk estimates are shown in Table 4. The dietary cancer risk estimates are shown in Table 5. Table 4. Results of Chronic Dietary Exposure Analysis Population Subgroup cPAD 1 (mg/ kg/ day) Exposure (mg/ kg/ day) % cPAD U. S. Population (total) 0. 03 mg/ kg/ day 0. 000004 <1% All Infants (< 1 year) 0. 03 mg/ kg/ day 0. 000002 <1% Children 1­ 6 years 0. 03 mg/ kg/ day 0. 000005 <1% Children 7­ 12 years 0. 03 mg/ kg/ day 0. 000004 <1% Females 13­ 50 0.03 mg/ kg/ day 0. 000004 <1% Males 13­ 19 0.03 mg/ kg/ day 0. 000003 <1% Males 20+ years 0. 03 mg/ kg/ day 0. 000004 <1% Seniors 55+ 0.03 mg/ kg/ day 0. 000005 <1% cPAD 1 = Chronic PAD = Chronic Population Adjusted Dose = 0.03 mg/ kg/ day Table 5. Results of Dietary Cancer 1 Exposure Analysis Population Subgroup Exposure (mg/ kg/ day) Cancer Risk Estimate U. S. Population (total) 0. 000004 1.06 X 10 ­7 1 Q1 * = 0.0259 mg/ kg/ day ­1 Because the estimated exposure is well below the chronic and cancer levels of concern, and conservative assumptions were used, any uncertainties are unlikely to cause the exposure to exceed a level of concern. However, there are some conservative assumptions that may have introduced some uncertainties into this assessment. Tolerance level residues and 100 % CT was used for endives, dried peas, cranberries and radicchio. The LOD was used instead of ½LOD for the non­ detects in the PDP data. For the animals ARs the maximum percent crop treated was assumed instead of the average percent crop treated. Default DEEM processing factors were used for many processed foods. 28 4.3 Dietary Exposure from Water Sources 4.3.1. Environmental Fate According to the May 1994 Reregistration Eligibility Decision for pronamide, results from environmental fate studies indicate that pronamide is very persistent in soil and water with half­ lifes of many months. Pronamide is very stable in water and photolytically persistent in water and on soil. It is very persistent in soil under aerobic conditions, with an estimated half­ life of 13 months, and even more persistent under anaerobic conditions. Pronamide is persistent but relatively mobile in soil. Additionally, rotational crop studies show accumulation in several crop types at one, six and twelve months after application. For these reasons, residues of pronamide, per se, are the residues of concern in assessing drinking water exposures. 4.3.2 Drinking Water Exposure Estimates Although there is no legal requirement under the Safe Drinking Water Act to monitor for pronamide, it has been detected in surface and groundwater in various locations in the U. S. The maximum level detected was 0.365 ppb (surface water) at Zollner Creek near Mt. Abgel, OR on Nov. 16, 1998 and the range was 0.0037 to 0.365 (surface water) ppb or ug/ liter (USGS ­ NAWQA Data Retrieval). The maximum ground water detection at Benton Ozark, AK was 0.82 ppb on April 13, 1994, and ranging from 0.005 ­ 0.82 ppb (ground water). A Tier I Drinking Water Assessment for pronamide was calculated (L. Shanaman, 2001) using the SCIGROW model for groundwater concentration estimates. The Tier I groundwater estimates were predicted from application of pronamide at maximum label rate (2 lbs active ingredient per acre four times per year) for ornamental herbaceous plants, and represent upper­ bound estimates of the concentrations that might be found in groundwater due to the use of pronamide/ propyzamine. The resulting modeled groundwater screening concentration is 3.0 ppb. The Tier II PRZM­ EXAMS model (L. Shanaman, 2002) was used to predict EECs for pronamide in surface water, i. e., 90 th percentile average annual concentration values for use in chronic exposure assessments, and 36­ year mean concentration values for use in "cancer" exposure assessments. Maximum label application rates were used for major use crops. Chronic exposure values ranged from 1.5 to 6.4 ppb, and cancer average exposure values ranged from 0.535 to 4.3 ppb. Conservative inputs were used for the environmental (soil and water metabolism) assumptions, i. e., 2­ 3x uncertainty factors were applied to soil and water half­ lives used in the PRZM­ EXAMS assessment. 4.4 Residential Exposure 4.4.1 Residential/ Recreational Postapplication Exposure and Risk Pronamide is a restricted­ use herbicide, so the public/ consumers are prohibited from handling this chemical. Therefore only postapplication exposures were assessed. Earth Care, Division of United Industries Corp., (previously Pursell Industries) has requested voluntary cancellation of the product GREEN UP KERB 50W, EPA Reg. No. 8660­ 85, which is the only end use product label that allows professional application in a residential/ recreational setting. Pending 29 cancellation of this use, a residential/ recreational exposure assessment was conducted. The agricultural label (EPA Reg. No. 707­ 159) allows one application per year to grasses grown for turf for sod or seed. Based on the application rate, timing, and residue dissipation data, there are no concerns for residential/ recreational exposure to the treated turf from a sod farm. This label No. 8660­ 85 indicates a maximum application rate of 1.5 lb ai/ acre for pre­ emergence applications by lawn care operators (LCOs) to lawns, playing fields, and golf courses as a single application. The maximum application rate for post­ emergence applications is 1.0 lb ai/ acre. This residential label does not specify or restrict the number of applications allowed per year to turf. Applications to turf are only made in the late Fall or late Winter. For residential turf, HED assumed one application per year to estimate short­ term exposures. The scenarios assessed for the purpose of determining screening­ level risk estimates included adults and children (toddlers) performing high­ contact play or work activities on treated lawns, and adults mowing lawns or golfing (see Tables 6a, 6b, and 6c) . Small children (toddlers) were also assessed for incidental oral exposure from ingestion of soil, object­ to­ mouth activity (turfgrass mouthing), and hand­ to­ mouth activity while playing on treated lawns. Some of these exposures were combined, where it was deemed reasonably likely that activities would co­ occur. Residential risk estimates utilized data from a submitted turf transferable residue (TTR) study, as well as the EPA's original and revised Draft SOPs for Residential Exposure Assessment. 3, 5 For pronamide short­ term non­ occupational risks, HED has established a level of concern for MOEs < 300. Results from a recent turf transferable residue study on turf using pronamide (i. e. MRID 44952501) indicate that the half­ life of turf transferrable (TTR) residues was slightly less than two days. The residential label (EPA Reg. No. 8660­ 85) instructs applicators to lightly irrigate within a day of application if no rain occurs. Such irrigation occurred at 24 hours after application in the TTR study. Since the compound is soluble in water, and therefore mobile, it is likely the irrigation dissolves the compound and transports it from the turf into the soil. Study data showed that residues dissipate to below the level of quantification by day 14 following application. Therefore, only short­ term (i. e., one day to one month) exposures would be anticipated, since most of the pesticide should move into the soil, and any remaining foliar residues should dissipate within a month. While residues in soil could persist for greater than 30 days, it is unlikely that children will play on or contact soil for greater than 30 consecutive days during the winter months. Risk estimates based on residue data from the TTR study for short­ term dermal contact with treated turf during high contact lawn activities on day zero following application (DAT 0) exceed HED's level of concern, i. e. result in MOEs < 300 for adults (MOE = 71) and children (MOE = 42). However, using DAT 2 residue data from the TTR study yielded MOEs that do not exceed the level of concern (MOEs $ 300) for adults (MOE = 890) and children (MOE = 530) during high contact lawn activities. Note that the test plots were irrigated immediately after the DAT 1 samples were taken, i. e. 24 hours after application of pronamide, as specified on the label. Using DAT 2 residue data from the TTR study yielded MOEs that do not exceed the level of concern (MOEs $ 300) for adults (MOE = 890) and children (MOE = 530) during high contact lawn activities. The data show that thorough watering­ in the pronamide product clearly alleviates the risk concerns for dermal exposure. Risk estimates for shortterm dermal contact with residues on treated turf during the low contact activities of grass mowing or golfing on the day of treatment do not exceed the level of concern (MOEs $ 300) for adults (MOEs 2050 and 1025, respectively). 30 Based on the pesticide label, a typical residential/ recreational lawn application rate of 1.0 lb/ acre, with an application frequency of once per year, was assumed for the residential cancer risk assessment. Pronamide is applied in the dormant season, which reduces the number of contact days expected. A single exposure is deemed more likely, but up to 14 days exposure could occur based on the residue dissipation pattern. The 14­ day average turf residues from the TTR study (MRID 44952501) were used (i. e. 0.07913 µg/ cm 2 , when adjusted to a typical application rate of 1.0 lb ai/ acre); since residues in the TTR study dissipated to the level of quantitation by 14 days after application. The average residue, and an exposure frequency of one day per year, or 50 days in a lifetime, was assumed for high contact activities (e. g. playing and working on lawns and turf) and low contact activities (e. g. mowing or golfing). An adult mowing a treated lawn one day each year has a cancer risk of 5.7 x 10 ­8 . The average golfer plays 18 times per year, so one day's exposure is possible if pronamide is applied once per year on average. The adult golfer cancer risk is estimated at 1.2 x 10 ­7 . An adult performing dermal high contact activities on turf during the 2 week period of residue dissipation has a cancer risk of 8.4 x 10 ­7 . The HED endeavors to reduce estimated cancer risks for the general population to less than one in one million (10 ­6 ). In order to exceed the cancer risk (1.0 x 10 ­6 ), exposure frequencies of 17.5, 8.7 and 1.2 days per year would be needed for the activities of mowing, golfing and high contact work, respectively. Both the short­ term exposure estimates and the cancer risk estimate relied on a 100% dermal absorption factor, which results in a high­ end dose estimate. The short­ term dose selection from a developmental study is based on a weight­ of­ evidence evaluation of the entire pronamide database, but is considered protective of all populations. 31 Table 6a: Pronamide Residential Postapplication Activities on Treated Turf: Dermal Exposure and Non­ Cancer Risk Estimates Short­ term Risk Estimates at DAT 0 using TTR Data from Turf Study Short­ term Risk Estimates at DAT 2 using TTR Data from Turf Study Activity Transfer Coefficient (cm 2 /hr) (a) TTR µg/ cm 2 DAT 0 (b) Dermal Dose (mg/ kg/ day) (c) MOE (d) TTR µg/ cm 2 DAT 2 (b) Dermal Dose (mg/ kg/ day) (c) MOE (d) high contact lawn activities: adults 14,500 0.2886 0.1196 71 0.023 0.00953 890 high contact lawn activities: toddler 5,200 0.2886 0.2001 42 0.023 0.0159 530 mowing turf: adults 500 0.2886 0.00413 2100 0.023 0.000329 26,000 golf course reentry: adult 500 0.2886 0.00825 1000 0.023 0.000657 13,000 a Transfer coefficients from the Residential SOP's (02/ 01). b TTR Source: MRID # 44952501 turf transferable residue study ­ see study review for raw data and regression statistics. Mean observed residue values from DAT 0 through DAT 0.5 were used for the DAT 0 short­ term assessments. Mean observed residue values from DAT 2 were used for the DAT 2 short­ term assessments. c Dermal Dose = TTR (µg/ cm 2 ) x TC (cm 2 /hr) x conversion factor (1 mg/ 1,000 µg) x exposure time (2 hrs/ day playing & mowing; 4 hrs golfing) x Dermal Absorption Factor (100%/ 100)/ body weight (70 kg adult or 15 kg child 1­ 6 yrs). Short­ term MOEs were calculated using DAT 0 or DAT 2 values. d MOE = NOAEL (8. 46 mg/ kg/ day; based on an oral study) / dermal dose; Note: Target MOE is 300 or greater; numbers are rounded to two significant figures. Note: TTR = turf transferable residue DAT = days after treatment MOEs in bold exceed HEDs level of concern (i. e. MOEs < 300). 32 Table 6b: Pronamide Postapplication Dermal Cancer Risk Estimates for Activities on Treated Turf Activity Typical Application Rate (lb ai/ acre) (a) Days of Exposure per Year (b) 14­ day avg TTR, adjusted for "typical" rate (µg/ cm 2 ) (c) Transfer Coefficient (cm2/ hr) (d) Absorbed Dermal Daily Dose (mg/ kg/ day) (e) LADD (mg/ kg/ day) (f) Cancer Risk (g) Days of Exposure per Year to Exceed 1.0E­ 06 High­ contact activities 1. 0 1 0. 07913 7300 1.65E­ 02 3. 23E­ 05 8. 36E­ 07 1. 2 Mowing 1.0 1 0.07913 500 1.13E­ 03 2. 21E­ 06 5. 73E­ 08 17.5 Golfing 1. 0 1 0. 07913 500 2.26E­ 03 4. 42E­ 06 1. 15E­ 07 8. 7 a Typical (not maximum) application rates were used to adjust TTR study residue data; rate confirmed per label and registrants' comments. b Average or typical days per year for cancer risk estimates, based upon a single annual application and a fairly rapid foliar dissipation rate (half life of 1.8 days, from TTR study, i. e. MRID # 44952501). c TTR source: MRID # 44952501 turf transferable residue study ­ see residential exposure assessment for raw data and regression statistics. Mean observed residue values for DAT 0 through DAT 14 were used for the assessment. The study was conducted in NC using a maximum application rate of 1.5 lb ai/ acre. When assessing activities involving a different application rate than what was used in the study, the TTR values are adjusted proportionately to reflect the different application rate. For example, for the "typical" application rate of 1.0 lb ai/ acre : normalized (adjusted) TTR = Turf study TTR x 1.0 lb ai/ A assessed rate / 1.5 lb ai/ A study rate; 0.1187 µg/ cm 2 x 1.0 lb ai/ A assessed rate / 1.5 lb ai/ A study rate = 0.07913 µg/ cm 2 . d Transfer coefficient from the updated Residential SOP's (02/ 01). e Absorbed daily dose = Average day 0­ 14 TTR (µg/ cm 2 ) x intermediate­ term transfer coefficient (cm 2 /hr) x mg/ 1,000 µg x exposure duration (2 hrs/ day for playing/ gardening/ mowing; 4 hrs/ day to play golf) x dermal absorption factor (100%) / body weight (70 kg adult). f LADD = absorbed daily dose (mg/ kg/ day) x days of exposure/ year x 50 years of expected exposure/ (365 days/ year x 70 year lifetime); g Cancer Risk = LADD x Q 1 * , where Q 1 * = 2.59 x 10 ­2 (mg/ kg/ day) ­1 TTR used for cancer risk estimate = 0­ 14 DAT average residue normalized for typical application rate. TTR = turf transferable residue DAT = days after treatment 33 HED also assessed short­ term risks to small children from incidental oral ingestion of pronamide residues following application to residential lawns. The risk calculations for small children's nondietary ingestion of pronamide on treated turf indicate that risks do not exceed the level of concern (i. e. MOEs $ 300) for hand­ to­ mouth (MOE = 380), incidental ingestion of soil (MOE = 11,000), and incidental object to mouth (MOE = 1500). The small children's combined oral hand­ to­ mouth scenarios (MOE = 300) also do not exceed the level of concern. When risks from dermal exposures from pronamide to small children are combined with risks from incidental oral exposures, the combined short­ term risk estimates exceed the level of concern (MOEs < 300), with an MOE at 37. Note that the high­ contact dermal exposure is driving the overall risk. Also, the likelihood of all of the assessed incidental oral exposures co­ occuring with dermal exposures is low. Table 6c. Residential Oral Nondietary Short­ term Postapplication Risks to Children from "Hand­ to­ Mouth" and Ingestion Exposure When Reentering Lawns Treated with Pronamide Type of Exposure Short­ term Oral Dose a (mg/ kg/ day) Short­ term MOE b (1) Hand to Mouth Activity 0.0224 380 (2) Incidental Object to Mouth (Turfgrass Mouthing) 0.0056 1500 (3) Incidental Ingestion of Soil 7.51E­ 5 113,000 Combined Oral Nondietary c 0.028 300 Combined Oral and Dermal d ­­­ 37 a Application rate for the short­ term estimates represents maximum label rate from current EPA registered label: EPA Reg. No. 8660­ 85 wettable powder product formulation, max rate is 1.5 lb ai/ acre. Incidental oral doses were calculated using formulas presented in the Residential SOPs (updated 1999­ 2000). Short­­ term doses were calculated using the following formulas: (1) Hand­ to­ mouth oral dose to children on the day of treatment (mg/ kg/ day) = [application rate (lb ai/ acre) x fraction of residue dislodgeable from potentially wet hands (5%) x 11.2 (conversion factor to convert lb ai/ acre to µg/ cm 2 )] x median surface area for 1­ 3 fingers (20 cm 2 /event) x hand­ to­ mouth rate (20 events/ hour) x exposure time (2 hr/ day) x 0.001 mg/ : g] x 50% extraction by saliva / bw (15 kg child 1­ 6 yrs). This formula is based on proposed changes to the December 1999 Residential SOPs. (2) Turf mouthing oral dose to child on the day of treatment (mg/ kg/ day) = [application rate (lb ai/ acre) x fraction of residue dislodgeable for transfer to mouth (20%) x 11.2 (conversion factor to convert lb ai/ acre to µg/ cm 2 ) x ingestion rate of grass (25 cm 2 /day) x 0.001 mg/ : g] / bw (15 kg child 1­ 6 yrs). (3) Soil ingestion oral dose to child on the day of treatment (mg/ kg/ day) = [( application rate (lb ai/ acre) x fraction of residue retained on uppermost 1 cm of soil (100% or 1.0/ cm) x 4.54e+ 08 µg/ lb conversion factor x 2.47e­ 08 acre/ cm 2 conversion factor x 0.67 cm 3 /g soil conversion factor) x 100 mg/ day ingestion rate x 1.0e­ 06 g/ µg conversion factor] / bw (15 kg; child 1­ 6 yrs). Short term dose based residue on the soil on day of application. b Short­ term MOE = NOAEL (8.46 mg/ kg/ day) / Oral Dose (mg/ kg/ day). NOAEL from a non­ developmental toxicity study in rabbits; target MOE of 100. Numbers are rounded to two significant figures. c Combined MOEs = NOAEL / [sum of incidental oral doses], with a target MOE of 100. d Combined Dermal + Incidental Oral MOEs = 1/ [1/ MOEdermal + 1/ MOEoral ]; see Table 6a for dermal MOE for high­ contact short­ term activity for toddlers on turf (MOE = 42). MOEs in bold exceed HEDs level of concern (i. e. MOEs < 300). The exposure estimates generated for the residential/ recreational turf uses used the HED SOPs that are based on some upper­ percentile assumptions (i. e., duration of exposure and maximum application rate for short­ term assessments) and are considered to be representative of high end exposures. The 34 uncertainties associated with this assessment stem from the use of assumptions regarding the transfer of pronamide residues. The exposure estimates are believed to be reasonably high­ end estimates, since the maximum application rate is used, a 100% dermal absorption factor is assumed, and exposures are assumed to occur on the day of treatment. 4.4.2 Spray Drift Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from groundboom application methods. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off­ target drift and risks associated with aerial as well as other application types where appropriate. 5.0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION FQPA requires an aggregate risk assessment to be conducted considering all non­ occupational sources, including exposure from water, food, and residential use. Because there are potential exposures to treated turf, the aggregate exposure assessment for pronamide includes exposure estimates from residential sources as well as food and drinking water. HED has calculated drinking water levels of comparison (DWLOCs) for chronic exposure to pronamide in surface and groundwater which are presented in Tables 7a, 7b and 7c. DWLOCs were calculated using default body weights and drinking water consumption figures. Assumptions used in calculating the DWLOCs include 70 kg body weight for the U. S. population, 60 kg body weight for adult females, 10 kg body weight for children, two liters of water consumption per day for adults, and one liter consumption for children. Generally, risks from drinking water are assessed by comparing the DWLOCs to the estimated environmental concentrations (EECs) in surface water and groundwater. In the case of pronamide, there are monitoring data available for surface and ground water. The monitoring database used in the risk assessment is considered to be of good quality (USGS), but the data are not from sampling specifically targeted for pronamide use areas. These data have been compared to the model results to characterize the Tier I and Tier II estimates for the groundwater and surface water, respectively. As can be seen from that comparison, the monitoring data are typically at least 10­ fold lower than the model estimates. The USGS monitoring data are also lower than the short­ term and chronic DWLOC. However, the model estimates for Northwest pears and apples, and alfalfa grown in CA indicate that an extreme case using highest label rates might present a concern for cancer. Typical rates for the fruit are one­ half , and alfalfa is one­ quarter the rates used in the model, according to the latest QUA report. The model estimates would therefore be decreased proportionately for those crops if pronamide were applied 35 at the lower or more typical use rate. See Tables 7a, 7b, 7c. 5.1 Acute Risk Acute aggregate risk was not estimated as no acute toxicological endpoints were identified for pronamide. 5.2 Short­ Term Risk 5.2.1 Aggregate Short­ Term Risk Assessment Because the short­ term dermal postapplication exposure estimates for children exceeded the level of concern, an aggregate exposure estimate combining dermal exposure with food and drinking water intake was not conducted for that population. Adults engaged in high­ contact activities on newly treated turf also had dermal exposures which exceeded the level of concern. However, an aggregate short­ term exposure assessment was conducted for the low­ contact adult golfing exposure scenario. This shortterm risk estimate may be useful in risk management decisions. The short­ term aggregate exposure estimate which included the golfer dermal exposure did not exceed the level of concern (golfer MOE = 1000) . 5.2.2 Short­ Term DWLOC Calculations Since the drinking water calculations were based on modeling estimates, Drinking Water Levels of Comparison (DWLOCs) were calculated for short­ term exposure. The DWLOC is the concentration of a chemical in drinking water that would be acceptable as an upper limit in light of total aggregate exposure to that chemical from food, water, and (for short­ term estimate) non­ occupational (residential) sources. Comparisons are made between DWLOCs and the estimated concentrations of pronamide in surface water and ground water generated via PRZM/ EXAMS and SCI­ GROW, respectively. If the model estimate is less than the DWLOC, there is generally no drinking water concern. Monitoring data for pronamide in surface water had a maximum value from all samples and all years of 0.365 ppb, and 0.82 ppb for groundwater. Monitoring data ranged from 0.0037 to 0.365 ppb in surface water, and from 0.82 ­ 0.005 ppb in ground water. Results showed that for low­ contact adult activities, such as, mowing and golfing, modeled and measured concentrations of pronamide are considerably less than the DWLOCs (range 560 ­700 ppb) for all populations. Consequently, for these adult, low­ contact activities, there is no short­ term concern for drinking water from surface or groundwater sources. However, as noted above, short­ term postapplication dermal/ incidental oral exposures of children to pronamide on lawns after application result in risk estimates that exceed HED's levels of concern. Aggregating children's exposures through food, water, and residential uses results in risk estimates that further exceed levels of concern. 36 Table 7a. Short­ Term Aggregate Risk and DWLOC Calculations for Adult Low­ Contact Activities only Population Short­ Term Scenario NOAEL mg/ kg/ day Target MOE 1 Max Exposure 2 mg/ kg/ day Average Food Exposure mg/ kg/ day Residential Exposure 3 mg/ kg/ day Aggregate MOE (food and residential) 4 Max Water Exposure 5 mg/ kg/ day Ground Water EEC 6 (µg/ L) Surface Water EEC 6 (µg/ L) Short­ Term DWLOC 7 (µg/ L) Adult Male 8 8.46 300 0.0282 4 e­ 06 0.00825 1000 0.020 3 1. 6­ 6.5 700 Adult Female 4 e­ 06 0.0096 880 0.0186 560 Child 5 e­ 06 0.20 9 NA 9 0 0 Highest Exposed Adult Subpop 10 5 e­ 06 0.0096 880 0.0186 560 1 Based on 10x uncertainty for interspecies and 10x for intraspecies variation and 3x for FQPA for endocrine effects; body weights used are 70kg male, 60 kg female, 10 kg child) 2 Maximum Exposure (mg/ kg/ day) = NOAEL/ Target MOE 3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure] 4 Aggregate MOE = [NOAEL ÷ (Avg Food Exposure + Residential Exposure)] 5 Maximum Water Exposure (mg/ kg/ day) = Target Maxium Exposure ­ (Food Exposure + Residential Exposure) 6 The crop producing the highest level was used. 7 DWLOC( µg/ L) = [maximum water exposure (mg/ kg/ day) x body weight (kg)] ; where male bw = 70 kg; female bw= 60 kg; child 1­ 7 bw = 10 kg; [water consumption (L) x 10 ­3 mg/ µg] water consumption 2 L/ day (adults); 1 L/ day ( infants and children) 8 While the high­ contact dermal exposure estimate alone exceeds the level of concern, the lower­ contact exposure from golfing does not and was aggregated to illustrate the total risk for this non­ residential, recreational use scenario 9 NA = doses not aggregated, as the small child estimated hand­ mouth incidental oral exposure alone exceeds the level of concern 10 Exposure refers to the highest dietary exposure, in this case for female seniors. 5.3 Intermediate­ Term Risk Based on the label use pattern, including seasonal applications, and residue dissipation on turf in 14 days, no intermediate or long­ term residential non­ dietary exposures to pronamide are anticipated. An intermediate­ term risk assessment was not conducted as there were no exposures of applicable (30 days to six months) duration. 5.4 Chronic Risk 37 5.4.1 Chronic Aggregate Risk Assessment Due to the short­ term, intermittent nature of residential or recreational exposure to pronamide, only dietary and water intake were included in the chronic aggregate exposure estimate. The DWLOC chronic is the concentration in drinking water as a part of the aggregate chronic exposure that occupies no more than 100% of the chronic PAD when considered together with other sources of exposure. To calculate the DWLOC for chronic exposure relative to a chronic toxicity endpoint, the chronic dietary food exposure (from DEEM™) was subtracted from the chronic PAD to obtain the acceptable chronic exposure to pronamide in drinking water. The DWLOC was calculated and compared to the EECs. The EECs for average concentrations of pronamide were based on PRZM­ EXAMS for surface water and SCI­ GROW for groundwater. The chronic DWLOCs (300 ­ 1050 ug/ L) were greater than the EECs for modeled surface water (1.6­ 6.5 ug/ L), and modeled groundwater (3 ug/ L). In addition, non­ targeted USGS monitoring data ranged from 0.0037 to 0.365 ppb in surface water, and from 0.005 ­ 0.82 ppb in ground water. HED concludes the chronic aggregate risk estimates do not exceed the level of concern. 5.4.2 Chronic DWLOC Calculations Table 7b. Pronamide ­ Summary of Chronic DWLOC Calculations Population Subgroup cPAD (mg/ kg/ day) Food Exposure (mg/ kg/ day) Available Water Exposure (mg/ kg/ day) Chronic DWLOC (µg/ L) EFED Generated EECs 1 USGS SW / GW Monitoring 6 (µg/ L) Ground Water SCI GROW) (µg/ L) PRZM­ EXAMS Chronic (µg/ L) U. S. Population a 0.03 4 e­ 06 0.03 1050 3 1.6 ­ 6.5 SW: 0.0037 ­ 0.365 GW: 0.005 ­ 0.82 Females 13­ 50 yrs b 4 e­ 06 900 Children 1­ 6 yrs 25 e­ 06 300 All Infants 2 e­ 06 300 Chronic aggregate exposures represent only dietary and water consumption; no chronic non­ dietary exposures anticipated 1 EEC = Estimated Environmental Concentrations 2 Pronamide surface water EECs are from FIRST modeling . DWLOC = water exposure X body weight (where water exposure = cPAD ­ food exposure) Liters of water X 10 ­3 Body weight = 70 kg for U. S. Population, 60 kg for females, 10 kg for infants and children Consumption = 2L/ day for Adults and 1L/ day for infants and children 5 USGS ­ NAWQA Data Retrieval; Maximum ground water detection at Benton Ozark, AK at 0.82 ppb on April 13, 1994, data ranging form 0.82 ­ 0.005 ppb (ground 38 water). 5.5 Cancer Risk Estimates 5.5.1 Cancer Aggregate Risk Assessment The estimated cancer risk from one day per year of postapplication (high or low contact) exposure to average pronamide residues on treated turf did not exceed the Agency's level of concern of 1.0 x 10 ­6 (one in a million). High contact activities for more than one day would exceed the level of concern. Based on the seasonal use pattern, only one to several days postapplication exposure are considered likely, and it is unlikely that a single person would have have daily high contact exposure during the 14­ day dissipation period. The use of a 100 % dermal absorption factor adds to the conservatism of the cancer risk estimate. For average dietary consumption, the dose did not result in a cancer risk estimate of concern. Therefore the cancer estimates from each route can be aggregated. 5.5.2 Cancer DWLOC Calculations The estimated DWLOC for cancer from food, drinking water, and residential exposure is <0.1 ppb. The Tier 2 PRZM/ EXAMS 37 year mean concentration estimates range from less than 1 ppb to 4.3 ppb. The available USGS surface and groundwater monitoring data ranged from 0.0037 to 0.365 ppb in surface water, and from 0.82 ­ 0.005 ppb in ground water. Further refinement of the drinking water modeling estimates and/ or detailed analysis of water monitoring data might be useful for risk assessment and risk management decisions, once the final disposition of residential/ recreational uses is known.. 39 Table 7c. Cancer DWLOC Calculations USGS SW / GW Monitoring 6 (µg/ L) Population Target Max Exposure 2 mg/ kg/ day Chronic Food Exposure mg/ kg/ day Residential Exposure (LADD) mg/ kg/ day Aggregate cancer risk (food and residential) Max Water Exposure 3 mg/ kg/ day Cancer DWLOC 5 (µg/ L) Ground Water EEC 4 (µg/ L) PRZM EXAMS Cancer (µg/ L) U. S. Pop 3. 86 e­ 05 4 e­ 06 3.2 e­ 05 9.3 e­ 07 2.6 e­ 06 <0.1 3 0. 535 ­ 4.35 SW: 0.0037 ­ 0.365 GW: 0.005 0.82 1 EPA's goal is to mitigate cancer risk to 1 x 10 ­6 . 2 Target Maximum Exposure (mg/ kg/ day) = [negligible risk/ Q*] ; negligible risk = 1.0 e­ 06; Q 1 * = 0.0259 3 Maximum Water Exposure (mg/ kg/ day) = [Target Maximum Exposure ­ (Chronic Food Exposure + Residential Exposure (Lifetime Average Daily Dose))] 4 The crop producing the highest level was used. 5 Cancer DWLOC( µg/ L) = [maximum water exposure (mg/ kg/ day) x body weight (kg)] [water consumption (L) x 10 ­3 mg/ µg] 2 Body weight = 70 kg for U. S. Population Consumption = 2L/ day for Adults and 1L/ day for infants and children 6 USGS ­ NAWQA Data Retrieval; Maximum ground water detection at Benton Ozark, AK at 0.82 ppb on April 13, 1994, data ranging form 0.82 ­ 0.005 ppb (ground water). The estimated cancer risk from one day per year of postapplication (high or low contact) exposure to pronamide treated turf did not exceed the Agency's level of concern of 1.0 x 10 ­6 (one in a million). However, more than one day's exposure to treated turf while golfing could result in a cancer risk estimate greater than 1.0 x 10 ­6 . For average dietary consumption, the dose did not result in a cancer risk estimate of concern. However, when the golfing exposure is added to the chronic food exposure, the estimated DWLOC for cancer is <0.1 ppb, which is below most of the screening level drinking water concentrations estimated by EFED, and therefore exceeds the level of concern. Some of the surface and groundwater monitoring data are greater than the DWLOC, which generates a concern for cancer. Therefore, HED has some concerns for exposures to pronamide in drinking water for cancer risk. The model estimates for Northwest pears and apples, and alfalfa grown in CA indicate that an extreme case using highest label rates might present a concern for cancer. Typical rates for the fruit are one­ half , and alfalfa is one­ quarter the rates used in the model, according to the latest QUA report. The model estimates 40 would therefore be decreased proportionately for those crops if pronamide were applied at the lower or more typical use rate. The registrant for pronamide has requested cancellation of the turf use in a letter dated January 14, 2002. If the turf use is canceled, there will be no residential or recreational non­ dietary exposures, and the only remaining risk of concern will be the aggregate food and drinking water cancer estimate. Without residential/ recreational exposure, the cancer DWLOC will be 1.2 ppb. Additional monitoring data, targeted at water sources near pronamide high use sites, such as lettuce fields in Monterey County, CA, could help refine the cancer risk assessment. Uncertainties Aggregate risk estimates as conducted in this document are considered to be high­ end or conservative estimates, and can generally be refined, if necessary, with chemical­ specific data. The postapplication dermal risk estimates were based on the Office of Pesticide's Residential SOPs (1997, 2001), which utilize both central tendency and upper­ percentile assumptions (i. e., duration of exposure and maximum application rate for short­ term assessments) and are considered to be representative of high end exposures. The adult and children's transfer coefficients are based on the Jazzercise protocol and an upper percentile exposure duration value. Where study data were used with the SOP formulae, these risk estimates were better refined, and hence, less conservative. Therefore, the exposure estimates related to turf skin contact (which were based on study data) are more refined than the estimates of incidental ingestion In addition, dermal doses assumed a 100% dermal absorption factor, and exposures are assumed to occur on the day of treatment (highest residue). 6.0 CUMULATIVE EXPOSURE TO SUBSTANCES WITH A COMMON MECHANISM OF TOXICITY The Food Quality Protection Act (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non­ occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low­ level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. HED did not perform a cumulative risk assessment as part of this risk assessment for pronamide because HED has not yet initiated a review to determine if there are any other chemical substances that have a mechanism of toxicity common with that of pronamide. For purposes of this tolerance reassessment review, EPA has assumed that pronamide does not have a common mechanism of toxicity with other substances. 41 7.0 INCIDENT DATA A review of incident data sources found that relatively few incidents of pronamide poisonings were reported (J. Blondell, M. Spann, August 10, 2001). There are only two Poison Center reports, no incident reports in OPPs Incident Data System and only two reports from the California Pesticide Illness Surveillance Program. On the list of the top 200 chemicals for which National Pesticide Telecommunications Network (NPTN) received calls from 1984­ 1991 inclusively, pronamide was not reported to be involved in human incidents. 8.0 TOLERANCE REASSESSMENT RECOMMENDATIONS 8.1 Tolerance Reassessment Recommendation Pronamide tolerances are established under 40 CFR §180.317( a), (b), and (c). The tolerance expression, listed in (a) and (c), is in terms of the combined residues of the herbicide propyzamide and its metabolites (containing the 3,5­ dichlorobenzoyl moiety and calculated as 3,5­ dichloro­ N­( 1,1­ dimethyl2 propynyl) benzamide). The tolerance expression, listed in (b), is in terms of the parent only. HED recommends that the tolerance expression under (b) be modified to include the metabolites (containing the 3,5­ dichlorobenzoyl moiety and calculated as 3,5­ dichloro­ N­( 1,1­ dimethyl­ 2­ propynyl) benzamide). A summary of pronamide tolerance reassessments is presented in Table 8. For a full discussion of tolerances see the HED Residue Chemistry Chapter (J. Morales, February 28). Tolerances for inadvertent residues of pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety should be proposed for: (1) the forage of cereal grains crop at 0.6 ppm; (2) the straw of cereal grains crop at 0.3 ppm; and (3) the hay of cereal grains crop at 0.2 ppm. The required tolerance proposal is concomitant with a recommendation for a label revision to establish a 180­ day plantback interval for Crop Group 16. . Table 8. Tolerance Reassessment Summary for Pronamide Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity Definition Tolerances Listed Under 40 CFR §180.317( a) Apples 0.1 0. 1 Apple Artichokes 0. 1 0.051 Artichoke Blackberries 0.05 0.05 Blackberry Blueberries 0.05 0.05 Blueberry Boysenberries 0.05 0.05 Boysenberry Cattle, fat 0. 02 0. 20 Cattle, kidney 0. 4 0.4 Cattle, liver 0.4 0. 4 Cattle, mbyp (except kidney, liver) 0.02 0.02 Cattle, meat 0.02 0.02 Eggs 0.02 0.02 Table 8. Tolerance Reassessment Summary for Pronamide Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity Definition 42 Endive (escarole) 1.0 1. 0 Goats, fat 0. 02 0. 20 Goats, kidney 0. 4 0.4 Goats, liver 0.4 0. 4 Goats, mbyp (except kidney, liver) 0.02 0.02 Goats, meat 0.02 0.02 Grapes 0.1 0. 1 Grape Hogs, fat 0. 02 0. 20 Hogs, kidney 0. 4 0.4 Hogs, liver 0.4 0. 4 Hogs, mbyp (except kidney, liver) 0.02 0.02 Hogs, meat 0.02 0.02 Horses, fat 0. 02 0. 20 Horses, kidney 0. 4 0.4 Horses, liver 0.4 0. 4 Horses, mbyp (except kidney, liver) 0.02 0.02 Horses, meat 0.02 0.02 Lettuce 1.0 1. 0 Lettuce, head Only head lettuce is supported by acceptable data; leaf lettuce uses must be removed from the label. Alternatively, the label may be revised to specify a practical PHI (35­ day) for leaf lettuce and supporting data be submitted. Milk 0.02 0.02 Nongrass animal feeds 10.0 10.0 Nongrass animal feeds (forage, fodder, straw, and hay) group Pears 0. 1 0.1 Pear Poultry, fat 0. 02 0. 02 Poultry, kidney 0. 2 Revoke Tolerances are typically not established for poultry kidneys. Poultry, liver 0.2 0. 2 Poultry, mbyp (except kidney, liver) 0.02 0.02 Poultry, mbyp (except liver) Poultry, meat 0.02 0.02 Radicchio, greens (tops) 2. 0 2.0 Raspberries 0.05 0.05 Raspberry Sheep, fat 0. 02 0. 20 Sheep, kidney 0. 4 0.4 Sheep, liver 0.4 0. 4 Table 8. Tolerance Reassessment Summary for Pronamide Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity Definition 43 Sheep, mbyp (except kidney, liver) 0.02 0.02 Sheep, meat 0.02 0.02 Stone fruits 0.1 0. 1 Stone fruits group Tolerances To Be Proposed Under 40 CFR §180.317( a) Alfalfa, seed ­­ 10.0 Tolerance recommendation is contingent upon required label revision to specify a 50­ day PHI and a maximum seasonal rate of 2.0 lb ai/ A. Tolerances Listed Under 40 CFR §180.317( b) Cranberries 0.05 [with 12/ 31/ 01 expiration date] 0.05 Cranberry Grass, forage 1.0 [with 12/ 31/ 01 expiration date] 1.0 Additional data are required for the establishment of permanent tolerances on grass forage and hay. Grass, hay 0.5 [with 12/ 31/ 01 expiration date] 0.5 Tolerances Listed Under 40 CFR §180.317( c) Peas, dried (winter) 0.05 TBD Pea, field, seed Rhubarb 0.1 0. 1 Tolerances To Be Proposed Under 40 CFR §180.317( c) Pea, field, hay ­­ TBD Pea, field, vines – TBD CODEX HARMONIZATION No Codex MRLs have been established or proposed for residues of pronamide. Therefore, issues of compatibility with respect to U. S. tolerances and Codex MRLs do not exist. 9.0 DATA NEEDS Product Chemistry Most pertinent product chemistry data requirements are satisfied for the Rohm and Haas 94.6% T/ TGAI, except additional data are required concerning the materials used to produce the product and UV/ Visible absorption (OPPTS 830.1600 and 7050). Additional data are also required for the Rohm and Haas 51% FI concerning oxidation/ reduction, explodability, storage stability, and corrosion characteristics (OPPTS 830.6314, 6316, 6317, and 6320). Provided that the registrant submits the data required in the attached data summary tables for the pronamide T/ TGAI and FI, and either certifies that the suppliers of beginning materials and the manufacturing processes have not changed since the last comprehensive product chemistry reviews or submits complete updated product chemistry data packages, HED has no 44 objections to the reregistration of pronamide with respect to product chemistry data requirements. Toxicology Although there is confidence in the overall scientific quality of the available toxicity data, several data gaps were identified: a developmental toxicity study in rats, a 21­ day dermal toxicity study, 28­ day inhalation toxicity study, a dermal penetration study and a comparative thyroid rat assay in adult animals and offspring. Residue Chemistry A review of the product labels and the supporting residue data indicate the following label amendments and data submissions are required: C additional residue data are required for: use on grasses, dried winter peas (outstanding), the vines and hay of winter peas, grass forage, and hay. C label amendments are required for alfalfa grown for seed, lettuce, and peas (winter); see chemistry chapter for details; C label revisions should be made for rotational crops as listed: 1. 30­ day plantback interval for leafy vegetables (except Brassica vegetables) (Crop Group 4); 2. 90­ day plantback interval for root and tuber vegetables (Crop Group 1); 3. 360­ day plantback interval for cereal grains (Crop Group 15) and the forage, fodder, and straw of cereal grains (Crop Group 16). For purposes of reregistration, no additional plant metabolism studies are required; however, because the available metabolism studies were only conducted on alfalfa and lettuce, the Agency may require additional metabolism studies in the future should the registrants seek for additional uses on other crop groups. The registrant is required to further optimize/ improve the revised animal enforcement method (TR 34­ 91­ 68) to yield acceptable recoveries at a fortification level equal to established animal tolerances. Following method improvement, the registrant is required to submit bridging independent laboratory validation data; the required ILV data should include two control samples fortified at 0.4 ppm, the reassessed tolerance level for the kidney and liver of ruminants. Additional confirmatory storage stability data for the regulated pronamide metabolites on alfalfa, apples, grapes, lettuce, and peaches or plums are required.

epa

2024-06-07T20:31:42.743838

regulations

EPA-HQ-OPP-2002-0159-0011

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES July 5, 2002 CERTIFIED MAIL Dear Registrant: This is the Environmental Protection Agency's (hereafter referred to as EPA or the Agency) "Report of FQPA Tolerance Reassessment Progress and Interim Risk Management Decision" (TRED) for pronamide that was completed on July 5, 2002. A Notice of Availability, soliciting public comment for a 30 day period, will be published in the Federal Register (FR) shortly. The Federal Food Drug and Cosmetic Act (FFDCA), as amended, requires EPA to reassess all the tolerances for registered chemicals in effect on or before the date of the enactment of the Food Quality Protection Act (FQPA) in August of 1996 against the new safety standard adopted in the FQPA. In reassessing these tolerances, the Agency must consider, among other things, aggregate risks from non­ occupational sources of pesticide exposure, whether there is increased susceptibility to infants and children, and the cumulative effects of pesticides with a common mechanism of toxicity. The tolerances are considered reassessed once the safety finding has been made or a modification or revocation occurs. A reregistration eligibility decision (RED) for pronamide, was completed May 1994, prior to FQPA enactment. Therefore, it needed to be updated to reassess the tolerances under the FQPA standard. The Agency has evaluated the dietary risk associated with pronamide and has determined that, provided the risk mitigation measures outlined in this document are implemented, there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to pronamide when considering dietary exposure and all other non­ occupational sources of pesticide exposure for which there is reliable information. Therefore, the tolerances established for residues of pronamide in/ on raw agricultural commodities are now considered reassessed as safe under section 408( q) of the FFDCA. FQPA requires that EPA consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity." The reason for consideration of other substances is due to the possibility that lowlevel exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect, as would a higher level of exposure to any of the other substances individually. ­2­ EPA did not perform a cumulative risk assessment as part of this tolerance reassessment review of pronamide, because the Agency has not determined if there are any other chemical substances that have a mechanism of toxicity common with that of pronamide. If EPA identifies other substances that share a common mechanism of toxicity with pronamide, then a cumulative risk assessment will be conducted that includes pronamide once the final framework EPA will use for conducting cumulative risk assessments is available. Further, EPA is in the process of developing criteria for characterizing and testing endocrine disrupting chemicals and plans to implement an Endocrine Disruptor Screening Program. Pronamide will be reevaluated at that time and additional studies may be required. The Agency's human health findings for the pesticide pronamide, were discussed in a closure conference call held on June 28, 2002, and are summarized in the attached chemical overview of the risk assessments. These risk assessments and other documents pertaining to the pronamide tolerance reassessment decision are listed at the end of this document and are available on the Internet at http:// www. epa. gov/ pesticides/ reregistration/ status. htm and in the public docket for viewing. Pronamide tolerances are established under 40 CFR §180.317 (a), (b) and (c). The tolerance expression, listed in (a) and (c), is in terms of the combined residues of the herbicide propyzamide and its metabolites (containing the 3, 5­ dichlorobenzoyl moiety and calculated as 3, 5 dichloro­ N­ (1,1­ dimethyl­ 2­ propynyl) benzamide). The tolerance expression, listed in (b), is in terms of the parent only. The Agency recommends that the tolerance expression under (b) be modified to include the metabolites. The Agency also recommends the following: C Decreasing the established tolerance for artichokes; C Increasing the tolerances for cattle fat, goat fat, hog fat, horses fat, and sheep fat; C Revoking the tolerance for poultry kidney and grass, forage; and, C Proposing a tolerance for alfalfa seed and pea vines and hay. The Table below summarizes EPA's tolerance reassessment decision which accounts for 47 tolerance reassessments. The Codex Commission has established several maximum residue limits (MRLs) for residues of pronamide in/ on various raw agricultural and processed commodities. The Codex MRLs are expressed in terms of pronamide per se. The Codex MRLs and the U. S. tolerances will be incompatible when the U. S. tolerance expression for plant commodities is revised to include residues of pronamide and the metabolites. ­3­ Tolerance Reassessment Summary for Pronamide Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity definition Tolerances Listed Under 40 CFR §180.317( a) Apples 0.1 0. 1 Artichokes 0.1 0. 01 Residues of pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety were nondetectable (less than the level of concern (LOC) of 0.01ppm) in/ on each sample of artichokes harvested 61 days following a single application of a representative pronamide formulation at 4.0 or 8.0 lb ai/ A. Blackberries 0.05 0.05 Blueberries 0.05 0.05 Boysenberries 0.05 0.05 Cattle, fat 0.02 0.20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the Maximum theoretical dietary burdens (MTDB) Cattle, kidney 0. 4 0.4 Cattle, liver 0.4 0. 4 Cattle, mbyp (except kidney, liver) 0. 02 0. 02 Cattle, meat 0.02 0.02 Eggs 0.02 0.02 Endive (escarole) 1.0 1. 0 Goats, fat 0.02 0.20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the MTDB Goats, kidney 0.4 0. 4 Goats, liver 0.4 0. 4 Goats, mbyp (except kidney, liver) 0. 02 0. 02 Goats, meat 0.02 0.02 Grapes 0.1 0. 1 Hogs, fat 0. 02 0. 20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the MTDB Hogs, kidney 0. 4 0.4 Hogs, liver 0.4 0. 4 Hogs, mbyp (except kidney) 0.02 0.02 Hogs, meat 0.02 0.02 Horses, fat 0. 02 0. 20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the MTDB Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity definition ­4­ Horses, kidney 0. 4 0.4 Horses, liver 0.4 0. 4 Horses, mbyp (except kidney) 0.02 0.02 Horses, meat 0.02 0.02 Lettuce 1.0 1. 0 Lettuce Head Only head lettuce is supported by acceptable data; leaf lettuce uses must be removed from the label. Alternatively, the label may be revised to specify a practical PHI (35­ day) for leaf lettuce and supporting data be submitted. Milk 0.02 0.02 Non­ grass animal feeds 10.0 10.0 Non­ grass animal feeds (forage, fodder, straw, and hay) group Pears 0. 1 0.1 Poultry, fat 0. 02 0. 02 Poultry, kidney 0. 2 Revoke Tolerances are typically not established for poultry kidneys. Poultry, liver 0.2 0. 2 Poultry, mbyp (except kidney, liver) 0.02 0.02 Poultry, meat 0.02 0.02 Radicchio, greens (tops) 2. 0 2.0 Raspberries 0.05 0.05 Sheep, fat 0. 02 0. 20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the MTDB Sheep, kidney 0. 4 0.4 Sheep, liver 0.4 0. 4 Sheep, mbyp (except kidney, liver) 0.02 0.02 Sheep, meat 0.02 0.02 Stone fruit 0.1 0. 1 Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity definition ­5­ Tolerances To Be Proposed Under 40 CFR §180.317( a) Alfalfa Seed ­­ 10.0 Tolerance recommendation is contingent upon required label revision to specify a 50­ day PHI and a maximum seasonal rate of 2.0 lb ai/ A Tolerances Listed Under 40 CFR §180.317( b) Cranberries 0.05 ­­ Temporary tolerance associated with a FIFRA section 18 that will expire 12/ 31/ 03. Grass, forage 1.0 ­­ Tolerance expired 12// 31/ 01. Tolerances Listed Under 40 CFR §180.317( c) Peas, dried 0. 05 TBD Pea, field, seed. European data currently used to support tolerance. Registrant needs to submit field trial data as confirmatory data. Rhubarb 0.1 0. 1 Tolerances To Be Proposed Under 40 CFR §180.317( c) Pea, field, hay – TBD Pea, field vines – TBD *TBD= To Be Determined Risk Mitigation: As a result of risk concerns for children identified in the March 8, 2002 risk assessment, Dow AgroSciences agreed to voluntarily cancel all product labeled for residential use (EPA Reg. No. 8660­ 85; see 67 FR 13627). Additionally, in order to further address this risk concern and minimize the likelihood of non­ dietary exposure to children, the following label statement must appear on Pronamide end­ use products: "This product may only be used on turf grown for seed or sod or on nonresidential sites including golf course, industrial and office building sites, stadium fields or professional athletic fields." To minimize adult non­ occupational exposure, the following label statement must appear on Pronamide end­ use products: "For all uses except those specified below, do not enter or allow others to enter until sprays have dried. When applied to stadium or professional athletic fields, water­ in immediately after application or, do not enter or allow others to enter treated area for 24­ hours after application. If product is watered­ in after treatment, do not enter or allow other persons to enter until area had dried" ­6­ The risk assessment also identified a slight cancer risk due to pronamide exposure in drinking water from surface water sources (EECs are 4.3 ppb compared to the cancer DWLOC of 1.1 ppb). However, the Agency is not concerned because of the conservative inputs used in the surface water modeling. The PRZM­ EXAMS assessment was based on the maximum label rates for pronamide, whereas typical rates for many crops are 25%­ 50% less. The model also assumed a Percent Crop Area (PCA) of 87%, which is likely to be an overestimate for the crops being considered. In addition, pronamide data exists for only one soil in the aerobic soil metabolism study. When aerobic soil metabolism data is only available in one soil, a conservative extrapolation factor is used which is likely to contribute to over­ estimating potential persistence and exposure. As a result, Dow AgroSciences has agreed to conduct an aerobic soil metabolism study (two additional soils) and an aerobic aquatic metabolism study as confirmatory data. The Agency will be issuing a generic Data Call­ In (DCI) that outlines further data requirements for this chemical. The following additional data are required for pronamide. The registrants of pronamide must respond within 90 days of receipt of this letter from the Agency. Most pertinent product chemistry data requirements are satisfied for technical grade active ingredients. The following is required: ° Product Chemistry GDLN Description 860.1200 Direction for use 860.1380 Storage Stability Data Additional data are also required for the 51% Formulation Intermediate (FI) concerning the following: GDLN Description 830.6314 oxidation/ reduction 830.6316 explodability 830.6317 storage stability 830.6320 corrosion characteristics The registrant must either certify that the supplier of beginning materials and the manufacturing processes have not changed since the last comprehensive product chemistry reviews or submit complete updated product chemistry data packages. ­7­ Although there is confidence in the overall scientific quality of the available toxicity data, several data gaps were identified which are required to fulfill the OPPTS harmonized test guidelines: ° Toxicity GDLN Description 870.3700 developmental study in rats Non GDLN comparative thyroid rat assay in adult animals and offspring 870.3200 21­ day dermal toxicity study Non GDLN 28­ day inhalation study 870.7600 dermal penetration study A review of registered uses and the supporting residue chemistry data indicates the following residue data are required: ° Residue (GDLN 860.1500 Crop Field Trials) dried winter peas vines and hay of winter peas Confirmatory storage stability data (GDLN 860.1380) are required for regulated pronamide metabolites on the following: alfalfa apples grapes lettuce peaches plums A confirmatory aerobic soil metabolism study (835.4100) and an aerobic aquatic metabolism study (835.4300) are required. The registrant is required to further optimize/ improve the revised animal enforcement method (TR 34­ 91­ 68) to yield acceptable recoveries at a fortification level equal to established animal tolerances. Following method improvement, the registrant is required to submit bridging independent laboratory validation (ILV) data; the required ILV data should include two control samples fortified at 0.4 ppm, the reassessed tolerance level for the kidney and liver of ruminants. ­8­ The following label amendments are required for lettuce, peas, and alfalfa grown for seed: GDLN Description 860.1850 Confined Accumulation in Rotational Crops 860.1900 Field Accumulation in Rotational Crops ° 30­ day plant­ back interval for leafy vegetables (except Brassica vegetables) ° 90­ day plant­ back interval for root and tuber vegetables ° 360­ day plant­ back interval for cereal grains, forage and fodder, and straw of cereal grain If you have questions on this document, please contact the Chemical Review Manager, Cecelia Watson, at (703) 305­ 4329. For questions regarding label changes and registration action, please contact Jim Tompkins of the Registration Division at (703) 305­ 5697. Sincerely, Lois A. Rossi, Director Special Review and Reregistration Division Enclosures: C Overview and Summary of Pronamide (Propyzamide) Risk Assessment C Hazard Identification Assessment Review Committee (HIARC) report (M. Centra, December 10, 2001) C Report of the FQPA Safety Factor Committee (C. Christensen, December 19, 2001) C Toxicology Chapter of the Tolerance Reassessment Eligibility Decision (TRED) (M. Centra, March 7, 2002) C Report of the Mechanism of Toxicity Assessment Review Committee (MTARC) (M. Centra, January 21, 2001) C Review of Pronamide Incident Reports ( J. Blondell & M.. Spann, August 12, 2001) C Chronic and Cancer Dietary Exposure Assessments (D. Soderberg, et al., February 7, 2002) C Pronamide Residue Chemistry chapter (J. Morales, February 28, 2002) C Residential Risk Assessment, (B. O'Keefe, March 7, 2002) C Drinking Water Assessment to Support TRED for Propyzamide (Pronamide) (L. Shanaman, May 16, 2001) C Addendum to EPA March 8, 2002: Pronamide. Tolerance Reassessment Eligibility Decision (TRED). (G. Bangs May 21, 2002) C Tier II Water Assessment to Support TRED for Pronamide (Propyzamide) (L. Shanaman, May 31, 2002).

epa

2024-06-07T20:31:42.761689

regulations

EPA-HQ-OPP-2002-0159-0012

Supporting & Related Material

OVERVIEW OF PRONAMIDE (Propyzamide) RISK ASSESSMENT Introduction The Agency has completed its review of the available data for the herbicide pronamide and is announcing its tolerance reassessment decision. This document summarizes EPA's human health findings and conclusions as presented fully in the documents entitled "Pronamide Tolerance Reassessment Eligibility Decision (TRED)" dated March 8, 2002, "Pronamide Revised Aggregate Risk Estimates Addendum to EPA March 8, 2002" dated May 21, 2002 and related documents supporting this decision. The purpose of this overview is to assist the reader by identifying the key features and findings of the risk assessment in order to enhance understanding of the conclusions reached in the tolerance reassessment decision. The Agency's reassessment of aggregate risk, including exposure through food, drinking water, and residential exposure is required by the Federal Food, Drug, and Cosmetic Act (FFDCA). The Agency must review tolerances and tolerance exemptions that were in effect when the Food Quality Protection Act (FQPA) was enacted in August 1996 to ensure that these existing pesticide residue limits for food and feed commodities meet the safety standard of the new law. FFDCA requires the Agency to review all the tolerances for registered chemicals in effect on or before the date of the enactment of FQPA. In reviewing these tolerances, the Agency must consider, among other things, aggregate risks from non­ occupational sources of pesticide exposure, whether there is increased susceptibility to infants and children, and the cumulative effects of pesticides with a common mechanism of toxicity. The tolerances are considered reassessed once the safety finding has been made or a tolerance revocation occurs. A RED for pronamide was issued in May 1994, prior to enactment of FQPA; therefore it needed to be updated to consider the provisions of the Act. FQPA requires that the Agency, when considering whether to establish, modify, or revoke a tolerance, consider "available information" concerning the cumulative effects of the particular pesticide's residues and "other substances that have a common mechanism of toxicity." The Agency does not, at this time, have sufficient reliable information available to determine whether pronamide has a common mechanism of toxicity with other substances. Therefore, for the purposes of this risk assessment, the Agency has not assumed that pronamide has a common mechanism of toxicity with other substances. If EPA identifies other substances that share a common mechanism of toxicity with pronamide, a cumulative risk assessment for those substances will be performed. The risk assessment and documents pertaining to the Agency's report on FQPA tolerance reassessment progress and risk management decision for pronamide are available on the Internet at http:// www. epa. gov/ pesticides/ reregistration/ status. htm and in the public docket. The Agency's report on FQPA tolerance reassessment progress and risk management decision for pronamide will be announced in the Federal Register. ­2­ Use Profile Herbicide: Pronamide is a selective, pre­ emergence herbicide registered for the control of grassy and broadleaf weeds on terrestrial food crops [artichoke, blackberry, blueberry, boysenberry, cherry, endive (escarole), lettuce, nectarine, peach, pear, plum, prune, raspberry, (black, red), rhubarb]; terrestrial food and feed crops (agricultural fallow/ idleland, apples, grapes, peas, sugar beets); terrestrial non­ food crops (Christmas trees, clover plantations, golf course turf, ornamental herbaceous plants, recreation area lawns) and outdoor residential areas (ornamental and/ or shade trees, ornamental woody shrubs and vines). Formulations: Wettable powder 50% and 51% active ingredient (a. i.) and technical grade 92% a. i. Methods and Rates of Application: Pronamide is produced and formulated for use as a 50 WP wettable powder which is packaged in water soluble pouches and then mixed in water before application. Pronamide is applied as a liquid spray. It is a soil active systemic herbicide with uptake by susceptible weeds occurring through the roots. Application rates range from 0.5 to 4 lbs a. i. per acre per application per year. Most crop sites have only one application per year. However, artichokes have 2 applications per year (at 2 lbs per application) and gladiolas have 4 applications per year (at 2 lbs per application, up to 8 lbs a. i. per acre per application could be applied). It is applied to various food/ feed crops using ground spray equipment, by hand­ held sprayer, soil incorporation, or by aircraft. Use Summary: Based on available pesticide usage data for 1991 through 2001, total annual domestic usage of pronamide is approximately 225,000 pounds. In terms of pounds a. i., total usage is allocated mainly to head lettuce (29%), other lettuce (19%), seed crops (13%), fallow land (11%), hay (other than alfalfa) (8%), horticulture (3%) and alfalfa (3%). Sites with 5% or more of acreage treated include lettuce (other than head) (49%), head lettuce (36%), California endive/ escarole (31%), artichokes (21%), blackberries (6%) and raspberries (5%). States with significant usage in terms of pound a. i. include Arizona, California, Oregon and Washington. Pre­ harvest intervals, where specified, are generally long, ranging from 25 to 180 days. Classification: Pronamide is a restricted use pesticide. Registrant: Dow AgroSciences (recently purchased from Rohm and Haas). ­3­ Human Health Risk Assessment Acute Dietary (Food) Risk (For a complete discussion, see section 4.2 of the Human Health Risk Assessment) No toxicologic endpoint was identified as appropriate from a single (acute) dose of pronamide. Consequently an acute dietary risk assessment was not performed for pronamide. Chronic Dietary (Food) Risk (For a complete discussion, see section 4.2 of the Human Health Risk Assessment Chronic dietary risk is calculated by using the average consumption value for food and average residue values on those foods over a 70­ year lifetime. A risk estimate that is less than 100% of the chronic population adjusted dose (cPAD) (the dose at which an individual could be exposed over the course of a lifetime and no adverse health effects would be expected) is not of concern. The cPAD is the chronic reference dose (cRfD) adjusted for the FQPA Safety Factor. The assessment showed that the chronic dietary risk estimates are not of concern, <1% of the cPAD, for the U. S. population and for all subgroups. ° The toxicity endpoint for the chronic dietary assessment is based on increased relative liver weight and non­ neoplastic histological changes in the liver, thyroid, and ovaries in a combined chronic toxicity/ carcinogenicity study in the rat. The no observable adverse effect level (NOAEL) is 8.46 mg/ kg/ day. The lowest observed adverse effect level (LOAEL) is 42.6 mg/ kg/ day. ° The Uncertainty Factor (UF) is 100X; 10X for intraspecies variation and 10X for interspecies extrapolation. ° The 10x FQPA Safety Factor was reduced to 3x for the following reasons: 1. The toxicological database is adequate for FQPA assessment. 2. There was no quantitative or qualitative evidence of increased susceptibility of rabbits to in utero exposure or to rats following pre/ postnatal exposure. Although the developmental toxicity study, was unacceptable because a definitive NOAEL as well as a LOAEL were not established, no increased susceptibility was seen at the highest dose tested. 3. A developmental neurotoxicity study is not required. 4. The dietary (food and drinking water) and residential exposure assessments will not underestimate the potential exposures for infants and children. 5. A 3x was retained because of evidence of endocrine organ toxicity in the thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus. ­4­ For a more complete discussion see the December 3, 2001 FQPA Safety Factor Committee report and section 5.6 of the Pronamide (Propyzamide): Report of the Hazard Identification Assessment Review Committee (HIARC) Meeting for the Herbicide, Pronamide. ° The Dietary Exposure Evaluation Model (DEEM) was used to estimate chronic dietary exposure. A refined Tier 3 analysis was performed using: 1) percent crop treated; 2) anticipated residues for meat, milk, poultry and eggs; 3) FDA and PDP monitoring data; and, 4) tolerance level residues for 4 crops. ° The cPAD is 0.03 mg/ kg/ day (chronic RfD 0.08 mg/ kg/ day ÷ 3x FQPA safety factor). Cancer Dietary Risk (Food) (For a complete discussion, see section 4.2 of the Human Health Risk Assessment) The cancer risk is calculated by using the average consumption value for food and average residue values on those foods over a 70­ year lifetime. The chronic exposure value is typically combined with a linear, low­ dose approach (Q1 ( ) to determine the lifetime (cancer) risk estimate. The Agency generally considers risks greater than 1x10 ­6 (i. e., greater than one in a million) not of concern. ° Pronamide was previously classified as a Group B2 chemical, probable human carcinogen, based on thyroid follicular cell adenomas (males and females) and benign testicular interstitial cell tumors (males) in rats and hepatocellular carcinomas in male mice. ° A linear, low dose approach (Q1 ( ) is used for human risk characterization. The cancer potency unit risk (Q1 ( ) based on male mouse liver adenoma and/ or carcinoma combined tumor rates is 2.59x10 ­2 (mg/ kg/ day) ­1 in human equivalents [converted from animals to humans by use of the (mg/ kg body weight) ¾ interspecies scaling factor]. ° The cancer food risk estimate is 1.06x10 ­7 for the U. S. population, and does not exceed the Agency's level of concern (1.0x10 ­6 or one in one million). Residential Risk (For a complete discussion, see section 4.4 of the Human Health Risk Assessment) As a result of risk concerns for children identified in the March 8, 2002 risk assessment, the registrant agreed to voluntarily cancel a product labeled for the residential use (EPA Reg. No. 8660­ 85; see 67 FR 13627). Additionally, the registrant agreed to further limit use to turf grown for seed or sod and non­ residential sites including golf courses, industrial and office building sites, stadium fields or professional athletic fields. These risk mitigation measures ­5­ make children's non­ dietary exposure unlikely. To minimize adult residential exposure related to the sites listed above, the registrant has agreed to amend pronamide labels to require 24 hour restricted entry interval or require watering­ in as soon as possible after application. Given these proposed restrictions on the use of pronamide on turf, high contact dermal scenarios are not likely to occur. Therefore, the sole exposure scenario for the residential risk assessment is based on low contact activity which is represented and estimated by golf course reentry. The route of exposure is dermal. The population at risk is adults. The dermal exposure estimates are considered somewhat refined, since turf transferrable residue (TTR) data from a pronamide TTR field study was used. However, both the short­ term exposure estimates and the cancer risk estimates relied on a 100% dermal absorption factor, which results in high­ end dose estimates. Therefore, a dermal absorption study would help to reduce these risk estimates. A 3x FQPA Safety Factor is required for all population subgroups when assessing residential exposures of all durations. The rationale for reducing the safety factor is the same as listed under the chronic dietary risk discussion. Short­ Term C For short term (1­ 30) incidental oral exposures an adjusted dose of 8.46 mg/ kg/ day was established for use in the risk assessment. This dose is derived from the NOAEL from a chronic toxicity/ carcinogenicity study in rats, where the effects are increased liver weight and non­ neoplastic histologic changes in the liver, thyroid, and ovaries observed at the LOAEL of 42.6 mg/ kg/ day. The dose selection is based on a maternal toxicity NOAEL of 5 mg/ kg/ day and clinical signs of toxicity (soiled anal area and anorexia) and liver effect (punctate vacuolation of hepatocytes) observed at the LOAEL of 20 mg/ kg/ day in the developmental toxicity study conducted in rabbits. Although this study is of the appropriate route (oral) and duration (13 days), the NOAEL (5 mg/ kg/ day) in this study is lower than the NOAEL (8.46 mg/ kg/ day) established in the chronic toxicity/ carcinogenicity study in the rat. The apparent disparity between these NOAELs is driven by the doses of pronamide selected for testing in these studies. The Agency concluded that using a more realistic NOAEL of 8.46 mg/ kg/ day, rather than 5 mg/ kg/ day, would provide a sufficiently protective dose for risk assessment. ° The short­ term dermal endpoint has a 10x UF for intraspecies variability and 10x UF for interspecies extrapolation. When considering the FQPA Safety Factor of 3x, MOEs must be $ 300 to be above the Agency's level of concern. ° The short­ term exposure estimates are considered high­ end estimates, since the maximum application rate is used, a 100% dermal absorption factor is assumed and exposures are assumed to occur on the day of treatment. ° The exposure scenario is based on low contact activity golf course reentry. The route of exposure is dermal. The population at risk are adults. ­6­ ° The short­ term Margin of Exposure (MOE) for golf course reentry using zero day after treatment (DAT 0) turf transferable residue data from the turf study is 1000. Therefore, the Agency is not concerned about short term residential exposure to pronamide. Intermediate­ Term No intermediate or long term exposure scenarios (i. e., greater than 30 days) are anticipated based on the results of the turf transferable residue (TTR) study which showed that residues dissipate to below the level of quantification by day 14 following application. Cancer­ Risk ° As stated previously, pronamide is classified as a Group B2 chemical, probable human carcinogen with inadequate evidence in humans. ° The cancer potency (Q1*) is 2.59 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents. ° The adult golfer cancer risk is estimated at 1.15 x 10 ­7 . In order to exceed the cancer risk (1.0 x 10 ­6 ), an exposure frequency of 8.7 days per year would be needed for the activity of golf. Because pronamide is applied one time per year, the Agency does not believe this exposure frequency will occur. Therefore, the cancer risk for golfers does not exceed the Agency's level of concern. Drinking Water Dietary Risk (For a complete discussion, see section 4.3 of the Human Health Risk Assessment) Drinking water exposure to pesticides can occur through groundwater and surface water contamination. EPA considers both acute (one day) and chronic (lifetime) drinking water risks and uses either modeling or actual monitoring data, if available, to estimate those risks. ° A Tier I Drinking Water Assessment for pronamide was conducted using the SCI­ GROW model for groundwater. The Tier I groundwater estimates were predicted from application of pronamide at the maximum label rate (2 lbs active ingredient per acre four times per year) for ornamental herbaceous plants, and represent upper­ bound estimates of the concentrations that might be found in groundwater due to the use of pronamide/ propyzamide. The resulting modeled groundwater screening concentration is 1.1 ppb. ° The Tier II PRZM­ EXAMS model was used to predict EECs for pronamide in surface water. Conservative inputs were used for the environmental (soil and water metabolism) assumptions, (i. e., 2x and 3x extrapolation factors were applied to soil and water halflives used in the PRZM­ EXAMS assessment). Maximum label application rates were ­7­ used for major crops. The chronic EEC values ranged from 0.53 to 4.45 ppb (the low end crop was lettuce in Florida, and the high end crop was alfalfa in California). Using the 36­ year mean concentration values for cancer risk estimates, the average exposure values ranged from 0.54 to 4.3 ppb. ° Although there is no legal requirement under the Safe Drinking Water Act to monitor for pronamide, it has been detected in surface and groundwater in various locations in the U. S. The maximum level detected was 0.365 ppb (surface water) at Zollner Creek near Mt. Abgel, Oregon on Nov. 16, 1998 and the range was 0.0037 to 0.365 ppb (surface water) (USGS ­ NAWQA). The maximum ground water detection was at Benton Ozark, AK at 0.82 ppb on April 13, 1994, and ranging from 0.005 ­ 0.82 ppb. ° Short­ term and chronic drinking water exposure to pronamide did not result in a risk estimate of concern for non­ cancer risks. The short term EECs ranged between 3.7 to 10.3 ppb, depending on the crop, compared to the DWLOC which ranged from 560 to 700 ppb. The chronic non­ cancer EECs ranged between 0.53 to 4.45 ppb, depending on the crop, compared to the chronic DWLOC which ranged between 300 to 1050 ppb. ° There are cancer risk estimates which slightly exceed the Agency's level of concern. While the modeled groundwater EEC is 1.1 ppb compared to the cancer DWLOC 1.06 ppb, the modeled surface water EECs exceed the DWLOC for some crops (the surface water cancer EECs range from 0.54 to 4.3 ppb). Aggregate Risk (For a complete discussion, see section 5.0 of the Human Health Risk Assessment and Addendum to EPA March 8, 2002: Pronamide. Tolerance Reassessment Eligibility Decision (TRED)) FQPA requires an aggregate risk assessment to be conducted considering all nonoccupational sources, including exposure from water, food, and residential use. Because there are potential exposures to treated turf, the aggregate exposure assessment for pronamide includes exposure estimates from residential sources as well as food and drinking water. The Agency uses a drinking water level of comparison (DWLOC) as a surrogate to capture risk associated with exposure from pesticides in drinking water. The DWLOCs represent the maximum contribution to the human diet (in ppb or : g/ L) that may be attributed to residues of a pesticide in drinking water after dietary exposure is subtracted from the chronic Population Adjusted Dose (cPAD) or cPAD. Risks from drinking water are assessed by comparing the DWLOCs to the estimated environmental concentrations (EECs) in surface water and groundwater. If the EEC is less than the DWLOC, there is generally no drinking water concerns. The EECs for average concentrations of pronamide were based on PRZM­ EXAMS for surface water and SCI­ GROW for groundwater. Drinking water modeling is considered to be an unrefined assessment and provides high­ end estimates. ­8­ Short Term Risk The short­ term food, water, and low­ contact dermal (golfing) pronamide exposures were aggregated in the Risk Assessment, and the estimated environmental concentration (EECs) for surface water (3.69 to 10.3 ppb) and ground water (1.1 ppb), modeled using SCI­ GROW and PRZM­ EXAMS, did not exceed the DWLOC (range 560­ 700 ppb). Therefore, risk estimates for all pathways of exposure are not of concern for pronamide short­ term exposure when pronamide use is restricted per the label changes cited above. Chronic Risk Due to the short­ term, intermittent nature of residential exposure to pronamide, only dietary and water intake were included in the chronic aggregate exposure estimate. The chronic DWLOC is the concentration in drinking water as a part of the aggregate chronic exposure that occupies no more than 100% of the cPAD when considered together with other sources of exposure. To calculate the chronic DWLOC exposure relative to a chronic toxicity endpoint, the chronic dietary food exposure (from DEEM™) was subtracted from the chronic PAD to obtain the acceptable chronic exposure to pronamide in drinking water. The DWLOC was calculated and compared to the EECs. ° The chronic DWLOCs (300 ­ 1050 ppb) were greater than the EECs for modeled surface water (0.53 ­ 4.45 ppb), and modeled groundwater (1.1 ppb). In addition, non­ targeted USGS monitoring data ranged from 0.0037 to 0.365 ppb in surface water, and from 0.005 ­ 0.82 ppb in ground water. The Agency concludes the chronic aggregate risk estimates do not exceed the level of concern. Cancer Risk Aggregate cancer risk estimates will be reduced by restricting non­ agricultural uses to turf for sod and seed, ornamental landscaping, industrial sites, professional athletic fields, and golf courses. Golfing is believed to be a representative scenario for likely exposures to the public. ° The cancer risk estimate for golfing a single day per year is about the same as the dietary cancer risk estimate, or 1 x 10 ­7 . After considering both dietary and non­ dietary exposure, the cancer DWLOC is 1.06 ppb. Without golf course exposure (i. e., no recreational turf uses at all), the cancer DWLOC would be 1.2 ppb based on food exposure alone. ° The Tier 2 PRZM­ EXAMS 36 year mean EECs are 0.535­ 4.35 ppb. The modeled groundwater EEC using SCI­ GROW is 1.1 ppb. ­9­ ° While the modeled EECs (4.35 ppb) are slightly higher than the cancer DWLOC (1.06 ppb), the Agency is not concerned because of the conservative inputs used in the surface water modeling. The PRZM­ EXAMS assessment was based on the maximum label rates for pronamide, whereas typical rates for many crops are 25%­ 50% less. The model also assumed a Percent Crop Area (PCA) of 87%, which is likely to be an overestimate for the commodities being assessed. In addition, pronamide data exists for only one soil in the aerobic soil metabolism study. When aerobic soil metabolism data is only available in one soil, a conservative extrapolation factor is used which is likely to contribute to overestimating potential persistence and exposure. As a result, Dow AgroSciences has agreed to conduct an aerobic soil metabolism study (two additional soils) and an aerobic aquatic metabolism study as confirmatory data. ° Further refinement of drinking water modeling estimates and/ or targeted monitoring of water sources in high pronamide use areas would provide more confidence in the risk assessment. Additionally, information concerning the behavior of pronamide following drinking water treatment regimes would also help refine exposure estimates. Tolerance Reassessment Summary Pronamide tolerances are established under 40 CFR §180.317 (a), (b) and (c). The tolerance expression, listed in (a) and (c), is in terms of the combined residues of the herbicide propyzamide and its metabolites (containing the 3, 5­ dichlorobenzoyl moiety and calculated as 3, 5 dichloro­ N­ (1,1­ dimethyl­ 2­ propynyl) benzamide). The tolerance expression, listed in (b), is in terms of the parent only. The Agency recommends that the tolerance expression under (b) be modified to include the metabolites. The Agency also recommends the following: decreasing the established tolerance for artichokes; increasing the tolerances for cattle fat, goat fat, hog fat, horse fat, and sheep fat, revoking the tolerance for poultry kidney, grass, forage: and, proposing a tolerance for alfalfa seed. The Table below summarizes EPA's tolerance reassessment decision which accounts for 47 tolerance reassessments. The Codex Commission has established several maximum residue limits (MRLs) for residues of pronamide in/ on various raw agricultural and processed commodities. The Codex MRLs are expressed in terms of pronamide per se. The Codex MRLs and the U. S. tolerances will be incompatible when the U. S. tolerance expression for plant commodities is revised to include residues of pronamide and the metabolites. ­10­ Tolerance Reassessment Summary for Pronamide Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity definition Tolerances Listed Under 40 CFR §180.317( a) Apples 0.1 0. 1 Artichokes 0.1 0. 01 Residues of pronamide and its metabolites containing the 3,5­ dichlorobenzoyl moiety were nondetectable (less than the level of concern (LOC) of 0.01ppm) in/ on each sample of artichokes harvested 61 days following a single application of a representative pronamide formulation at 4.0 or 8.0 lb ai/ A. Blackberries 0.05 0.05 Blueberries 0.05 0.05 Boysenberries 0.05 0.05 Cattle, fat 0.02 0.20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the Maximum theoretical dietary burdens (MTDB) Cattle, kidney 0. 4 0.4 Cattle, liver 0.4 0. 4 Cattle, mbyp (except kidney, liver) 0. 02 0. 02 Cattle, meat 0.02 0.02 Eggs 0.02 0.02 Endive (escarole) 1.0 1. 0 Goats, fat 0.02 0.20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the MTDB Goats, kidney 0.4 0. 4 Goats, liver 0.4 0. 4 Goats, mbyp (except kidney, liver) 0. 02 0. 02 Goats, meat 0.02 0.02 Grapes 0.1 0. 1 Hogs, fat 0. 02 0. 20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the MTDB Hogs, kidney 0. 4 0.4 Hogs, liver 0.4 0. 4 Hogs, mbyp (except kidney) 0.02 0.02 Hogs, meat 0.02 0.02 Horses, fat 0. 02 0. 20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the MTDB Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity definition ­11­ Horses, kidney 0. 4 0.4 Horses, liver 0.4 0. 4 Horses, mbyp (except kidney) 0.02 0.02 Horses, meat 0.02 0.02 Lettuce 1.0 1. 0 Lettuce Head Only head lettuce is supported by acceptable data; leaf lettuce uses must be removed from the label. Alternatively, the label may be revised to specify a practical PHI (35­ day) for leaf lettuce and supporting data be submitted. Milk 0.02 0.02 Non­ grass animal feeds 10.0 10.0 Non­ grass animal feeds (forage, fodder, straw, and hay) group Pears 0. 1 0.1 Poultry, fat 0. 02 0. 02 Poultry, kidney 0. 2 Revoke Tolerances are typically not established for poultry kidneys. Poultry, liver 0.2 0. 2 Poultry, mbyp (except kidney, liver) 0.02 0.02 Poultry, meat 0.02 0.02 Radicchio, greens (tops) 2. 0 2.0 Raspberries 0.05 0.05 Sheep, fat 0. 02 0. 20 Fat tolerance raised due to linear extrapolation of maximum residues observed in fat at 40 ppm feeding level relative to the MTDB Sheep, kidney 0. 4 0.4 Sheep, liver 0.4 0. 4 Sheep, mbyp (except kidney, liver) 0.02 0.02 Sheep, meat 0.02 0.02 Stone fruit 0.1 0. 1 Commodity Established Tolerance (ppm) Reassessed Tolerance (ppm) Comment Correct Commodity definition ­12­ Tolerances To Be Proposed Under 40 CFR §180.317( a) Alfalfa Seed ­­ 10.0 Tolerance recommendation is contingent upon required label revision to specify a 50­ day PHI and a maximum seasonal rate of 2.0 lb ai/ A Tolerances Listed Under 40 CFR §180.317( b) Cranberries 0.05 ­­ Temporary tolerance associated with a FIFRA section 18 that will expire 12/ 31/ 03. Grass, forage 1.0 ­­ Tolerance expired 12// 31/ 01. Tolerances Listed Under 40 CFR §180.317( c) Peas, dried 0. 05 TBD Pea, field, seed. European data currently used to support tolerance. Registrant needs to submit field trial data as confirmatory data. Rhubarb 0.1 0. 1 Tolerances To Be Proposed Under 40 CFR §180.317( c) Pea, field, hay – TBD Pea, field vines – TBD *TBD= To Be Determined Summary of Pending Data Most pertinent product chemistry data requirements are satisfied for technical grade active ingredients. The following information is required: ° Product Chemistry GDLN Description 860.1200 Direction for use 860.1380 Storage Stability Data ° Additional data are also required for the 51% Formulation Intermediate (FI) concerning the following: GDLN Description 830.6314 oxidation/ reduction 830.6316 explodability 830.6317 storage stability 830.6320 corrosion characteristics ­13­ The registrant must either certify that the supplier of beginning materials and the manufacturing processes have not changed since the last comprehensive product chemistry reviews or submit complete updated product chemistry data packages. Although there is confidence in the overall scientific quality of the available toxicity data, several data gaps were identified which are required to fulfill the OPPTS harmonized test guidelines: ° Toxicity GDLN Description 870.3700 Developmental study in rats Non GDLN Comparative thyroid rat assay in adult animals and offspring 870.3200 21­ day dermal toxicity study Non GDLN 28­ day inhalation study 870.7600 dermal penetration study A review of registered uses and the supporting residue chemistry data indicates the following residue data are required: ° Residue (GDLN 860.1500 Crop Field Trials) dried winter peas vines and hay of winter peas ° Confirmatory storage stability data (GDLN 860.1380) are required for regulated pronamide metabolites on the following: alfalfa apples grapes lettuce peaches plums ° A confirmatory aerobic soil metabolism study (835.4100) and an aerobic aquatic metabolism study (835.4300) are required. The registrant is required to further optimize/ improve the revised animal enforcement method (TR 34­ 91­ 68) to yield acceptable recoveries at a fortification level equal to established animal tolerances. Following method improvement, the registrant is required to submit bridging independent laboratory validation (ILV) data; the required ILV data should include two control samples fortified at 0.4 ppm, the reassessed tolerance level for the kidney and liver of ruminants. ­14­ ° The following label amendments are required for lettuce, peas, and alfalfa grown for seed: GDLN Description 860.1850 Confined Accumulation in Rotational Crops 860.1900 Field Accumulation in Rotational Crops ° 30­ day plant­ back interval for leafy vegetables (except Brassica vegetables) ° 90­ day plant­ back interval for root and tuber vegetables ° 360­ day plant­ back interval for cereal grains, forage and fodder, and straw of cereal grain

epa

2024-06-07T20:31:42.765359

regulations

EPA-HQ-OPP-2002-0159-0013

Supporting & Related Material

Summary of Pronamide Uses ° Pronamide is a restricted use pesticide. ° It is a selective, pre­ emergence herbicide registered for the control of grassy and broadleaf weeds on terrestrial food crops [artichoke, blackberry, blueberry, boysenberry, cherry, endive (escarole), lettuce, nectarine, peach, pear, plum, prune, raspberry, (black, red), rhubarb]; terrestrial food and feed crops (agricultural fallow/ idleland, apples, grapes, peas, sugar beets); terrestrial nonfood crops (Christmas tree plantations, golf course turf, ornamental herbaceous plants, recreation area lawns, and outdoor residential (ornamental and/ shade trees, ornamental woody shrubs and vines). Health Effects ° Pronamide is a liver toxicant. Other target organs include thyroid, testes, kidney, adrenal gland, thymus, heart, and brain. ° Pronamide was previously classified as a Group B2 chemical, probable human carcinogen based on thyroid follicular cell adenomas (male and female) and benign interstitial cell tumors (males) in rats and heptacelluar carcinomas in male mice. ° Carcinogenicity studies in rodents indicate two types of tumors, benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas; and one type of tumor in the mouse, hepatocellular carcinomas. ° The cancer potency estimate for pronamide using the Q1* model is 2.59 x 10 ­2 (mg/ kg/ day) ­1 . FQPA Safety Factor ° A 3x FQPA Safety Factor is required for all population subgroups when assessing non­ occupational exposures of all durations. Dietary Food Risk ° No appropriate toxicologic endpoint was identified for acute dietary exposure. Consequently an acute dietary risk assessment was not performed for pronamide. ° Chronic dietary risk estimates from exposure to food do not exceed the Agency's level of concern. The chronic dietary risk estimate is <1% of the cPAD, for U. S. population and for all subgroups. ° The cancer dietary risk estimate is 1.06 x 10 ­7 for the U. S. population, and does not exceed the Agency's level of concern (1.0 x 10 ­6 or one in one million). Residential Risk ° Registrant has voluntarily cancelled the residential use product. ° The registrant has agreed to limit use to turf grown for seed or sod and non­ residential sites including golf courses, industrial and office building sites, stadium fields or professional athletic fields. These risk mitigation measures make children's non­ dietary exposure unlikely. To minimize adult non­ occupational exposure, the registrant has agreed to amend pronamide labels to require a 24 hour restricted entry interval or require watering­ in as soon as possible after application. ° As a result of the risk assessment, the sole exposure scenario for the non­ occupational risk assessment is based on low contact activity which is represented and estimated by golf course reentry. The route of exposure is dermal. The population at risk is adults. ° The short­ term Margin of Exposure (MOE) for golf course reentry using zero day after treatment (DAT 0) turf transferable residue data from the turf study is 1000. Therefore, the Agency is not concerned about short term residential exposure to pronamide. ° No intermediate or long term exposure scenarios (i. e., greater than 30 days) are anticipated based on the results of the turf transferable residue (TTR) study which showed that residues dissipate to below the level of quantification by day 14 following application. ° The adult golfer cancer risk is estimated at 1.15 x 10 ­7 . In order to exceed the cancer risk (1.0 x 10 ­6 ), an exposure frequency of 8.7 days per year would be needed for the activity of golf. Because pronamide is applied one time per year, the Agency does not believe this exposure frequency will occur. Therefore, the cancer risk for golfers does not exceed the Agency's level of concern. Drinking Water Assessment ° Short­ term and chronic drinking water exposure to pronamide did not result in a risk estimate of concern for non­ cancer risks. The short term EECs ranged between 3.7 to 10.3 ppb, depending on the crop, compared to the DWLOC which ranges from 560 to 700 ppb. The chronic non­ cancer EECs range between 0.53 to 4.45 ppb, depending on the crop, compared to the chronic DWLOC which ranged between 300 to 1050 ppb. ° There are cancer risk estimates which slightly exceed the Agency's level of concern. While the modeled groundwater EEC is 1.1 ppb compared to the cancer DWLOC 1.06 ppb, the modeled surface water EECs exceed the DWLOC for some crops (the surface water cancer EECs range from 0.54 to 4.3 ppb). ­3­ Aggregate Risk ° Risk estimates for all pathways of exposure are not of concern for pronamide short­ term exposure when pronamide use is restricted per the label changes cited above. The chronic aggregate risk estimates do not exceed the level of concern. ° The short­ term food, water, and low­ contact dermal (golfing) pronamide exposures were aggregated in the Risk Assessment, and the estimated environmental concentration (EECs) for surface water (3.69 to 10.3 ppb) and ground water (1.1 ppb), modeled using SCI­ GROW and PRZM­ EXAMS did not exceed the DWLOC (range 560­ 700 ppb). Therefore, risk estimates for all pathways of exposure are not of concern for pronamide short­ term exposure when pronamide use is restricted per the label changes. ° The chronic DWLOCs (300 ­ 1050 ppb) were greater than the EECs for modeled surface water (0.53 ­ 4.45 ppb), and modeled groundwater (1.1 ppb). In addition, non­ targeted USGS monitoring data ranged from 0.0037 to 0.365 ppb in surface water, and from 0.005 ­ 0.82 ppb in ground water. The Agency concludes the chronic aggregate risk estimates do not exceed the level of concern. ° While the modeled EECs (4.35 ppb) are slightly higher than the cancer DWLOC (1.06 ppb), the Agency is not concerned because of the conservative inputs used in the surface water modeling. The PRZM­ EXAMS assessment was based on the maximum label rates for pronamide, whereas typical rates for many crops are 25%­ 50% less. The model also assumed a Percent Crop Area (PCA) of 87%, which is likely to be an overestimate for the commodities being assessed. In addition, pronamide data exists for only one soil in the aerobic soil metabolism study. When aerobic soil metabolism data is only available in one soil, a conservative extrapolation factor is used which is likely to contribute to overestimating potential persistence and exposure. As a result, Dow AgroSciences has agreed to conduct an aerobic soil metabolism study (two additional soils) and an aerobic aquatic metabolism study as confirmatory data. Tolerance Reassessment Summary ° Pronamide tolerances are established under 40 CFR §180.317 (a), (b) and (c). The tolerance expression, listed in (a) and (c), is in terms of the combined residues of the residues of the herbicide propyzamide and its metabolites (containing the 3, 5­ dichlorobenzoyl moiety and calculated as 3, 5 dichloro­ N­ (1,1­ dimethyl­ 2­ propynyl) benzamide). The tolerance expression, listed in (b), is in terms of the parent only. The Agency recommends that the tolerance expression under (b) be modified to include the metabolites. The Agency also recommends the following: decreasing the established tolerance for artichokes, increasing the tolerances for cattle fat, goat fat, hog fat, horse fat, and sheep fat, revoking the tolerance for poultry, kidney; grass, forage and proposing a tolerance for alfalfa seed. ­4­ Data Requirements Most pertinent product chemistry data requirements are satisfied for technical grade active ingredients. The following information is required: ° Product Chemistry GDLN Description 860.1200 Direction for use 860.1380 Storage Stability Data ° Additional data are also required for the 51% Formulation Intermediate (FI) concerning the following: GDLN Description 830.6314 oxidation/ reduction 830.6316 explodability 830.6317 storage stability 830.6320 corrosion characteristics The registrant must either certify that the supplier of beginning materials and the manufacturing processes have not changed since the last comprehensive product chemistry reviews or submit complete updated product chemistry data packages. Although there is confidence in the overall scientific quality of the available toxicity data, several data gaps were identified which are required to fulfill the OPPTS harmonized test guidelines: ° Toxicity GDLN Description 870.3700 developmental study in rats 870.3200 21­ day dermal toxicity study Non GDLN 28­ day inhalation study 870.7600 dermal penetration study Non GDLN comparative thyroid rat assay in adult animals and offspring A review of product labels and the supporting residue chemistry data indicates the following reside, data are required: ° Residue (GDLN 860.1500 Crop Field Trials) Description dried winter peas vines and hay of winter peas ­5­ ° The following label amendments are required for rotational crops lettuce, peas (winter), and alfalfa grown for seed: GDLN Description 860.1850 Confined Accumulation in Rotational Crops 860.1900 Field Accumulation in Rotational Crops ° 30­ day plant­ back interval for leafy vegetables (except Brassica vegetables) ° 90­ day plant­ back interval for root and tuber vegetables ° 360­ day plant­ back interval for cereal grains, forage and fodder, and straw of cereal grain ° Confirmatory storage stability data (GDLN 860.1380) are required for regulated pronamide metabolites on the following: Description alfalfa apples grapes lettuce peaches plums ° A confirmatory aerobic soil metabolism study (835.4100) and the aerobic aquatic metabolism study (835.4300). The registrant is required to further optimize/ improve the revised animal enforcement method (TR 34­ 91­ 68) to yield acceptable recoveries at a fortification level equal to established animal tolerances. Following method improvement, the registrant is required to submit bridging independent laboratory validation (ILV) data; the required ILV data should include two control samples fortified at 0.4 ppm, the reassessed tolerance level for the kidney and liver of ruminants.

epa

2024-06-07T20:31:42.771060

regulations

EPA-HQ-OPP-2002-0159-0016

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION PESTICIDES AND TOXIC SUBSTANCES TXR Number: 0050338 MEMORANDUM DATE: January 21, 2002 SUBJECT: Pronamide (Propyzamide): Report of the Mechanism of Toxicity Assessment Review Committee (MTARC) Evaluation of the Available Mechanistic Information for the Active Ingredient, Pronamide. PC Code: 101701. DP Barcode: D279550. Submission Number: S597844. FROM: Michelle M. Centra, Pharmacologist Reregistration Branch III Health Effects Division (7509C) THRU: Pauline Wagner, Co­ Chair Karl Baetcke, Co­ Chair Mechanism of Toxicity Science Assessment Review Committee (MTARC) Health Effects Division (7509C) TO: Jess Rowland, Co­ Chair Elizabeth Doyle, Co­ Chair Hazard Identification Assessment Review Committee (HIARC) Health Effects Division (7509C) cc: Anna Lowit MTARC Secretary Health Effects Division (7509C) and Catherine Eiden, Branch Senior Scientist Jose Morales, Risk Assessor Reregistration Branch III Health Effects Division (7509C) On October 23, 2001, the Mechanism of Toxicity Assessment Review Committee (MTARC) met to prescreen the available Pronamide toxicology data submitted in support of a proposed threshold mechanism for the induction of thyroid and testicular neoplasms and to determine whether a full MTARC review is required. The Committee's data evaluation and conclusions are presented in this report. 2 Committee Members in Attendance Members present were: Karl Baetke, Karen Hammernik, Anna Lowit Member( s) in absentia: Pauline Wagner Data evaluation prepared by: Michelle M. Centra, Reregistration Branch III (RRB III) Also in attendance were: Steve Knizner (RRBIII), Jose Morales (RRBIII) Data Evaluation / Report Presentation Michelle M. Centra Pharmacologist 3 Cl Cl O C CH 3 N H CH CH 3 I. MTARC DECISION Based on the absence of any additional information as well as the MTARC's evaluation of the existing pronamide toxicology data base and the Agency's previous hazard characterization of this active ingredient (Memorandum: N. Thoa, May 26, 1993), the Committee determined that the postulated threshold mechanism for the induction of thyroid and testicular neoplasms remains incomplete and is not supported by the available data. Therefore, a full Committee review for pronamide is not required. II. BACKGROUND INFORMATION A. Introduction Pronamide [3, 5­ dichloro­ N­( 1, 1­ dimethyl­ 2­ propynyl) benzamide], trade name Kerb ® , is a selective, systemic, pre­ and post­ emergence herbicide which inhibits root and shoot growth from seedlings and is used to control a wide range of annual and perennial grasses as well as certain broadleaf weeds. It is produced and formulated for use as a 50­ W wettable powder in water soluble pouches (EPA Reg. No. 707­ 159) by Rohm and Hass Co., Springhouse, Pennsylvania. It is registered for use in/ on several food and feed crops (alfalfa, apples, globe artichokes, birdsfoot trefoil, blackberries, blueberries, cherries, clover, crown vetch, endive, grapes, lettuce, nectarines, peaches, pears, plums, prunes, raspberries, and sainfoin). Pronamide is also registered for terrestrial non­ domestic, non­ food use on woody ornamentals (azalea, holly, juniper, pine, rhododendron, and yew), Christmas trees, nursery stocks (forsythia, holly, juniper, pine, rhododendron, and yew) and for domestic outdoor uses on lawns, turfs, and fallow land to control bermudagrass, centipedegrass, St. Augustinegrass, and zoysiagrass. B. Chemical Identification Chemical Structure: Empirical Formula: C12H11NOCl2 Common Synonyms: propyzamide; 3,5­ dichloro ­N­ (1,1­ dimethyl­ 2­ propynyl) benzamide, Kerb ® 9CI Name: 23950­ 58­ 5 Physical Properties: Technical pronamide is a white crystalline solid. Molecular Weight: 256.13 Melting point: 155­ 156 0 C Specific gravity: 0. 48 g/ cc Water Solubility: The solubility of pronamide in water at 25 0 C is 15 ppm. 4 Pronamide is soluble in dimethyl sulfoxide and dimethyl formamide at 33 ppm; in mesityl oxide, isophorone, methyl ethyl ketone, and cyclohexanone at 20 ppm; in methanol, isopropanol, and chlorobenzene at 12­ 15 ppm; in butyl cellosolve, xylene, acetonitrile, and kerosene at 10 ppm; and in nitrobenzene and ethylene dichloride at 5 ppm. CAS No.: 23950­ 58­ 5 PC Code: 101701 C. Toxicity Summary Pronamide appears to be a liver toxicant. Adverse liver­ related effects (increases in liver weight and/ or liver­ related serum enzymes and/ or histopathology) were consistently observed in every animal species studied, including the rat (subchronic, chronic, and 2­ generation reproduction studies), mouse (carcinogenicity studies), rabbit (developmental study), and dog (subchronic and chronic studies). Other target organs included the thyroid in rats (increase in weight and/ or histopathology observed in the chronic toxicity/ carcinogenicity and the 2­ generation reproduction studies as well as a subchronic, special 13­ week thyroid function study), the testes in rats (histopathology in the chronic toxicity/ carcinogenicity study) and the kidneys, adrenal glands thymus, heart, testes, and brain in dogs (increase in organ weights in the chronic toxicity study), and the pituitary in rats (histopathology observed in the subchronic and 2­ generation reproduction studies). Many chemicals belonging to the class of organochlorine chemicals are known to produce disruption of the endocrine system 1 . Pronamide belongs to this class of chemicals. The Carcinogenicity Peer Review Committee (CPRC) classified Pronamide as a group B2 ­ probable human carcinogen with inadequate evidence in humans (Memorandum: N. B. Thoa and E. Rinde, May 26, 1993). This decision was based on the finding of two types of tumors in the rat (benign testicular interstitial cell tumors and uncommon thyroid follicular cell adenomas), and one type of tumor in the mouse (hepatocellular carcinomas). A linear, low dose approach (Q1 *) was used for human risk characterization. The most potent unit risk Q1 *, based on male mouse liver adenoma and/ or carcinoma combined tumor rates, is 2. 59 x 10 ­2 (mg/ kg/ day) ­1 in human equivalents [converted from animal to humans by use of the (mg/ kg body weight) 3/ 4 interspecies scaling factor] (Memorandum: L. Brunsman, October 26, 2001). In addition to the required guideline toxicity studies, two special studies were conducted to evaluate pronamide's effect on hormonal balance in support of a threshold mechanism for the induction of thyroid and testicular neoplasms. The CPRC also considered this data in its weight­ of­ evidence deliberations and concluded the following: ° The data provided on thyroid mechanism were suggestive of a thyroid­ pituitary hormonal control mechanism but were not conclusive, based on the Agency's six criteria for a threshold model of thyroid neoplasia (See Appendix, Carcinogenicity Peer Review of Pronamide 3 rd ). For example, there were no dose­ related and/ or sustained increases in TSH levels, no dose­ related increases in incidence of thyroid hypertrophy/ hyperplasia, and no information on thyroid hormone synthesis. 5 ° The Agency has no policy which implements a threshold model for testicular neoplasia. Endocrine function of the testis may or may not be regulated through a feedback mechanism similar to that controlling thyroid function, e. g. through an involvement of the anterior pituitary. Even if a testis­ pituitary hormonal control mechanism existed, the evidence supporting pronamide­ induced testicular tumors in the rat via a disruption in the testis­ pituitary balance is very limited. There was no clear increase in interstitial cell hypertrophy/ hyperplasia, no alteration in testosterone level, no information on testicular hormone synthesis and no reversibility of testicular lesions. Although several endocrine effects have been observed in pronamide toxicity studies, the data provided in special studies conducted to explore potential mechanisms of endocrine toxicity, are incomplete. Based on the CPRC's weight­ of­ evidence evaluation of this data base, it was determined that even if a hormonal mechanism could be demonstrated for tumors in the rat, the mouse liver tumors can not be discounted (the Q1 * is based on the incidence of liver tumors in mice). Therefore, a mechanistic approach to risk assessment for the active ingredient pronamide is not plausible. 1 Hileman, B., March 19, 1993. Concerns broaden over chlorine and chlorinated hydrocarbons­ calls for gradual phaseout of classes of chlorinated organics are being made in response to evidence of adverse health effects on humans and wild life. C & E News, volume 71, No. 16, pp 11­ 20. 6 III. Data Presentation A. Listing and Presentation of Available Data Table 1. Endocrine/ Other Effects Observed in Pronamide Toxicity Studies Study Type (MRID Number) Dose and Exposure Duration Endocrine and Other Effects Study Citation and Study Classification Chronic Toxicity/ Car cinogenicity Study ­ Rats (MRID 41714001, 41714002) Pronamide was administered to Crl: CD( BR) VAF/ Plus Rats in the diet at either 0, 25, 100, or 400 ppm for the first 2 weeks, followed by 0, 35, 140, or 560 ppm for the next 3 weeks and thereafter, 0, 40, 200, or 1000 ppm (equal to 0, 1. 73, 8.46, and 42.59 mg/ kg/ day for males and 0, 2. 13, 10.69, and 55.09 mg/ kg/ day for females, respectively). Increased incidences of non­ neoplastic lesions were observed in the liver, thyroid, and ovaries of high­ dose (1000 ppm) rats. In the liver, centrilobular hypertrophy was observed in males and females at 12 months (65% in males; 95% in females) and 24 months (20% in males; 48% in females). Hypertrophy was accompanied by eosinophilic cell alteration at 24months (positive trend in both sexes; pair­ wise comparison in high­ dose/ controls for males and females). In the thyroid, follicular cell hypertrophy was observed (positive trend in males and in females) at 12 months but not at 24 months. The increased incidence observed at 1000 ppm was only significant (pair­ wise comparison in high­ dose/ controls) in females. At 24 months, follicular cell hyperplasia was observed in females (positive trend) but the increased incidence observed at 1000 ppm was not statistically significant. In the ovaries, sertoliform tubular hyperplasia (positive trend) was observed in females at 24 months and the increase in incidence observed at 1000 ppm was significant by pair­ wise comparison. Bailey, D. E. (1990): Kerb ® Herbicide (Technical, no clay): 24 Month Dietary Chronic Toxicity/ Oncogenicity Study in Rats; Hazleton Laboratories America, Inc. for Rohm & Haas Co.; HLA 417­ 426S, HLA 417­ 426M; November 2, 1990 (Unpublished Study) Acceptable­ Guideline Table 1. Endocrine/ Other Effects Observed in Pronamide Toxicity Studies Study Type (MRID Number) Dose and Exposure Duration Endocrine and Other Effects Study Citation and Study Classification 7 Non Guideline Endocrine Study ­ Male Rats (MRID 42093401) Pronamide was administered to male Crl: CD ® BR Rats in the diet at concentrations of 0, 40, 1000 or 4000 ppm Pronamide for either 4 or 15 weeks. Parameters of thyroid function, T4 hepatic metabolism, and exogenous 125 I biliary clearance were investigated, in support of Pronamide's thyroid tumorigenic mechanism of action involving disruption of the thyroid­ pituitary hormonal balance. At 1000 ppm, pronamide treatment resulted in decreased body weights and food consumption, increased absolute and/ or relative weights of the liver and thyroid (absolute after 4 weeks; absolute and relative after 15 weeks), increased serum TSH (at 4 weeks but not at 13 weeks), decreased serum T4, and an increased incidence of thyroid and pituitary hypertrophy/ hyperplasia. The highest dose tested (4000 ppm) produced more profound effects on the body weights, liver weights and serum T4 than was seen in the mid dose (1000 ppm). Pronamide exposure resulted in increased thyroid (relative) weight and increased incidences of thyroid and pituitary hypertrophy/ hyperplasia which were comparable to the mid­ dose, but did not statistically change serum TSH levels. Specific parameters were investigated only at the high dose: T4 hepatic metabolism and 125 I biliary clearance were both increased and all of the thyroid­ and liver­ related changes occurring after 4 weeks of dosing, were either reduced in severity or absent 11 weeks following discontinuation of the dosing. Based on the six Agency criteria for thyroid effects, there is suggestive evidence that the thyroid tumors in the rat associated with pronamide administration may result from disruption of the thyroid­ pituitary hormonal balance. This evidence is weakened by the lack of a dose­ related and sustained increase in serum TSH, and the lack of a dose­ related increase in the incidence of thyroid follicular cell hypertrophy/ hyperplasia. There was also no investigation of T4 hepatic metabolism and biliary clearance at the high dose level (1000 ppm) which was also a test dose used in the rat chronic toxicity/ carcinogenicity study that demonstrated thyroid adenomas. Hazelton, G. A., Didonato, L. J., Donofrio, K. F, Kulwich, B. A. (1991): Pronamide (Kerb ® Herbicide): Thyroid Function and Hepatic Clearance of Thyroxine inMale Rats; Rohm & Haas Co., Toxicology Department for Rohm & Haas Co.; 90R­ 178; October 9, 1991 (Unpublished Study) Acceptable­ Nonguideline Table 1. Endocrine/ Other Effects Observed in Pronamide Toxicity Studies Study Type (MRID Number) Dose and Exposure Duration Endocrine and Other Effects Study Citation and Study Classification 8 Non Guideline, Pilot Endocrine Study ­ Male Rats (MRID 42139601) Pronamide was administered to male Crl: CD ® BR Rats in the diet at concentrations of either 0, or 4000 ppm for 13 weeks. Clinical chemistry and histopathological parameters of testicular function, as well as hepatic metabolism of testosterone were investigated, to lend support to Pronamide's testicular tumorigenic mechanism of action involving disruption of the pituitary­ testis hormonal balance. Clinical chemistry parameters were also measured in male rats treated with 0, 40, 1000, or 4000 ppm pronamide for 4 weeks. In the 13 week study, pronamide (4000 ppm) produced decreased body weight (weeks 1­ 13) and food consumption (weeks 1­ 8), increased serum LH and FSH levels (respective increases at 4 and 13 weeks were 60% and 58% for FSH, and 100% and 77% for LH), increased liver weight (absolute and relative to body and brain weight), microsomal protein content, oxidation of testosterone, activity of cytochrome P450 , cytochrome­ B5, NADPH cytochrome­ C­ reductase, and gross pathology of the liver (enlarged/ dark), and increased testicular relative (to body) weight , and testicular interstitial cell hyperplasia. In the 4­ week study, alterations in clinical chemistry parameters (increases in serum LH and FSH) were noted only at 4000 ppm and were comparable to the increases observed after 13 weeks of dosing. The most positive supporting evidence for the involvement of the pituitary in testicular neoplasia is the increase in serum LH and FSH levels after 4 and 15 weeks of treatment. There was, however, no concomitant decrease in serum testosterone. Futhermore, studies were not conducted which may have demonstrated that this lack of effect was produced by some additional effect of pronamide (e. g., an increase in testosterone clearance accompanying the moderate stimulatory effect [54% increase/ g liver] on testosterone metabolism). There also was no evidence of testicular lesion progression and/ or lesion reversibility. The CPRC concluded that this data is, at best, incomplete and additional studies should be conducted in order to support the Registrant's theory of a pronamide­ induced testicular neoplastic effect via disruption of the pituitary­ testis hormonal balance. Hazelton, G. A., Didonato, L. J., Donofrio, K. F., Kulwich, B. A. (1991): Pronamide (Kerb ® Herbicide): Effects on Endocrine Regulation of the testis in Rats ­ Pilot Study; Rohm & Haas Co., Toxicology Department for Rohm & Haas Co.; 90R­ 179; December 6, 1991 (Unpublished Study) Acceptable­ Nonguideline Table 1. Endocrine/ Other Effects Observed in Pronamide Toxicity Studies Study Type (MRID Number) Dose and Exposure Duration Endocrine and Other Effects Study Citation and Study Classification 9 Two Generation Reproduction Study ­ Rats (MRID 41540301) Pronamide was administered to Crl: CD ® BR Rats in the diet at concentrations of 0, 40, 200 or 1500 ppm (equal to 3.1, 16.0 and 120.7 mg/ kg/ day for females and 3.6, 18.0 and 130.1 mg/ kg/ day for males for the 40, 200 and 1500 ppm dose groups, respectively) through 2 generations (one mating period per generation). Parental systemic effects were observed in rats treated with 1500 ppm pronamide: decreased body weight and feed consumption in both sexes and increased incidences of histopathology of the liver (centrilobular hepatocytes hypertrophy; both sexes), adrenal glands (zona glomerulosa cellular hypertrophy; both sexes), thyroid gland (follicular cell hypertrophy; females), and anterior pituitary gland (cellular hypertrophy; males) in both P1 and P2 generations, and increased incidences of uterine gross pathology (black foci/ serosal surface) in P2 females. Solomon, H. M., Brown, W. R. (1990): Pronamide: Two­ Generation Reproduction Study in Rats; Rohm andHaas Company, Toxicology Department for Rohm and Haas Company; Study Number: 88P­ 309; Report No. 88R­ 257; June 14, 1990 (Unpublished) Acceptable­ Guideline Table 1. Endocrine/ Other Effects Observed in Pronamide Toxicity Studies Study Type (MRID Number) Dose and Exposure Duration Endocrine and Other Effects Study Citation and Study Classification 10 Subchronic Toxicity Study ­ Rats (MRID 42669403) Pronamide was administed to Crl: CD ® BR Rats in the diet at concentrations of 0, 40, 200, 1000, or 4000 ppm (equal to 0, 2.5, 12.3, 60.0, and 254.0 mg/ kg/ day for males and 0, 3.1, 15.0,74.6, and 289.2 mg/ kg/ day for females, respectively) for 3 months At 1000 ppm, pronamide treatment resulted in increases in liver relative (to body) weight, and incidence of liver centrilobular hypertrophy in both sexes, decreases in body weight/ weight gain and feed consumption in females, and increases in blood cholesterol levels in males. Additional toxicities observed at 4000 ppm included an increase in clinical signs (brown and/ or yellow staining of the anogenital area) in males, decreases in body weight/ weight gain and feed consumption in males and further exacerbation of the later in females. In addition, more pronounced effects were observed in the liver, thyroid and pituitary at the highest dose tested: increases in cholesterol (both sexes), SGOT and alkaline phosphatase (males), triglycerides (females), liver absolute/ relative weights (both sexes), incidence/ severity of liver centrilobular hypertrophy (both sexes), incidence of thyroid follicular hypertrophy (both sexes) and anterior pituitary cellular hypertrophy (males). The liver, thyroid and pituitary appear to be target organs. After 4 weeks of recovery, most of the adverse effects observed at the high dose were partially or totally reversed but the increase in the incidence of pituitary cellular hypertrophy in males was not diminished. Anderson, D. M., Kulwich, B. A., Hazelton, G. A. (1989): Pronamide Technical (no clay): Three­ Month Dietary Toxicity Study in Rats; Rohm & Haas Co. Tox Dept for Rohm & Haas Co.; Report No. 88R 053; September 15, 1989 (Unpublished Study) Acceptable­ Guideline Table 1. Endocrine/ Other Effects Observed in Pronamide Toxicity Studies Study Type (MRID Number) Dose and Exposure Duration Endocrine and Other Effects Study Citation and Study Classification 11 Chronic Toxicity Study ­ Dogs (MRID 41807601, 41807602) Pronamide was administered to Beagle Dogs in the diet at concentrations of 0, 300, 875, or 1750 ppm (equal to 0, 11.9, 33.1, 67.7 mg/ kg/ day for males and 0, 11.9, 36.1, 69.0 mg/ kg/ day for females, respectively) for 52 weeks. At 875 ppm, pronamide treatment produced toxicity in several organs. In the liver, systemic toxicity included increases in serum alkaline phosphatase activity (males), increases in absolute and relative (to body) liver weight (males and females), increases in the incidence of hepatocytic hypertrophy/ hyperplasia and granular brown pigmentation and mononuclear infiltration of Kupffer cells (males and females). At 1750 ppm, further increases in serum alkaline phosphatase activity were observed in both sexes, along with increases in serum gamma glutamyl transferase (males and females) and alanine amino transferase activities (females). The incidence/ severity of the histopathologic alterations in the liver were also exacerbated. Other organs affected at 1750 ppm dose included the kidneys (increase in relative weight in females and occurrence of brown pigmentation in proximal tubules in both sexes), thyroid gland (increase in relative weight in females), adrenal glands (increase in relative weight in males and absolute/ relative weights in females), thymus (increase in relative weight in females), and heart and testes (increases in relative weights in males). Briffaux, J. P. (1991): Pronamide (Kerb ® Technical Herbicide): 52 week oral (dietary) toxicity study in the Beagle Dog; Hazleton France (HF) for Rohm & Haas Co.; HF Project ID No. 616/ 503, Report No. HF 505069, Rohm & Haas Report No.: 89RC 110; February 20, 1991 (Unpublished Study) Acceptable­ Guideline 12 B. Data Evaluation The following data is excerpted from the CPRC document (Memorandum: N. Thoa, May 26, 1993): Study Citation Bailey, D. E. (1990): Kerb ® Herbicide (Technical, no clay): 24­ Month Dietary Chronic Toxicity/ Oncogenicity Study in Rats; Hazleton Laboratories America, Inc. for Rohm & Haas Co.; HLA 417­ 426S, HLA 417­ 426M; November 2, 1990 (Unpublished Study); MRID Number 41714001 and 41714002. Increased incidences of non­ neoplastic lesions were observed in the liver, thyroid, and ovaries of highdose rats. In the liver, a positive trend (p < 0.01) in the incidence of centrilobular hypertrophy was observed in males and females in both phases (12­ and 24­ month); the increases observed at 1000 ppm were significant by pair­ wise comparison (p < 0.01, both sexes) and appeared more pronounced in the 12­ month phase (rate = 65% in males and 95% in females) than in the 24­ month phase (rate = 20% in males and 48% in females). Hypertrophy was accompanied by eosinophilic cell alteration in the 24month phase( p< 0. 01forpositivetrendin both sexes; pair­ wisecomparison in high­ dose/ controls, p < 0. 05 in males and p < 0. 01 in females). In the thyroid, a positive trend (p < 0. 05 in males and p < 0. 01 in females) in the incidence of follicular hypertrophy was observed in the 12­ month phase but not the 24­ month phase. The increased incidence observed at 1000 ppm was only significant (p < 0.01, high­ dose/ controls) in females, but the increased incidence observed at 1000 ppm was not statistically significant. In the ovaries, a positive trend (p < 0.01) in the incidence of sertoliform tubular hyperplasia was observed in females in the 24­ month phase, and the increase in incidence observed at 1000 ppm was significant (p < 0.01) by pair­ wise comparison. Discussion of Tumor Data At 1000 ppm, in the 24­ month phase, both male and female rats had increased rates of thyroid follicular cell adenomas, and male rats had an increased incidence of benign testicular interstitial cell tumors. Thyroid tumors were not observed until weeks 53 and 82 for males and females, respectively, and testicular tumors were not observed until week 67. The increase in thyroid tumor rate was statistically significant by pair­ wise comparison (p < 0. 01) only in males, but there was a positive trend (p < 0. 01) for both sexes. Both high dose male and female tumor rates (21% and 10%, respectively) exceeded the historical control range which was 0­ 14.8% (a mean value of 5% for males) and 0­ 9. 5% (a mean value of 2% for females). Historical control data for SD rats was obtained from 13 studies conducted between 1985 and 1990 at Hazleton Laboratories, Vienna, VA. There were no significant differences in thyroid follicular cell carcinoma rates between groups. There were increasing trends and/ or rates in combined incidences of thyroid follicular cell adenomas and carcinomas (trend p < 0. 01 in males, p < 0. 05 in females; pair­ wise comparison of high dose males/ controls, p < 0. 05) which were a reflection of the treatment­ related changes in thyroid follicular cell adenoma rates. The increase in testicular interstitial cell benign tumor rate was statistically significant by pair­ wise comparison (p < 0.05) and there was a positive trend (p < 0.01). In high dose males, the tumor rate (27%) exceeded the historical range of 4. 8­ 18.2% with a mean value of 5. 6% (Hazleton Laboratories, Vienna, VA: historical control data for SD rats obtained from 11 studies conducted between 1985 and 1990). In 13 the 12­ month phase, thyroid follicular cell and testicular interstitial cell neoplasia were not observed in any group. Benign pituitary adenomas of the pars distalis were observed in every dose group during both the 12­ and 24­ month phases, but the tumor rates were statistically comparable among all groups. The respective tumor rates for the 0, 40, 200, and 1000 ppm dose groups were 1/ 19, 0/ 19, 0/ 20, and 3/ 20 in males and 0/ 20, 2/ 20, 1/ 19, and 3/ 20 in females for the 12­ month phase and 31/ 60, 33/ 60, 35/ 60, and 34/ 60 in males and 49/ 60, 49/ 60, 49/ 60, and 54/ 60 in females for the 24­ month phase. Adequacy of the Dose Levels Tested The dosing was considered to be adequate for assessing the carcinogenic potential of Pronamide, based on body weight gain depressions (p < 0.05) of
10% observed at 1000 ppm (weeks 0­ 26 in males; weeks 0­ 52 in females). Feed consumption was also depressed (p < 0.05) at 1000 ppm in males during weeks 1­ 13 (7%), 1­ 26 (7%), and 1­ 52 (5%). Survival rate was comparable between groups. The statistical evaluation of mortality indicates no significant incremental changes with increasing doses of Pronamide in either male or female rats. Survival rate was comparable between groups. The statistical evaluation of mortality indicates no significant incremental changes with increasing doses of pronamide in either male or female rats. Study Citation Hazelton, G. A., Didonato, L. J., Donofrio, K. F., Kulwich, B. A. (1991): Pronamide (Kerb ® Herbicide): Thyroid Function and Hepatic Clearance of Thyroxine in Male Rats; Rohm & Haas Co., Toxicology Department for Rohm & Haas Co.; 90R­ 178; October 9, 1991 (Unpublished Study); MRID Number 42093401. Histopathology of the Thyroid Treatment with 1000 and 4000 ppm pronamide for 4 or 15 weeks was associated with similar increases (p < 0. 05) in incidence of diffuse hypertrophy/ hyperplasia of the thyroid follicular cells. There was a positive trend after both 4 and 15 weeks. The lesions were observed throughout the thyroid and were characterized by follicular cells with increased height, and by follicles reduced in size and in colloid content. The increase in incidences observed after 4 weeks of treatment with the highdose (10/ 10) was reduced (5/ 9) after the recovery period. The severity of the lesions was greater at 4000 ppm than at 1000 ppm. Thyroid Hormone and TSH (4 and 15 week observations at 1000 and 4000 ppm in male rats) Treatment with 40­ 4000 ppm pronamide for 4 or 15 weeks was not associated with any reduction in T3 or rT3 .T4 was moderately reduced (decreased at 1000 ppm: 61% after 4 weeks and 48% after 15 weeks; decreased at 4000 ppm: 87% after 4 weeks and 84% after 15 weeks). Except for a moderate increase (72%) observed after 4 weeks of treatment with 1000 ppm pronamide, TSH remained unaffected. The decrease in T4 which observed after 4 weeks of treatment with 4000 ppm pronamide was absent after 11 weeks of recovery. 14 T4 ­Hepatic Uridine Diphosphate Glucuronosyl Transferase (UDPGT) Activity Treatment with 4000 ppm pronamide for 4 or 15 weeks was associated with a 2­ 2. 5 fold increase in UDP­ GT activity (enzyme activity was expressed as nmol T4 ­glucuronide formed/ min/ mg liver microsomal protein). The increased activity observed after 4 weeks of treatment with 4000 ppm pronamide was absent after 11 weeks of recovery. Bile flow and Biliary Clearance of 125 I­ T4 Treatment with 4000 ppm pronamide for 4 or 15 weeks was associated with significant (p < 0.05) increases in bile flow (  65%), biliary clearance of 125 I­ T4 (7­ 10 fold) and 125 I­ T4 glucuronide (1 ­2 fold), and 125 I bile/ plasma ratio after 4 weeks of treatment. The alterations in bile flow and biliary clearance were completely reversed after 11 weeks of recovery. Adequacy of Dosing for Assessment of Thyroid Effects The dosing was considered to be adequate for assessing the thyroid effects of pronamide, based on significant (p < 0.05) depressions of body weight (2­ 5% at 1000 ppm, weeks 1­ 4; 17­ 24% at 4000 ppm, weeks 1­ 15) and feed consumption (4­ 10% at 1000 ppm, weeks 1­ 4; 11­ 38% at 4000 ppm, weeks 1­ 15). Absolute (abs) and/ or relative (rel) liver weight was significantly increased (p < 0. 05) at
1000 ppm, in a dose­ related manner (4 week increases: 29% abs and 36% rel at 1000 ppm, 50% abs and 91% rel at 4000 ppm; 15 week increases: 32% rel at 1000 ppm; 42% abs and 86% rel at 4000 ppm). Thyroid weight was significantly increased (p < 0. 05) at
1000 ppm in a non dose­ related manner (4 week increases: 29% abs and 36% rel at 1000 ppm, 32% rel at 4000 ppm. 15 week increases: 21% rel at 1000 ppm, 33% rel at 4000 ppm). Study Citation Hazelton, G. A., Didonato, L. J., Donofrio, K. F., Kulwich, B. A. (1991): Pronamide (Kerb ® Herbicide): Effects on Endocrine Regulation of the testis in Rats ­ Pilot Study; Rohm & Haas Co., Toxicology Department for Rohm & Haas Co.; 90R­ 179; December 6, 1991 (Unpublished Study). MRID 42139601. Histopathology of the Testes Treatment with 4000 ppm pronamide for 13 weeks was associated with an increase in the number of testicular interstitial cells. The incidences were 1/ 20 for the control group and 7/ 20 for the treated group. Interstitial cells are located between the seminiferous tubules, normally in 2­ 3 cell focal clusters instead of layers. In this study, the observed increase was determined to be equivocal because of "the small degree of change being evaluated and the possibility of producing this appearance through fortuitous tangential sectioning of seminiferous tubules." The CPRC determined that this type of sectioning could be seen in all dose groups. Clinical Chemistry Changes Treatment with 4000 ppm pronamide for 4 or 13 weeks was associated with increases in serum LH and FSH. The increases were moderate and were slightly higher at 4 weeks than at 13 weeks (respective increases at 4 and 13 weeks were 60% and 58% for FSH, and 100% and 77% for LH). Serum LH and FSH levels were not affected by the mid­ level dose (1000 ppm). Serum testosterone levels were not affected by treatment with pronamide. 15 Liver Microsomal Enzymes Activity Treatment with 4000 ppm pronamide for 13 weeks increased the activity of the liver microsomal enzymes (cytochrome­ P450, cytochrome­ B5, and NADPH­ cytochrome­ C­ reductase) and the rate of oxidation of testosterone, expressed as  mol product/ whole liver. Concomitant increases in liver weight (50%) and liver microsomal protein content (34%) were observed, which suggests that oral administration of relatively high doses of pronamide (4000 ppm) for a certain period of time (13 weeks) may result in induction of the liver enzymes responsible for its metabolism. Adequacy of Dosing for Assessment of Testicular Effects The dosing (4000 ppm) was considered to be adequate for assessing the testicular effects of pronamide, based on significant (p < 0.05) depressions of body weight (14­ 17%, weeks 1­ 13) and feed consumption (37%, week 1; 9­ 12%, weeks 2­ 8). Testicular relative (to body) weights were slightly increased (26%; p < 0. 05) and liver absolute and relative (to body) weights were moderately increased (59% absolute; 92% relative; p < 0. 05). The liver­ related enzymes, SGPT and SGOT, were not affected by treatment with pronamide. IV. Conclusions Based on an evaluation of the pronamide toxicology data presented in this report , the MTARC reaffirmed the following conclusions of the CPRC (Memorandum: N. Thoa, May 26, 1993): ° The postulated mechanism of action is at best incomplete; the Registrant's postulated threshold mechanism for the induction of thyroid and testicular neoplasms is not supported by the available data. ° Even if a hormonal mechanism could be demonstrated for tumors in the rat, the mouse liver tumors can not be discounted (the Q1 * is based on the incidence of liver tumors in mice) Therefore, a mechanistic approach to risk assessment for the active ingredient pronamide is not plausible. ° Additional studies should be conducted to evaluate the potential for a pronamideinduced thyroid and testicular neoplastic effect via disruption of the pituitary­ thyroid and pituitary­ testis hormonal balance, respectively. In the absence of any additional data, the MTARC prescreening committee determined that a full MTARC review of the toxicology data base for the active ingredient pronamide is not required. V. Attachment (not available electronically) Carcinogenicity Peer Review of Pronamide (3rd; Memorandum: N. Thoa, May 26, 1993) 16 ATTACHMENT Carcinogenicity Peer Review of Pronamide (3rd; Memorandum: N. Thoa, May 26, 1993) An electronic version of this document is not available. See the hard copy file.

epa

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regulations

EPA-HQ-OPP-2002-0165-0003

Supporting & Related Material

OPP Docket 2002­ 0165 Page 1 of 1 RESPONSE TO COMMENTS Draft Guidance on Submitting Requests for Threshold of Regulation (TOR) Decisions; Draft Standard Operating Procedures (SOP) for Making TOR Decisions Comment: The American Chemistry Council Biocides Panel commented on the TOR policy as it applies to the use of antimicrobial pesticides. [Item 004, OPP Docket 00795] Response: The policy issues raised in this comment were not relevant to the procedural issues discussed in the draft PR Notice or Draft Standard Operating Procedures for implementing the TOR policy. The comment was sent to the Antimicrobials Division for its consideration. The Antimicrobial Division will respond directly to the commenter.

epa

2024-06-07T20:31:42.803993

regulations

EPA-HQ-OPP-2002-0166-0001

Notice

Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

51260 Federal Register / Vol. 67, No. 152 / Wednesday, August 7, 2002 / Notices IV. Public Docket Complete lists of registrations canceled for non­ payment of the maintenance fee will also be available for reference during normal business hours in the OPP Public Docket, Room 119, Crystal Mall # 2, 1921 Jefferson Davis Highway South, Arlington VA, and at each EPA Regional Office. Product specific status inquiries may be made by telephone by calling toll­ free 1 800 444 7255. List of Subjects Environmental protection, Fees. Dated: July 25, 2002. Marcia E. Mulkey, Director, Office of Pesticide Programs. [ FR Doc. 02 19982 Filed 8 6 02; 8: 45 a. m.] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0166; FRL 7190 4] Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: This notice announces the initial filing of a pesticide petition proposing the establishment of regulations for residues of a certain pesticide chemical in or on various food commodities. DATES: Comments, identified by docket ID number OPP 2002 0166, must be received on or before September 6, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. C. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002 0166 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By mail: Treva Alston, Registration Support Branch, Registration Division ( 7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 308 8373; e­ mail address: treva. alston@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? You may be affected by this action if you are an agricultural producer, food manufacturer or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Categories NAICS codes Examples of potentially affected entities Industry 111 Crop production 112 Animal production 311 Food manufacturing 32532 Pesticide manufacturing This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in the table could also be affected. The North American Industrial Classification System ( NAICS) codes have been provided to assist you and others in determining whether or not this action might apply to certain entities. If you have questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up the entry for this document under the `` Federal Register Environmental Documents.'' You can also go directly to the Federal Register listings at: http:// www. epa. gov/ fedrgstr/. 2. In person. The Agency has established an official record for this action under docket ID number OPP 2002 0166. The official record consists of the documents specifically referenced in this action, any public comments received during an applicable comment period, and other information related to this action, including any information claimed as confidential business information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Highway, Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002­ 0166 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in Wordperfect 6.1/ 8.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP 2002 0166. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI That I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or VerDate 11< MAY> 2000 21: 23 Aug 06, 2002 Jkt 197001 PO 00000 Frm 00100 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 07AUN1. SGM pfrm11 PsN: 07AUN1 51261 Federal Register / Vol. 67, No. 152 / Wednesday, August 7, 2002 / Notices all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person identified under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Make sure to submit your comments by the deadline in this notice. 7. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. What Action is the Agency Taking? EPA has received a pesticide petition as follows proposing the establishment and/ or amendment of regulations for residues of a certain pesticide chemical in or on various food commodities under section 408 of the Federal Food, Drug, and Cosmetic Act ( FFDCA), 21 U. S. C. 346a. EPA has determined that this petition contains data or information regarding the elements set forth in section 408( d)( 2); however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition. List of Subjects Environmental protection, Agricultural commodities, Feed additives, Food additives, Pesticides and pests, Reporting and recordkeeping requirements. Dated: July 25, 2002. Peter Caukins, Acting Director, Registration Division, Office of Pesticide Programs. Summary of Petition The petitioner summary of the pesticide petition is printed below as required by section 408( d)( 3) of the FFDCA. The summary of the petition was prepared by the petitioner and represents the view of the petitioner. EPA is publishing the petition summary verbatim without editing it in any way. The petition summary announces the availability of a description of the analytical methods available to EPA for the detection and measurement of the pesticide chemical residues or an explanation of why no such method is needed. Akzo Nobel Surface Chemistry LLC PP 7E4807 EPA has received a pesticide petition PP 7E4807 from Akzo Nobel Surface Chemistry LLC, 300 South Riverside Plaza, Chicago, IL 60606, proposing, pursuant to section 408( d) of the Federal Food, Drug, and Cosmetic Act ( FFDCA), 21 U. S. C. 346a( d), to amend 40 CFR part 180. To establish an exemption from the requirement of a tolerance for [ 2­ ethylhexyl glucopyranoside] to be applied to growing crops only. EPA has determined that the petition contains data or information regarding the elements set forth in section 408( d)( 2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The plant metabolism of 2­ ethylhexyl glucopyranoside has not been investigated. However, due to the structural similarity, the metabolic pathway for 2­ ethylhexyl glucopyranoside is expected to be similar to that of other alkyl glucosides which have been previously granted an exemption from the requirement of a tolerance, and also of those alkyl glucosides of similar structure that appear on EPA's current List 4B Inert Ingredient List. 2. Analytical method. The inert ingredient, impurities and oligomer distribution can be analyzed using high temperature gas chromatography with cold on column injection after derivatization with silylating reagents. Low levels of the inert ingredient can be detected by HPLC. 3. Magnitude of residues. Given the current extensive and widespread use of structurally similar nonionic surfactants in herbicide formulations, the added use of 2­ ethylhexyl glucopyranoside will not significantly contribute to the total use­ volume of these materials. The expected concentration of 2ethylhexyl glucopyranoside when used in an herbicide formulation will be much lower than the concentration of any coformulated pesticide active ingredient. Therefore, the comparable application rate, on a grams/ acre basis will be significantly lower than that of any coformulated active ingredient. It is then reasonable to assume that any potential residues resulting from the use of 2­ ethylhexyl glucopyranoside in a pesticide formulation would be insignificant. B. Toxicological Profile 1. Acute toxicity. The results of acute toxicity testing for 2­ ethylhexyl glucopyranoside are as follows: Acute oral LD50 ( rat) > 2.0 gram/ kilogram ( g/ kg); Acute dermal LD50 ( rat) > 2.38 g/ kg; moderate to severe eye irritant ( rabbit); non­ irritating to skin ( rabbit); not a skin sensitizer ( guinea pig). 2. Genotoxicty. 2­ Ethylhexyl glucoside was negative in the Ames test, and did not induce chromosomal aberrations in human lymphocytes cultured in vivo. 3. Reproductive and developmental toxicity. Although the final report has not yet been issued, the preliminary results from a one­ generation reproduction toxicity study with 2­ ethylhexyl glucoside administered in male and female Wistar rats are available. The results indicate gavage treatment of male and female Wistar rats with 2­ ethylhexyl glucoside at dose levels of 15, 150 or 750 milligram/ kilogram ( mg/ kg) body weight/ day during one generation, revealed parental toxicity in animals receiving 750 mg/ kg b. w./ day. Reproductive parameters and development of the pups were not affected up to 750 mg/ kg b. w./ day. Parental toxicity consisted of affected mortality, clinical signs, body weights, and food consumption for animals treated at 750 mg/ kg body weight/ day. Based on the results in this onegeneration study, the definitive parental no observed adverse effect level ( NOAEL) was established as being 150 mg/ kg body weight/ day. The definitive reproductive and developmental NOAEL was established as being 750 mg/ kg body weight/ day. 4. Subchronic toxicity. A 28­ day oral toxicity study in the rat was conducted VerDate Aug< 2,> 2002 19: 43 Aug 06, 2002 Jkt 197001 PO 00000 Frm 00101 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 07AUN1. SGM pfrm17 PsN: 07AUN1 51262 Federal Register / Vol. 67, No. 152 / Wednesday, August 7, 2002 / Notices on 2­ ethylhexyl glucopyranoside. The results were that in the rat, 750 mg/ kg/ day represents the no­ observed­ toxic effect level ( NOTEL) and 150 mg/ kg/ day represents the no­ observed effect level ( NOEL). 5. Chronic toxicity. Based on the NOTEL and NOEL results of the 28­ day study conducted on 2­ ethylhexyl glucopyranoside, there are no chronic health concerns. 6. Animal metabolism. Animal metabolism studies have not been conducted on 2­ ethylhexyl glucopyranoside. However, structurally similar radiolabeled alkyl glucopyranosides were studied after oral administration to mice. The results indicate that the glycosidic bond was rapidly hydrolyzed in the intestine and liver to sugars and the parent alcohol. The sugars and alcohols then entered the pathways of lipid and carbohydrate metabolism. 7. Metabolite toxicology. The metabolites of 2­ ethylhexyl glucopyranoside are expected to be the cleavage products at the glycosidic bond, 2­ ethylhexanol and glucose. The toxicity of these two metabolites is well known. 8. Endocrine disruption. No evidence of endocrine disruption was observed in any of the studies conducted on 2­ ethylhexyl glucopyranoside, nor are there any known reports of any estrogenic and adverse effects to human population as a result of the use of 2­ ethyhexyl glucopyranoside. C. Aggregate Exposure 1. Dietary exposure. Based on the metabolism study that indicates alkyl glucopyranosides are readily metabolized in the liver and intestine to glucose and the alcohol, exposure to 2­ ethylhexyl glucopyranoside should not pose a dietary risk under any foreseeable circumstances to the U. S. population including infants and children. i. Food. Exposures to 2­ ethylhexyl glucopyranoside due to ingestion of food is not expected to occur. ii. Drinking water. Exposures to 2­ ethylhexyl glucopyranoside due to ingestion of water is not expected to occur. 2. Non­ dietary exposure. Structurally similar alkyl glucopyranosides are currently being used in a number of institutional and household cleaning applications. These current uses are expected to result in significantly higher exposures than exposure due to the insignificant residue levels resulting from the use under the proposed exemption from the requirement of a tolerance applied to growing crops only. D. Cumulative Effects. From the results of the tests conducted on 2­ ethylhexyl glucopyranoside, no evidence of any specific target organ toxicity has been produced. Therefore, there is no evidence of a common mechanism of toxicity with any other substance, and there is no reason to expect that the use of 2­ ethyhexyl glucopyranoside will contribute to any cumulative toxicity resulting from exposures to other substances having a common mechanism of toxicity. E. Safety Determination 1. U. S. population. The results of the acute, genotoxic, subacute and developmental toxicity studies conducted on 2­ ethylhexyl glucopyranoside indicate a relatively low order of toxicity. Structurally similar alkyl glucopyranosides currently exempted from the requirement of a tolerance, also appear on EPA's List 4B Inert List. Therefore, due to the low order of toxicity of 2­ ethylhexyl glucopyranoside and the lack of known adverse human health effects associated with this class of chemicals, the exemption from the requirement of a tolerance on growing crops only is not expected to result in any new, or adverse effects to human health or the environment. 2. Infants and children. Exposure to 2­ ethylhexyl glucopyranosides to infants and children is not expected to occur. The substance will be used as an inert ingredient at low levels on growing crops only, and any residual levels are expected to be insignificant and consistent with structurally similar alkyl glucopyranosides currently exempted from the requirement of a tolerance. F. International Tolerances No codex maximum residue levels have been established for 2­ ethyhexyl glucopyranoside. [ FR Doc. 02 19805 Filed 8 6 02; 8: 45 am] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0151; FRL 7188 6] Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: This notice announces the initial filing of a pesticide petition proposing the establishment of regulations for residues of a certain pesticide chemical in or on various food commodities. DATES: Comments, identified by docket ID number OPP 2002 0151, must be received on or before September 6, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. C. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002 0151 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By mail: Sidney Jackson, Registration Division ( 7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 305 7610; e­ mail address: jackson. sidney@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? You may be affected by this action if you are an agricultural producer, food manufacturer or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Categories NAICS codes Examples of potentially affected entities Industry 111 Crop production 112 Animal production 311 Food manufacturing 32532 Pesticide manufacturing This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in the table could also be affected. The North American Industrial Classification System ( NAICS) codes have been provided to assist you and others in determining whether or not this action might apply to certain entities. If you have questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. VerDate Aug< 2,> 2002 19: 43 Aug 06, 2002 Jkt 197001 PO 00000 Frm 00102 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 07AUN1. SGM pfrm17 PsN: 07AUN1

epa

2024-06-07T20:31:42.806879

regulations

EPA-HQ-OPP-2002-0180-0001

Notice

Chlorpropham Tolerance Reassessment Decision; Notice of Availability.

< PRE> [ Federal Register: September 18, 2002 ( Volume 67, Number 181)] [ Notices] [ Page 58795­ 58797] From the Federal Register Online via GPO Access [ wais. access. gpo. gov] [ DOCID: fr18se02­ 77] ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ENVIRONMENTAL PROTECTION AGENCY [ OPP­ 2002­ 0180; FRL­ 7198­ 7] Chlorpropham Tolerance Reassessment Decision; Notice of Availability AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ SUMMARY: This notice constitutes the Agency's report on the Food Quality Protection Act ( FQPA) tolerance reassessment progress and risk management decision for chlorpropham, announces the Agency's decision, and releases the human health risk assessment and related documents supporting this decision to the public. This notice of tolerance reassessment for chlorpropham starts the 30­ day public comment period during which the public is invited to submit comments on the Agency's `` Report of the FQPA Tolerance Reassessment Progress and Risk Management Decision ( TRED)'' for chlorpropham. If any comment causes the Agency to revise its decision on tolerance reassessment for chlorpropham, the Agency will publish a notice of its amendment in the Federal Register. The Agency's reassessment of dietary risk, including public exposure through food and drinking water as required by the Federal Food, Drug, and Cosmetic Act ( FFDCA), as amended by FQPA, indicate that dietary risk from stored potatoes treated with chlorpropham per se, poses no risk concerns within the limits of the reassessed tolerances associated with chlorpropham use on potatoes. DATES: Comments must be submitted on or before October 18, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP­ 2002­ 0180 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Gary Mullins, Special Review and Reregistration Division ( 7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 308­ 8044; e­ mail address: < A HREF=" mailto: mullins. gary@ epa. gov"> mullins. gary@ epa. gov</ A>. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general. This action may, however, be of interest to those persons who are or may be required to conduct testing of chemical substances under the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) or the FFDCA. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at < A HREF=" http:// frwebgate. acc ess. gpo. gov/ cgi­ bin/ leaving. cgi? from= leavingFR. html& log= linklog& to= http:// www. ep a. gov/"> http:// www. epa. gov/</ A>. To access this document, on the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up [[ Page 58796]] the entry for this document under the `` Federal Register­­ Environmental Documents.'' You can also go directly to the Federal Register listings at < A HREF=" http:// frwebgate. access. gpo. gov/ cgi­ bin/ leaving. cgi? from= leavingFR. h tml& log= linklog& to= http:// www. epa. gov/ fedrgstr/"> http:// www. epa. gov/ fedrgstr/</ A >. To access TRED documents electronically, go directly to the TREDs table on the EPA Office of Pesticide Programs Home Page, at < A HREF=" http:// frwe bgate. access. gpo. gov/ cgi­ bin/ leaving. cgi? from= leavingFR. html& log= linklog& to= http :// www. epa. gov/ pesticides/ reregistration/ status. htm"> http:// www. epa. gov/ pesticides/ reregistration/ status. htm</ A>. 2. In person. The Agency has established an official record for this action under docket ID number OPP­ 2002­ 0180. The official record consists of the documents specifically referenced in this action, any public comments received during an applicable comment period, and other information related to this action, including any information claimed as Confidential Business Information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall < greek­ i> 2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305­ 5805. C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP­ 2002­ 0180 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, Rm. 119, Crystal Mall < greek­ i> 2, 1921 Jefferson Davis Hwy., Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305­ 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: < A HREF=" mailto: opp­ docket@ epa. gov"> opp­ docket@ epa. gov</ A>, or you ca n submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0/ 9.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP­ 2002­ 0180. Electronic comments may also be < strong> filed</ strong> online at many Federal Depository Libraries. D. How Should I Handle CBI that I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the notice or collection activity. 7. Make sure to submit your comments by the deadline in this notice. 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. Background A. What Action is the Agency Taking? This notice constitutes and announces the availability of the chlorpropham TRED. This decision has been developed as part of the public participation process that EPA and the U. S. Department of Agriculture ( USDA) are using to involve the public in the reassessment of pesticide tolerances under FFDCA. EPA must review tolerances and tolerance exemptions that were in effect when FQPA was enacted in August 1996, to ensure that these existing pesticide residue limits for food and feed commodities meet the safety standard of the new law. In reviewing these tolerances, the Agency must consider, among other things, aggregate risks from non­ occupational sources of pesticide exposure, whether there is increased susceptibility to infants and children, and the cumulative effects of pesticides with a common mechanism of toxicity. The tolerances are considered reassessed once the safety finding has been made that aggregate risks are not of concern. A reregistration eligibility decision ( RED) was completed for chlorpropham in April 1995, prior to FQPA enactment, and therefore needed an updated assessment to consider the provisions of the Act. The FQPA requires that the Agency consider `` available information'' concerning the cumulative effects of a particular pesticide's residues and `` other substances that have a common mechanism of toxicity.'' The reason for consideration of other substances is due to the possibility that low­ level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. EPA did not perform a cumulative risk assessment as part of this reregistration review of chlorpropham, because the Agency has not determined if there are any other chemical substances that have a mechanism of toxicity common with that of chlorpropham. If EPA identifies other substances that share a common mechanism of toxicity with chlorpropham, then a cumulative risk assessment will be conducted that includes chlorpropham. Further, EPA is in the process of developing criteria for characterizing and testing endocrine disrupting chemicals and plans to implement an Endocrine Disruptor [[ Page 58797]] Screening Program. Chlorpropham will be reevaluated at that time and additional studies may be required. Additionally, the Agency has evaluated the dietary risk associated with chlorpropham and has determined that provided the Special Local Need ( SLN) registration for Easter lily bulb use is amended to reduce the maximum rate of application from 3.99 pounds active ingredient/ acre to 2.0 pounds active ingredient/ acre, as agreed upon by stakeholders, there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to chlorpropham when considering dietary exposure and all other non­ occupational sources of pesticide exposure for which there is reliable information. Therefore, with this mitigation measure in place, 15 tolerances are now considered reassessed and 9 new tolerances will be established for residues of chlorpropham in/ on raw agricultural commodities under section 408( q) of the FFDCA. All registrants of pesticide products containing the active ingredient listed in this document have been sent the appropriate TRED document, and must respond to labeling requirements within 8 months of receipt. In addition, the Agency requests a response to the generic Data Call­ In ( DCI) letter from technical registrants within 90 days of receipt. The reregistration program is being conducted under Congressionally­ mandated time frames, and EPA recognizes both the need to make timely reregistration decisions and to involve the public. All comments received within 30 days of publication of this Federal Register notice will be considered by the Agency. If any comment significantly impacts this TRED, the Agency will amend its decision by publishing a Federal Register notice. B. What is the Agency's Authority for Taking this Action? The legal authority for this TRED falls under FIFRA, as amended in 1988 and 1996. Section 4( g)( 2)( A) of FIFRA directs that, after submission of all data concerning a pesticide active ingredient, `` the Administrator shall determine whether pesticides containing such active ingredient are eligible for reregistration,'' and either reregistering products or taking `` other appropriate regulatory action.'' List of Subjects Environmental protection, Pesticides, Tolerances. Dated: September 10, 2002. Lois A. Rossi, Director, Special Review and Reregistration Division, Office of Pesticide Programs. [ FR Doc. < strong> 02</ strong>­< strong> 23593</ strong> < strong> Filed</ strong> 9­ 17­ < strong> 02</ strong>; 8: 45 am] BILLING CODE 6560­ 50­ S </ PRE>

epa

2024-06-07T20:31:42.818826

regulations

EPA-HQ-OPP-2002-0180-0020

Supporting & Related Material

1 United States Prevention, Pesticides November 2002 Environmental Protection and Toxic Substances EPA 738­ F­ 02­ 015 Agency ( 7508C) Chlorpropham TRED Facts EPA has assessed the risks of chlorpropham and completed a Report of the Food Quality Protection Act ( FQPA) Tolerance Reassessment Progress and Risk Management Decision ( known as a TRED) for this pesticide. Provided that risk mitigation measures are adopted, as outlined in the TRED, individual and aggregated risks are within acceptable levels. The Federal Food, Drug and Cosmetic Act ( FFDCA), as amended by FQPA, requires EPA to review all the tolerances ( legal limits for residues in food) for registered chemicals in effect on or before the date of the enactment of the FQPA. In reviewing these tolerances, the Agency must consider, among other things, aggregate risks from non­ occupational sources of pesticide exposure, whether there is increased susceptibility to infants and children, and the cumulative effects of pesticides with a common mechanism of toxicity. The tolerances are considered reassessed once the safety finding has been made or a revocation occurs. EPA completed a chlorpropham reregistration eligibility decision ( RED) prior to FQPA of 1996 enactment; therefore, tolerances needed to be reassessed to meet the FQPA standard. The Agency has evaluated the dietary ( food and drinking water) risk associated with chlorpropham and has determined that provided the Special Local Need registration ( SLN) for Easter lily bulb use is amended to reduce the maximum rate of application as agreed upon by stakeholders, there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to chlorpropham when considering dietary exposure and all non­ occupational sources of pesticide exposure. Therefore, with the implementation of this mitigation measure, fifteen ( 15) tolerances established for residues of chlorpropham in/ on raw agricultural commodities are now considered reassessed as safe under section 408( q) of the FFDCA. Uses ° Chlorpropham is a herbicide primarily registered for use on post­ harvest potatoes for sprout control. There are four SLN registrations for use of Easter lilies ( on approximately 150 acres annually in Oregon and California); gingko trees in the District of Columbia; and post­ harvest potatoes stored in high humidity conditions in the state of Maine, which requires a higher application rate. ° Approximately 445,600 pounds of chlorpropham active ingredient ( a. i.) are used annually. 2 Health Effects ° Parent chlorpropham has been classified by the Agency as a " Group E" human carcinogen ( no evidence of carcinogenicity). However, some chlorpropham is metabolized to 3­ chloroaniline ( 3­ CA) on potatoes and some anilines are known carcinogens. The Agency does not have data on 3­ CA necessary to conduct a carcinogenicity assessment, but does have data for 4­ chloroaniline ( 4­ CA), which is structurally similar, but not expected to be formed in the breakdown of chlorpropham in potatoes. The cancer potency factor ( or Q 1*) for 4­ CA was used as a surrogate to assess the potential cancer risk from 3­ CA and is expected to overestimate potential cancer risk. ° There is no evidence of endocrine disruption from exposure to chlorpropham. Dietary ( Food and Drinking Water) Risks ° Acute and chronic ( non­ cancer and cancer) dietary exposures from eating food crops treated with chlorpropham are not of concern for the entire U. S. population and all subgroups that were assessed. ° Acute and chronic ( non­ cancer) exposure through surface and ground water sources of drinking water is negligible, and not of concern to the Agency. However, there are risks of concern from chronic ( cancer) exposure to chlorpropham from ground water sources of drinking water from the limited Easter lily bulb use. These risks are addressed through the mitigation measures described below. Occupational and Ecological Risks ° Occupational and ecological risk have not been assessed. Occupational and ecological risk management decisions were made as part of the 1996 chlorpropham registration eligibility decision ( RED). No new data has been received to warrant reconsideration of these risks. Risk Mitigation/ Label Amendments In completing this TRED, the Agency has identified certain label amendments which need to be implemented to mitigate risks of concern and ensure consistency among the labels. ° To mitigate chronic ( cancer) food and drinking water risks of concern from Easter lily bulb use, product labels need to be amended to reduce the maximum application rate from 3.99 lb a. i. per acre to 2.0 lb a. i. per acre. ° For aerosol ready­ to­ use ( RTU) products used on stored potatoes, the labels which specify a maximum application rate of 165% of the typical rate ( 0.017 lbs a. i. per 1000 lbs of potatoes), need to clearly state a total seasonal rate of 0.028 lb a. i. per 1000 pounds of potatoes. For the same product labels which specify a maximum application rate of 145% of the typical rate, 3 product labels need to clearly state a total seasonal rate that does not exceed 0.025 lbs a. i. per 1000 pounds of potatoes. ° For Emulsifiable Concentrate ( EC) products, a maximum seasonal rate of 0.0104 lb a. i. per 1000 pounds of potatoes needs to be specified. ° For entry into enclosed treatment / storage areas after application of products heated above 250 ° F, handlers must wear a respirator with either an organic­ vapor removing cartridge with a prefilter approved for pesticides, or a canister approved for pesticides. Tolerance Reassessment Decisions A total of fifteen ( 15) tolerances for chlorpropham have been reassessed. Thirteen ( 13) tolerances are to raised, one ( 1) tolerance is to be lowered, and one ( 1) tolerance is to be revoked. In addition, nine ( 9) new tolerances are to be established for residues in/ on raw agricultural commodities under section 408( q) of the FFDCA. Availably of Supporting Documents A Notice of Availability of the chlorpropham TRED and other supporting documents, including the risk assessments and response to comments, has bee published in the Federal Register on September 18, 2002 ( 67 FR 58795). A copy of the TRED and all supporting documents will also be available on the Agency's website at: http:// www. epa. gov/ pesticides/ reregistration/ status. htm EPA has established an official public docket for this action under docket ID number OPP­ 2002­ 0180, an electronic version of which is available through EPA's electronic public docket and comment system, EPA Dockets. You may use EPA Dockets at http:// www. epa. gov/ edocket/ to submit or view public comments, access the index listing of the contents of the official public docket, and to access those documents in the public docket that are available electronically. Additionally, you may still access any of the publicly available docket materials through the OPP docket facility. Once in the system, select " search," then key in the appropriate docket ID number.

epa

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regulations

EPA-HQ-OPP-2002-0182-0001

Notice

Guidance for Developing & Performing Quality Control of Water Modeling Standard Scenarios and Standard Scenario Metadata Files; Notice of Availability.

54206 Federal Register / Vol. 67, No. 162 / Wednesday, August 21, 2002 / Notices Pennsylvania Avenue, NW., Washington, DC 20460. Telephone: 202Ð 564Ð 3261; fax: 202Ð 565Ð 0050. Correction In the Federal Register of August 14, 2002, in FR Doc. 02Ð 20581, on page 53001, in the first column, correct the ADDRESSES caption to read: ADDRESSES: The document is available electronically through the NCEA Web site at (www. epa. gov/ ncea) under the Publications menus. A limited number of paper copies will be available from EPA's National Service Center for Environmental Publications (NSCEP), P. O. Box 42419, Cincinnati, Ohio 45242; telephone: 1Ð 800Ð 490Ð 9198 or 513Ð 489Ð 8190; facsimile: 513Ð 489Ð 8695. Please provide your name and mailing address and the title and EPA number of the requested publication. Dated: August 16, 2002. Art Payne, Acting Director, National Center for Environmental Assessment. [FR Doc. 02Ð 21425 Filed 8Ð 20Ð 02; 8: 45 am] BILLING CODE 6560– 50– P ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0182; FRL– 7193– 5] Guidance for Developing and Performing Quality Control of Water Modeling Standard Scenarios and Standard Scenario Metadata Files; Notice of Availability AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: EPA is soliciting comments on two documents, `` PRZM Field and Orchard Crop Scenario Metadata'' and `` Standard Procedures for Conducting Quality Control and Quality Assurance for Pesticide Root Zone Model (PRZM) Field and Orchard Crop Scenarios. '' Interested parties may request a copy of the draft proposed procedures and scenario documentation as a set in Unit I. B. of this notice. The PRZM Field and Orchard Crop Scenario Metadata documents the crop­ specific parameters (specific value used and its reference) which are key elements of the exposure scenario used to determine surface water concentrations in ecological and drinking water assessments. Standard Procedures for Conducting Quality Control and Quality Assurance for PRZM Field and Orchard Crop Scenarios provides a defined set of steps (methods of selecting or estimating specific scenario values and available references) to develop and/ or ensure the quality of a crop scenario. Both documents provide a transparent description of each environmental modeling scenario and the procedures used to create them while providing consistent and reproducible products. DATES: Comments, identified by docket ID number OPPÐ 2002Ð 0182, must be received on or before October 21, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPPÐ 2002Ð 0182 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Sid Abel, Environmental Fate and Effects Division (7507C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 305Ð 7346; fax number: (703) 305Ð 6309; e­ mail address: abel. sid@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general. This action may, however, be of interest to those who are or may be conducting surface water modeling assessments on behalf of pesticide registration, risk assessments or those who may be involved in developing information directly related to data necessary to develop a modeling scenario. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of these documents, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations, '' `` Regulations and Proposed Rules, '' and then look up the entry for this document under the `` Federal RegisterÑ Environmental Documents. '' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. To access information about Standard Procedures for Conducting Quality Control and Quality Assurance for Pesticide Root Zone Model (PRZM) Field and Orchard Crop Scenarios and PRZM Field and Orchard Crop Scenario Metadata, go directly to the Home Page for the Office of Pesticide Programs at: http:// www. epa. gov/ oppefed1/ models/ water/ op scenario metadata df 061602. htm and http:// www. epa. gov/ oppefed1/ models/ water/ qa qc documentation ver2 .htm 2. By mail. You may obtain copies of these documents, and certain other related documents that might be available by contacting the person listed under FOR FURTHER INFORMATION CONTACT. C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPPÐ 2002Ð 0182 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305Ð 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described in this unit. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPPÐ 2002Ð 0182. Electronic comments may also be filed online at many Federal Depository Libraries. VerDate Aug< 2,> 2002 17: 26 Aug 20, 2002 Jkt 197001 PO 00000 Frm 00043 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 21AUN1. SGM pfrm17 PsN: 21AUN1 54207 Federal Register / Vol. 67, No. 162 / Wednesday, August 21, 2002 / Notices D. How Should I Handle CBI that I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the notice or collection activity. 7. Make sure to submit your comments by the deadline in this notice. 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. What Action is the Agency Taking? The Agency is seeking comment on two documents that describe how EPA develops and uses pesticide surface water modeling scenarios in ecological and drinking water exposure and risk assessments. These documents are entitled `` Pesticide Root Zone Model (PRZM) Field and Orchard Crop Scenario Metadata'' and `` Standard Procedures for Conducting Quality Control and Quality Assurance for PRZM Field and Orchard Crop Scenarios'' and can be found at the following web addresses: http:// www. epa. gov/ oppefed1/ models/ water/ op scenario metadata df 061602. htm and http:// www. epa. gov/ oppefed1/ models/ water/ qa qc documentation ver2 .htm Modeling scenarios are defined as the set of characteristics of the agricultural crop to which a pesticide may be applied (e. g., cotton) and the field information on which the crop is actually grown (e. g., soils) that are necessary to estimate pesticide transport to surface water. The modeling sites, or scenarios, the OPP uses to estimate environmental concentrations in surface water are documented in and developed through the use of these documents. These documents were developed to support the following activities: OP Cumulative Risk Assessment, the Agency's Information Quality Guideline, data quality guidelines and to improve environmental assessments. The first document, `` PRZM Field and Orchard Crop Scenario Metadata, '' provides a detailed listing of the parameters and associated values specific to a crop and field combination (e. g., a cotton field in Yazoo County, Mississippi). OPP evaluated several approaches to documenting the parameters from a modeling scenario used to estimate environmental exposures. This format is believed to provide the most appropriate means to readily document and recall critical information contained in a given scenario. Users of this format, whether Agency staff or the public, will be able to quickly document a scenario in a consistent manner that meets quality standards implemented by the OPP. In addition, users who retrieve information or wish to understand the content of a crop­ field scenario for a pesticide assessment will be assured of a standardized format which simplifies review. Information in this document reflects the results of the second document `` Standard Procedures for Conducting Quality Control and Quality Assurance for PRZM Field and Orchard Crop Scenarios. '' Standard Procedures for Conducting Quality Control and Quality Assurance for PRZM Field and Orchard Crop Scenarios describes the set of procedures, methods, and references to `` construct'' or review for consistency the information contained in a cropfield scenario. The steps and recommendation described in this guidance provide a sound scientific basis for selecting information with relevance to what is observed in an actual agricultural field such as cotton. The methodology is intended to give the regulated community, decision­ makers and the public confidence that assessments resulting from the use of scenarios representing an agricultural field reflect conditions that are likely to occur in the `` real world. '' Numerous methods and sources of credible scientific information are given in this document and are considered readily available to the public through voice contact, public information sources (e. g., public libraries) or the world wide web. The Agency has identified and described as best possible information to support this guidance and seeks comments on what additional information would help improve modeling scenarios. List of Subjects Environmental protection, Environmental modeling, Pesticide Root Zone Model, PRZM, Surface water exposure, Pesticides, Crops, Modeling Guidance. Dated: August 5, 2002. Sidney Abel, III, Chief, Environmental Risk Branch I, Office of Pesticide Programs. [FR Doc. 02Ð 20874 Filed 8Ð 20Ð 02; 8: 45 am] BILLING CODE 6560– 50– S ENVIRONMENTAL PROTECTION AGENCY [FRL– 7264– 3] Peak Oil Superfund Site; Notice of Proposed de Minimis Settlement AGENCY: Environmental Protection Agency (EPA). ACTION: Notice of proposed de minimis settlement. SUMMARY: Under section 122( g)( 4) of the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA), the Environmental Protection Agency has offered a de minimis settlement at the Peak Oil Superfund Site (Site) under an Administrative Order on Consent (AOC) to settle claims for past and future response costs at the Site. Approximately 263 parties have returned signature pages accepting EPA's settlement offer. For thirty (30) days following the publication of this notice, EPA will receive written comments relating to the settlement. EPA may withdraw from or modify the proposed settlement should such comments disclose facts or considerations which indicate the proposed settlement is inappropriate, improper, or inadequate. Copies of the proposed settlement are available from: VerDate Aug< 2,> 2002 17: 26 Aug 20, 2002 Jkt 197001 PO 00000 Frm 00044 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 21AUN1. SGM pfrm17 PsN: 21AUN1

epa

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regulations

EPA-HQ-OPP-2002-0188-0001

Notice

Availability of the Risk Assessment on FQPA Tolerance Reassessment Progress of the TRED Hexazimone

65118 Federal Register / Vol. 67, No. 205 / Wednesday, October 23, 2002 / Notices submitted by Roquette in its Lycasin 80/ 55 petition regarding numerous studies relating to the safety of the ingredient, including reports on: Digestion, absorption, distribution and excretion; acute oral toxicity, subchronic toxicity, genotoxicity, reproduction, biological tolerance, human exposure, and laxation effects. 1. Acute toxicity. The acute oral toxicity of HSH has been evaluated. The acute oral lethal dose (LD50) of HSH is greater than 10 grams/ kilogram (g/ kg). 2. Genotoxicty. As stated in Roquette's GRAS submission of Lycasin 80/ 55, HSH is nonmutagenic and nonclastogenic in short­ term in vivo, and in vitro studies. 3. Reproductive and developmental toxicity. Again as noted in Roquette's GRAS submission of Lycasin 80/ 55 HSH products, when administered to rats over 3­ generations, produce no significant effects on reproduction. 4. Subchronic toxicity. In Roquette's GRAS submission for Lycasin 80/ 55, it is noted that when administered orally to rats and dogs in amounts of 5 g/ kg to 15 g/ kg of body weight per day for 90 days, HSH produced no toxicologically meaningful effects which could not be accounted for by the presence of sorbitol. The possible treatment related effects are aggregates in the renal pelvis of some rats, diarrhea in most dogs, and minimal ectasia in the renule tubules of some dogs. 5. Chronic toxicity. HSH is used extensively in foods. Grain Processing Corporation is not aware of any chronic toxic effects associated with this product. 6. Animal metabolism. The GRAS submission for Lycasin 80/ 55 developed by Roquette Freres states that over 96% of HSH (Lycasin 80/ 55) is broken down by the mammalian digestive system into the GRAS substances, glucose and sorbitol, the remaining 4% is in the form of maltitol. One half of the maltitol is excreted in the feces and the majority of the remainder is excreted in the urine. Within the first 2 hours after oral administration of HSH (Lycasin 80/ 55), virtually all of the glucose to glucose bonds are broken down in the digestive system, producing a resulting mixture of glucose, sorbitol, and maltitol. Within 7 hours, 95% of the total maltitol, is broken down into glucose and sorbitol. Of the remaining 5% of maltitol, 2% is found in the digestive tube and fecal contents, less than 1% is found in the plasma, and approximately 1% is excreted in the urine. There is no accumulation of maltitol in the plasma, liver, kidneys, or spleen of rats fed 13.5 g/ kg/ day of Lycasin 80/ 55 for 10 days irrespective of whether measurements are made 12 hours or 10 days after cessation of dosing. Lycasin 80/ 55 at the dose levels tested, 30 to 180 grams per day, produces no significant variations in the clinical chemical, hematological or urinary profile of humans with the exception of glucose and insulin peaks which are less than 50% of those produced by equivalent amounts of glucose, and 50 to 90% of those produced by sucrose. The only significant clinical effects are flatulence and diarrhea, which can be accounted for by the presence of free and bound sorbitol. The mean laxative threshold in adult males is approximately 180 grams per day, while in females the threshold is approximately 100 grams per day. In children, the threshold is approximately 60 grams per day, about half that of adults. 7. Metabolite toxicology. None of the metabolites of HSH are considered to be of toxicological significance for the use of this product as a pesticide inert ingredient. 8. Endocrine disruption. Grain Processing Corporation is not aware of any endocrine disruption with the use of this product. C. Aggregate Exposure 1. Dietary exposure. This product is already used extensively in foods. Studies have shown that it is safe even when consumed at levels of up to 100 g/ day. i. Food. As a pesticide inert ingredient HSH will not result in any harmful exposure. The proposed use will not result in any dietary exposure beyond what is currently present in commonly consumed foods. ii. Drinking water. There is no anticipated human exposure to HSH through drinking water. HSH is expected to be degraded by soil microorganisms to carbon dioxide and water before it reaches surface or ground water. Moreover, in water, HSH hydrolyses to glucose and sorbitol. 2. Non­ dietary exposure. No significant non­ dietary human exposure to HSH is anticipated. D. Cumulative Effects HSH is a widely used food ingredient, is readily digested by humans, and there are no cumulative effects. Except for possible occupational exposure of the pesticide mixer/ loader/ applicator, the proposed use of HSH will not result in the exposure of other persons. E. Safety Determination 1. U. S. population. The proposed use of HSH does not pose a safety concern for the U. S. population due to the nontoxic nature of the compound and the absence of exposure. 2. Infants and children. Infants and children will not be exposed to HSH from its proposed use as a pesticide inert ingredient. F. International Tolerances Grain Processing Corporation is unaware of any international tolerances for this product. HSH was developed by a Swedish company in the 1960's and has been widely used by the food industry for many years, especially in confectionery products. Roquette's petition indicates that Roquette's Lycasin products have been approved for use in food in Europe since 1963, as indicated below. Country Year of Approval Sweden 1963 (reaffirmed in 1975) Switzerland 1968 Norway 1975 Finland 1975 (reaffirmed in 1980) Denmark 1976 [FR Doc. 02– 26993 Filed 10– 22– 02; 8: 45 am] BILLING CODE 6560– 50– S ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0188; FRL– 7199– 7] Availability of the Risk Assessments on FQPA Tolerance Reassessment Progress and Tolerance Reassessment Decision (TRED) for Hexazinone AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: This notice announces the availability of EPA's tolerance reassessment decision and related documents for hexazinone including the Hexazinone Overview, Hexazinone Summary, Hexazinone Decision Document (TRED), and supporting risk assessment documents. EPA has reassessed the 25 tolerances, or legal limits, for residues of hexazinone in or on raw agricultural commodities. These tolerances are now considered safe under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by VerDate 0ct< 09> 2002 17: 58 Oct 22, 2002 Jkt 200001 PO 00000 Frm 00032 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 23OCN1. SGM 23OCN1 65119 Federal Register / Vol. 67, No. 205 / Wednesday, October 23, 2002 / Notices the Food Quality Protection Act (FQPA) of 1996. DATES: Comments on the tolerance reassessment decision for hexazinone, must be received by EPA on or before November 22, 2002. In the absence of substantive comments, the tolerance reassessment decision will be considered final. Comments on the human health and ecological effects risk assessments for hexazinone, must be received by EPA on or before November 22, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in the SUPPLEMENTARY INFORMATION section. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0188 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Dirk V. Helder, Special Review and Reregistration Division (7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 305– 4610; email address: helder. dirk@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general, but will be of interest to a wide range of stakeholders, including environmental, human health, and agricultural advocates; the chemical industry; pesticide users; and members of the public interested in the use of pesticides. The Agency has not attempted to describe all the persons or entities who may be interested in or affected by this action. If you have questions in this regard, consult the persons listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1.Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations, '' `` Regulations and Proposed Rules, '' and then look up the entry for this document under the `` Federal Register— Environmental Documents. '' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. You can obtain copies of the TRED and related documents discussed in this notice on EPA's website at http:// www. epa. gov/ pesticides/ reregistration/ status. htm. Information on pesticide reregistration and tolerance reassessment, including the purpose and status of Agency programs to complete Reregistration Eligibility Decisions (REDs), Interim REDs, and Tolerance Reassessment Decisions (TREDs), is available at http:// www. epa. gov/ pesticides/ reregistration. General information is available on the Office of Pesticide Programs' home page, http:// www. epa. gov/ pesticides/. 2. In person. The Agency has established an official record for this action under docket ID number OPP– 2002– 0188. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0188 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described in this unit. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0/ 9.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP– 2002– 0188. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI that I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the notice or collection activity. 7. Make sure to submit your comments by the deadline in this notice. VerDate 0ct< 09> 2002 15: 41 Oct 22, 2002 Jkt 200001 PO 00000 Frm 00033 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 23OCN1. SGM 23OCN1 65120 Federal Register / Vol. 67, No. 205 / Wednesday, October 23, 2002 / Notices 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. What Action is the Agency Taking? EPA has reassessed the risks associated with current food uses of the pesticide hexazinone, reassessed 25 existing tolerances, and reached a tolerance reassessment and risk management decision. The Agency is issuing for comment the resulting report on FQPA tolerance reassessment progress, including the Hexazinone Overview, Hexazinone Summary, Hexazinone Decision Document (TRED), and supporting risk assessment documents. EPA must review tolerances and tolerance exemptions that were in effect when FQPA was enacted in August 1996, to ensure that these existing pesticide residue limits for food and feed commodities meet the safety standard established by the new law. Tolerances are considered reassessed once the safety finding has been made or a revocation occurs. EPA has reviewed and made the requisite safety finding for the tolerances and exemptions included in this notice. EPA completed the hexazinone Reregistration Eligibility Decision (RED) prior to the 1996 enactment of the FQPA; therefore, while no reregistration decision is required at present, risks from non­ occupational exposure to hexazinone through food, drinking water, and residential uses must be reassessed. There are no residential uses of hexazinone. The Agency has reassessed the 25 tolerances for hexazinone and determined that residues in food and drinking water are not expected to pose risk concerns. Because existing data were inadequate to calculate residue estimates for pasture and rangeland grass and grass hay, EPA constructed the maximum theoretical dietary burden (MTDB) of hexazinone to livestock using protective assumptions for the contributions of other hexazinone treated feed items. Thus, tolerances for meats and milk can be reassessed. Additional field trial data for grass forage and grass hay, as well as rotational crop studies for corn and wheat are required. Because of the relatively low volume of use on pasture and rangeland, data from these confirmatory studies are not expected to significantly change current dietary risk estimates. Some tolerances may be revised once additional data has been submitted to and reviewed by the Agency. The current tolerance expression for hexazinone in 40 CFR 180.396 is for `` combined residues of the herbicide hexazinone (3­ cyclohexyl­ 6­ (dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione) and its metabolites, calculated as hexazinone. '' The tolerance expression should be modified to include specific metabolites A, B, C, D, and E, identified by the appropriate chemical name. Final tolerances are being proposed as part of this Tolerance Reassessment Decision (TRED). In addition, occupational and ecological risk management decisions were made as part of the 1994 hexazinone RED. EPA works with affected parties to reach the tolerance reassessment decisions. The Agency therefore is issuing the hexazinone decision as a final decision with a public comment period. All comments received during the public comment period will be considered by the Agency. If any comment significantly affects the Agency's decision, EPA will publish an amendment to the decision in the Federal Register. In the absence of substantive comments, the tolerance reassessment decisions reflected here will be considered final. List of Subjects Environmental protection, Chemicals, Pesticides and pests. Dated: October 4, 2002. Betty Shackleford, Acting Director, Special Review and Reregistration Division, Office of Pesticide Programs. [FR Doc. 02– 26577 Filed 10– 22– 02; 8: 45 am] BILLING CODE 6560– 50– S ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0223; FRL– 7274– 1] Availability of the Report on FQPA Tolerance Reassessment Progress and Risk Management Decision (TRED) for Metolachlor AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: This notice announces the availability of the report on the Food Quality Protection Act (FQPA) tolerance reassessment progress and Risk Management Decision (TRED) for metolachlor for public comment. EPA has reassessed the 81 tolerances, or legal limits, established for residues of metolachlor in/ on raw agricultural commodities (RACs). These tolerances are now considered safe under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the FQPA of 1996. DATES: Comments, identified by docket ID number OPP– 2002– 0223, must be received on or before November 22, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0223 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Anne Overstreet, Special Review and Reregistration Division (7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 308– 8068; fax number: (703) 308– 8005; e­ mail address: overstreet. anne@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general, but will be of interest to a wide range of stakeholders, including environmental, human health, and agricultural advocates; the chemical industry; pesticide users; and members of the public interested in the use of pesticides. The Agency has not attempted to describe all the persons or entities who may be interested in or affected by this action. If you have questions in this regard, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations, '' `` Regulations and Proposed Rules, '' and then look up the entry for this document under the `` Federal Register— Environmental Documents. '' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. You can obtain copies of the TRED and related documents discussed in this notice on EPA's website at http:// www. epa. gov/ pesticides/ reregistration/ status. htm. VerDate 0ct< 09> 2002 15: 41 Oct 22, 2002 Jkt 200001 PO 00000 Frm 00034 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 23OCN1. SGM 23OCN1

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regulations

EPA-HQ-OPP-2002-0188-0002

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES August 1, 2002 CERTIFIED MAIL Tom Stommel Dupont Stine­ Haskell Research Center PO Box 30 Newark, DE 19714 Dear Mr. Stommel: This is the Environmental Protection Agency's (hereafter referred to as EPA or the Agency) "Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Hexazinone," which was approved on August 1, 2002. A Notice of Availability of this tolerance reassessment decision will be published in the Federal Register (FR) shortly. The Federal Food, Drug and Cosmetic Act (FFDCA), as amended by FQPA, requires EPA to reassess all the tolerances for registered chemicals in effect on or before the date of the enactment of the FQPA, which was August of 1996. In reassessing these tolerances, the Agency must consider, among other things, aggregate risks from non­ occupational sources of pesticide exposure, whether there is increased susceptibility to infants and children, and the cumulative effects of pesticides with a common mechanism of toxicity. Once a safety finding has been made that aggregate risks are not of concern, the tolerances are considered reassessed. A Reregistration Eligibility Decision (RED) for hexazinone was completed in September, 1994, prior to FQPA enactment. Therefore, the tolerances need to be reassessed to meet the FQPA standard. The Agency has evaluated the dietary risk associated with hexazinone and has determined that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to hexazinone when considering dietary, drinking water, and residential exposure and all other non­ occupational sources of pesticide exposure for which there is reliable information. There are no registered residential uses for hexazinone. FQPA requires that EPA consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity." The reason for considering other substances is because of the possibility that low­ level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect, as would a higher level of exposure to any of the other substances individually. EPA did not perform a cumulative risk assessment as part of this review of hexazinone, 2 because the Agency has not determined that there are any other chemical substances that have a mechanism of toxicity common with that of hexazinone. If EPA identifies other substances that share a common mechanism of toxicity with hexazinone, then a cumulative risk assessment will be conducted that includes hexazinone once the final framework EPA will use for conducting cumulative risk assessments is available. Further, EPA is in the process of developing criteria for characterizing and testing endocrine disrupting chemicals and plans to implement an Endocrine Disruptor Screening Program. Hexazinone will be reevaluated at that time and additional studies may be required. The Agency's human health findings for the pesticide hexazinone, were discussed in a closure conference call, and are summarized in the enclosed Hexazinone Overview and Hexazinone Summary of the risk assessments. The risk assessments and other documents pertaining to the hexazinone tolerance reassessment decision are available on the Internet at http:// www. epa. gov/ pesticides/ reregistration/ status. htm and are in the public docket for viewing. The Agency has reassessed all 25 tolerances for hexazinone and can make a FQPA safety determination. Anticipated residues for commodities included in the dietary risk assessment are equal to the tolerance levels and it was assumed that 100% of each crop was treated. Acute and chronic dietary risks from exposure to hexazinone does not exceed the Agency's level of concern. Tolerances for residues of hexazinone in/ on plant, livestock, and processed commodities are currently expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). Because existing data were inadequate to calculate residue estimates for pasture and rangeland grass and grass hay, EPA constructed the maximum theoretical dietary burden (MTDB) of hexazinone to livestock using protective assumptions for the contributions of other hexazinone­ treated feed items. Thus, tolerances for meats and milk can be reassessed. Additional field trial data for grass forage and grass hay, as well as rotational crop studies for corn and wheat are required. Because of the relatively low volume of use on pasture and rangeland, data from these confirmatory studies are not expected to significantly change current dietary risk estimates. Final tolerances are being proposed as part of this Tolerance Reassessment Decision (TRED). Some revisions to these tolerance values may be needed once the field trial data and rotational crop studies have been submitted to and reviewed by the Agency. Tolerance Reassessment Summary for Hexazinone. Commodity Current Tolerance (ppm) a Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition Tolerances presently listed under 40 CFR §180.396( a): Alfalfa green forage 2.0 2.0 Alfalfa, forage Alfalfa hay 8.0 4.0 Tolerance should be reduced based on re­ calculation of expected residues. Alfalfa, hay Blueberries 0.2 0.6 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Blueberry Commodity Current Tolerance (ppm) a Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition 3 Cattle, fat 0.1 Revoke b Cattle, mbyp 0.1 0.1 Cattle, meat 0.1 0.1 Goat, fat 0.1 Revoke b Goat, mbyp 0.1 0.1 Goats, meat 0.1 0.1 Grasses, pasture 10 TBD c Grass, forage Grasses, rangeland 10 TBD c Grass, hay Hog, fat 0.1 Revoke b Hog, mbyp 0.1 Revoke b Hog, meat 0.1 Revoke b Horses, fat 0.1 Revoke b Horses, mbyp 0.1 0.1 Horses, meat 0.1 0.1 Milk 0.5 0.2 Tolerance should be reduced based on re­ calculation of expected residues. Pineapple 0.5 0.6 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Sheep, fat 0.1 Revoke b Sheep, mbyp 0.1 0.1 Sheep, meat 0.1 0.1 Tolerances needed under 40 CFR §180.396( a): Alfalfa, seed 2.0 Tolerances presently listed under 40 CFR §180.396( c): Sugarcane 0.2 0.6 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Sugarcane molasses 5.0 4.0 Tolerance should be reduced based on re­ calculation of expected residues. Commodity Current Tolerance (ppm) a Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition 4 Sugarcane molasses d 5.0 4.0 Tolerance should be reduced based on re­ calculation of expected residues. a Expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). b Tolerances for fat are not required (Category 3, 40 CFR §180.6). c TBD: These tolerances require additional field trial data and may be revised once the data have been submitted to and reviewed by the Agency. d For reassessment counting purposes, the Agency will count the sugarcane molasses tolerances as two reassessments to reflect the tolerances which existed both in 40 CFR Part 185 (185.3575) and Part 186 (186.3575) at the start of FQPA. No maximum residue limits (MRLs) for hexazinone and its metabolites have been established or proposed by Codex for any agricultural commodity. Therefore, no compatibility questions exist with respect to U. S. tolerances. Note that you will be sent a Section 3( c)( 2)( B) Data­ Call­ In (DCI) letter under the Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) in a separate mailing. If you have questions on this or any of the attached documents, please contact the Chemical Review Manager, Dirk V. Helder, at (703) 305­ 4610. Sincerely, Lois A. Rossi, Director Special Review and Reregistration Division Enclosures: "Hexazinone Overview" and "Hexazinone Summary"

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regulations

EPA-HQ-OPP-2002-0188-0003

Supporting & Related Material

OVERVIEW OF HEXAZINONE RISK ASSESSMENT Introduction This document summarizes EPA's human health findings and conclusions for the herbicide hexazinone, as presented fully in the documents: HED Chapter for the Hexazinone Tolerance Reassessment Eligibility Decision, dated June 5, 2002, and Tier I Estimated Environmental Concentrations of Hexazinone, dated April 16, 2002 and addenda. The purpose of this overview is to assist the reader in better understanding the conclusions reached in the tolerance reassessment decision by identifying the key features and findings of the risk assessment. This overview was developed in response to comments and requests from the public, which indicated that the risk assessments were difficult to understand, that they were too lengthy, and that it was not easy to compare the assessments for different chemicals due to the use of different formats. The Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act (FQPA) of 1996, requires EPA to review all the tolerances for registered chemicals in effect on or before the date of the enactment of FQPA. In reviewing these tolerances, the Agency must consider, among other things, aggregate risks from non­ occupational sources of pesticide exposure, whether there is increased susceptibility to infants and children, and the cumulative effects of pesticides with a common mechanism of toxicity. The tolerances are considered reassessed once the safety finding has been made or a revocation occurs. A Reregistration Eligibility Decision (RED) for hexazinone was completed in September 1994, prior to FQPA enactment; therefore, it needed to be updated to consider the provisions of the Act. FQPA stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other nonoccupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low­ level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. EPA did not perform a cumulative risk assessment as part of the Tolerance Reassessment Decision (TRED) for hexazinone because the Agency has not yet initiated a comprehensive review to determine if there are any other chemical substances that have a mechanism of toxicity common with that of hexazinone. For purposes of this risk assessment, EPA has assumed that hexazinone does not have a common mechanism of toxicity with other substances. 2 In the future, the registrant may be asked to submit, upon EPA's request and according to a schedule determined by the Agency, such information as the Agency directs to be submitted in order to evaluate issues related to whether hexazinone shares a common mechanism of toxicity with any other substance and, if so, whether any tolerances for hexazinone need to be modified or revoked. The Agency has developed a framework for conducting cumulative risk assessments on substances that have a common mechanism of toxicity. This guidance was issued on January 16, 2002 (67 FR 2210­ 2214) and is available from the OPP Website at: http:// www. epa. gov/ pesticides/ trac/ science/ cumulative_ guidance. pdf. The risk assessment, and documents pertaining to the Agency's report on FQPA tolerance reassessment progress and risk management decision for hexazinone are available on the Internet at http:// www. epa. gov/ pesticides/ reregistration/ status. htm and in the public docket for viewing. The Agency's report on FQPA tolerance reassessment progress and risk management decision for hexazinone will be announced in the Federal Register. Use Profile Herbicide: Hexazinone is a herbicide registered for use on alfalfa, blueberries, pasture and range grasses, pineapple, and sugarcane. It is also registered for use on ornamental plants, forest trees, and non­ crop areas. Hexazinone works through the inhibition of photosynthesis and is used to control a variety of woody plants and weed species including geratum, alder, and alexander grass. There are no registered residential uses of hexazinone products. Formulations: Hexazinone is formulated as a dry flowable (DF), emulsifiable concentrate (EC), soluble concentrate (SC), and as a granular (G). The range of percentage of active ingredient in the product formulations is 10­ 90%. Rates, Methods and Timing of Application: The application rates range from 0.5­ 5.0 lbs. active ingredient per acre. For agricultural uses, the number of applications per year (or season) are typically limited to one. For forestry uses, the number of applications are typically 1­ 2 applications over a 20 to 40 year period in the East and 1­ 2 applications over a 60 to 80 year period in the West. Hexazinone formulations may be applied pre­ or post­ emergence by layby, broadcast, directed spray, or basal soil treatments using ground or aerial equipment. Hexazinone is mainly an early season use, pre­ harvest intervals (PHIs) range from 180­ 234 days for most uses, but PHIs are 30 and 45 days for alfalfa and blueberry, respectively. Use Summary: Approximately 975,000 pounds of hexazinone active ingredient are used in the U. S. annually. Major Use Sites For Hexazinone: Alfalfa represents approximately 35% of the total hexazinone usage and forestry approximately 60% of the usage. None of the crops that comprise the remaining 5% of use represents more than 1% of the total usage. 3 Registrant: Dupont Human Health Risk Assessment Acute Dietary (Food) Risk (For a complete discussion, see section 4.2.2 of the Human Health Risk Assessment) Because no effects attributed to a single exposure were identified for the general population, the acute dietary exposure and risk assessment includes females 13­ 50 only. Acute dietary risk from food is calculated considering what is eaten in one day (in this instance, the full range of consumption values as well as the range of residue values in food). A risk estimate that is less than 100% of the acute Population Adjusted Dose (aPAD) (the dose at which an individual could be exposed on any given day and no adverse health effects would be expected) does not exceed the Agency's level of concern. The aPAD is the reference dose (RfD) adjusted for the FQPA Safety Factor. Table 1 presents the results of the acute dietary (food) exposure and risk analysis for females (13­ 50 years of age). Table 1. Acute Dietary (Food) Exposure and Risk Population Subgroup Exposure (mg/ kg/ day) % aPAD Females (13­ 50 years) 0.003611 <1.0 ° The acute dietary risk estimate does not exceed the aPAD. The acute dietary risk estimate for females 13­ 50 years old is <1.0% of the aPAD. ° Because the toxic endpoint for acute dietary exposure concerns in utero exposure, the risk assessment is done for females of childbearing age (13­ 50) only. For the female (13­ 50 years) population subgroup, the acute No Observed Adverse Effect Level (NOAEL) of 400 mg/ kg/ day was established, based on decreased fetal weight, malformed kidneys, & skeletal abnormalities in a rat developmental toxicity study. The LOAEL was 900 mg/ kg/ day. ° An uncertainty factor (UF) of 100 was applied to the doses selected for the risk assessment to account for interspecies extrapolation (10x) and intraspecies variability (10x). ° For acute dietary exposure, the FQPA safety factor was reduced to 1X since the toxicology database for hexazinone contains acceptable developmental and reproduction studies in the rat and rabbit, and there is no quantitative or qualitative evidence of increased susceptibility in the fetuses or offspring in these studies. The risk assessment will not underestimate the exposure and risks posed by hexazinone. 4 ° The acute RfD for females 13­ 50: 400 mg/ kg/ day (NOAEL) ÷ 100 (UF) = 4.0 mg/ kg/ day. The acute PAD for females 13­ 50: 4.0 mg/ kg/ day ÷ 1 (FQPA) = 4.0 mg/ kg/ day. ° The acute dietary exposure analysis is based on the Dietary Exposure Evaluation Model (DEEM ™ ). The DEEM ™ analysis evaluated individual food consumption as reported by respondents in the USDA 1989­ 92 Continuing Surveys for Food Intake by Individuals (CSFII). The data are based on the reported consumption of more than 10,000 individuals over three days. For the acute exposure assessment, individual one­ day food consumption data are used on an individual­ by­ individual basis. ° The acute dietary exposure assessment for hexazinone is a tier I analysis. This is the most conservative type of analysis done by the Agency and it assumes that residues on foods as consumed are equal to the tolerance levels and that 100% of each crop is treated. ° The dietary exposure assessment included residue estimates of hexazinone (parent) and metabolites B, C, C­ 1, C­ 2, and F for ruminant commodities and metabolites A, B, C, D, and E for plant commodities. The metabolites and parent hexazinone are assumed to have equal toxicity based upon similarity in chemical structure. ° Because existing data were inadequate to calculate residue estimates for pasture and rangeland grass and grass hay, EPA constructed the maximum theoretical dietary burden (MTDB) of hexazinone to livestock using protective assumptions for the contributions of other hexazinonetreated feed items. Thus, tolerances for meats and milk can be reassessed. Additional field trial data for grass forage and grass hay, as well as rotational crop studies for corn and wheat are required. Because of the relatively low volume of use on pasture and rangeland, data from these confirmatory studies are not expected to significantly change current dietary risk estimates. Chronic Dietary (Food) Risk (For a complete discussion, see section 4.2.3 of the Human Health Risk Assessment) Chronic dietary risk from food is calculated by using the average consumption values for food and average residue values for those foods over a 70­ year lifetime. A risk estimate that is less than 100% of the chronic PAD (cPAD) (the daily dose at which an individual could be exposed over the course of a lifetime and no adverse health effects would be expected) does not exceed the Agency's level of concern. Table 2 presents the results of the chronic dietary (food) exposure and risk analysis. Table 2. Chronic Dietary (Food) Exposure and Risk Population Subgroup Exposure (mg/ kg/ day) % cPAD General U. S. 0.002167 4.3 Population Subgroup Exposure (mg/ kg/ day) % cPAD 5 All infants (< 1 year) 0.003752 7.5 Children (1­ 6 years) 0.0077449 15.5 Children (7­ 12 years) 0.003964 7.9 Females (13­ 50 years) 0.001308 2.6 ° The chronic dietary risk estimate for all population subgroups does not exceed the cPAD, all population subgroups are <16% of the cPAD. ° For all populations, the chronic NOAEL of 5.00 mg/ kg/ day was established, based on severe body weight decrement, decreased food consumption, and clinical chemistry changes such as anemia, decreases in RBC counts, hemoglobin, and hematocrit in a one year chronic dog study at the LOAEL of 38 mg/ kg/ day. ° An uncertainty factor (UF) of 100 was applied to the doses selected for the risk assessment to account for interspecies extrapolation (10x) and intraspecies variability (10x). ° For chronic dietary exposure, the FQPA safety factor was reduced to 1X for the same reasons noted above for acute dietary exposure. ° The chronic RfD: 5.0 mg/ kg/ day (NOAEL) ÷ 100 (UF) = 0.05 mg/ kg/ day. The chronic PAD: 0.05 mg/ kg/ day ÷ 1 (FQPA) = 0.05 mg/ kg/ day. ° The chronic dietary exposure analysis is based on the Dietary Exposure Evaluation Model (DEEM ™ ). For chronic dietary (food) assessments, a three­ day average of consumption for each population subgroup is combined with average residues in commodities to determine average exposures in mg/ kg/ day. ° The chronic dietary (food) exposure assessment for hexazinone was a tier I analysis. This is the most conservative type of analysis the Agency performs and it assumes that residues on foods as consumed are equal to the tolerance levels and that 100% of each crop is treated. Drinking Water Dietary Risk (For a complete discussion, see section 4.3 of the Human Health Risk Assessment) Drinking water exposure to pesticides can occur through surface and/ or ground water contamination. EPA considers acute (one day) and chronic (lifetime) drinking water risks and uses 6 either modeling or actual monitoring data, if available, to estimate those risks. Modeling is carried out in tiers of increasing refinement, but is designed to provide a conservative estimate of potential exposure. To determine the maximum allowable contribution from water allowed in the diet, EPA first looks at how much of the overall allowable risk is contributed by food and then determines a Drinking Water Level of Comparison" (DWLOC) to ascertain whether modeled or monitored Estimated Environmental Concentrations (EECs) exceed this level. The hexazinone drinking water exposure assessment is based upon review of environmental fate studies which suggest that the parent and degradates are likely to be persistent and mobile in the environment. Leaching and runoff are expected to be the primary dissipation routes. Estimated Environmental Concentrations (EECs) in surface waters were estimated using Tier I modeling (FIRST). The EECs in groundwater were estimated using an available small­ scale prospective groundwater monitoring study from California. In addition, there are monitoring data available from the state of Maine that were used for comparison purposes only. ° The use of hexazinone on alfalfa was modeled for the purpose of assessing surface drinking water exposure to the chemical and its degradates. Alfalfa is the food/ feed item with the greatest percent of crop treated with hexazinone. ° Estimated Environmental Concentrations (EECs) for surface water were estimated using FIRST (Tier I) modeling. This model is a screening tool designed to provide high­ end estimates of the concentrations that might be found in a small drinking water reservoir due to the use of the pesticides. ° EECs for ground water are based on monitoring data from the small­ scale prospective groundwater monitoring study in California. The results of this study were compared and confirmed with monitoring done in the State of Maine. ° The parent­ hexazinone, G3170, and all degradates with conjoined cyclohexyl and triazine rings (specifically, A, A­ 1, B, C, D, 1 (JS472), and 2 (JT677)) are residues of concern for risk assessment in water. The Agency assumes they have similar toxicity as the parent. Drinking water DWLOCs and EECs are compared in Table 3. 7 Table 3. Acute and Chronic Drinking Water DWLOC and EEC Comparisons Population Subgroup Acute Scenario Chronic Scenario Acute DWLOC Ground Water EEC Surface Water EEC Chronic DWLOC Ground Water EEC Surface Water EEC U. S. General 420 42 47 Females (13­ 50 years) 120,000 42 130 420 42 47 All infants 420 42 47 Children (1­ 6 years) 420 42 47 ° For acute drinking water risk, potential (peak) EECs of hexazinone in either ground water (42 ppb) or surface water (130 ppb) are below the acute DWLOC for females (13­ 50 years) (120,000 ppb). ° For chronic drinking water risk, the potential (average) EECs of hexazinone in either ground water (42 ppb) or surface water (47 ppb) are below the chronic DWLOC for all population subgroups (420 ppb). Blueberry Use In Maine A significant portion of the wild blueberry crop in the state of Maine is treated with hexazinone. It may be applied pre­ or post­ emergence at use rates of 0.5 to 2 lb ai/ acre. Wild blueberries produce a berry crop every other season, with hexazinone being typically applied in the non­ bearing year. A Special Local Need (SLN) label for Maine, allows use 45 days before harvest. Hexazinone is the primary factor in increasing the wild blueberry crop three­ fold over the past 15 years. Hexazinone has a half life of 90 days, is highly soluble, and prone to leaching. Because most of the wild blueberry fields are on highly leachable sandy loam soils, there is concern that ground and surface water may be impacted by hexazinone use. Water monitoring has been conducted since 1985 and hexazinone is detected in both ground and surface water. Long term test well data from 1989­ 1995 found concentrations of hexazinone in the 25­ 29 ppb. In response, the Maine Board of Pesticides Control implemented a Best Management System in 1996 to reduce surface and groundwater impact. The measures implemented by the State, include classifying hexazinone as a Restricted Use Pesticide. Users must become certified applicators by attending training on proper application techniques. In addition, on­ going field training is provided for workers using hexazinone. Application is not allowed within 50 feet of a water source or well, airblast application is prohibited, low use rates are suggested except when weed pressure is high, and alternative weed control measures are recommended, such as cutting/ mowing, burning, and hand pulling of weeds. Recent monitoring from 1998­ 2001 found 8 concentrations from 0.08 ­3.8 ppb in both ground and surface water which are significant reductions from the levels found in the previous monitoring. The Best Management System implemented by the State appears to be lowering the levels of hexazinone in ground and surface water. The Agency supports these efforts and anticipates their continued modification and improvement may further reduce the levels of hexazinone in ground and surface water from hexazinone application to blueberries. Nonetheless, the levels of hexazinone found in ground and surface water in Maine are well below the acute DWLOC (12,000 ppb) and the chronic DWLOC (430 ppb) and thus, below the Agency's level of concern. Forestry Use and Tribal Communities About 60% of hexazinone usage is on forestry sites for woody plant and weed control. Shortly following a logging operation, hexazinone may be applied to control brush in preparation for the replanting of tree seedlings. Depending on weed intensity, hexazinone may be applied a second time the next season after the seedlings have been planted. The goal is to suppress the competing vegetation and allow the seedlings the opportunity to establish their root system and help them increase their growth size above the competing vegetation. In Eastern forests, because of the species of trees grown, hexazinone may typically be applied 1­ 2 times during a 20 to 40 year period. In Western forests, hexazinone may typically be applied 1­ 2 times during a 60 to 80 year period. In some forested areas where hexazinone is applied, Native Americans gather plant materials that are used in their diets, in the making of traditional basketry, for medicinal purposes, and in ceremonial activities. USEPA, (Region IX) is working with the California Department of Pesticide Regulation (DPR), the U. S. Forest Service (USFS) and Native American tribes in California to determine the potential exposure to forestry herbicides, including hexazinone, glyphosate, and triclopyr, that may be occurring to Native Americans through their use of forest plant materials. In response to the health concerns raised by the Native American communities, DPR and Region IX launched a risk assessment effort in 1997. This effort includes five steps: DPR measured plant residue and surface water levels following herbicide application; DPR agreed to assess the total exposures and risks involved using, where appropriate, the monitoring data collected; informing tribal physicians of state regulations requiring pesticide illness reporting; participation in mediated meetings with Native American communities to determine the key issues surrounding herbicide use; and a video production about inadvertent exposure to herbicides. In addition, the USFS is working with local Indian tribes, and has established "no spray" zones where plant materials may be gathered free of pesticide residues. They are also working to reduce pesticide usage, prevent runoff, and minimize exposure by posting application sites and providing bulletins alerting the public where applications have, or will occur. EPA is aware of this ongoing work and will continue to coordinate with the registrant­ Dupont, Region IX, California DPR, U. S. Forest Service, and other entities, as appropriate, to ensure that potential exposures and risks are better characterized. In addition, the Agency is working to develop risk analysis software that will assess risk from chemicals in food, air, water, and other sources for 9 Native American and Alaska native sub­ populations whose subsistence ways of life may result in exposures to toxic chemicals that are significantly different from those of other population sub­ groups. Residential Risk Hexazinone is not registered for home use nor is it used in and around schools, or parks. Based on present use patterns and labeled uses, there should be no residential exposure to hexazinone. Thus, there is no residential exposure to assess or aggregate with the dietary and drinking water exposure. Aggregate Risk (For a complete discussion, see section 5.0 of the Human Health Risk Assessment) Aggregate risk examines the combined risk from exposure through food, drinking water, and residential uses. Using the DWLOC approach, all risks from these exposures must be less than 100% of the aPAD or cPAD. For hexazinone, the aggregate risks are limited to food and water exposure, because there are no residential uses. ° Combining both the acute dietary (food) risk estimates with the surface and ground water EECs (drinking water) for hexazinone, the acute aggregate (food + drinking water) risk is less than 100% of the aPAD; and therefore, is not of concern to the Agency. ° Combining both the chronic dietary (food) risk estimate with the surface and ground water EECs (drinking water) for hexazinone, the chronic aggregate (food + drinking water) risk is less than 100% of the cPAD, and therefore, is not of concern to the Agency. Occupational and Ecological Risk (For a complete discussion, see section 4.2 of the Human Health Risk Assessment) Because hexazinone is under review for tolerance reassessment only, no occupational or ecological risk assessment would normally be conducted. Occupational and ecological risk management decisions were made as part of the 1994 Hexazinone RED. The Agency reevaluated labeled uses and determined the personal protective equipment and restricted entry intervals included in the RED are health protective. In addition, ecological tests indicate hexazinone is non­ toxic to birds, bees, and fish. 10 Tolerance Reassessment Summary (For a complete discussion, see Hexazinone Residue Chemistry Chapter for the Tolerance Reassessment Eligibility Decision (TRED), dated 5/ 20/ 2002.) The Agency has reassessed all 25 tolerances for hexazinone and can make an FQPA safety determination. Anticipated residues for commodities included in the dietary risk assessment are equal to the tolerance levels and it was assumed that 100% of each crop was treated. Acute and chronic dietary risks from exposure to hexazinone do not exceed the Agency's level of concern. Tolerances for residues of hexazinone in/ on plant, livestock, and processed commodities are currently expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). Field trial data for pasture and rangeland grass hay will be required as well as rotational crop studies for corn and wheat, and are considered confirmatory. Final tolerances are being proposed as part of this Tolerance Reassessment Decision (TRED). Additional tolerances may be revised once the field trial data and rotational crop studies have been submitted to and reviewed by the Agency. Table 4. Tolerance Reassessment Summary for Hexazinone. Commodity Current Tolerance (ppm) a Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition Tolerances presently listed under 40 CFR §180.396( a): Alfalfa green forage 2.0 2.0 Alfalfa, forage Alfalfa hay 8.0 4.0 Tolerance should be reduced based on re­ calculation of expected residues. Alfalfa, hay Blueberries 0.2 0.6 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Blueberry Cattle, fat 0.1 Revoke b Cattle, mbyp 0.1 0.1 Cattle, meat 0.1 0.1 Goat, fat 0.1 Revoke b Goat, mbyp 0.1 0.1 Goats, meat 0.1 0.1 Grasses, pasture 10 TBD c Grass, forage Commodity Current Tolerance (ppm) a Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition 11 Grasses, rangeland 10 TBD c Grass, hay Hog, fat 0.1 Revoke b Hog, mbyp 0.1 Revoke b Hog, meat 0.1 Revoke b Horses, fat 0.1 Revoke b Horses, mbyp 0.1 0.1 Horses, meat 0.1 0.1 Milk 0.5 0.2 Tolerance should be reduced based on re­ calculation of expected residues. Pineapple 0.5 0.6 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Sheep, fat 0.1 Revoke b Sheep, mbyp 0.1 0.1 Sheep, meat 0.1 0.1 Tolerances needed under 40 CFR §180.396( a): Alfalfa, seed 2.0 Tolerances presently listed under 40 CFR §180.396( c): Sugarcane 0.2 0.6 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Sugarcane molasses 5.0 4.0 Tolerance should be reduced based on re­ calculation of expected residues. Sugarcane molasses d 5.0 4.0 Tolerance should be reduced based on re­ calculation of expected residues. a Expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). b Tolerances for fat are not required (Category 3, 40 CFR §180.6). c TBD: These tolerances require additional field trial data and may be revised once the data have been submitted to and reviewed by the Agency. d For reassessment counting purposes, the Agency will count the sugarcane molasses tolerances as two reassessments to reflect the tolerances which existed both in 40 CFR Part 185 (185.3575) and Part 186 (186.3575) at the start of FQPA. 12 CODEX HARMONIZATION No maximum residue limits (MRLs) for hexazinone and its metabolites have been established or proposed by Codex for any agricultural commodity. Therefore, no compatibility questions exist with respect to U. S. tolerances. Summary of Pending Data The Agency is requesting a 28­ day inhalation study on a formulation with hexazinone because of the concern for potential inhalation exposure. Additional field trial data for grass hay and rotational crop studies for corn and wheat are required.

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regulations

EPA-HQ-OPP-2002-0188-0005

Supporting & Related Material

July 1, 2002 Mr. Dirk V. Helder Office of Pesticide Programs (H7508C) U. S. Environmental Protection Agency 1921 Jefferson Highway Arlington, VA 22202 Dear Mr. Helder Subject: Dupont Response to Draft Hexazinone Tolerance Reassessment Eligibility Document (TRED) We appreciate the opportunity to comment on the draft TRED for hexazinone. First, we compliment the Agency on the depth completeness of the data base review. In some areas covered in the review we have no significant comments and in others, particularly toxicology, we have extensive comments which are contained in the attached documents identified for each section. The most significant recommendation, in our view, contained in the draft documents pertains to the revocation of tolerances associated use of hexazinone on grass. We acknowledge that guidelines and interpretations regarding the practicality of grower over cattle grazing intervals have changed since data supporting this use pattern were last submitted. However, as indicated review, this is a rather minor use and our information indicates that the current label restrictions regarding cutting and grazing being complied with. Therefore, the tolerances supporting the use are sufficient. Given the foregoing, we request that the existing tolerances and use pattern be maintained while we conduct new residue work to support EPA's interpretation regarding a zero grazing interval. We understand that our recently submitted Rabbit Developmental Toxicity Study (DuPont­ 7405, MRID 45677801) was not in time to be included in the Draft TRED. In view of the pivotal importance of this study to the overall conclusions of the final (specifically, the current proposal to declare a significant gap in the toxicology data base, the selection of appropriate end points regulatory purposes and the imposition of an additional 10X safety factor due to an incomplete data base), we respectfully request this study be reviewed as quickly as possible to be included in the final TRED. We also note in the toxicology review that "Gene mutation – bacterial" is listed as an unsatisfied requirement. We have recently submitted (June 28, 2002, no MRID yet assigned) a new Ames assay with the 75 DF formulation which we believe will satisfy requirement. Finally, we do not believe a 28­ day inhalation study should be required until the existing and submitted 21­ day inhalation study (MRID 00063972) has been reviewed Again, we appreciate this opportunity to comment and look forward to our continued collaboration. Sincerely, Thomas F. Stommel Global Product Reg. Mgr.

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2024-06-07T20:31:42.849118

regulations

EPA-HQ-OPP-2002-0188-0006

Supporting & Related Material

HEXAZINONE TOLERANCE REASSESSMENT ELIGIBILITY DECISION HED CHAPTER – 6/ 5/ 02 DuPONT COMMENTS 1.0 Executive Summary The most significant recommendation, in our view, contained in the draft documents pertains to the revocation tolerances and associated use of hexazinone on grass. We acknowledge that guidelines and interpretations regarding the practicality of grower control over cattle grazing intervals have changed since data supporting this use pattern were last submitted. However, as indicated in your review, this is a rather minor use and our information indicates that the current label restrictions regarding cutting and grazing are being complied with. Therefore, the tolerances supporting the use are sufficient. Given the above, we request that the existing tolerances and use pattern be maintained while we conduct new residue work to support EPA's interpretation regarding a zero day grazing interval. We understand that our recently submitted Rabbit Developmental Toxicity Study (DuPont­ 7405, MRID 45677801) was not reviewed in time to be included in the Draft TRED. In view of the pivotal importance of study to the overall conclusions of the final TRED (specifically, the current proposal to declare a significant gap in the toxicology data base, the selection of appropriate end points for regulatory purposes and the imposition an additional 10X safety factor due to an incomplete data base), we respectfully request that this study be reviewed as quickly as possible to be included in the final TRED. We also note in the toxicology review that "Gene mutation – bacterial" is listed as an unsatisfied requirement. have recently submitted (June 28, 2002, no MRID yet assigned) a new Ames assay with the 75 DF formulation which we believe will satisfy this requirement. Finally, we do not believe a 28­ day inhalation study should be required until the existing and submitted 21­ day inhalation study (MRID 00063972) has been reviewed. 3.0 Hazard Characterization 3.1 Hazard Profile Table 1: Acute Toxicity: For Inhalation LC50> 3.94 mg/ L (4 hour), add (25% formulation) Table 2: Toxicity Profile: 870.3465, "A 28­ day inhalation study is required." As noted in the HIARC document, an unreviewed 21­ day inhalation study is available (MRID 00063972) which indicates that repeated exposure to hexazinone dust poses negligible inhalation risks and that no further inhalation testing should be required. The Registrant requests that existing data be reviewed before additional testing is required. 870.3700b Prenatal Developmental Toxicity Unacceptable/ Upgradeable. The registrant has submitted a new rabbit developmental study (DuPONT­ 7405, MRID 45677801) which addressed the deficiencies and supports the conclusions of the original study 870.5100 Reverse mutation in Samonella Strains Unacceptable: DuPont has conduct a Ames assay for the 75DF formulation in both Salmonella and E. Coli at up to 5000 ug/ plate (= 3750 ug/ plate a. i.) that can be submitted, if needed, to satisfy this requirement. The results were negative for gene mutations in both species. 870.5385 In vivo Rat Bone Marrow Cytogenetics Assay Unacceptable. Add, "However this Guideline is fulfilled by an acceptable mouse micronucleus study." 3.2 FQPA Considerations and 3.3 Dose Response Assessment: Acute Reference Dose Females 13­ 50 The Agency assigned an additional 10x database uncertainty factor because a rabbit developmental study was unacceptable due to uncertainties in the LOEL. A new rabbit developmental study (DuPont­ 7405, MRID 45677801) to the Agency which addresses the deficiencies and supports the previous study. Once the new rabbit study is reviewed, the registrant believes the extra 10x uncertainty factor should be removed. 5.1 Acute Aggregate Risk Assessment The headings for the last three columns for Table 11 (page 42) should specify ug/ l rather than g/ l.

epa

2024-06-07T20:31:42.851538

regulations

EPA-HQ-OPP-2002-0188-0007

Supporting & Related Material

HEXAZINONE TOLERANCE REASSESSMENT ELIGIBILITY DECISION REPORT OF THE FQPA SAFETY FACTOR COMMITTEE ­ 5/ 15/ 02 DuPONT COMMENTS I. HAZARD IDENTIFICATION 3. Degree of Concern and Residual Uncertainties For setting the acute reference dose (ARfD) for females of childbearing age, the Agency assigned an additional 10x database uncertainty factor (UFdb) because a rabbit developmental study was unacceptable due to uncertainties in the LOEL. A UFdb factor of 10x rather than 3x was used because, based on extrapolation to the rabbit pilot NOEL of 50 mg/ kg in the previous study, it was concluded the difference between rabbits and rats may be greater than 3x. Immediately after the HIARC report issued, the Registrant submitted a new rabbit developmental study (DuPont­ 7405, MRID 45677801) to the Agency. The new rabbit developmental study was conducted using current guidelines and confirmed the results of the previous rabbit developmental study. The maternal and fetal rabbit NOAEL was 50 mg/ kg/ day. The maternal and fetal LOAEL was 125 mg/ kg/ day based on weight effects, which were only slight in the fetus. A higher dose, 175 mg/ kg/ day produced severe maternal toxicity. Once the new rabbit study is reviewed, if it is selected as the basis of the ARfD, the registrant believes the extra 10x UFdb should be removed.

epa

2024-06-07T20:31:42.853933

regulations

EPA-HQ-OPP-2002-0188-0008

Supporting & Related Material

HEXAZINONE TOLERANCE REASSESSMENT ELIGIBILITY DECISION TOXICOLOGY CHAPTER FOR THE TRED 5/ 30/ 02 DuPONT COMMENTS 2.0 REQUIREMENTS · Guideline Numbers need to be filled in for Structural Chromosome Aberrations (870. 5375 and 870.5385) and Other Genotoxic Effects (870.5550) · Although not listed as a data gap, 870.5100 "Gene mutation – bacterial" is listed as a requirement that is not satisfied. DuPont has an Ames assay for the 75DF formulation that was conducted for another country. That assay was conducted in both Salmonella and E. Coli at up to 5000 ug/ plate (= 3750 ug/ plate a. i.) and was negative for gene mutations in both. That study can be submitted, if needed, to satisfy this requirement. 1.03 DATA GAPS 1. It is unclear as to why a 28­ day inhalation study is being requested. For which risk assessment is it needed? There are no residential uses of hexazinone. Most of the use patterns are outside the scope of WPS. The Agency comments on page 24 of the HIARC document, that it already has an unreviewed 21­ day inhalation study (MRID # 00063972, HLR 447­ 76). In that study, groups of ten male rats were exposed 6 hours/ day, 5 day/ week for 3 weeks to 0 (control) or 2.5 mg/ L of 90% wettable powder formulation of hexazinone (~ 600 mg a. i./ kg/ day). Histopathology examination indicated that lung changes were similar between control and hexazinone exposed rats. Intermittent weight losses were noted throughout the test period but all rats showed a normal rate of weight gain during the recovery period. The Registrant acknowledges that this is an old study which was conducted prior to issuance of current guidelines. However, it indicates that repeated exposure to hexazinone dust poses negligible inhalation risks and that no further inhalation testing should be required. 2. A new Rabbit Developmental Toxicity Study has recently been submitted. (DuPONT­ 7405, MRID 45677801) 1.03 HAZARD ASSESSMENT 4.1 Acute Toxicity Page 5 References: The references for all the acute tox citations have been omitted from the reference list. Should they be included? Acute Dermal Rabbit Add date (1973) Acute Inhalation: Is not correct as written since an LC50> 3.94 mg/ L (4 hour) would be a toxicity category IV. Either add a note similar to that used in the HIARC document (Section 8) that this was on a 25% formulation AND/ OR cite the 1973 study on the technical material 00104975 LC50> 7.5 mg/ L (1 hour) ~ LC50 1.9 mg/ L (4 hours) that was mentioned in the HIARC report Section 8.0. Either study (3.94 x 0.25 or 7.5/ 4) would result in a toxicity category III. 4.2 Subchronic Toxicity 870.3200 Subchronic Dermal Page 7 Should read " 870.3200 21/ 28 Day Dermal Toxicity – Rabbit" since the guideline is for either rats or rabbits and the study was conducted in rabbits. 870.3465 Page 8 90­ Day Inhalation As described above, the registrant does not agree that this is a data gap because the Agency has an unreviewed 21­ day repeated dose inhalation study 870.3700b Prenatal Developmental Toxicity Study – Rabbit Page 10 This should be updated to reflect that a new rabbit developmental study was submitted (5/ 19/ 02 MRID 45677801) 4.7 Mutagenicity For clarification, we recommend inserting the following wording into the last sentence of the mutagenicity overview (additions are in bold). "Because unambiguous positive results were achieved, it was concluded that the study provided adequate evidence that INA­ 3674­ 112 (hexazinone technical) is clastogenic in vitro in an acceptable study. However, negative results were obtained in two studies which assessed chromosome damage in vivo." 4.7.3 Page 20 870.5375 Mid paragraph "In the presence of S­ 9 mix, no statistically significant increases in chromosome aberrations were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix." Delete the latter part of the sentence; it is incorrect. Positive control values in both trials produced strong positive results (Trial 1 28­ 32% abnormal cells, Trial 2 36­ 40% abnormal cells). 4.7.4 Page 21 870.5385 After, "Unacceptable…. The study does not satisfy the requirement for FIFRA Test Guidelines." Add, "However this Guideline is fulfilled by an acceptable mouse micronucleus study." 4.7.5 Page 22 870.5395 Change the last sentence from "It satisfy the requirements…." to "It satisfies the requirements…." 6.0 FQPA CONSDERATIONS 6.1 Page 25 The Agency assigned an additional 10x database uncertainty factor (UFdb) because a rabbit developmental study was unacceptable due to uncertainties in the LOEL. Immediately after the HIARC report issued, the Registrant submitted a new rabbit developmental study (DuPont­ 7405, MRID 45677801) to the Agency. The new rabbit developmental study was conducted using current guidelines and confirmed the results of the previous rabbit developmental study. The maternal and fetal rabbit NOAEL was 50 mg/ kg/ day. The maternal and fetal LOAEL was 125 mg/ kg/ day. Once the new rabbit study is reviewed, if it is selected as the basis of the ARfD, the registrant believes the extra 10x UFdb should be removed. 8.0 REFERENCES Acute Toxicity references have been omitted. 9.0 APPENDICES Insert page break before appendices 9.1.1 Acute Toxicity Table Header should read: "Acute Toxicity Data on HEXAZINONE" NOT "Acute Toxicity Data on FENBUTATIN­ OXIDE" 9.1.2 Subchronic, Chronic, and Other Toxicity Tables Registrant comments have been made above regarding removal of the 28­ day inhalation study requirement, the submission/ MRID of a new prenatal developmental study, and the availability of an unsubmitted gene mutation assay (with a 75DF formulation) in Salmonella and E. Coli. 9.2 Summary of Toxicological Endpoints Registrant restates that additional 10x UFdb should be removed after new rabbit developmental toxicity study is reviewed and questions the need for establishment of long­ term occupational endpoints.

epa

2024-06-07T20:31:42.855699

regulations

EPA-HQ-OPP-2002-0188-0009

Supporting & Related Material

HEXAZINONE TOLERANCE REASSESSMENT ELIGIBILITY DECISION REPORT OF THE HAZARD IDENTIFICATION ASSESSMENT (HIARC) REVIEW OF 4/ 25/ 02 DuPONT COMMENTS 2 HAZARD IDENTIFICATION 1.1 Acute Dietary Reference Dose Females 13­ 50 pp. 3­ 5 For setting the acute reference dose (ARfD) for females of childbearing age, the Agency has selected a rat developmental study with NOAELs of 100 and 400 mg/ kg for maternal and fetal effects, respectively. The Agency assigned an additional 10x database uncertainty factor (UFdb) because a rabbit developmental study was unacceptable due to uncertainties in the LOEL. A UFdb factor of 10x rather than 3x was used because, based on extrapolation to the rabbit pilot NOEL of 50 mg/ kg in the previous study, it was concluded the difference between rabbits and rats may be greater than 3x. The resulting ARfD was 0.4 mg/ kg (400 mg/ kg / 1000). Immediately after the HIARC report issued, the Registrant submitted a new rabbit developmental study (DuPont­ 7405, MRID 45677801) to the Agency. The new rabbit developmental study was conducted using current guidelines and confirmed the results of the previous rabbit developmental study. The maternal and fetal rabbit NOEL was 50 mg/ kg/ day. The maternal and fetal LOEL was 125 mg/ kg/ day based on weight effects, which were only slight in the fetus. A higher dose, 175 mg/ kg/ day produced severe maternal toxicity. Once the new rabbit study is reviewed, if it is selected as the basis of the ARfD, the registrant believes the extra 10x UFdb should be removed. If selected, this would result in an ARfD of 0.5 mg/ kg (50 mg/ kg / 100). This is essential the same (slight improvement) as the current ARfD, and thus there will be essentially no change in the acute dietary risk assessment. 2.3 Chronic Reference Dose Last line page 6 – typographical error. "The LOAEL is… based on…[ findings listed] and clinical observations of thinnest in one male." Should read "thin appearance in one male." 1.4 Occupational/ Residential Exposure It is not clear to the Registrant why the occupational and residential exposure Sections 2.4.1 through 2.6 were included in a food Tolerance Reassessment. There are no residential uses of hexazinone, that could contribute to the aggregate exposure. It is the Registrant's understanding that occupational exposure assessment is beyond the scope of Tolerance Reassessment. Occupational exposure was addressed under the 1994 Reregistration Eligibility Document. It was noted that a number of the major uses of hexazinone were outside the scope of the Worker Protection Standard (WPS). While agricultural uses and use on sod farms was within WPS; use on pastures, rangeland, plants grown for other than commercial purposes, ornamental plants in parks and golf course, and no­ agricultural uses such as vegetation along rights­ of­ way were outside of the scope of WPS. No worker exposure assessment was conducted. Therefore the Registrant considers the selection of Occupational/ Residential endpoints (e. g., dermal and inhalation exposure scenarios) to not be relevant to Tolerance Reassessment. Nonetheless, we offer the following comments to the endpoint selection, should these endpoints be considered relevant in the future. 2.4.2 Dermal Absorption The review states that "No dermal absorption study is available." It would be clearer to say that "No dermal penetration study is available. For an estimate of dermal penetration, the NOAEL from the 21­ day rabbit dermal toxicity study…." Also, for clarification, add the MRID of the rabbit 21­ day study (MRID 41309005). The Agency extrapolated a dermal absorption factor by comparing the NOAEL in a 21­ day dermal study in rabbits to the LOAEL from a rabbit developmental range­ finding study. A 25% dermal absorption factor was derived. Rabbit Pilot Developmental LOAEL (oral) = 250 mg/ kg = 25% Rabbit 21­ Day Dermal NOAEL 1000 mg/ kg However, the new rabbit developmental study (DuPont­ 7405, MRID 45677801) indicates there is a greater difference between oral and dermal toxicity than indicated by the above calculation. Further, since no LOAEL was actually established on the Rabbit 21­ Day Dermal study, use of a dermal NOAEL in comparison to an oral LOAEL, overestimates the potential dermal penetration. Based on the new rabbit developmental study, dermal absorption is no greater than 12.5% Rabbit Developmental LOAEL (oral) = 125 mg/ kg =< 12.5% Rabbit 21­ Day Dermal NOAEL > 1000 mg/ kg 2.4.3 Short­ Term (1 Day – 1 Month) Dermal Exposure and 2.4.4 Intermediate Term (1­ 6 Months) and Long­ Term (> 6 Months) Dermal Exposures Under 2.4.3, the Agency states the Dose and Endpoint for Risk Assessment for short­ term dermal Exposure is Not Applicable and that No Hazard and No Quantification are required (based on no effects in the 21­ day dermal study in rabbits). However, in the next section (2.4.4) the Agency proceeds to select longer­ term dermal endpoints based on the chronic dog study NOEL (5 mg/ kg/ day) and a 25% dermal absorption factor (i. e. equivalent to 20 mg/ kg/ day). For intermediate­ term scenarios, we believe selection of a subchronic endpoint would be more appropriate than selection of the chronic dog study with a 25% absorption factor. It is also consistent wit the Agency guidance document, Toxicology Endpoint Selection Process (February, 1997). Based on the labeled uses for hexazinone, we do not believe a long­ term dermal exposure scenario is relevant. It is difficult to identify a scenario where there would be daily, lifetime uninterupted dermal exposure to hexazinone. · The registrant believes that the route specific rabbit dermal study is the most appropriate study to estimate subchronic human dermal exposure. The Agency has concluded that the repeated dose rabbit study (MRID 41309005) meets guidelines and is acceptable. It measured the proper endpoints to identify hexazinone toxicity (including body weights, clinical chemistry, liver histology). Considering lifespan differences, it is of appropriate duration for short term and intermediate endpoint selection. · However, if the Agency deems that the duration of the subchronic rabbit dermal study is insufficient, acceptable subchronic oral studies of longer duration (90 days) are available. The NOAELs from the rat and dog 90­ day studies were 84 and 29 mg/ kg, respectively. Again the dog is the most sensitive species, but the subchronic NOAEL is more appropriate. · As noted in the discussion above, the 25% absorption factor derived by comparing a LOAEL on a rabbit pilot developmental study to the NOAEL on the rabbit subchronic dermal study overestimated the Dermal Absorption Factor which, in reality, is likely to be less than 12.5%. Using the dog subchronic NOAEL (29 mg/ kg/ day) and applying a more appropriate dermal absorption factor <12.5% would result in an estimated dermal endpoint of > 232 mg/ kg/ day. This is much more comparable to the actual dermal NOAEL determined from the 21­ day rabbit study. Also typographical error in 2.4.4 "thinnest in one males" should read "thin appearance in one male" 2.4.6 Intermediate (1­ 6 Months) and Long­ Term (> 6 Months) Inhalation Exposure Typographical error "thinnest in one males" should read "thin appearance in one male" 4 MUTAGENICITY For clarification, we recommend inserting the following wording into the last sentence of the mutagenicity overview (additions are in bold). "Because unambiguous positive results were achieved, it was concluded that the study provided adequate evidence that INA­ 3674­ 112 (hexazinone technical) is clastogenic in vitro in an acceptable study. However, negative results were obtained in two studies which assessed chromosome damage in vivo." General Comment: for consistency with the rest of the document, INA­ 3674­ 112 should be changed to hexazinone or hexazinone technical. Guideline 870.5300: Gene Mutation Assay in Mammalian Cells Conclusion should be bolded as with others studies. "There was, however, no indication that INA­ 3674­ 112 induced mutagenic effect in either the presence or the absence of S9 activation." Guideline 870.5395: Mouse Bone Marrow Micronucleus Assay Change the last sentence from "It satisfy the requirements…." to "It satisfies the requirements…." Guideline 870.5375: Structural Chromosome Aberration Assay; In vitro Cytogenetic Assay Mid paragraph "In the presence of S­ 9 mix, no statistically significant increases in chromosome aberrations were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix." Delete the latter part of the sentence; it is incorrect. Positive control values in both trials produced strong positive results (Trial 1 28­ 32% abnormal cells, Trial 2 36­ 40% abnormal cells). Guideline 870.5385: Structural Chromosome Aberration Assay; In vivo Cytogenetic Assay Fourth sentence of second paragraph, "Few or no analyzable cell were available…" should be "Few or no analyzable cells were available…" After, "Unacceptable…. The study does not satisfy the requirement for FIFRA Test Guidelines." add, "However, this Guideline is fulfilled by an acceptable mouse micronucleus study." 5 FQPA CONSIDERATIONS 4.3 Developmental Toxicity 5.3.2. Developmental Toxicity in the Rabbit Last paragraph should be upgraded to indicate a Rabbit Developmental Toxicity (45677801) has just been submitted but not yet been reviewed. 5.7 Determination of the Need for Developmental Neurotoxicity Study 4.6.1 Evidence that suggest requiring a Developmental Neurotoxicity Study Atrazine should not be considered as evidence suggesting requirement of a developmental neurotoxicity. Although atrazine and hexazinone contain a triazine ring, there are significant structural differences that contribute substantial differences in the biological response to these molecules by laboratory animals. EPA reached a similar conclusion in the Toxicology Disciplinary Chapter for the Tolerance Reassessment and Evaluation Decision Document, Section 1.0 – Hazard Characterization (May 16, 2002). The critical structural differences include substitutions of a cyclohexyl and a methyl group on the ring nitrogens and the presence of two ring oxo groups in hexazinone. As a result, hexazinone is less aromatic in character than the chloro­ s­ triazines. Collectively, these structural differences are considered to contribute differences in toxicological properties. Hexazinone has been classified as a triazine­ dione by EPA, which further indicates this Agency acknowledges its differences from the chloro­ striazine herbicide class. Hexazinone has been extensively tested for safety to mammals. A key difference between hexazinone and atrazine and other members of the chloro­ s­ triazine class is that chronic exposures to the latter produce a characteristic mammary tumor response in Sprague­ Dawley rats. The mode of action for this chloro­ s­ triazine induced tumor response has been associated with altered endocrine activity unique to this rat strain. In contrast hexazinone does not induce rat mammary tumors, which indicates the absence of the endocrine modulation responsible for this effect. Additional evidence supporting the absence of endocrine effects with hexazinone includes the absence of endocrine organ effects and effects on reproduction and development. The differences in chemical structures are considered to be critical to the observed differences in toxicological response between hexazinone and the chloro­ s­ triazines. 7. Data Gaps "HIARC has requested a 28­ day inhalation study because of the concern for inhalation exposure based on the use pattern" · It is unclear as to which use pattern is being considered. There are no residential uses of hexazinone. Most of the use patterns are outside the scope of WPS. Since no use patterns of concern are identified, it is impossible to determine duration of exposure. · On the same page that it requests a 28­ day inhalation study, the Agency notes that it already has an unreviewed 21­ day inhalation study (MRID # 00063972, HLR 447­ 76). In that study, groups of ten male rats were exposed 6 hours/ day, 5 day/ week for 3 weeks to 0 (control) or 2.5 mg/ L of 90% wettable powder formulation of hexazinone. Using the guidance in (Whalan EPA, 1997) this represents an exposure of greater than 600 mg/ kg/ day (2.25 mg hexazinone a. i./ L x 11.38 L/ hr respiration x 6 hr/ day exposure/ 0.25 kg body weight ). Histopathology examination indicated that lung changes were similar between control and hexazinone exposed rats. Intermittent weight losses were noted throughout the test period but all rats showed a normal rate of weight gain during the recovery period . The Registrant acknowledges that this is an old study which was conducted prior to issuance of current guidelines. However, it clearly indicates that repeated exposure to hexazinone dust poses negligible inhalation risk. It also suggests that no further inhalation testing is required since no lung toxicity was identified and since the exposure producing minimal to moderate toxicity was two orders of magnitude higher than the chronic NOAEL that has just been selected by the Agency to set an inhalation endpoint. Therefore the oral endpoint selected is overly protective. In the interest of conservation of animals we strongly urge that available information be considered before the Agency request another study and the repeated dose inhalation be removed as a data gap. For the rabbit developmental toxicity data gap we recommend changing the statement "is expected to be submitted" to "was not submitted in enough time for review prior to issuance of this document"

epa

2024-06-07T20:31:42.858512

regulations

EPA-HQ-OPP-2002-0188-0010

Supporting & Related Material

HEXAZINONE TOLERANCE REASSESSMENT ELIGIBILITY DECISION ACUTE AND CHRONIC DIETARY RISK ASSESSEMENT DATED 05/ 14/ 2002 DuPONT COMMENTS: General comments ­ Dietary Risk Assessment 1. An acute endpoint is only given for females 13­ 50. We assume this group is considered by EPA to be the most sensitive sub­ population. 2. In several places we note the risk assessment is 'based on the reassessed tolerances for blueberry, pineapple, and sugarcane. ' For blueberries and pineapple 0.3 ppm is utilized, presumably one­ half of the new proposed tolerance of 0.6ppm. However, for sugarcane 0.6 ppm (tolerance) is utilized. This appears to be an inconsistency. Stated differently, it is not clear to us why 0.3ppm was selected for blueberry and pineapple while 0.6 was selected for sugarcane. 3. Clarity is needed around the definition of LOQ. There are both enforcement methods (sum of LOQs is 0.55 ppm) and data collection methods (sum of LOQs is 0.3 ppm). We recommend that the enforcement LOQs be used consistently throughout the document. 4. We note that a more up to date consumption database exists, CSFII 94­ 96/ 98. Why was the older database, CSFII 89­ 92, used? Editorial Comment ­ Typo: p2 Third full paragraph, 2nd line from bottom: residue

epa

2024-06-07T20:31:42.861811

regulations

EPA-HQ-OPP-2002-0188-0011

Supporting & Related Material

U. S. ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460 . OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES PC Code: 107201 DP Barcode: D215026; D268715 MEMORANDUM SUBJECT: Tier I Estimated Environmental Concentrations of Hexazinone, for use in Human Health Risk Assessment FROM: Larry Liu, Ph. D., Environmental Scientist ERB V, Environmental Fate and Effects Division (7507C) THROUGH: Mah T. Shamim, Ph. D., Chief Environmental Risk Branch V Environmental Fate and Effects Division (7507C) TO: Margaret Rice, Chief Dirk Helder, Chemical Reviewer Manager Reregistration Branch II Special Review and Reregistration Division (7508C) and Sherrie Kinard, Residue Chemist Carol Christenson, Risk Assessor RRB II, Health Effects Division (7509C) This memorandum presents the Tier I Estimated Environmental Concentrations (EECs) for the herbicide hexazinone for use in the human health risk assessment. EEC's on surface waters were estimated using the Tier I model FIRST. The EEC's on groundwaters were estimated using an available small­ scale prospective groundwater monitoring study. This memorandum also provides information about the groundwater prospective small­ scale study conducted by the registrant, and how it was used to estimate the total hexazinone residues in ground waters. In addition, monitoring data available from the state of Maine was presented. The surface water concentrations, for hexazinone residues were as follows: acute (peak) value, 130 ppb, and the chronic annual average value, 47 ppb, based on the application of hexazinone on alfalfa, which is the major food crop for the chemical. The groundwater screening concentration for hexazinone residues is 41.8 ppb. These values represent upper­ bound estimates of the concentrations that might be found in surface water and groundwater due to the use of hexazinone on representative crops. It is noted that the groundwater screening concentration for hexazinone residues, based on the groundwater prospective monitoring study is of the same order of magnitude than the groundwater concentration estimated from the Tier I model SCIGROW (i. e., 20.2 ppb). 2 Should the results of this assessment indicate a need for further refinement, please, contact us as soon as possible so that we may schedule a Tier II assessment. Hexazinone Environmental Fate Properties Based on the available information, hexazinone appears to be persistent and mobile in soil and aquatic environments. The mobility of hexazinone was demonstrated in batch equilibrium data. The field and forestry dissipation data also confirm that hexazinone is persistent and mobile. Furthermore, the batch equilibrium data also suggest that its degradates are very mobile. Based on the environmental fate properties of hexazinone and its degradates, it can be concluded they may be of concern for surface water and groundwater contamination.. The following table summarizes the environmental fate properties of hexazinone, and the adsorption data for its degradates: Water solubility = 33,000 ppm (25 C) Vapor pressure = 2x10­ 7 mm Hg Kow = 15 Henry's Law Constant = 2x10– 12 atm­ m3/ mol Summary of Environmental Fate Properties of Hexazinone: Study Type/ Hexazinone Half­ Life Source (MRID) Hydrolysis pH 5 stable 41587301 (acceptable) pH 7 stable 41587301 (acceptable) pH 9 stable 41587301 (acceptable) Aqueous Photolysis (pH 7) stable 41300801 (acceptable) Soil Photolysis 82 days 41300802 (acceptable) Aerobic Soil 216 days 41807401; 42635001 (acceptable) Anaerobic Aquatic 230 days 41807402 (acceptable) Aerobic Aquatic 60 days 41811801 (acceptable) 3 Summary of Environmental Fate of Hexazinone (continued): Adsorption (Mobility) Studies Kd KOC Source (MRID) Hexazinone 0.45 37 41528101 (acceptable) Hexazinone 0.18 50 43621501 (supplemental) Degradate A­ 1 0.03 27 43621501 (supplemental) Degradate 2 0.15 45 43621501 (supplemental) Degradate H 0.31 51 43621501 (supplemental) Degradate D 0.34 59 43621501 (supplemental) Degradate B 0.44 90 43621501 (supplemental) Degradate 1 0.20 122 43621501 (supplemental) Degradate A 0.69 176 43621501 (supplemental) Field Studies/ Hexazinone Half­ Life Source (MRID) Field Dissipation Delaware ­ 123 day (parent was detected < 30 cm) 42377901 (acceptable) Mississippi ­ 154 day (parent was detected > 60­ 75 cm) 42377901 (acceptable) Forest Dissipation Litter covered soil ­ 265 days 42379201 (supplemental) Degradate Profile The following table summarizes the degradates detected in the laboratory fate studies and/ or monitored in the field dissipation and the groundwater study (i. e., Degradates A, A­ 1, C, D, 1, 2, and G3170). It should be noted that: C although Degradate C was not found in any of the laboratory fate studies, the field dissipation and the small­ scale prospective groundwater monitoring study monitored this degradate; the registrant indicated that the degradate was observed in aerobic soil metabolism studies with acidic soils; C Degradates D and 2 were the major degradates found in the anaerobic aquatic metabolism study; however, the field dissipation and the small­ scale prospective groundwater monitoring studies did not monitor these two degradates. Therefore, the fate of Degradates D and 2 could not be assessed under natural environment; the registrant believed that both field studies were mostly aerobic and the degradates were unlikely to be observed; and, 4 C the field dissipation studies did not monitor the fate of Degradate G­ 3170 which was the degradate detected at the highest concentrations in the small­ scale prospective groundwater monitoring study (MRID 45132801); this degradate was not observed; however, in the aerobic soil metabolism study. C Summary of Degradates Found in the Environmental Fate Studies Maximum Degradate Concentration (% of applied) and Time (days) to Maximum Concentration in Study: Degradates Analyzed in Study: Degradate Soil Photo. Aerobic Soil Anaerobic. Aquatic Aerobic Aquatic Field Diss. Ground Water A (T3937) 5.5% (365d) yes yes A­ 1 (G3453) 18.7% (365d) <10.0% (56d) yes yes B (A3928) 10.1% (30d) 2.3% (365d) <10.0% (56d) yes yes C (T3935) yes yes D (B2838) 4.8% (365d) 24.0% (365d) <10.0% (56d) 1 (( JS472) 10.9% (365d) <10.0% (56d) yes yes 2 (JT677) 25.0% (365d) G3170 yes Background Information on FIRST FIRST is a new screening model designed to estimate the pesticide concentrations found in water for use in drinking water assessments. It provides high­ end values on the concentrations that might be found in a small drinking water reservoir due to the use of pesticide. Like GENEEC, the model previously used for Tier I screening level, FIRST is a single­ event model (one run­ off event), but can account for spray drift from multiple applications. FIRST uses a Drinking Water Reservoir instead of a pond as the standard scenario. The FIRST scenario includes a 427 acres field immediately adjacent to a 13 acres reservoir, 9 feet deep, with continuous flow (two turnovers per year). The pond receives a 5 spray drift event from each application plus one runoff event. The runoff event moves a maximum of 8% of the applied pesticide into the pond. This amount can be reduced due to degradation on field and the effect of binding to soil. Spray drift is equal to 6.4% of the applied concentration from the ground spray application and 16% for aerial applications. FIRST also makes adjustments for the percent crop area. While FIRST assumes that the entire watershed would not be treated, the use of a PCA is still a screen because it represents the highest percentage of crop cover of any large watershed in the US, and it assumes that the entire crop is being treated. Various other conservative assumptions of FIRST include the use of a small drinking water reservoir surrounded by a runoff­ prone watershed, the use of the maximum use rate, no buffer zone, and a single large rainfall. Background Information on SCI­ GROW SCI­ GROW provides a groundwater screening exposure value to be used in determining the potential risk to human health from drinking water contaminated with the pesticide. Since the SCI­ GROW concentrations are likely to be approached in only a very small percentage of drinking water sources, i. e., highly vulnerable aquifers, it is not appropriate to use SCI­ GROW for national or regional exposure estimates. SCI­ GROW estimates likely groundwater concentrations if the pesticide is used at the maximum allowable rate in areas where groundwater is exceptionally vulnerable to contamination. In most cases, a large majority of the use area will have groundwater that is less vulnerable to contamination than the areas used to derive the SCIGROW estimate. Small­ Scale Prospective Groundwater Monitoring Study The registrant submitted a small­ scale prospective groundwater monitoring study for hexazinone (MRID45132801). Results indicated that hexazinone and its degradates are very mobile and persistent. As indicated earlier, the Degradates D and 2 (which were the major degradates found in the anaerobic aquatic metabolism study), were not monitored in the small­ scale prospective groundwater monitoring studies. No information about the fate of Degradates D and 2 under natural environment is currently available. The following table provides a summary with the maximum concentrations of the parent and its degradates, detected in the small­ scale prospective groundwater monitoring study. These concentrations (see column 2) were expressed in parent equivalents (see Column 3). The maximum total residues of hexazinone and its degradates detected in the groundwater study were 41.8 ppb (expressed as parent equivalents). 6 Summary of Small­ Scale Prospective Groundwater Monitoring Study Column 1 Column 2 Column 3 Chemical Maximum Concentration in Groundwater (ppb) Maximum Concentration in Groundwater (ppb, expressed as parent equivalent) Parent 9.2 9.2 A­ 1 (G3453) 3 2.8 B (A3928) 7.2 7.6 C (T3935) 1.2 1.1 1 (( JS472) 2.1 2.0 G3170 12.9 19.1 Total Residues (parent equivalent) Not applicable 41.8 Concise Facts and Results About the Small­ Scale Prospective GroundWater Study Hexazinone [Velpar L, 2 lb a. i/ gallon water­ dispersable liquid] was broadcast applied once at 0.75 lb a. i./ A in January 1996 onto a field of alfalfa underlain with sandy soil in Merced County, California. The site is located within the recharge area for a shallow unconfined aquifer. The treated area consisted of five 100 x 300 foot strips separated by irrigation berms, and the control area was 100 feet distant and upgradient from the treated area. The organic matter content of the soil was #0.7%, the pH was 7.5­ 8.9 in the upper 1.5 feet, and there were no continuous impeding layers. The first rainfall was received at 7 days and the first irrigation event was at 75 days. The cumulative net daily water budget was <0.0 inches through 19 days, 0.10 inches at 21 days, and 0.93 inches at 21 days. The monthly cumulative precipitation plus irrigation ranged from 111 to 195% of baseline. The depth of the water table ranged from 8 to 15 feet below ground surface (bgs) during the study. Potassium bromide was used as a tracer; breakthrough into the shallow groundwater occurred at about 152 days posttreatment. Soil (to 2 feet), soil pore water (lysimeters at 3, 6, 9, and 12 feet), and groundwater (wells screened at 14­ 19 and 20­ 25 feet bgs) samples were collected at up to 1063 days posttreatment and analyzed using HPLC for hexazinone and six transformation products: G3170, A, B, C, A1, and 1. Hexazinone dissipated from the upper 2 feet of soil with a calculated half­ life of 25 days (r 2 = 0.9997; first order kinetics). Hexazinone and its degradates exhibited a classic pattern of leaching through the soil profile and into the groundwater. Hexazinone concentrations above background (-0.05 ppb) were first detected in pore water at the 3­ foot depth at 60 days posttreatment and in the 6­ and 9­ foot 7 depths at 95 days. The breakthrough of hexazinone and degradate B into the shallow groundwater occurred at 152 days posttreatment. G3170 was the predominant degradate in the soil, soil pore water, and groundwater; breakthrough into the shallow groundwater occurred at 336 days. In the individual shallow groundwater wells (14­ 19 feet bgs), the maximum measured concentrations were as indicated in the table above. In the individual deep groundwater wells (20­ 25 feet bgs), the maximum measured concentrations were 2.33 ppb for hexazinone, 2.61 ppb for G3170, 1.32 ppb for B, 0.952 ppb for A1, and 1.32 ppb for C. The average concentrations of all compounds of interest in the shallow and deep groundwater were below their Limit of Quantitation (LOQ 2.0 ppb except 4.0 ppb for C and G3170) in water, except once at 363 days when hexazinone averaged 2.02 ppb in the shallow groundwater. There was a distinct difference in the movement of hexazinone through soil in the western and eastern portions of the site. Hexazinone residues were detected infrequently and at later intervals in groundwater in the eastern portion of the site, where soils were less sandy with thicker soil lens. Surface Water and Ground Water Monitoring Although this monitoring study was not considered for the estimation of the drinking water concentrations, it is presented for informative purposes, since it corroborates some of the conclusions made earlier. The Board of Pesticides Control in the Department of Agriculture, Food and Rural Resources in the State of Maine conducted a statewide assessment to determine the impact of highly leachable pesticides (including hexazinone, an herbicide used in the production of blueberries) on surface water and ground water in Maine. This assessment crossed a variety of agricultural and nonagricultural pesticide use sites. Surface water samples were collected in Narraguagus River and Pleasant River in Maine. Groundwater samples were collected from the wells at sites with the following characteristics: C they contain a private domestic well, currently used for drinking water; C they were within 1/ 4 mile of an active blueberry field in 1994; and C they are down gradient or of equal elevation with the blueberry field. Although the total amounts of hexazinone used on blueberry in Maine is very low (only approximately 1% of the total sale in the U. S.), it was detected in groundwater and surface water at very high frequency (43­ 59% of ground water samples, and 31­ 90% of surface water samples; refer to table below). Although this monitoring study is inherently different than the ground water prospective monitoring study, it was observed that the maximum concentrations of parent hexazinone observed in the ground waters in 1998 and 1999 (i. e. 2.15 and 1.97 ppb, respectively), were similar to the maximum concentration observed in the small scale ground water monitoring study (i. e. 9.2 ppb). Degradate B was also detected in surface water and groundwater; however, no detailed information was provided. Results are summarized in the following table. 8 Summary of Monitoring Information from the Board of Pesticides Control in the Department of Agriculture, Food and Rural Resources in the State of Maine Year No. of Samples Collected No. of Samples with Hexazinone Detected (% of Frequency) Range of Concentrations (ppb) Ground Water 1998 42 18 (43%) 0.14­ 2.15 1999 22 13 (59%) 0.22­ 1.97 Surface Water 1998 36 11 (31%) 0.22­ 0.94 1999 21 19 (90%) 0.13­ 3.80 2000 24 21 (88%) 0.13­ 2.65 2001 50 44 (88%) 0.08­ 2.45 Modeling Inputs and Results: The following tables summarize the input values used in the model runs for FIRST and SCIGROW, respectively. Fate parameters were obtained from studies submitted by the registrant and modified, if necessary, according to the Guidance for Selecting Input Parameters in Modeling the Environmental Fate and Transport of Pesticides, Version Il (February 28, 2002). Because the half­ lives used in the FIRST model are extremely long and the chemicals structures for degradates are very similar to the parent compound (except for G3170), the output values were used to represent hexazinone residues (including its degradates). 9 Environmental Fate Input Parameters for FIRST. Parameter Hexazinone Value Source/ MRID PC Code 107201 OPP Water Solubility (20° C, distilled water) 33,000 mg/ L registrant Hydrolysis Half­ Life (pH 7) Stable 41587301 Aerobic Soil Metabolism Half­ Life 216x3= 648 days 41807401; 42635001 Aerobic Aquatic Metabolism Half­ Life 60x3= 180 days 41811801 Aqueous Photolysis Half­ Life (at pH 7) Stable 41300801 Soil Water Partition Coefficient (Kd) 0.45 41528101 Pesticide is Wetted­ In No label PCA 0.87 OPP Depth of Incorporation (Aerial) 0.0 Label Environmental Fate Input Parameters for SCIGROW. Parameter Hexazinone Value Source (MRID) Organic Carbon Partition Coefficient (KOC) 37 41528101 Aerobic Soil Metabolism Half­ Life 216 days 41807401; 42635001 Application Information and Modeling Results for Use of Hexazinone on Alfalfa. Parameter Hexazinone value Source Crop Alfalfa label Application Method Aerial spray label Application Rate 1.5 lbs a. i/ acre label Application Frequency once/ year label Incorporation Depth 0 inches lbel Application Interval (days) N/ A label 10 The modeling results associated with maximum allowable rate per year for representative crops are presented in the following table. Attached to this memo (Appendix 1) are copies of the original printouts generated from FIRST and SCIGROW runs. In addition, the chemical structures of Hexazinone and its major degradation products are presented in Appendix 2. Modeling Results Model Hexazinone value Source FIRST 1.0 Peak Untreated Water Concentration 129.8 ppb Output FIRST 1.0 Annual Average Untreated Water Concentration 47.1 ppb Output SCI­ GROW Ground Water Concentration 20.2 ppb Output 11 Appendix 1. Printouts of Electronic Outputs Obtained from FIRST and SCIGROW With Use of Hexazinone on Alfalfa at 1.5 lb a. i./ A FIRST run RUN No. 200 FOR hexazinone ON alfalfa * INPUT VALUES * ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RATE (#/ AC) No. APPS & SOIL SOLUBIL APPL TYPE %CROPPED INCORP ONE( MULT) INTERVAL Kd (PPM ) (% DRIFT) AREA (IN) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 1.500( 1.500) 1 1 .4 30000.0 AERIAL( 16.0) 87.0 .0 FIELD AND RESERVOIR HALFLIFE VALUES (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED (FIELD) RAIN/ RUNOFF (RESERVOIR) (RES.­ EFF) (RESER.) (RESER.) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 648.00 2 N/ A .00­ .00 180.00 180.00 UNTREATED WATER CONC (MICROGRAMS/ LITER (PPB)) Ver 1.0 AUG 1, 2001 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ PEAK DAY (ACUTE) ANNUAL AVERAGE (CHRONIC) CONCENTRATION CONCENTRATION ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 129.789 47.139 SCIGROW run RUN No. 300 FOR hexazinone INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APPL (#/ AC) APPL. URATE SOIL SOIL AEROBIC RATE NO. (#/ AC/ YR) KOC METABOLISM (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 1.500 1 1.500 37.0 216.0 GROUND­ WATER SCREENING CONCENTRATIONS IN PPB ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 20.177970 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ A= 211.000 B= 42.000 C= 2.324 D= 1.623 RILP= 5.524 F= 1.129 G= 13.452 URATE= 1.500 GWSC= 20.177970 A= 211.000 B= 55.000 C= 2.324 D= 1.740 RILP= 5.252 F= .963 G= 9.178 URATE= 1.500 GWSC= 13.766800 12 N N N O O CH 3 N( CH 3 ) 2 S N N N O O CH 3 N( CH 3 ) 2 HO S N N N O O CH 3 N( CH 3 ) 2 OH S Appendix 2. Chemical Structures of Hexazinone and its Major Metabolites Nomenclature for the Degradates Structure of Hexazinone, A3674 Metabolite A, T3937 Metabolite A1, G3453 13 N N N O O CH 3 NHCH 3 S N N N O O CH 3 N( CH 3 ) 2 O Metabolite C, T3935 Metabolite B, A3928 Metabolite 1, JS472 14 N N N O OH CH 3 N( CH 3 ) 2 IN­ G3170 Nomenclature: Metabolite A, T3937 3­( 4­ hydroxycyclohexyl)­ 6­( demethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione Metabolite A1, G3453 3­( 2­ hydroxycyclohexyl)­ 6­( demethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione Metabolite C, T3935 3­( 4­ hydroxycyclohexyl)­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione Metabolite B, A3928 3­ cyclohexyl­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione Metabolite 1, JS472 3­( 4­ ketocyclohexyl)­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione IN­ G3170, N­ Demethyl B3170 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H) dione

epa

2024-06-07T20:31:42.864104

regulations

EPA-HQ-OPP-2002-0188-0012

Supporting & Related Material

TXR# 0050775 TXR# 0050775 May 30, 2002 May 30, 2002 OFFICE OF PREVENTION, PESTICIDES AND MEMORANDUM: TOXIC SUBSTANCES Subject: 107201: The Toxicology Chapter for the TRED for Hexazinone. DP Barcode: D275620 Submission: S598837 ReReg Case# 0266 CAS#: 51235­ 04­ 02 From: David G Anderson RRB­ 2 HED (7509C) To: Carol Christensen, Risk Assessor RRB­ 2 HED (7509C) Thru: Alan Nielsen, BSS RRB­ 2, HED (7509C) cc Pauline Wagner The Toxicology Chapter for the Tolerance Reassessment Evaluation Decision (TRED) for Hexazinone is attached. ­1­ Hexazinone PC Code: 107201 Toxicology Disciplinary Chapter for the Tolerance Reassessment Evaluation Decision Document Date completed: May 16, 2002 Prepared for: Health Effects Division Office of Pesticide Programs U. S. Environmental Protection Agency Arlington, VA 22202 Prepared by: David G Anderson form: FINAL June 21, 2000 ­2­ TABLE OF CONTENTS 1.0 HAZARD CHARACTERIZATION ........................................ ­3­ 2.0 REQUIREMENTS ..................................................... ­4­ 3.0 DATA GAP( S) ........................................................ ­5­ 4.0 HAZARD ASSESSMENT ............................................... ­5­ 4.1 Acute Toxicity ................................................... ­5­ 4.2 Subchronic Toxicity ............................................... ­5­ 4.3 Prenatal Developmental Toxicity ...................................... ­8­ 4.4 Reproductive Toxicity ............................................ ­11­ 4.5 Chronic Toxicity ................................................. ­13­ 4.6 Carcinogenicity ................................................. ­14­ 4.7 Mutagenicity ................................................... ­18­ 4.8 Neurotoxicity ................................................... ­21­ 4.9 Metabolism .................................................... ­22­ 4.10 Special/ Other Studies ............................................. ­23­ 5.0 TOXICITY ENDPOINT SELECTION .................................... ­23­ 5.1 See Section 9.2 for Endpoint Selection Table. ........................... ­23­ 5.2 Dermal Absorption ............................................... ­23­ 5.3 Classification of Carcinogenic Potential ................................ ­23­ 6.0 FQPA CONSIDERATIONS ............................................ ­24­ 6.1 Special Sensitivity to Infants and Children .............................. ­24­ 6.2 Recommendation for a Developmental Neurotoxicity Study ................. ­24­ 7.0 OTHER ISSUES ...................................................... ­24­ 8.0 REFERENCES ....................................................... ­24­ Other references ...................................................... ­27­ 9.0 APPENDICES ..................................................... ­28­ 9.1 Toxicity Profile Summary Tables ..................................... ­29­ 9.1.1 Acute Toxicity Table ....................................... ­29­ 9.1.2 Subchronic, Chronic and Other Toxicity Tables ................... ­29­ 9.2 Summary of Toxicological Dose and Endpoints .......................... ­34­ HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­3­ 1.0 HAZARD CHARACTERIZATION Hexazinone is a herbicide used to control a broad spectrum of weeds including woody plants in alfalfa, rangeland, pastures, woodlands, pineapple, sugarcane and blue berries. Non­ crop areas include ornamental plants and forests. Hexazinone is used as a pre­ emergent, post emergence herbicide. It is applied by direct spray to plants and to soils. There are no non­ occupational (residential) uses. Hexazinone is a triazine herbicide, which structurally dissimilar and toxicology different from other triazines, such as atrazine. The selectivity of triazine herbicides depends on the plant's ability to degrade or metabolize the parent compound. Sensitive plants have limited ability to metabolize hexazinone. Hexazinone acts through inhibition of photosynthesis. Hexazinone has low acute toxicity by the oral (Category III), dermal (Category IV ) and inhalation routes (Category III). Primary eye irritation is severe, causing corneal opacity and moderate irritation in unwashed eyes (Category I). It causes mild skin irritation and is classified Category IV for skin irritation. It is not a skin sensitizer in the Guinea pig. The 21­ day dermal study in the rabbit showed no systemic toxicity and mild dermal irritation at the limit dose. Body weight decrement and liver toxicity were the most frequent effects shown in studies with hexazinone. Liver toxicity was seen in the chronic dog and mouse studies. Body weight decrement was seen in the chronic rat studies and the studies on reproduction. No quantitative or qualitative susceptibility was shown in the prenatal or reproduction studies. In a reproduction study, pup weight decrement occurred at the same dose as parental body weight decrement. No reproductive effects were seen in the study other than pup weight decrement. The rat prenatal study showed fetal weight decrement and possibly renal malformations but no increased susceptibility. The rabbit study possibly showed skeletal anomalies and delayed ossifications at the highest dose tested, however it is classified as unacceptable and susceptibility in this species could not be assessed. The chronic study in dogs showed severe body weight decrement, changes in liver related clinical chemistry values, and microscopic lesions. Body weight decrement was seen in a chronic carcinogenicity studies in rats and mice. Liver toxicity was seen in mice. The mouse carcinogenicity study showed an increased trend for liver carcinomas, but no pair wise significant increases. The rat study showed no carcinogenic potential. Based on these studies in rats and mice, hexazinone was classified in a group D, not classifiable as a carcinogen. Hexazinone is clastogenic in one in vitro test for chromosomal aberrations, but negative in the remaining six other mutagenicity studies including an in vivo micronucleus test in mouse bone marrow. Rat metabolism studies showed that hexazinone was rapidly absorbed and excreted and essentially no difference in the metabolism of males and females at high or low dose levels. Almost no parent hexazinone was recovered in urine or feces. Two major metabolites were recovered from feces and urine, in addition to lesser amounts of a third metabolite and individually small amounts of conjugated products from urine. The HIARC requested a 28­ day inhalation study with hexazinone because of the concern for potential inhalation exposure based on the use pattern. The rabbit developmental toxicity study is classified as unacceptable. A 10X uncertainty factor was applied until this data gap is fulfilled. Another study in the rabbit, requested by Cal EPA, is expected to be submitted to OPP as well. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­4­ 2.0 REQUIREMENTS The requirements (40 CFR 158.340) for food and non food use for HEXAZINONE are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Table 1. Test Technical Required Satisfied 870.1100 Acute Oral Toxicity .............................. 870.1200 Acute Dermal Toxicity ............................ 870.1300 Acute Inhalation Toxicity ......................... 870.2400 Primary Eye Irritation ............................. 870.2500 Primary Dermal Irritation .......................... 870.2600 Dermal Sensitization .............................. Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 870.3100 Oral Subchronic (rodent) .......................... 870.3150 Oral Subchronic (nonrodent) ...................... 870.3200 21­ Day Dermal ................................... 870.3250 90­ Day Dermal ................................... 870.3465 90­ Day Inhalation ................................ Yes Yes Yes No 1 No 2 Yes Yes Yes Yes No 870.3700a Developmental Toxicity (rodent) ................... 870.3700b Developmental Toxicity (nonrodent) ............... 870.3800 Reproduction ................................... Yes Yes Yes Yes No 3 Yes 870.4100a Chronic Toxicity (rodent) ......................... 870.4100b Chronic Toxicity (nonrodent) ...................... 870.4200a Oncogenicity (rat) ............................... 870.4200b Oncogenicity (mouse) ............................ 870.4300 Chronic/ Oncogenicity ........................... Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 870.5100 Mutagenicity— Gene Mutation ­ bacterial ........... 870.5300 Mutagenicity— Gene Mutation ­ mammalian ......... 870.5xxx Mutagenicity— Structural Chromosomal Aberrations . 870.5xxx Mutagenicity— Other Genotoxic Effects ............ Yes Yes Yes Yes No Yes Yes Yes 870.6100a Acute Delayed Neurotox. (hen) .................... 870.6100b 90­ Day Neurotoxicity (hen) ........................ 870.6200a Acute Neurotox. Screening Battery (rat) ............ 870.6200b 90 Day Neuro. Screening Battery (rat) .............. 870.6300 Develop. Neuro .................................. No 4 No 4 No 5 No 5 No 5 870.7485 General Metabolism .............................. 870.7600 Dermal Penetration .............................. Yes No 6 Yes No Special Studies for Ocular Effects 7 Acute Oral (rat) .................................. Subchronic Oral (rat) ............................. Six­ month Oral (dog) ............................. 1 Study not required by use pattern. 2 A 28­ day inhalation study was recommended by the HIARC and is required. 3 Data gap, another rabbit developmental toxicity is required 4 Required of organophosphates only. 5 Not required by toxicity pattern. 6 Study is optional. 7 Not required for this class of pesticides. 3.0 DATA GAP( S) HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­5­ 1. 28­ Day Inhalation Study (Contact Agency before conducting test) 2. A Rabbit Developmental Toxicity Study is required (Guideline# 870.3700b) 4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of data base for acute toxicity: The data base for acute toxicity is considered complete. No additional studies are required at this time. The acute toxicity data on HEXAZINONE technical is summarized below. Acute Toxicity of Hexazinone Guideline No. Study Type MRIDs # Results Toxicity Category 81­ 1 Acute Oral/ Rat 41235004 (1989) LD50 = 1200 mg/ kg III 81­ 2 Acute Dermal/ Rabbit 00104974 LD50 >5278 mg/ kg IV 81­ 3 Acute Inhalation 41756701 (1991) LC50 > 3.94 mg/ L( 4 hour) III 81­ 4 Primary Eye Irritation 00106003 (1982) Irreversible corneal opacity, Severe I 81­ 5 Primary Skin Irritation 00106004 (1982) Mild IV 81­ 6 Dermal Sensitization 41235005 (1989) NA Not a skin sensitizer 4.2 Subchronic Toxicity Adequacy of data base for subchronic toxicity: The data base for subchronic toxicity is considered adequate for reregistration. Only a 28­ day inhalation study is required at this time. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­6­ 870.3100 90­ Day Oral Toxicity ­ Rat EXECUTIVE SUMMARY: In this subchronic oral toxicity study (MRID 00104977), hexazinone (INA­ 3674; purity not provided; Lot/ Batch # not provided) was administered in the diet to 16 ChRCD rats/ sex/ group at nominal doses of 0, 200, 1000, or 5000 ppm (equivalent to 0/ 0, 16.0/ 16.4, 81.0/ 87.3, or 440.4/ 450.7 mg/ kg for males/ females) for 13 weeks. After 4, 8, and 13 weeks on the test diet, 10 of the 16 rats/ sex/ dose were subjected to hematology, clinical chemistry, and urinalysis tests. After 13 weeks, 10 rats/ sex/ group were sacrificed for necropsy and histopathological examination. The remaining 6 rats/ sex/ group continued on the test diet for at least 3 weeks in a onegeneration one­ litter reproduction study. There were no treatment­ related effects on mortality, clinical signs, food consumption, hematology, urinalysis, organ weights, or histopathology. No data were provided for gross pathology. In the 200 and 1000 ppm animals, all parameters examined were comparable to controls. Body weights were decreased in the 5000 ppm animals (94­ 15%) throughout the study. Likewise, overall body weight gains (calculated by the reviewers) were decreased in this group (98­ 20%). Although food consumption was comparable among treated animals and controls, overall (Days 0­ 91) mean food efficiency was decreased (statistics not performed) in the 5000 ppm males (911%) and females (915%) compared to controls. Food efficiency in males and females was unchanged for the first 28 days of the study. Males showed a 6% and 9% decrement for days 28­ 56 and days 56­ 91, respectively at 5000 ppm. Females showed a 25% and 64% decrement in food efficiency for the same respective days. The progressive nature of the reduced food efficiency, especially in females, supports a body weight decrement at 5000 ppm from toxicity. Alanine aminotransferase (ALT) was increased (statistics not performed) in the 5000 ppm females at 1 (863%), 2 (863%), and 3 (825%) months. However, because there were no treatmentrelated changes in liver weights or histology, increases in ALT were considered of equivocal toxicological significance. For all other clinical chemistry parameters examined, treatment groups were either comparable to controls, sporadic, or differences were not dose­ related. Additionally, in the one­ generation, one­ litter reproduction study, there were no treatmentrelated differences in pregnancy rate (fertility), gestation, number of pups born, pup viability, or lactation. However, the mean pup weight was lower (924%; statistics not performed) in the 5000 ppm group than in controls. The LOAEL for this study is 5000 ppm (equivalent to 440.4/ 450.7 mg/ kg/ day for male/ females) based on decreased body weights and food efficiency. The NOAEL is 1000 ppm (equivalent to 81.0/ 87.3 mg/ kg/ day for males/ females). The submitted study is classified as acceptable does satisfy the guideline (§ 82­ 1a; OPPTS 870.3100) requirements for a subchronic oral toxicity study in the rat. 870.3100 90­ Day Oral Toxicity ­ Mouse No study is available. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­7­ 870.3150 90­ Day Oral Toxicity ­ Dog EXECUTIVE SUMMARY: In this subchronic oral study (MRID 00114484), hexazinone INA3674 97.5% a. i.; Lot/ Batch# not provided) was administered in the diet to 4 beagle dogs/ sex/ group at doses of 0, 200, 1000, or 5000 ppm (equivalent to 0/ 0, 5.1/ 7.0, 25.9/ 31.6, 122.5/ 137.3 mg/ kg/ day for males/ females) for 13 weeks. Homogeneity, concentration, and stability analyses were not performed on the test diets. No mortalities occurred during the study. Clinical signs and hematology were unaffected by the test substance. At 5000 ppm, the negative overall (Weeks 0­ 13) body weight gains show that these animals were unable to maintain body weight (­ 0.9 kg in males, ­0.3 kg in females). Food consumption was decreased in the females in this dose group at Weeks 1 (941%) and 2 (915%). In the males, food consumption was comparable among treated and control groups throughout the study. Findings in organ weights and clinical chemistry at 5000 ppm indicate liver toxicity as an effect of treatment. Absolute liver weights were increased in the males at 200 (810%), 1000 (821%), and 5000 (826%) ppm and in the females at 5000 (833%) ppm. However, relative liver weights were only increased at 5000 ppm in the males (827%) and females (840%), indicating the increases in absolute liver weights at 200 and 1000 ppm were most likely due to increased body weights in these animals compared to controls. Alkaline phosphatase levels were increased in the males and females in this dose group at 1 (846­ 75%), 2 (886­ 125%), and 3 (8124­ 214%) months. Serum levels of this enzyme increased as the study progressed. In the 5000 ppm males, proteinuria was observed at Months 2 and 3 (1/ 4 each treated vs 0/ 4 in any other dose group). Vacuolation of the cytoplasm of the cells lining the Loop of Henle was observed in the males (1/ 4 treated vs 0/ 4 controls) and females (1/ 4 treated vs 0/ 4 controls) in this dose group. The LOAEL was 5000 ppm (equivalent to 122.5/ 137.3 mg/ kg/ day in males/ females) based on decreased body weight gains, increased relative liver weights, and increased alkaline phosphatase levels in both sexes and transiently decreased food consumption in the females. The NOAEL for this study is 1000 ppm (equivalent to 25.9/ 31.6 mg/ kg/ day for males/ females). The submitted study is classified as acceptable and does satisfy the guideline (§ 82­ 1b; OPPTS 870.3150) requirement for a subchronic oral toxicity study in the dog. The deficiencies in the parameters reported did not appear to compromise the study results. 870.3200 21/ 28­ Day Dermal Toxicity – Rat EXECUTIVE SUMMARY: In a repeated dose dermal toxicity study (MRID 41309005), groups of five male and five female New Zealand White rabbits received applications of 0, 50, 400, or 1000 mg/ kg/ day Hexazinone technical (> 98%, Lot No. T02118994) in distilled water, 6 hours/ day for 21 consecutive days. There were no treatment­ related deaths, clinical signs, hematological or clinical chemistry HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­8­ effects, organ weight effects or gross or histopathological effects attributable to treatment. No treatment­ related body weight, food consumption, or food efficiency effects were observed. Treatment­ related dermal irritation was observed on rabbits in all treatment groups, including controls. Slight erythema was noted on 3/ 5 control females, 4/ 5 low­ dose males, 4/ 5 low­ dose females, and all mid­ and high­ dose males and females. Slight edema was noted on 1/ 5 control female, 1/ 5 high­ dose male, and 1/ 5 high­ dose female. These dermal effects were not considered toxicologically significant. The systemic and dermal NOAEL for Hexazinone technical in male and female rabbits is the limit dose of 1000 mg/ kg/ day. The systemic and dermal LOAEL were not identified. This study is classified as Acceptable/ Guideline and does satisfy the guideline requirements for a repeated­ dose dermal study [OPPTS 870.3200 (§ 82­ 2)] in rabbits. 870.3465 90­ Day Inhalation – Rat No study is available. The HIARC determined that a 28­ day inhalation study is required to address the concern for inhalation exposure due in part to the irritating properties of hexazinone. The Agency should be contacted prior to conducting this study. 4.3 Prenatal Developmental Toxicity Adequacy of data base for Prenatal Developmental Toxicity: The data base for prenatal developmental toxicity is not complete. The HIARC declared the Rabbit developmental toxicity study unacceptable/ upgradable. Another study is required. There was no quantitative or qualitative evidence of increased susceptibility following in utero exposure to the acceptable rat study or the unacceptable rabbit study. In rats, maternal toxicity was seen at a lower dose than developmental toxicity, and in rabbits, developmental effects may have been at the same dose level as maternal toxicity. 870.3700a Prenatal Developmental Toxicity Study ­ Rat EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 40397501), hexazinone (99.26% a. i.; Lot# S30306A, Batch# 2/ 36) in 0.5% methylcellulose was administered orally via gavage to 25 Crl: CD ® BR female rats/ group at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day (GD) 7 through 16. The dosing volume was 10 mL/ kg (calculated by reviewers). All dams were sacrificed on GD 22 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in clinical signs, gross pathology, pregnancy rate, live fetuses, resorptions, pre­ or post­ implantation loss, corpora lutea, or implantations were noted at any dose level tested. No treatment­ related findings were noted in the 100, or 40 mg/ kg groups. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­9­ In the 900 mg/ kg dams, one treatment­ related death occurred; alopecia and an enlarged stomach containing fluid and food were noted at necropsy. Decreased (p< 0.05) body weight gains were noted during GDs 15­ 17 (937%) and 17­ 22 (917%). In addition, body weight gains were decreased (p< 0.05) for the overall (GDs 7­ 17) treatment interval (930%). Gravid uterine weights were not reported; however, adjusted (for gravid uterine weight) terminal body weights were slightly decreased (96%; p#0.05). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 9­ 11, 15­ 17, 7­ 17, and 17­ 22. Decreased (p#0.05) food consumption was observed throughout treatment (GDs 7­ 17; 916­ 22%) and post­ treatment (GDs 17­ 22; 99%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 7­ 9, 9­ 11, 11­ 13, 13­ 15, 15­ 17, 7­ 17, and 17­ 22. Also a significantly decreased food consumption was seen at 400 mg/ kg/ day (GD9­ 11; 91%) and (GD 7­ 17; 98%). In addition, relative (to body) liver weights were increased (p#0.05) in the 400 (5.2%) and 900 (5.6%) mg/ kg dams compared to concurrent controls (4.9%). Decreased (p#0.05) terminal body weights were noted at 900 mg/ kg (96%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for relative liver weights and adjusted terminal body weights. In addition, a significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for absolute liver weights. Despite this trend, the observed increases in absolute liver weights at 100, 400, and 900 mg/ kg (81­ 8%) were not statistically significant. Liver weight findings are considered equivocal. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. The maternal NOAEL is 100 mg/ kg/ day. In the 900 mg/ kg/ day group, male and female fetal weights were decreased (921%; p#0.05); a significant (p#0.05) trend by Jonckheere's test was noted for this parameter. At 400 mg/ kg/ day, only female fetal weights were significantly decreased by 2% (insufficient to be considered an effect). At necropsy, an increased (p#0.05) incidence of misaligned sternebrae (1), a variation, was observed (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0066; litter incidence: 0.09). In addition, an increased (p#0.05) incidence of misaligned sternebrae (2+), a variation, was noted (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0033; litter incidence: 0.04). Furthermore, an increased incidence of kidneys with no papilla was observed (fetal incidence: 0.0347; litter incidence: 0.25) relative to concurrent controls (fetal incidence: 0.0062; litter incidence: 0.04). Although the incidence was not statistically significant, a dose­ related trend (p#0.05) was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day based on decreased male and female fetal weight, increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The developmental toxicity NOAEL is 400 mg/ kg/ day. The developmental toxicity study in the rat is classified acceptable/ guideline (OPPTS 870.3700; §83­ 3 a) and satisfies the guideline requirement for a developmental toxicity study in the rat. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­10­ 870.3700a Prenatal Developmental Toxicity Study ­ Rat EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 00114486), hexazinone (97.5% a. i.; Code# INA­ 3674­ 19, Lot/ Batch# N. B. 6849­ 30 [6842­ 29]; no further information provided) was administered orally in the diet to 25­ 27 ChR­ CD female rats/ group at dose levels of 0, 200, 1000, or 5000 ppm (equivalent to 0, 18.9, 94.5, and 482.0 mg/ kg) on GD 6 through 15. All dams were sacrificed on GD 21 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in food consumption, or number of implantations, live fetuses, dead fetuses, or premature deliveries were noted. It was stated that no treatment­ related changes in mortality, clinical signs, or gross pathology were observed; however no data were provided. Gravid uterine weights were not reported. Sex ratios, the number of corpora lutea, pre­ implantation loss, and post­ implantation loss were not reported and could not be calculated without individual data (not provided). Throughout the study, standard deviations were not calculated, individual data were not provided, and statistical analyses were not performed. Mean body weight gains and food efficiency were decreased during treatment (GDs 6­ 16). At 5000 ppm, mean body weight gains were decreased by 74% compared to concurrent controls. In addition, food efficiency during the treatment interval was 0.84 (vs. 3.0 in controls). At 5000 ppm, markedly decreased body weights were observed at GDs 16 (919%) and 21 (912%). Additionally at 5000 ppm, the number of females showing partial resorption (excluding complete resorptions) was 56.5%. This incidence exceeded the concurrent control incidence (39.1%); however, it was within the range of historical controls (mean was 40.6%, range was10.5­ 77.8%). The maternal LOAEL is 5000 ppm (equivalent to 482 mg/ kg/ day) based on decreased body weights, body weight gains, and food efficiency. The maternal NOAEL is 1000 ppm (equivalent to 94.5 mg/ kg/ day). No treatment­ related findings were noted in the fetuses at 200, 1000, or 5000 ppm. The developmental toxicity LOAEL was not observed. The developmental toxicity NOAEL is 5000 ppm (equivalent to 482.0 mg/ kg/ day). This developmental toxicity study in the rat is classified unacceptable/ upgradable pending submission of the following information: ­ Individual maternal and fetal data ­ Statistical analyses of the data ­ Environmental conditions of the testing laboratory ­ Gross pathology data. ­ Sex ratios, the number of corpora lutea, pre­ implantation loss, and post­ implantation loss ­ Litter incidence for fetal necropsy findings ­ Clinical signs and mortality data HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­11­ 870.3700b Prenatal Developmental Toxicity Study ­ Rabbit EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 00028863), hexazinone (100% a. i.; Lot/ batch # E21216A) was administered orally via gavage in a dosing volume of 1 mL/ kg) to 17 female New Zealand White rabbits/ group at dose levels of 0, 20, 50, or 125 mg/ kg on GD 6 through 19. All does (except those that died or delivered prematurely) were sacrificed on GD 29, and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in mortality, clinical signs, body weights, gross pathology, fetal weights, sex ratios, pre­ implantation or post­ implantation losses, or the number of corpora lutea, implantations, resorptions, live fetuses, or dead fetuses were observed. At 125 mg/ kg, food consumption was decreased (p#0.05), relative to concurrent controls, at the beginning of treatment from GD 7 through 11 (961­ 89%). Decreases in food consumption, that were not statistically significant, continued throughout treatment (GDs 12­ 19; 92­ 37%). Diminished food consumption resulted in decreased (not statistically significant) body weight gains in the does 241.5 g) relative to concurrent controls (­ 7.2 g) during GDs 6­ 11. However, weight gain in these animals recovered quickly and was higher than control animals during subsequent treatment intervals (GDs 11­ 15 and 15­ 19). The maternal LOAEL is 125 mg/ kg/ day based on transient decreases in food consumption and body weight gains. The maternal NOAEL is 50 mg/ kg/ day. At 125 mg/ kg/ day, the following skeletal variations were noted (data presented as fetal incidence vs. 0 controls): (i) lagging ossification in extremities (0.0882); (ii) malaligned thoracic vertebrae (0.0294); and (iii) flexed wrist( s) (0.0294). In addition, non­ ossified thumb, an anomaly, was noted at an increased incidence (0.0294) relative to concurrent controls (0). In the absence of historical control data, these findings are considered treatment­ related. In addition, it could not be determined how many of these nominally increased incidences were from different litters, which would have increased concern for developmental toxicity. The developmental toxicity LOAEL is 125 mg/ kg/ day, based on possible skeletal abnormalities and total abnormalies. The developmental toxicity NOAEL is 50 mg/ kg/ day. The developmental toxicity study in the rat is classified unacceptable/ upgradable, pending submission of acceptable purity, concentration, stability and litter data and historical control data. A letter dated 9/ 26/ 01 from the registrant provided no additional information about this rabbit developmental toxicity study other than the doses were not analyzed and that a repeat rabbit developmental toxicity was currently being conducted. 4.4 Reproductive Toxicity Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered complete. No additional studies are required at this time. There was no evidence of qualitative or quantitative susceptibility in a two­ generation study HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­12­ of reproduction. 870.3800 Reproduction and Fertility Effects ­ Rat Executive Summary: In a two­ generation reproduction study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 30 male and 30 female Sprague­ Dawley rats in the diet at concentrations of 0, 200, 2000, or 5000 ppm (MRID 42066501). One litter was produced in the first generation and two litters were produced in the second generation. Test substance intake for the treated F0 groups was 11.8, 117, and 294 mg/ kg/ day, respectively, for males and 14.3, 143, and 383 mg/ kg/ day, respectively, for females. Test substance intake for the treated F1 groups was 15.3, 154, and 399 mg/ kg/ day, respectively, for males and 17.7, 180, and 484 mg/ kg/ day, respectively, for females. F0 and F1 parental animals were administered test or control diet for 73 or 105 days, respectively, prior to mating, throughout mating, gestation, and lactation, and until necropsy. Deaths of several F0 and F1 parental animals were considered incidental to treatment. No treatment­ related clinical signs of toxicity were observed in the adult animals of either generation. Gross necropsy was unremarkable and no microscopic lesions were observed in selected tissues from the reproductive tracts of male and female parental animals. Body weights and body weight gains of the F0 males were not affected by treatment. Premating body weight gains by the mid­ and high­ dose F0 females were 76% and 62% (p # 0.05 for both), respectively, of the control level resulting in final premating body weights 93% and 87% (p # 0.05), respectively, of the controls. Body weights of the high­ dose F1 males and females were significantly reduced (p # 0.05) during the premating interval with overall weight gains 87% and 82%, respectively, of the control group amounts. Reductions in body weights and body weight gains during premating for the mid­ and high­ dose F0 and high­ dose F1 dams continued during gestation and lactation. Food consumption during premating was similar between the treated and control groups for males and females of both generations. However, during gestation significantly (p # 0.05) lower food consumption was noted for the high­ dose F1 dams during production of both litters and for the middose F1 dams during production of the second litter. There was a statistically significant increase in absolute P0 testes weight that appeared to be dose related, but a nominally decrease absolute F1 adult testes weight in the 5000 ppm dose groups. The F1 testes weight change did not appear to dose related. The testes weight changes in males would appear to be incidental. Therefore, the systemic toxicity LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced body weight and body weight gains by F1 males and F0 and F1 females. The systemic toxicity NOAEL is 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). No reproductive effects were seen in the study except for the weight effects on offspring. Live birth and viability indices and litter survival were similar between the treated and control groups. The lactation index for the F2b high­ dose litters was 85.8% (p # 0.05) compared to 97.5% for the control group. Pup body weights were decreased throughout lactation in the mid­ and high­ dose groups of all litters as compared with the control groups with statistical significance (p # 0.05) attained HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­13­ at most time points. The lower pup body weights were more pronounced in females than in males. F1 and F2a female pup weights were statistically significantly decreased at birth, day 7 and 14 of lactation at $2000 ppm. There were no obvious reproductive effects other than the pup weight decrement. Therefore, the offspring LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced female pup body weights at birth and during lactation. The reproductive toxicity NOAEL was 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a reproductive toxicity study [OPPTS 870.3800 (§ 83­ 4)] in rats. 4.5 Chronic Toxicity Adequacy of data base for chronic toxicity: The data base for chronic toxicity is considered complete. No additional studies are required at this time. The chronic study in dogs showed severe body weight decrement, changes in liver related clinical chemistry values, and microscopic lesions. Body weight decrement was seen in a chronic carcinogenicity studies in rats and mice. Liver toxicity was seen in mice. 870.4100a Chronic/ Carcinogenic Toxicity ­ Rat See Section below on Carcinogenicity study in rats (870.4300 Chronic/ Carcinogenicity in rats). 870.4100b Chronic Toxicity ­ Dog EXECUTIVE SUMMARY: In a one­ year chronic toxicity study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 5 male and 5 female beagle dogs in the diet at concentrations of 0, 200, 1500, or 6000 ppm (MRID 42162301). Time­ weighted average doses for the treated groups were 5.00, 41.24, and 161.48 mg/ kg/ day, respectively, for males and 4.97, 37.57, and 166.99 mg/ kg/ day, respectively, for females. All animals survived to scheduled necropsy. Treatment­ related clinical signs of toxicity included the observation of thinness in 1/ 5 mid­ dose males, 3/ 5 high­ dose males, and 1/ 5 high­ dose females. Body weights of the high­ dose groups were significantly (p # 0.05) less than those of the control throughout most of the study. Final body weights of the high­ dose males and females were 78% and 67%, respectively, of the control levels. Food consumption by the high­ dose groups was slightly (n. s.) less than that of the controls throughout the study with statistical significance (p # 0.05) attained for females at week 52. Overall food consumption (weeks 1­ 52) for high­ dose males and females was 85% (n. s.) and 74% (p # 0.05), respectively, of the control group levels. Body weights HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­14­ and food consumption for the low­ and mid­ dose groups were not affected by treatment. No treatment­ related ophthalmological lesions, changes in urinalysis parameters, or gross necropsy findings were noted. A moderate macrocytic anemia was observed in the high­ dose groups as evidenced by slight or significant (p # 0.05) decreases in RBC counts, hemoglobin, and hematocrit and increases in MCV and MCH in one or both sexes throughout the study. Cholesterol levels were significantly (p # 0.05) decreased in the high­ dose groups beginning at week 13 for males (52­ 64% of controls) and at week 26 for females (45­ 51% of controls). Albumin levels were significantly (p # 0.05) decreased in the mid­ dose males (93% of controls) at week 13 only, and in the high­ dose males (74­ 78% of controls) and females (75­ 82% of controls) throughout the study. Beginning on week 13 or 26, the high­ dose groups had aspartate aminotransferase levels 140­ 203% (p # 0.05) of the control values and alanine aminotransferase levels 206­ 276% (p # 0.05) of the control values. Alkaline phosphatase levels were significantly (p # 0.05) increased in the mid­ dose males (259­ 409% of controls) and females (163­ 194% of controls; n. s.) beginning at week 26 and in the high­ dose males (346­ 1363% of controls) and females (307­ 559% of controls) beginning at week 13. For the high­ dose animals, decreases in absolute testes weights in males and kidney, heart, and brain weights in females (­ 12%) and increases in relative liver weights in males and females were considered due to lower final body weights of these animals as compared with controls. Microscopic lesions in the liver of high­ dose animals included concentric membranous bodies in 4 males and 5 females, centrilobular single cell necrosis in 3 males and 3 females, hepatocellular pigment in 3 males and 3 females, and vacuolation in 3 males and 4 females. In addition vacuolation was observed in one mid­ dose male and pigment and membranous bodies were each observed in one mid­ dose female. These lesions were not seen in control or low­ dose animals. Therefore, the LOAEL for hexazinone in male and female beagle dogs is 1500 ppm (41.24 and 37.57 mg/ kg/ day, respectively) based on thinness in one male and hepatotoxicity as evidenced by changes in clinical chemistry parameters and microscopic lesions. The NOAEL is 200 ppm (5.00 and 4.97 mg/ kg/ day, respectively). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a chronic toxicity study [OPPTS 870.4100 (§ 83­ 1b)] in dogs. 4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The data base for carcinogenicity is considered complete. No additional studies are required at this time. HED's Carcinogenicity Peer Review Committee classified hexazinone as a Group D chemical (not classifiable as to human carcinogenicity) (7/ 27/ 94). This classification was based on the following weight of evidence considerations. In rats, females showed no evidence for carcinogenicity; males showed a significant trend only for thyroid adenomas. In mice, the evidence of carcinogenicity was equivocal: a positive trend test for liver tumors was observed only in female mice, but no significant difference was seen by pair­ wise comparison (CPRC Report dated July 27, 1994). HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­15­ 870.4200b Carcinogenicity (feeding) ­ Mouse EXECUTIVE SUMMARY: In this mouse oncogenicity study (MRIDs 00079203, 41359301, 42509301 and 43202901), hexazinone ($95% a. i.; Lot/ Batch #: H­ 11, 265 and 265­ 2) was administered in the diet to CD­ 1 mice (80/ sex/ group) for up to 104 weeks at nominal doses of 0, 200, 2500 or 10,000 ppm (equivalent to 28, 366 and 1635 mg/ kg/ day in males and 0, 34, 450 and 1915 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, food consumption, food efficiency or hematology. Hepatotoxicity was evident at the terminal sacrifice. Macroscopic liver nodule/ mass (% treated vs % controls; n = 28­ 55) was observed in males at 2500 (39% vs 7%) and 10,000 ppm (33%). Increased incidences (% treated vs 0% controls; n = 38­ 55) in the following microscopic liver lesions were observed: hyperplastic nodule( s) (includes both foci of cellular alteration and adenoma) in males at 2500 (39% vs 20%) and 10,000 ppm (36%) and in females at 10,000 ppm (15% vs 3%); and necrosis (severity and type unspecified) in the 10,000 ppm males (36% vs 7%). Centrilobular hepatocyte hypertrophy was observed (% treated vs % controls) at the terminal sacrifice (n = 38­ 55) in males at 2500 (18% vs 0%) and 10,000 ppm (98%) and in females at 10,000 ppm (46% vs 0%) and in the dead and moribund males (n = 25­ 40) at 2500 (44% vs 0%) and 10,000 ppm (60%). Increased (p#0.05 or 0.01) liver/ gall bladder weights were observed at 10,000 ppm in males in both absolute and relative to body weights and in females in relative to body weight. Other signs of toxicity were evident. Distal tail tip sloughing and/ or discoloration was observed at 10,000 ppm in males at Weeks 13­ 104 and in females at Weeks 5 and 13­ 104. Macroscopically, tip of tail missing/ sloughed was observed at the terminal sacrifice in the 10,000 ppm males (31% vs 5%) and females (61% vs 11%) and in the dead and moribund 10,000 ppm females (46% vs 2%). The toxicological significance of these findings was unclear. Minor decreases (p#0.05 or 0.01) in body weights were observed in the 10,000 ppm treatment groups at Weeks 13­ 104 in both sexes. Overall body weight gains (calculated by the reviewers) were decreased in the 10,000 ppm males (925%) and females (931%). The LOAEL is 2500 ppm for males (equivalent to 366 mg/ kg/ day) based on gross liver nodules/ masses, hyperplastic nodules in the liver and centrilobular hepatocyte hypertrophy and 10,000 ppm for females (equivalent to 1915 mg/ kg/ day [limit dose]) based on decreased body weights, increased relative liver/ gall bladder weights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. The NOAEL is 200 ppm (equivalent to 28 mg/ kg/ day) for males and 2500 ppm (equivalent to 450 mg/ kg/ day) for females. Liver samples were first evaluated using the term hyperplastic nodule which did not clearly distinguish neoplasia from non­ neoplasia. Re­ evaluation was conducted to make this distinction, and no significant differences were observed between the treatment groups and the concurrent controls. However positive trends (p< 0.05) were observed (% treated vs % controls) in focus/ foci of cellular alteration in males, hepatocellular neoplasm( s) (including adenoma, sarcoma, carcinoma, leukemia, and HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­16­ lymphoma) in females, and singular hepatocellular adenoma in females. Focus/ foci of cellular alteration were observed in males at 2500 (11.3% vs 5.0%) and 10,000 ppm (24.1%) and females at 10,000 ppm (12.5% vs 3.8%) beginning at Week 57. Singular hepatocellular adenoma was observed in the 10,000 ppm females (7.5% vs 2.5%) beginning at Week 77. Hepatocellular neoplasm( s) were observed in the 10,000 ppm females (8.8% vs 2.5%). A carcinoma in the 10,000 ppm treatment groups was first observed at Week 65. The incidence of carcinomas were within historical control ranges for each sex, while the incidence of adenomas were increased by 3.21% in the 10,000 ppm females. A dose­ dependent increase in adenomas was not observed in males. The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) concluded that hexazinone should be classified as a Group D (not classifiable as to human carcinogenicity)( 7/ 27/ 94). Under the conditions of this study, evidence of carcinogenic potential was equivocal: a positive trend test for neoplasia was observed in female mice, but no significant difference was determined by pair­ wise comparison. The submitted study is classified as acceptable for guideline 870­ 4200 carcinogenicity study in mice. 870.4300 Chronic/ Carcinogenicity Study ­ rat EXECUTIVE SUMMARY: In this combined chronic/ oncogenicity study (MRID 00108638), hexazinone (94­ 96% a. i.; Lot/ Batch #: 6897­ 40 and 74.25) was administered in the diet to ChR­ CD rats (36/ sex/ group) for up to 25 months at nominal doses of 0, 0, 200, 1000, or 2500 ppm (equivalent to 0, 0, 10.2, 53.4, and 138.3 mg/ kg/ day in males and 0, 0, 12.5, 67.5, and 178.6 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, clinical signs, food consumption, hematology, clinical chemistry, organ weights, and gross or microscopic pathology. No adverse effects were observed in the 200 ppm animals. There were several signs of general toxicity, but a target organ could not be clearly identified at any dose. Terminal body weights were decreased 8% in1000 ppm and 20%, p#0.05, in the 2500 ppm females. A decrease in overall body weight gain (Days 0­ 728; calculated by the reviewers) was also observed in the 1000 (­ 10%) and 2500 ppm (­ 25%) females. Nominal decreases in body weight and body weight gain (­ 3 to ­5%) occurred in males at 1000 ppm during the study, which may have been biologically significant at the end of the study (­ 12% body weight and ­14% for body weight gain). Decreases (p­ values not calculated) in total food efficiency were observed in females at 1000 (­ 10%) and 2500 ppm (­ 25%) and in males at 1000 ppm during the study with overall decrement in food efficiency in 1000 ppm males (­ 10%). In males at 2500 ppm, food efficiency was depressed for the first 6 months of the study (­ 25%), but from 6 months to the end of the study, it was increased 139%. The reviewer noted problems interpreting the body weights and food efficiency in males at the top dose level, which were not consistent with the mid­ dose level. For the first 6 months of the study in males, a body weight decrement due to probable toxicity was seen at 1000 and 2500 ppm. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­17­ After 6 months food efficiency in males at the 1000 ppm remained less than controls (­ 56%) while food efficiency at 2500 ppm in males was higher than controls (+ 139%)( Table 4). By the end of the study, male body weight at 1000 ppm was ­12% and body weight gain ­14%, where as body weight and body weight gain in males at 2500 ppm was +3% for both weight and gain. The reason for this recovery in male body weight decrement at 2500 ppm is unknown, but it appears to be real. [Since absolute and relative liver weights were decreased in males at 2500 ppm, liver enzyme induction allowing the recovery seems unproven.] The body weight decrement at 1000 and 2500 ppm with recovery in body weight at 2500 ppm indicates the an adequate dose level to test for carcinogenicity in males was approached, but probably not attained. Other treatment groups were similar to the average of concurrent controls. Dosing was considered adequate based on decreased body weights, body weight gains, and food efficiency in the 2500 and 1000 ppm females and food efficiency and body weights in the 2500 ppm males for the first 6 months. Body weight (­ 12%) and body weight gain 14 in males at 1000 ppm were decreased at the end of the study, in addition overall food efficiency (­ 14%) was decreased by the end of the study. Thus female body weight and body weight gain was decreased sufficiently to adequately test for carcinogenicity. Male body weight and body weight gain at 1000 ppm appeared to be adequate to test for carcinogenicity by the end of the study, but the lack of dose response in male body weight and body weight gain at 2500 ppm (showing recovery after 6 months such that body weight and body weight gain were higher than control values) may indicate problems with the interpretation of the body weights and body weight gains at 1000 ppm. In the 2500 ppm males, creatinine was increased (NS) in the urine at months 18 and 24 and bilirubin was detected at month 18 and 24. The Sponsor reported that the urine was more alkaline in the 2500 ppm treatment groups (data not reported). Also at 2500 ppm, decreased (p#0.05) absolute and relative liver and kidney organ weights were observed in the males and increased (p#0.05) relative (to body) stomach and kidney organ weights were observed in the females. However, histopathological data did not corroborate these findings. The LOAEL is 1000 ppm for males and females (equivalent to 53.3 for males and 67.5 mg/ kg/ day for females) based on decreased body weight and food efficiency in males and females. In males at 2500 ppm the body weight decrement and food efficiency decrement occurred only for the first 6 months of the study. The NOAEL is 200 ppm for males and females (10.2 for males and 12.5 mg/ kg/ day for females). Neoplasm data were evaluated by two pathologists. An increase incidence of thyroid Ccell adenomas was observed in the 2500 ppm males, but when analyzed by the Fisher's exact test (p> 0.10) or life­ table methods (p> 0.20) no significant differences were observed between controls and treated groups. Using life­ table analyses a significant (p< 0.05) dose­ response trend was observed in thyroid C­ cell tumors in only one of the two pathology reports. Female rats did not show any potential for C­ cell thyroid adenomas. The incidence, malignancy and latency of tumors were comparable among control and treated rats of both sexes. Under the conditions of this study, carcinogenic potential of hexazinone is considered negative. The submitted study is classified as acceptable for guideline 870.4300 combined HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­18­ chronic/ carcinogenicity study in rats. 4.7 Mutagenicity Adequacy of data base for Mutagenicity: The data base for Mutagenicity is considered adequate based on pre­ 1991 mutagenicity guidelines. Hexazinone was found to be positive for mutagenicity in one chromosomal aberration assay (in vitro cytogenics) (MRID# 00130709), but negative in the remaining studies. It is concluded that the test material was clastogenic in both of the non­ activated trials and was also clastogenic in the one adequate S9­ activated trials. Under both test conditions, concentrations providing evidence of clastogenicity induced an acceptable level of cytotoxicity (> 50% relative cell survival). Thus, the findings can not be considered to be a secondary effect of cytotoxicity. Nevertheless, the outcome of the induced structural damage (i. e., primarily chromatid and chromosome breaks) is unclear since these types of structural aberrations would not likely be passed on to daughter cells. Because unambiguous positive results were achieved, it was concluded that the study provided adequate evidence that INA3674 112 (hexazinone, technical) is clastogenic in an acceptable study. Gene Mutation 4.7.1 Guideline 870.5100, Reverse mutation in Salmonella EXECUTIVE SUMMARY: In a reverse gene mutation assay in bacteria (MRID 40826201), strains TA98, TA100, TA1535, TA1537 and TA1538 of S. typhimurium were exposed to S­ triazine2,4 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ (95% a. i.) in ethanol at concentrations of 200, 400, 600, 800 and 1000 :g/ plate without mammalian metabolic activation (S9­ mix) and at concentrations of 400, 800, 1200, 1600 and 2000 :g/ mL with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Crl: CD( SD) BR rat liver. The maximum concentrations of S­ triazine­ 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ tested produced little or no cytotoxicity, were not limited by solubility and were not a limit dose for the assay. No statistically significant increases in the number of revertants per plate or positive linear dose­ response were seen. The solvent and positive controls induced acceptable responses in the corresponding strains. There was no evidence of induced mutant colonies over background. This study is classified as Unacceptable. It does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5100 (§ 84­ 2)] for in vitro mutagenicity [bacterial reverse gene mutation] data and should have used higher doses. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­19­ 4.7.2 Guideline 870.5300, Gene mutation at HGPRT locus EXECUTIVE SUMMARY: In a mammalian cell gene mutation assay at the HGPRT locus (MRID No. 00076956), Chinese hamster CHO­ K1­ BH4 cells cultured in vitro were exposed to INA­ 3674­ 112, (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol in two trials. Concentrations used in Trial 1 were 2.0, 11.1, 13.1, 13.9 and 14.3 mM under nonactivated conditions and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM under activated conditions (S9­ mix). Concentrations used in Trial 2 were 2.0, 5.9, 11.1, 13.1 and 13.9 mM without S9­ mix and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Charles River CD® rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. In Trial 1, the cultures treated at 14.3 mM were not plated for mutation determination due to cytotoxicity and in both Trials 1 and 2, those cultures treated at 13.9 mM were excluded from analysis because no mutants were seen. No statistically significant increases in mutant frequency over solvent control values were seen with or without S9­ mix in either Trial 1 or 2. The expected marked increase in the mutation were seen with the positive controls. There was, however, no indication that INA­ 3674­ 112 induced a mutagenic effect either in the presence or the absence of S9 activation. This study is classified as acceptable. It satisfies the requirement for FIFRA Test Guideline OPPTS [870.5300 (§ 84­ 2)] for in vitro mutagenicity (mammalian forward gene mutation) data. 4.7.3 Guideline: 870.5375: In vitro mammalian cytogenics (chromosomal aberrations) in Chinese hamster CHO cells. EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (MRID No. 00130709), Chinese hamster ovary CHO­ K1 ­BH4 cell cultures were exposed to INA­ 3674­ 112 (Hexazinone, 95% a. i.) in ethanol in two separate trials. Exposure was for two hours with activation and for 10 hours without activation. Cells were harvested 10 hours after the start of treatment. In Trial 1, cells were treated at concentrations of 1.58, 3.94, 15.85 and 19.82 mM without metabolic activation (S9­ mix) and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. In Trial 2, cells were treated at concentrations of 1.58, 3.94, 7.93 and 15.85 without S9­ mix and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced CD rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. Based on the results of a preliminary cytotoxicity test, upper concentrations of 23.78 mM without S9­ mix and 47.56 mM with S9­ mix were selected for the first cytogenetic assay but these concentrations proved excessively cytotoxic and were not scored for chromosomal aberrations. Without S9 activation, statistically significant increases (p< 0.01) in structural aberrations per cell (excluding gaps), lesions per cell and percent abnormal cells were seen at 15.85 mM (Trials 1 and 2) and 19.82 mM (tested in Trial 1 only). Relative percent survival (RPS) at this level was .50%. The percent abnormal cells averaged over all cultures from both trials was 28.0% and 21.5% at 19.82 and 15.85 mM, respectively, compared to the solvent control values of 2.0% (0.5% ethanol in Trial 2) and 7.0% (0.75% ethanol in Trial 1). The percent abnormal cells in positive control cultures was 18% in both Trial 1 (4.83 mM EMS) and Trial 2 (6.44 mM EMS). In the presence of S9­ mix, no statistically significant increases in chromosomal HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­20­ aberration induction were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix. Statistically significant increases were seen at 15.85 mM in Trial 2; RPS at 15.85 mM was 75%. There was a statistically significant dose­ related trend for all three parameters. The statistically significant (p <0.01) increases at 15.85 mM remained when the data from Trial 1 and 2 were combined (average of 20% abnormal cells compared to 10% for the solvent control). The predominant aberrations with or without S9­ mix were chromatid and isochromatid breaks. Solvent and positive controls (except the positive control in Trial 1 with S9­ mix) induced the appropriate responses. INA­ 3674­ 112 was positive for the induction of structural chromosomal aberrations in both the presence and absence of S9­ mix. This study is classified as Acceptable/ guideline and satisfies the requirement for FIFRA Test 4.7.4 Guideline 870.5385: In vivo cytogenics assay in rat bone marrow cells EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (MRID 00131355), in bone marrow cells of Sprague­ Dawley CD rats, three rats/ dose/ sex/ harvest time were exposed to H# 14,555 in corn oil ( assumed 100% a. i.) at doses of 100, 300 and 1000 mg/ kg by oral gavage. Bone marrow cells were harvested at 6, 12, 24 and 48 hours post­ treatment. The highest dose tested (1000 mg/ kg) was lethal. A major limitation of this study was the number of animals treated and the number of cells analyzed per animal. At most, three rats/ sex/ dose/ harvest time were treated with, at most, 50 cells per rat analyzed. Few or no analyzable cell were available from many rats. Positive control values were significantly (p= 0.03) increased. There was no evidence that H# 14, 14,555 induced an increase in the incidence of chromosomal aberrations in the bone marrow cells of treated animals. This study is classified as Unacceptable. The number of cells analyzed and the number of rats treated was insufficient. The study does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5385 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. 4.7.5 Guideline 870.5395: Micronucleus assay in mouse bone marrow EXECUTIVE SUMMARY: In a Crl: CD­ 1 (ICR) BR mouse bone marrow micronucleus assay (MRID 45124401), 5 mice/ sex/ dose/ harvest time were treated orally with Hexazinone 25L (Lot No. 9912033, 25% Hexazinone a. i. (24.5% by analysis) and 75% inert ingredients) at doses of 1000, 2000 and 3000 mg/ kg. Bone marrow cells were harvested at 24 and 48 hours post­ treatment and examined for micronucleated polychromatic erythrocytes (MPCEs). The vehicle was Milli­ Q ® water. Signs of toxicity noted at 3000 mg/ kg included: death, convulsions, half­ shut eyes, head­ tilt, irregular respiration, lethargy, low carriage, pallor, prostration, uncontrollable spinning, shovel­ nosing, straining up on toes and tremors. Micronuclei were scored in bone marrow from mice treated at 3000 mg/ kg and from the solvent and positive controls. Mice from the two lower dose groups were not evaluated for micronuclei induction. No statistically significant increases in the frequency of MPCEs or HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­21­ in the PCE/ NCE ratio over the solvent control values were seen in either sex at either the 24 or 48 hour harvest time. The solvent and positive control values were appropriate and within the testing laboratory's historical control ranges. There was no evidence that Hexazinone 25L induced a clastogenic or aneugenic effect in bone marrow at any harvest time. This study is classified as Acceptable/ Guideline. It satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5395 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. 4.7.6 Guideline 8760.5550: Unscheduled DNA synthesis assay in rat hepatocytes EXECUTIVE SUMMARY: In an unscheduled DNA synthesis assay (MRID 00130708), primary rat hepatocyte cultures were exposed to INA­ 3674­ 112 (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol for 18 hours at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 10.0 and 30.0 mM in Trial 1 and at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 5.0, 10.0 and 30.0 mM in Trial 2. INA­ 3674­ 112 was tested up to the highest achievable concentration in the solvent. Two slides per dose, 25 cells per slide were evaluated for UDS induction in Trial 1. One slide per dose, 25 cells per slide were evaluated in Trial 2. The author did not report that the slides were coded prior to analysis. The average net nuclear grain counts of test material treated cells in Trial 1 were all less than zero with the exception of one slide at 1 x 10 ­5 mM (0.1 ± 9.6) and one slide at 1.0 mM (1.6 ± 5.2). The average net nuclear grain count was below zero for all test material concentrations in Trial 2 with the exception of 0.1 mM where the average net nuclear grain count was 0.0 ± 2.9. The criterion for a positive response was an average net nuclear grain count of at least five in two experiments at any tested concentration. The results were thus negative. The number of cells in repair was not reported. The solvent and positive (DMBA) controls induced the appropriate responses. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline; OPPTS 870.5550 [§ 84­ 2] for other genotoxic mutagenicity data. Compliance statements were not provided. 4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: No neurotoxicity data are required. 870.6100 Delayed Neurotoxicity Study ­ Hen Study is not required of hexazinone, which is not an organophosphate. 870.6200 Acute Neurotoxicity Screening Battery HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­22­ Study not required 870.6200 Subchronic Neurotoxicity Screening Battery Study not required. 870.6300 Developmental Neurotoxicity Study Study not required. 4.9 Metabolism Adequacy of data base for metabolism: The data base for metabolism is considered to be complete. No additional studies are required at this time. 870.7485 Metabolism ­ Rat EXECUTIVE SUMMARY: A metabolism study (MRID 00109237 & 00140162) was conducted to evaluate the absorption, distribution, metabolism, and excretion of hexazinone in male and female CD rats. Radiolabeled ( 14 C at position 2 or 4 on the cyclohexyl ring) hexazinone, (Lot # not reported, purity >95%, radiochemical purity >99%) was administered by gavage to groups of one male and one female rat at concentrations of 14 mg/ kg or 1000 mg/ kg. A third group of two male and two female rats received unlabeled hexazinone (~ 5 mg/ kg/ day) in the diet for three weeks before being given a single 14 mg/ kg radiolabeled gavage dose. Mass balance was excellent and ranged from 95­ 102% recovery for all treatment groups. Based on the amount of radiolabel recovered in the urine and cage wash, absorption of the test material was at least 83% with no dose­ or sex­ dependent differences noted. By 72 hours after treatment, essentially none of the radiolabeled test material was present in the tissues. Urine was the primary route of elimination accounting for ~83% of the administered dose. Urinary elimination was rapid and ~96% complete within 48 hours of treatment. No apparent sex or dose­ related differences were found. Fecal excretion was a minor route of elimination, accounting for ~16% of the dose and was rapid with ~95% occurring within 72 hours of treatment. Once again, no apparent sex or dose­ related differences were found. Essentially none of the parent compound was found in the urine (-83% of dose) or feces (-16% of dose) of male and female rats following multiple low­ dose or a single high­ dose treatment with hexazinone. (Molecular structures of the parent and metabolites can be found in Section IV, Appendix.) 3­( 4­ hydroxycyclohexyl)­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione (metabolite A) and 3­( 4­ hydroxycyclohexyl)­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H) dione (metabolite C) comprised ~66 and 28%, respectively, of the identified fecal metabolites in males and females. These two metabolites resulted from hydroxylation of the cyclohexyl ring and differed only by the metabolic conversion of the 6­ dimethyl amine to a secondary methyl amine. No sex­, or HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­23­ dose­ related differences in the formation and excretion of these metabolites were found. Three metabolites were identified in the urine of males and females (metabolite A and C, -57% and -28% of identified metabolites, respectively) . Two of the metabolites were identical to those found in the feces . The third metabolite (3­( cyclohexyl)­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione) (metabolite B, -9% of urinary metabolites) resulted from demethylation of the 6­ dimethyl amine group to form a secondary amine without hydroxylation of the 4­ position on the cyclohexyl ring. Approximately 3% of the urine metabolites were unidentified polar compounds and 5% were isolated from the hydrolyzed urine, suggesting they had undergone glucuronide or sulfate conjugation. No differences between the sexes or dose groups in the metabolic conversion of hexazinone were found. This metabolism and disposition study with rats is considered Acceptable/ Nonguideline and does satisfy the requirements for a Metabolism and Pharmacokinetics Study [OPPTS 870.7485 (§ 85­ 1)]. Major deficiencies include the use of 1­ 2 male and female rats/ group; no submission of test material lot numbers, stability, or dose confirmation data; and study dates. 4.10 Special/ Other Studies None available. 5.0 TOXICITY ENDPOINT SELECTION 5.1 See Section 9.2 for Endpoint Selection Table. 5.2 Dermal Absorption No dermal absorption study is available. For dermal absorption, the NOAEL from the 21­ day dermal toxicity study at the limit dose of 1000 mg/ kg/ day was considered a lower bound for the LOAEL, which was compared with LOAEL of 250 mg/ kg/ day from the range­ finding rabbit study (MRID# 00028863). The ratio of these two numbers was used to estimate a dermal absorption factor of 25%. The range­ finding study was chosen instead of the main rabbit developmental toxicity study (MRID# 00028863) for comparison because the main study was considered to be unacceptable for regulatory purposes. Dermal Absorption Factor: 25 % 5.3 Classification of Carcinogenic Potential 5.3.1 Conclusions There was no evidence of treatment related tumors in chronic rat or mouse studies. 5.3.2 Classification of Carcinogenic Potential HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­24­ The RfD/ Peer Review Committee has classified hexazinone as a group D chemical; no evidence of carcinogenicity in rats and in mice insufficient evidence of human carcinogenic potential. 5.3.3 Quantification of Carcinogenic Potential Not required. 6.0 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children There was no evidence of quantitative or qualitative postnatal susceptibility in a twogeneration study of reproduction. There was no quantitative or qualitative evidence of increased susceptibility following in utero exposure to rats or rabbits in developmental toxicity studies. However, the rabbit developmental toxicity study was unacceptable/ upgradable. Until another study is review, a 10X uncertainty factor for the data gap will remain. In rats, no developmental toxicity was seen at the highest dose level tested, and in rabbits, developmental effects were seen at a dose that was higher than that showing maternal toxicity. 6.2 Recommendation for a Developmental Neurotoxicity Study No neurotoxic potential was seen in any of the studies. A developmental neurotoxicity study is not required. 7.0 OTHER ISSUES None 8.0 REFERENCES: MRID 00028863. Unknown (1980) Teratology Study in Rabbits. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 201­ 522, February 14, 1980. Unpublished. MRID 00076956. McCooey, K. T., and Krahn, D. F. (1980). Chinese Hamster Ovary Cell Assay for Mutagenicity. E. I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, Newark, DE HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­25­ 19711. Haskell Laboratory Report No.: 56­ 81, MR No.: 0581­ 865, December 1, 1980. Unpublished. MRID 00079203. Unknown (1981) Two­ Year Feeding Study in Mice. International Research and Development Corporation, Mattawan, MI. Laboratory Project Id.: HLO414 81, June 23, 1981. Unpublished. MRID 00104977. Sherman, H. et. al. (1973) Ninety­ Day feeding Study in Rats with INA­ 3674. Haskell Laboratory. Laboratory Study Id.: 235­ 73, May 21, 1973. Unpublished. MRID 00108638. Kaplan, A. M., Frazier, C. V., et al. (1977) Long­ Term Feeding Study in Rats with INA­ 3674. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 353­ 77, May 13, 1977. Unpublished MRID 00109237. Repisarda, C. (1982). Metabolism of 14 C­ labeled hexazinone in the rat. E. I. duPont de Nemours and Co., Biochemicals Dept., Research Div., Experimental Station, Wilmington, DE 19898. Document No. AMR­ 79­ 82. Unpublished. MRID 00114484. Sherman, H. et al. (1973) Three­ Month Feeding Study in Dogs with INA3674 E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 408­ 73, September 12, 1973. Unpublished. MRID 00114486. Culik, R., et al. (1974) Teratogenic Study in Rats with INA­ 3674. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 265­ 74, April 9, 1974. Unpublished. MRID 00130708. Summers, J. C. (1983) Unscheduled DNA Synthesis/ Rat Hepatocytes In Vitro. E. I. du Pont de Nemours and Co., Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, P. O. Box 50, Newark, Delaware 19711. Laboratory Report No.: 766­ 82, MR No.: 4508­ 001, Date Issued: January 4, 1983. Unpublished. MRID 00130709. Valachos, D., Irr, J. and Krahn, D. F.( 1982) In Vitro Assay for Chromosome Aberrations in Chinese Hamster Ovary (CHO) Cells. E. I. du Pont Nemours and Co., Inc., Haskell Laboratory for Toxicology and Industrial Medicine, HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­26­ Elkton Road, P. O. Box 50, Newark, Delaware 19711. Laboratory Report No. 768­ 82, MR No. 4508­ 001, December 3, 1982. Unpublished. MRID 00131355. Farrow, M. G., Cortina, T. and Zito, M. (1982). In Vivo Bone Marrow Cytogenetic Assay in Rats with H# 14,555: Final Report. Hazleton Laboratories America, Inc., 9200 Leesburg Turnpike, Vienna, Virginia 22180. HLA Project number: 201­ 573, December 9, 1982. Unpublished. MRID 00140162. Rhodes, R. C., Jewell, R. A., Sherman, H. (No date). Metabolism of "Velpar" weed killer in the rat. E. I. duPont de Nemours and Co., Biochemicals Dept., Experimental Station and Haskell Laboratory for Toxicology and Industrial Medicine, Wilmington, DE 19898. No document or report number. Results published in J. Agric. and Food Chem., 28, 303 (1980) MRID 40397501. Mullin, L. S. (1987) Teratogenicity Study of INA­ 3674 in Rats. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 748­ 86, January 30, 1987. Unpublished. MRID 40826201. J. F. Russell Jr. and D. F. Krahn (1977). Mutagenicity Evaluation of Striazine 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ in Salmonella typhimurium. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, P. O. Box 50, Newark, Delaware 19714. Haskell Laboratory Report No. 588­ 77, MR No. 0581­ 693; Date Issued: July 29, 1977. Unpublished. MRID 41309005. Malek, D. (1989). Repeated Dose Dermal Toxicity: 21­ Day Study with DPXA3674 207 (Hexazinone) in Rabbits. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, P. O. Box 50, Elkton Road, Newark, DE 19714. Study No. HLA 673­ 89. November 22, 1989. Unpublished. MRID 41359301. Goldenthal, E. I. (1989) Supplement 1 to: Two­ Year Feeding Study in Mice with Hexazinone. International Research and Development Corporation, Mattawan, MI. Laboratory Project Id.: HLO­ 414­ 81, November 22, 1989. Unpublished. MRID 42066501. Mebus, C. A. (1991). Reproductive and fertility effects with IN­ A3674­ 207; multigeneration reproduction study in rats. Haskell Laboratory, Newark, Delaware. Study No. HLA­ 404­ 91. September 11, 1991. Unpublished. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­27­ MRID 42162301. Dalgard, D. W. (1991) Chronic toxicology study in dogs with DPX­ A3674­ 207 (Hexazinone). Hazleton Washington, Inc., 9200 Leesburg Turnpike, Vienna, VA 22182. Laboratory Study No. 201­ 905. November 5, 1991. Unpublished. MRID 42509301. Slone, Jr., T. W. (1992) Supplement 1 to: Two­ Year Feeding Study in Mice with Hexazinone. E. I. du Pont de Nemours and Company, Newark, DE. Laboratory Project Id.: HLO­ 414­ 81, October 2, 1992. Unpublished. MRID 43202901. Slone, Jr., T. W., (1994) Supplement No. 3: Two­ Year Feeding Study in Mice with Hexazinone. E. I. du Pont de Nemours and Company, Newark, DE. Laboratory Project Id.: HLO­ 414­ 81, April 11, 1994. Unpublished. MRID 45124401. Ford, L. S. (2000) Hexazinone 25L: Mouse Bone Marrow Micronucleus Assay. DuPont Pharmaceuticals Company, Safety Assessment Section, Stine Haskell Research Center, P. O. Box 30, Elkton Road, Newark, Delaware 19714­ 3507. Laboratory Project ID: DuPont 3852; Company Study Number: THA­ 00­ 02­ 47, April 12, 2000. Unpublished. Other references: U. S. EPA Report: Peer Review of Hexazinone (August 12, 1992). U. S. EPA Report: RfD/ Peer Review Report of Hexazinone (March 24, 1993). U. S. EPA Report: Carcinogenicity Peer Review of Hexazinone. (July 27, 1994). U. S. EPA Report: Hexazinone­ 2 nd Report of the Hazard Identification Assessment Review Committee (TXR# 0050695). U. S. EPA Report: HEXAZINONE ­ Report of the FQPA Safety Factor Committee (TXR# 0050750). HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­28­ 9.0 APPENDICES Tables for Use in Risk Assessment HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter ­29­ 9.1 Toxicity Profile Summary Tables 9.1.1 Acute Toxicity Table Acute Toxicity Data on FENBUTATIN­ OXIDE Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity 41235004 LD50 = 1200 mg/ kg III 870.1200 Acute dermal toxicity 00104974 LD50 > 5278 mg/ kg IV 870.1300 Acute inhalation toxicity 41756701 (1991) LC50 > 3.94 mg/ L( 4 hour) III 870.2400 Acute eye irritation 00106003 Irreversible corneal opacity I 870.2500 Acute dermal irritation 00106004 Mild IV 870.2600 Skin sensitization 41235005 Not a dermal sensitizer in the Buehler test in Guinea pigs NA 9.1.2 Subchronic, Chronic and Other Toxicity Tables Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90­ Day oral toxicity rats 0010977 (1973) Dose: 0, 200, 1000, 5000 ppm (equivalent to 0, 16.0/ 16.4, 81.0/ 87.3, 440/ 451 mg/ kg/ day, male/ female) Acceptable NOAEL = 1000 ppm (81.0/ 87.3 mg/ kg/ day male/ female) LOAEL = 5000 ppm (440/ 451 mg/ kg/ day male/ female) based decreased body weight and food efficiency. 870.3150 90­ Day oral toxicity in non­ rodents 00114484 (1973) Doses of 0, 200, 1000, or 5000 ppm (equivalent to 0/ 0, 5.1/ 7.0, 25.9/ 31.6, 122.5/ 137.3 mg/ kg/ day, males/ females) Acceptable NOAEL = 1000 ppm (equivalent to 25.9/ 31.6 mg/ kg/ day for males/ females). LOAEL = 5000 ppm (equivalent to 122.5/ 137.3 mg/ kg/ day in males/ females) based on decreased body weight gains, increased relative liver weights, and increased alkaline phosphatase levels in both sexes and transiently decreased food consumption in the females. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results ­30­ 870.3200 21/ 28­ Day dermal toxicity in rabbits 41309005 (1989) Doses: 0, 50, 400, or 1000 mg/ kg/ day Acceptable NOAEL = 1000 mg/ kg/ day. LOAEL = was not identified for systemic and dermal toxicity. 870.3250 90­ Day dermal toxicity Not required 870.3465 90­ Day inhalation toxicity The 90­ day inhalation study is not required, however a 28­ Day inhalation study is required (contact Agency prior to conducting study) 870.3700a Prenatal developmental in rats 40397501 (1980) Doses: 0, 40, 100, 400, or 900 mg/ kg Acceptable Maternal NOAEL = 100 mg/ kg/ day LOAEL = 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. Developmental NOAEL = 400 mg/ kg/ day LOAEL = 900 mg/ kg/ day based on decreased female fetal weight, and increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). 870.3700a Prenatal developmental in rats 00114486 (1974) Doses: 0, 200, 1000, or 5000 ppm (equivalent to 0, 18.9, 94.5, and 482.0 mg/ kg) Unacceptable/ Upgradable Maternal: NOAEL is 1000 ppm (equivalent to 94.5 mg/ kg/ day). LOAEL = 5000 ppm (equivalent to 482 mg/ kg/ day) based on decreased body weights, body weight gains, and food efficiency. Developmental: NOAEL = 5000 ppm (equivalent to 482.0 mg/ kg/ day). LOAEL was not observed. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results ­31­ 870.3700b Prenatal developmental in rabbits 00028863 (1980) Doses: 0, 20, 50, or 125 mg/ kg Unacceptable/ Upgradable Maternal NOAEL = 50 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on transient decreases in food consumption and body weight gains. Developmental NOAEL = 50 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on possible skeletal abnormalities and total abnormalies. 870.3800 Reproduction and fertility effects in rats 42066501 (1991) Acceptable 0, 200, 2000 or 5000 ppm M: 0, 11.8, 117 or 294 mg/ kg/ day F: 0, 14.3, 143 or 383 mg/ kg/ day Parental/ Systemic NOAEL = 14.3 mg/ kg/ day LOAEL = 143 mg/ kg/ day based on male body weight decrement. Reproductive NOAEL = 383 mg/ kg/ day LOAEL = None based on no effects on or organs of reproduction. Offspring NOAEL = 14.3 mg/ kg/ day LOAEL = 143 mg/ kg/ day based on reduced female pup weight at birth and during lactation. 870.4100a Chronic toxicity in rats See 870.4300 NOAEL = LOAEL = 870.4100b Chronic toxicity dogs 42162301 (1991) Doses: 0, 200, 1500, or 6000 ppm (equivalent to 5.00/ 4.97, 41.24/ 37.6 and 161/ 167 mg/ kg/ day, male/ female. Acceptable NOAEL = 200 ppm (5.0/ 5.0 mg/ kg/ day, male/ female) LOAEL = 1500 ppm (41.2 and 37.57 mg/ kg/ day, respectively) based on thinness in one male and hepatotoxicity as evidenced by changes in clinical chemistry parameters and microscopic lesions. 870.4200 Carcinogenicity rats See below 870.4300 No evidence of carcinogenicity HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results ­32­ 870.4200 Carcinogenicity mice 00079203 (1981), 41359301 (1989), 42509301 (1992) and 43202901 (1994) Doses: 0, 0, 200, 2500 or 10,000 ppm (equivalent to 28/ 34, 366/ 450 and 1635/ 1915 mg/ kg/ day, male/ female) Acceptable NOAEL = 200/ 2500 ppm (28/ 450 mg/ kg/ day, male/ female, respectively) LOAEL = 2500 ppm for males (equivalent to 366 mg/ kg/ day) based on gross liver nodules/ masses, hyperplastic nodules in the liver and centrilobular hepatocyte hypertrophy and 10,000 ppm for females (equivalent to 1915 mg/ kg/ day [limit dose]) based on decreased body weights, increased relative liver/ gall bladder weights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. Insufficient evidence for carcinogenicity. 870.4300 Combined chronic/ carcinogenicity/ rats 00108638 (1977) Doses: 0, 200, 1000, or 2500 ppm (equivalent to 0, 10.2/ 12.5, 53.4/ 67.5, or 138/ 179 mg/ kg/ day, male/ female) Acceptable NOAEL = 200 ppm for males and females (10.2/ 12.5 mg/ kg/ day, male/ female). LOAEL = 1000 ppm for males and females (equivalent to 53.3/ 67.5 mg/ kg/ day, male/ female) based on decreased body weight and food efficiency in males and females. In males at 2500 ppm the body weight decrement and food efficiency decrement occurred only for the first 6 months of the study. The carcinogenic potential of hexazinone is considered negative. Gene mutation 870.5100; Reverse mutation in Salmonella strains 40826201 (1977) 200, 400, 600, 800 and 1000 :g/ plate ­S9 and 400, 800, 1200, 1600 and 2000 :g/ mL + S9­ mix. Unacceptable No mutagenic potential was seen, but doses insufficent to cause cell toxicity. Gene mutation 870.5300; hamster CHO cells/ HPRT assay 00076956 (1980) Trial 1 were 2.0, 11.1, 13.1, 13.9 and 14.3 mM ­S9 and 2.0, 7.9, 8.9, 9.3 and 9.9 mM +S9. Trial 2 were 2.0, 5.9, 11.1, 13.1 and 13.9 mM ­S9 and 2.0, 7.9, 8.9, 9.3 and 9.9 mM + S9. Acceptable No evidence of mutagenic potential at cytotoxic doses. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results ­33­ Cytogenics 870.5375; Chromosomal aberrations in hamster CHO cells 00130709 (1982) In Trial 1, 1.58, 3.94, 15.85 and 19.82 mM ­S9 and 0.32, 3.17, 7.93 and 15.85 mM + S9. In Trial 2, 1.58, 3.94, 7.93 and 15.85 ­S9 0.32, 3.17, 7.93 and 15.85 mM + S9 Acceptable Positive for structural chromosomal aberrations with and without S9. Other Effects 870.5385, In vivo Rat bone marrow cytogenics assay 00131355 (1982) Rat doses: 100, 300 or 1000 mg/ kg Unacceptable No evidence of mutagenic potential, but insufficient animals and cells were tested. Other Effects 870.5395 Mouse bone marrow micronucleus test 45124401 (2000) Mouse doses: 1000, 2000 and 3000 mg/ kg Acceptable No evidence of clastogenic or aneugenic effect in bone marrow at toxic doses.. Other Effects 870.5550, UDS in rat hepatocytes 00130708 (1983) Trial 1: 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 10.0 and 30.0 mM and Trial 2: 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 5.0, 10.0 and 30.0 mM. Acceptable No evidence of mutagenic potential at precipitating dose levels. 870.6200a Acute neurotoxicity screening battery Not required 870.6200b Subchronic neurotoxicity screening battery Not required 870.6300 Developmental neurotoxicity Not required ­ HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results ­34­ 870.7485 Metabolism and pharmacokinetics 00140162 & 00109237 (1980 &1982) Acceptable No parent was seen in urine or feces, which was rapidly absorbed and excreted. Two identified metabolites resulted from hydroxylation of the cyclohexyl ring and differed only by the metabolic conversion of the 6­ dimethyl amine to a secondary methyl amine. No sex­, or doserelated differences in the formation and excretion of these metabolites were found. 870.7600 Dermal penetration Not required Special studies None submitted 9.2 Summary of Toxicological Dose and Endpoints for HEXAZINONE for Use in Human Risk Assessment Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Dietary Risk Assessments Acute Dietary females 13­ 50 years of age NOAEL = 400 UF = 1000 Acute RfD = 0.40 mg/ kg/ day 1x Developmental Toxicity ­ Rat LOAEL is 900 mg/ kg/ day based on decreased male and female fetal weight, kidneys with no papilla (malformation) and misaligned sternebrae (variation) Acute Dietary general population including infants and children An appropriate endpoint attributable to a single dose was not identified in the oral studies, including the rat and rabbit developmental studies. Chronic Dietary all populations NOAEL= 5.0 UF = 100 Chronic RfD = 0.05 mg/ kg/ day 1x Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment ­35­ Incidental Oral Short­ Term (1 ­ 30 Days) Residential Only There are no residential uses at the present time and therefore, endpoints were not selected. Incidental Oral Intermediate­ Term (1 ­ 6 Months) Residential Only There are no residential uses at the present time and therefore, endpoints were not selected. Non­ Dietary Risk Assessments Dermal Short­ Term (1 ­ 30 days) No hazard was identified, therefore quantification of risk is not required. No systemic toxicity was seen at the limit dose following repeat dermal application, and there were no concerns for developmental or reproductive toxicity. Residential Occupational Dermal Intermediate­ Term 1 (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= N/ A N/ A Occupational MOE= 100 N/ A Dermal Long­ Term 1 (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= N/ A N/ A Occupational MOE= 100 N/ A Inhalation Short­ Term 2 (1 ­ 30 days) Oral NOAEL= 100 mg/ kg/ day Developmental Toxicity ­ Rat LOAEL = 400 mg/ kg/ day based on decreases in maternal food consumption and dose related body weight decrement. Residential MOE= N/ A N/ A Occupational MOE= 100 N/ A HEXAZINONE/ 107201/ May/ 2002 TRED Toxicology Chapter Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment ­36­ Inhalation Intermediate­ Term (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE = N/ A N/ A Occupational MOE= 100 N/ A Inhalation Long­ Term (> 6 Months) Oral NOAEL= 5.0 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= N/ A N/ A Occupational MOE= 100 N/ A Cancer Classification: D ­ Not Classifiable as to human carcinogenicity 1 Since an oral NOAEL was selected 25% dermal absorption factor should be used for route to route exposures. 2 Absorption via the inhalation route is assumed to be equivalent to oral absorption. N/ A = Not Applicable; there are no residential uses.

epa

2024-06-07T20:31:42.870326

regulations

EPA-HQ-OPP-2002-0188-0013

Supporting & Related Material

TXR# DATE: 4/ 25/ 02 MEMORANDUM SUBJECT: HEXAZINONE ­ 2 nd Report of the Hazard Identification Assessment Review Committee. FROM: David G. Anderson Toxicologist. Reregistration Branch­ 2 Health Effects Division (7509C) THROUGH: Jess Rowland, Co­ Chair and Elizabeth Doyle, Co­ Chair Hazard Identification Assessment Review Committee Health Effects Division (7509C) TO: Carol Christensen, Risk Assessor Reregistration Branch­ 2 Health Effects Division (7509C) PC Code: 107201 On Dec 4, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for HEXAZINONE with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to HEXAZINONE was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. On April 02, 2002, HIARC evaluated the need for an additional database uncertainty factor for the lack of an acceptable prenatal developmental study conducted in the rabbit under the new OPP 10X guidance document. The conclusions drawn at both meetings are presented in this report. 2 Committee Members in Attendance Members present were: Ayaad Assaad, Bill Burnam, Jonathan Chen, Paula Deschamp, Pamela Hurley, John Liccione, Elizabeth Mendez, David Nixon, Jess Rowland, Virginia Fornillo Member( s) in absentia: Beth Doyle Data evaluation prepared by: David G. Anderson, RRB2 Also in attendance were: Sherrie Kinard, Ken Dockter, Pauline Wagner, Diana Locke Data Evaluation/ Report presentation David G. Anderson Toxicologist Report Concurrence Brenda Tarplee, Senior Scientist Science Information Management Branch 3 1. INTRODUCTION On December 4, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for HEXAZINONE with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to HEXAZINONE was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. On April 02, 2002, HIARC evaluated the need for an additional database uncertainty factor for the lack of an acceptable prenatal developmental study conducted in the rabbit under the new OPP 10X guidance document. The conclusions drawn at both meetings are presented in this report. The last review of the hexazinone toxicity data base was February 11, 1993, by the RfD/ Peer Review Committee. A Reregistration Eligibility Document was issued September, 1994 (EPA­ 738­ F­ 94­ 019). 2. HAZARD IDENTIFICATION 2.1 Acute Reference Dose (RfD)( Population Subgroup: Females 13­ 50) Study Selected: Developmental toxicity Study in Rats § 870.3700 MRID No.: 40397501 Executive Summary: In a developmental toxicity study (MRID 40397501), hexazinone (99.26% a. i.; Lot# S30306A, Batch# 2/ 36) in 0.5% methylcellulose was administered orally via gavage to 25 Crl: CD ® BR female rats/ group at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day (GD) 7 through 16. The dosing volume was 10 mL/ kg (calculated by reviewers). All dams were sacrificed on GD 22 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in clinical signs, gross pathology, pregnancy rate, live fetuses, resorptions, pre­ or post­ implantation loss, corpora lutea, or implantations were noted at any dose level tested. No treatment­ related findings were noted in the 100, or 40 mg/ kg groups. In the 900 mg/ kg dams, one treatment­ related death occurred; alopecia and an enlarged stomach containing fluid and food were noted at necropsy. Decreased (p< 0.05) body weight gains were noted during GDs 15­ 17 (937%) and 17­ 22 (917%). In addition, body weight gains were decreased (p< 0.05) for the overall (GDs 7­ 17) treatment interval (930%). Gravid uterine weights were not reported; however, adjusted (for gravid uterine weight) terminal body weights were slightly decreased (96%; p#0.05). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 9­ 11, 15­ 17, 7­ 17, and 17­ 22. Decreased (p#0.05) food consumption was observed throughout treatment (GDs 7­ 17; 916­ 22%) and post­ treatment (GDs 17­ 22; 99%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 7­ 9, 9­ 11, 11­ 13, 13­ 15, 15­ 17, 7­ 17, and 17­ 22. Also a significantly decreased food consumption was seen at 400 4 mg/ kg/ day (GD9­ 11; 91%) and (GD 7­ 17; 98%). In addition, relative (to body) liver weights were increased (p#0.05) in the 400 (5.2%) and 900 (5.6%) mg/ kg dams compared to concurrent controls (4.9%). Decreased (p#0.05) terminal body weights were noted at 900 mg/ kg (96%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for relative liver weights and adjusted terminal body weights. In addition, a significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for absolute liver weights. Despite this trend, the observed increases in absolute liver weights at 100, 400, and 900 mg/ kg (81­ 8%) were not statistically significant. Liver weight findings are considered equivocal. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. The maternal NOAEL is 100 mg/ kg/ day. In the 900 mg/ kg/ day group, male and female fetal weights were decreased (921%; p#0.05); a significant (p#0.05) trend by Jonckheere's test was noted for this parameter. At 400 mg/ kg/ day, only female fetal weights were significantly decreased (2%) but were not considered to biologically significantly depressed. At 900 mg/ kg/ day, an increased (p#0.05) incidence of misaligned sternebra (1), a variation, was observed (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0066; litter incidence: 0.09). In addition, an increased (p#0.05) incidence of misaligned sternebrae (2+), a variation, was noted (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0033; litter incidence: 0.04). Furthermore, an increased incidence of kidneys with no papilla was observed (fetal incidence: 0.0347; litter incidence: 0.25) relative to concurrent controls (fetal incidence: 0.0062; litter incidence: 0.04). Although the incidence was not statistically significant, a dose­ related trend (p#0.05) was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day, based on decreased male and female fetal weight and increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The developmental toxicity NOAEL is 400 mg/ kg/ day. The developmental toxicity study in the rat is classified acceptable/ guideline (OPPTS 870.3700; §83­ 3 a) and satisfies the guideline requirement for a developmental toxicity study in the rat. Dose and Endpoint for Establishing RfD: Developmental NOAEL is 400 mg/ kg/ day. The LOAEL is 900 mg/ kg/ day based on increased kidneys with no papillae and misaligned sternebrae. Uncertainty Factor (UF): 1000 (10X intraspecies variation; 10X interspecies extrapolation; and 10X additional database uncertainty factor) 5 Comments about Study/ Endpoint/ Uncertainty Factor: The malformations (kidneys with no papillae) are presumed to occur after a single and thus appropriate for acute risk assessment. An additional database uncertainty factor of 10X is required for lack of an acceptable prenatal developmental study conducted in the rabbit. The rabbit developmental toxicity study submitted to the Agency is classified as unacceptable because of uncertainties in the effects at the LOAEL (125 mg/ kg/ day based on possible skeletal and total abnormalities). Although this study is unacceptable, there is some confidence in the NOAEL of 50 mg/ kg/ day which is almost ten­ fold lower than that used to establish the acute RfD. A factor of 10X is necessary (rather than 3X) because when an additional 10X factor is applied to the NOAEL of 400 mg/ kg used to calculate the acute RfD, the resulting extrapolated dose is 40 mg/ kg (400 ÷ 10 = 40) which is comparable to the rabbit study NOAEL of 50 mg/ kg/ day. Therefore, an additional 10X database uncertainty factor is applied to the acute RfD for Females 13­ 50 to account for the possibility that a lower NOAEL/ LOAEL may be demonstrated in the rabbit. 2.2 Acute Reference Dose (RfD)( General Population) An appropriate endpoint attributable to a single dose was not identified in the oral studies, including the rat and rabbit developmental studies. 2.3 Chronic Reference Dose (RfD) Study Selected: One­ Year Chronic Dog Study Guideline #: 870.4100 MRID No.: 42162301 Executive Summary: In a one­ year chronic toxicity study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 5 male and 5 female beagle dogs in the diet at concentrations of 0, 200, 1500, or 6000 ppm (MRID 42162301). Time­ weighted average doses for the treated groups were 5.00, 41.24, and 161.48 mg/ kg/ day, respectively, for males and 4.97, 37.57, and 166.99 mg/ kg/ day, respectively, for females. All animals survived to scheduled necropsy. Treatment­ related clinical signs of toxicity included the observation of thinness in 1/ 5 mid­ dose males, 3/ 5 high­ dose males, and 1/ 5 high­ dose females. Body weights of the high­ dose groups were significantly (p # 0.05) less than those of the control throughout most of the study. Final body weights of the high­ dose males and females were 78% and 67%, respectively, of the control levels. Food consumption by the high­ dose groups was slightly (n. s.) less than that of the controls throughout the study with statistical significance (p # 0.05) attained for females at week 52. Overall food consumption (weeks 1­ 52) for high­ dose males and females was 85% (n. s.) and 74% (p # 0.05), respectively, of the control group levels. Body weights and food consumption for Acute RfD (Females 13­ 50) = 400 mg/ kg = 0.40 mg/ kg 1000 (UF) 6 the low­ and mid­ dose groups were not affected by treatment. No treatment­ related ophthalmological lesions, changes in urinalysis parameters, or gross necropsy findings were noted. A moderate macrocytic anemia was observed in the high­ dose groups as evidenced by slight or significant (p # 0.05) decreases in RBC counts, hemoglobin, and hematocrit and increases in MCV and MCH in one or both sexes throughout the study. Cholesterol levels were significantly (p # 0.05) decreased in the high­ dose groups beginning at week 13 for males (52­ 64% of controls) and at week 26 for females (45­ 51% of controls). Albumin levels were significantly (p # 0.05) decreased in the mid­ dose males (93% of controls) at week 13 only, and in the high­ dose males (74­ 78% of controls) and females (75­ 82% of controls) throughout the study. Beginning on week 13 or 26, the high­ dose groups had aspartate aminotransferase levels 140­ 203% (p # 0.05) of the control values and alanine aminotransferase levels 206­ 276% (p # 0.05) of the control values. Alkaline phosphatase levels were significantly (p # 0.05) increased in the mid­ dose males (259­ 409% of controls) and females (163­ 194% of controls; n. s.) beginning at week 26 and in the high­ dose males (346­ 1363% of controls) and females (307­ 559% of controls) beginning at week 13. For the high­ dose animals, decreases in absolute testes weights in males and kidney, heart, and brain weights in females (­ 12%) and increases in relative liver weights in males and females were considered due to lower final body weights of these animals as compared with controls. Microscopic lesions in the liver of high­ dose animals included concentric membranous bodies in 4 males and 5 females, centrilobular single cell necrosis in 3 males and 3 females, hepatocellular pigment in 3 males and 3 females, and vacuolation in 3 males and 4 females. In addition vacuolation was observed in one mid­ dose male and pigment and membranous bodies were each observed in one mid­ dose female. These lesions were not seen in control or low­ dose animals. Therefore, the LOAEL for hexazinone in male and female beagle dogs is 1500 ppm (41.24 and 37.57 mg/ kg/ day, respectively) based on thinness in one male and hepatotoxicity as evidenced by changes in clinical chemistry parameters and microscopic lesions. The NOAEL is 200 ppm (5.00 and 4.97 mg/ kg/ day, respectively). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a chronic toxicity study [OPPTS 870.4100 (§ 83­ 1b)] in dogs. Dose and Endpoint for Establishing RfD: NOAEL of 5.0 mg/ kg/ day. The LOAEL is 38 mg/ kg/ day based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and clinical observation of thinnest in one male (4 of 10 males and females at the next higher dose). 7 Uncertainty Factor( s): 100 Comments about Study/ Endpoint/ Uncertainty Factor( s): The study is of the appropriate duration. The RfD/ peer Review Committee chose the same value in 1994, which formed the basis of the Chronic RfD for the 1994 RED. An additional database uncertainty factor to account for the lack of an acceptable rabbit developmental study is not necessary when assessing chronic dietary exposure since the NOAEL of 5.0 mg/ kg/ day in the dog used to establish the chronic RfD is ten­ fold below that seen in the rabbit study and is considered to be adequately protective. 2.4 Occupational/ Residential Exposure 2.4.1 Short­ Term (1 Day ­ 1 Month) and Intermediate­ Term (1 Month ­6 Months) Incidental Oral Exposure Toxicity endpoints for incidental oral exposure were not selected since there are no residential exposure based on the current use pattern and none is anticipated in the future. 2.4.2 Dermal Absorption No dermal absorption study is available. For dermal absorption, the NOAEL from the 21­ day dermal toxicity study at the limit dose of 1000 mg/ kg/ day was considered a lower bound for the LOAEL, which was compared with LOAEL of 250 mg/ kg/ day from the range­ finding rabbit study (MRID# 00028863). The ratio of these two numbers was used to estimate a dermal absorption factor of 25%. The range­ finding study was chosen instead of the main rabbit developmental toxicity study (MRID# 00028863) for comparison because the main study was considered to be unacceptable for regulatory purposes. Dermal Absorption Factor: 25% Comments about Study/ Endpoint: The use of a 25% dermal absorption factor for route to route extrapolation of oral studies to occupational dermal exposure would be protective of the developmental effects seen in the rat study. 2.4.3 Short­ Term Dermal (1 Day ­ 1 Month) Exposure Chronic RfD = 5.0 mg/ kg/ day (NOAEL) = 0.05 mg/ kg/ day 100 (UF) 8 Study Selected: None MRID No.: None Executive Summary: None Dose and Endpoint for Risk Assessment: Not applicable Comments about Study/ Endpoint: No hazard and no quantification required. There were no systemic effects at 1000 mg/ kg/ day, limit dose, in the 21­ day dermal study in rabbits (MRID# 41309005). The oral developmental NOAEL (400 mg/ kg/ day) in conjunction with the use of 25% dermal absorption factor yields a dermal equivalent dose of 1600 mg/ kg/ day [( 400/ 0.25)= 1600 mg/ kg/ day], which is higher than the limit dose in the rabbit 21­ day dermal study and thus would address the concerns for developmental toxicity seen at 900 mg/ kg/ day. 2.4.4 Intermediate­ Term Dermal (1­ 6 Months) and Long­ Term Dermal (longer than 6 Months) Exposure Study Selected: Chronic Feeding Study in Dogs § 870.4100 MRID No.: 42162301 Executive Summary: [See Section 2.3 on the Chronic Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: NOAEL is based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and the clinical observation of thinnest in one males at 38 mg/ kg/ day. Comments about Study/ Endpoint: The elevation in clinical chemistry parameters were seen at 3 and 6 months and thus appropriate for the exposure period. Since an oral NOAEL was selected, a 25% dermal absorption factor should be used for route to route extrapolation. 2.4.5 Short­ Term Inhalation Exposure (1 day to 1 Month) Study Selected: Developmental Toxicity in the Rat § 870.3700 MRID No.: 40397501 Executive Summary: [See Section 2.1 Acute Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: The maternal NOAEL of 100 mg/ kg/ day based on based on maternal body weight and food consumption decrement at 400 mg/ kg/ day. 9 Comments about Study/ Endpoint: In the absence of a inhalation study an oral NOAEL was selected. Absorption via the inhalation route is assumed to be equivalent to oral absorption. 2.4.6 Intermediate­ Term inhalation (1 Month to 6 Months) and Long­ Term Inhalation (longer than 6 Months) Exposure. Study Selected: Chronic Feeding Study in Dogs § 870.4100 MRID No.: 42162301 Executive Summary: [See Section 2.3 on the Chronic Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: NOAEL of 5.0 mg/ kg/ day based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and clinical observation of thinnest in one males at 38 mg/ kg/ day. Comments about Study/ Endpoint: The affects seen in clinical chemistry values at 3, 6 and 12 months are appropriate for these exposure periods. Absorption via the inhalation route is presumed to be equivalent to oral absorption. 2.5 Margins of Exposure for Occupational/ Residential Risk Assessment A margin of exposure of 100 is adequate for occupational dermal and inhalation exposure. There is no non­ occupational (residential) exposures identified at this time. 2.6 Recommendation for Aggregate Exposure Risk Assessments Aggregate exposure risk assessment is not required since there are no non­ occupational (residential) uses at the present time. 3. CLASSIFICATION OF CARCINOGENIC POTENTIAL 3.1 Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No.: 00108638 Executive Summary: In this combined chronic/ oncogenicity study (MRID 00108638), hexazinone (94­ 96% a. i.; Lot/ Batch #: 6897­ 40 and 74.25) was administered in the diet to ChR­ CD rats (36/ sex/ group) for up to 25 months at nominal doses of 0, 0, 200, 1000, or 2500 ppm (equivalent to 0, 0, 10.2, 53.4, and 138.3 mg/ kg/ day in males and 0, 0, 12.5, 67.5, and 178.6 mg/ kg/ day in females). 10 No treatment­ related differences were observed in mortality, clinical signs, food consumption, hematology, clinical chemistry, organ weights, and gross or microscopic pathology. No adverse effects were observed in the 200 ppm animals. There were several signs of general toxicity, but a target organ could not be clearly identified at any dose. Terminal body weights were decreased 8% in1000 ppm and 20%, p#0.05, in the 2500 ppm females. A decrease in overall body weight gain (Days 0­ 728; calculated by the reviewers) was also observed in the 1000 (­ 10%) and 2500 ppm (­ 25%) females. Nominal decreases in body weight and body weight gain (­ 3 to ­5%) occurred in males at 1000 ppm during the study, which may have been biologically significant at the end of the study (­ 12% body weight and ­14% for body weight gain). Decreases (p­ values not calculated) in total food efficiency were observed in females at 1000 (­ 10%) and 2500 ppm (­ 25%) and in males at 1000 ppm during the study with overall decrement in food efficiency in 1000 ppm males (­ 10%). In males at 2500 ppm, food efficiency was depressed for the first 6 months of the study (­ 25%), but from 6 months to the end of the study, it was increased 139%. The reviewer noted problems interpreting the body weights and food efficiency in males at the top dose level, which were not consistent with the mid­ dose level. For the first 6 months of the study in males, a body weight decrement due to probable toxicity was seen at 1000 and 2500 ppm. After 6 months food efficiency in males at the 1000 ppm remained less than controls (­ 56%) while food efficiency at 2500 ppm in males was higher than controls (+ 139%)( Table 4). By the end of the study, male body weight at 1000 ppm was ­12% and body weight gain ­14%, where as body weight and body weight gain in males at 2500 ppm was +3% for both weight and gain. The reason for this recovery in male body weight decrement at 2500 ppm is unknown, but it appears to be real. [Since absolute and relative liver weights were decreased in males at 2500 ppm, liver enzyme induction allowing the recovery seems unproven.] The body weight decrement at 1000 and 2500 ppm with recovery in body weight at 2500 ppm indicates the an adequate dose level to test for carcinogenicity in males was approached, but probably not attained. Other treatment groups were similar to the average of concurrent controls. Dosing was considered adequate based on decreased body weights, body weight gains, and food efficiency in the 2500 and 1000 ppm females and food efficiency and body weights in the 2500 ppm males for the first 6 months. Body weight (­ 12%) and body weight gain (­ 14%) in males at 1000 ppm were decreased at the end of the study, in addition overall food efficiency (­ 14%) was decreased by the end of the study. Thus female body weight and body weight gain was decreased sufficiently to adequately test for carcinogenicity. Male body weight and body weight gain at1000 ppm appeared to be adequate to test for carcinogenicity by the end of the study, but the lack of dose response in male body weight and body 11 weight gain at 2500 ppm (showing recovery after 6 months such that body weight and body weight gain were higher than control values) may indicate problems with the interpretation of the body weights and body weight gains at 1000 ppm. In the 2500 ppm males, creatinine was increased (NS) in the urine at months 18 and 24 and bilirubin was detected at month 18 and 24. The Sponsor reported that the urine was more alkaline in the 2500 ppm treatment groups (data not reported). Also at 2500 ppm, decreased (p#0.05) absolute and relative liver and kidney organ weights were observed in the males and increased (p#0.05) relative (to body) stomach and kidney organ weights were observed in the females. However, histopathological data did not corroborate these findings. The LOAEL is 1000 ppm for males and females (equivalent to 53.3 for males and 67.5 mg/ kg/ day for females) based on decreased body weight and food efficiency in males and females. In males at 2500 ppm the body weight decrement and food efficiency decrement occurred only for the first 6 months of the study. The NOAEL is 200 ppm for males and females (10.2 for males and 12.5 mg/ kg/ day for females). Neoplasm data were evaluated by two pathologists. An increase incidence of thyroid C­ cell adenomas was observed in the 2500 ppm males, but when analyzed by the Fisher's exact test (p> 0.10) or life­ table methods (p> 0.20) no significant differences were observed between controls and treated groups. Using life­ table analyses a significant (p< 0.05) dose­ response trend was observed in thyroid C­ cell tumors in only one of the two pathology reports. Female rats did not show any potential for C­ cell thyroid adenomas. The incidence, malignancy and latency of tumors were comparable among control and treated rats of both sexes. Under the conditions of this study, carcinogenic potential of hexazinone is considered negative. The submitted study is classified as acceptable for guideline 870.4300 combined chronic/ carcinogenicity study in rats. Discussion of Tumor Data: Neoplasm data were evaluated by two pathologists. An increase incidence of thyroid C­ cell adenomas was observed in the 2500 ppm males, but when analyzed by the Fisher's exact test (p> 0.10) or life­ table methods (p> 0.20) no significant differences were observed between controls and treated groups. Using life­ table analyses a significant (p< 0.05) dose­ response trend was observed in thyroid C­ cell tumors in only one of the two pathology reports. Female rats did not show any potential for C­ cell thyroid adenomas. The incidence, malignancy and latency of tumors were comparable among control and treated rats of both sexes. The study in rats does not support a carcinogenic potential for hexazinone. Adequacy of the Dose Levels Tested: The dose levels in female rats was adequate to test for the carcinogenic potential hexazinone. There was an adequate body weight decrement and body weight 12 gain decrement at the two top dose levels. The dose levels in male rats approached an adequate dose level to test for carcinogenic potential of hexazinone. There may have been an adequate body weight and body weight gain at the mid­ dose level at the end of the study to test for carcinogenic potential of hexazinone, however body weights of males at the top dose level behaved atypically. At the top dose level, males showed a adequate body weight decrement only for the first 6 months of the study and by the end of the study, body weights were higher than the average of the two controls. The reason for this reversible body weight decrement is unknown, but the top dose level in males was one­ half the top dose level of 5000 ppm in the 90­ day subchronic study in males where liver toxicity was seen. These body weight decrements in males and females are supported by a corresponding decrements in food efficiency. 3.2 Carcinogenicity Study in Mice MRID No. 41359301,42509301 and 4320290 § 870.4200 Executive Summary: In this mouse oncogenicity study (MRIDs 00079203, 41359301, 42509301 and 43202901), hexazinone ($95% a. i.; Lot/ Batch #: H­ 11, 265 and 265­ 2) was administered in the diet to CD­ 1 mice (80/ sex/ group) for up to 104 weeks at nominal doses of 0, 200, 2500 or 10,000 ppm (equivalent to 28, 366 and 1635 mg/ kg/ day in males and 0, 34, 450 and 1915 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, food consumption, food efficiency or hematology. Hepatotoxicity was evident at the terminal sacrifice. Macroscopic liver nodule/ mass (% treated vs % controls; n = 28­ 55) was observed in males at 2500 (39% vs 7%) and 10,000 ppm (33%). Increased incidences (% treated vs 0% controls; n = 38­ 55) in the following microscopic liver lesions were observed: hyperplastic nodule( s) (includes both foci of cellular alteration and adenoma) in males at 2500 (39% vs 20%) and 10,000 ppm (36%) and in females at 10,000 ppm (15% vs 3%); and necrosis (severity and type unspecified) in the 10,000 ppm males (36% vs 7%). Centrilobular hepatocyte hypertrophy was observed (% treated vs % controls) at the terminal sacrifice (n = 38­ 55) in males at 2500 (18% vs 0%) and 10,000 ppm (98%) and in females at 10,000 ppm (46% vs 0%) and in the dead and moribund males (n = 25­ 40) at 2500 (44% vs 0%) and 10,000 ppm (60%). Increased (p#0.05 or 0.01) liver/ gall bladder weights were observed at 10,000 ppm in males in both absolute and relative to body weights and in females in relative to body weight. Other signs of toxicity were evident. Distal tail tip sloughing and/ or discoloration was observed at 10,000 ppm in males at Weeks 13­ 104 and in females at Weeks 5 and 13­ 104. Macroscopically, tip of tail missing/ sloughed was observed at the terminal sacrifice in the 10,000 ppm males (31% vs 5%) and females (61% vs 11%) and in the dead and moribund 10,000 ppm females (46% vs 2%). The toxicological significance of these findings was unclear. Minor decreases (p#0.05 or 0.01) in body 13 weights were observed in the 10,000 ppm treatment groups at Weeks 13­ 104 in both sexes. Overall body weight gains (calculated by the reviewers) were decreased in the 10,000 ppm males (925%) and females (931%). The LOAEL is 2500 ppm for males (equivalent to 366 mg/ kg/ day) based on gross liver nodules/ masses, hyperplastic nodules in the liver and centrilobular hepatocyte hypertrophy and 10,000 ppm for females (equivalent to 1915 mg/ kg/ day [limit dose]) based on decreased body weights, increased relative liver/ gall bladder weights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. The NOAEL is 200 ppm (equivalent to 28 mg/ kg/ day) for males and 2500 ppm (equivalent to 450 mg/ kg/ day) for females. Liver samples were first evaluated using the term hyperplastic nodule which did not clearly distinguish neoplasia from non­ neoplasia. Reevaluation was conducted to make this distinction, and no significant differences were observed between the treatment groups and the concurrent controls. However positive trends (p< 0.05) were observed (% treated vs % controls) in focus/ foci of cellular alteration in males, hepatocellular neoplasm( s) (including adenoma, sarcoma, carcinoma, leukemia, and lymphoma) in females, and singular hepatocellular adenoma in females. Focus/ foci of cellular alteration were observed in males at 2500 (11.3% vs 5.0%) and 10,000 ppm (24.1%) and females at 10,000 ppm (12.5% vs 3.8%) beginning at Week 57. Singular hepatocellular adenoma was observed in the 10,000 ppm females (7.5% vs 2.5%) beginning at Week 77. Hepatocellular neoplasm( s) were observed in the 10,000 ppm females (8.8% vs 2.5%). A carcinoma in the 10,000 ppm treatment groups was first observed at Week 65. The incidence of carcinomas were within historical control ranges for each sex, while the incidence of adenomas were increased by 3.21% in the 10,000 ppm females. A dosedependent increase in adenomas was not observed in males. The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) concluded that hexazinone should be classified as a Group D (not classifiable as to human carcinogenicity)( 7/ 27/ 94). Under the conditions of this study, evidence of carcinogenic potential was equivocal: a positive trend test for neoplasia was observed in female mice, but no significant difference was determined by pair­ wise comparison. The submitted study is classified as acceptable for guideline 870­ 4200 carcinogenicity study in mice. Discussion of Tumor Data: A dose­ dependent increase in adenomas was not observed in males. Under the conditions of this study, evidence of carcinogenic potential was equivocal: a positive trend test for neoplasia was observed in female mice, but no significant difference was determined by pairwise comparison. Adequacy of the Dose Levels Tested: Adequate dose levels were used in male and female mice to test for the carcinogenic potential of hexazinone. Liver toxicity was seen at the top dose level in males and females. 3.3 Classification of Carcinogenic Potential HED's Carcinogenicity Peer Review Committee classified hexazinone as a Group D Chemical (not 14 classifiable as to human carcinogenicity) (7/ 27/ 94). This classification was based on the following weight of evidence considerations. In rats, females showed no evidence for carcinogenicity; males showed a significant trend only for thyroid adenomas. In mice, the evidence of carcinogenicity was equivocal: a positive trend test for liver tumors was observed in female mice, but no significant difference was seen by pair­ wise comparison (CPRC Report dated July 27, 1994). 4. MUTAGENICITY The required mutagenicity testing is complete. This section was copied from the 1994 RED for Hexazinone and the updated DERs. One mutagenicity study was submitted since the 1994 RED was written; a negative in vivo mammalian micronucleus test in mouse bone marrow cells (MRID# 45124401). Hexazinone was found to be positive for mutagenicity in one chromosomal aberration assay (in vitro cytogenics) (MRID# 00130709), but negative in the remaining studies. It is concluded that the test material was clastogenic in both of the nonactivated trials and was also clastogenic in the one adequate S9­ activated trials. Under both test conditions, concentrations providing evidence of clastogenicity induced an acceptable level of cytotoxicity (> 50% relative cell survival). Thus, the findings can not be considered to be a secondary effect of cytotoxicity. Nevertheless, the outcome of the induced structural damage (i. e., primarily chromatid and chromosome breaks) is unclear since these types of structural aberrations would not likely be passed on to daughter cells. Because unambiguous positive results were achieved, it was concluded that the study provided adequate evidence that INA­ 3674­ 112 (hexazinone, technical) is clastogenic in an acceptable study. Guideline 870.5100 Gene Mutation Assay in Ames Test: Hexazinone was tested with metabolic activation (rat liver microsomal fraction commonly known as S­ 9 fraction, plus cofactors) at concentrations ranging from 400 to 2000 ug/ plate and without metabolic activation at concentrations ranging from 200 to 1000 ug/ plate. The strains of Salmonella typhimurium used were TA1535, TA1537, TA1538, TA98 and TA100. No increases in reverse mutations were observed at any concentration. Positive results were obtained with standard reference mutagens (positive controls)( MRID 00098982). Guideline 870.5100 Reverse mutation assay: In a reverse gene mutation assay in bacteria (MRID 40826201), strains TA98, TA100, TA1535, TA1537 and TA1538 of S. typhimurium were exposed to Striazine 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ (95% a. i.) in ethanol at concentrations of 200, 400, 600, 800 and 1000 :g/ plate without mammalian metabolic activation (S9­ mix) and at concentrations of 400, 800, 1200, 1600 and 2000 :g/ mL with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Crl: CD( SD) BR rat liver. The maximum concentrations of S­ triazine­ 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ tested produced little or no cytotoxicity, were not limited by solubility and were not a limit dose for the assay. No statistically significant increases in the number of revertants per plate or positive linear dose­ response were seen. The solvent and positive controls induced acceptable responses in the corresponding strains. There was no evidence of induced mutant colonies over background. 15 This study is classified as Unacceptable. It does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5100 (§ 84­ 2)] for in vitro mutagenicity [bacterial reverse gene mutation] data and should be repeated using higher doses. Guideline 870.5300: Gene Mutation Assay in Mammalian Cells: In a mammalian cell gene mutation assay at the HGPRT locus (MRID No. 00076956), Chinese hamster CHO­ K1­ BH4 cells cultured in vitro were exposed to INA­ 3674­ 112, (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol in two trials. Concentrations used in Trial 1 were 2.0, 11.1, 13.1, 13.9 and 14.3 mM under nonactivated conditions and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM under activated conditions (S9­ mix). Concentrations used in Trial 2 were 2.0, 5.9, 11.1, 13.1 and 13.9 mM without S9­ mix and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Charles River CD® rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. In Trial 1, the cultures treated at 14.3 mM ­S9 were not plated for mutation determination due to cytotoxicity in both Trials 1 and 2. Cytotoxicity was also noted at 9.9 mM +S9. No statistically significant increases in mutant frequency over solvent control values were seen with or without S9­ mix in either Trial 1 or 2. The expected marked increase in the mutation were seen with the positive controls. There was, however, no indication that INA­ 3674­ 112 induced a mutagenic effect either in the presence or the absence of S9 activation. This study is classified as acceptable. It satisfies the requirement for FIFRA Test Guideline OPPTS [870.5300 (§ 84­ 2)] for in vitro mutagenicity (mammalian forward gene mutation) data. Guideline: 870.5395 Mouse bone marrow micronucleus assay: In a Crl: CD­ 1 (ICR) BR mouse bone marrow micronucleus assay (MRID 45124401), 5 mice/ sex/ dose/ harvest time were treated orally with Hexazinone 25L (Lot No. 9912033, 25% Hexazinone a. i. (24.5% by analysis) and 75% inert ingredients) at doses of 1000, 2000 and 3000 mg/ kg. Bone marrow cells were harvested at 24 and 48 hours post­ treatment and examined for micronucleated polychromatic erythrocytes (MPCEs). The vehicle was Milli­ Q ® water. Signs of toxicity noted at 3000 mg/ kg included: death, convulsions, half­ shut eyes, head­ tilt, irregular respiration, lethargy, low carriage, pallor, prostration, uncontrollable spinning, shovel­ nosing, straining up on toes and tremors. Micronuclei were scored in bone marrow from mice treated at 3000 mg/ kg and from the solvent and positive controls. Mice from the two lower dose groups were not evaluated for micronuclei induction. No statistically significant increases in the frequency of MPCEs or in the PCE/ NCE ratio over the solvent control values were seen in either sex at either the 24 or 48 hour harvest time. The solvent and positive control values were appropriate and within the testing laboratory's historical control ranges. There was no evidence that Hexazinone 25L induced a clastogenic or aneugenic effect in bone marrow at any harvest time. This study is classified as Acceptable/ Guideline. It satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5395 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. 16 Guideline 870.5375 Structural Chromosome Aberration Assay; In vitro Cytogenetic Assay: In a mammalian cell cytogenetics assay (MRID No. 00130709), Chinese hamster ovary CHO­ K1 ­BH4 cell cultures were exposed to INA­ 3674­ 112 (Hexazinone, 95% a. i.) in ethanol in two separate trials. Exposure was for two hours with activation and for 10 hours without activation. Cells were harvested 10 hours after the start of treatment. In Trial 1, cells were treated at concentrations of 1.58, 3.94, 15.85 and 19.82 mM without metabolic activation (S9­ mix) and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. In Trial 2, cells were treated at concentrations of 1.58, 3.94, 7.93 and 15.85 without S9­ mix and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced CD rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. Based on the results of a preliminary cytotoxicity test, upper concentrations of 23.78 mM without S9­ mix and 47.56 mM with S9­ mix were selected for the first cytogenetic assay but these concentrations proved excessively cytotoxic and were not scored for chromosomal aberrations. Without S9 activation, statistically significant increases (p< 0.01) in structural aberrations per cell (excluding gaps), lesions per cell and percent abnormal cells were seen at 15.85 mM (Trials 1 and 2) and 19.82 mM (tested in Trial 1 only). Relative percent survival (RPS) at this level was .50%. The percent abnormal cells averaged over all cultures from both trials was 28.0% and 21.5% at 19.82 and 15.85 mM, respectively, compared to the solvent control values of 2.0% (0.5% ethanol in Trial 2) and 7.0% (0.75% ethanol in Trial 1). The percent abnormal cells in positive control cultures was 18% in both Trial 1 (4.83 mM EMS) and Trial 2 (6.44 mM EMS). In the presence of S9­ mix, no statistically significant increases in chromosomal aberration induction were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix. Statistically significant increases were seen at 15.85 mM in Trial 2; RPS at 15.85 mM was 75%. There was a statistically significant dose­ related trend for all three parameters. The statistically significant (p <0.01) increases at 15.85 mM remained when the data from Trial 1 and 2 were combined (average of 20% abnormal cells compared to 10% for the solvent control). The predominant aberrations with or without S9­ mix were chromatid and isochromatid breaks. Solvent and positive controls (except the positive control in Trial 1 with S9­ mix) induced the appropriate responses. INA­ 3674­ 112 was positive for the induction of structural chromosomal aberrations in both the presence and absence of S9­ mix. This study is classified as Acceptable/ guideline and satisfies the requirement for FIFRA Test Guideline [OPPTS 870.5375 (§ 84­ 2)] for in vitro cytogenetic mutagenicity data. Guideline 870.5385 Structural Chromosome Aberration Assay; In vivo Cytogenetic Assay: In a mammalian cell cytogenetics assay (MRID 00131355), in bone marrow cells of Sprague­ Dawley CD rats, three rats/ dose/ sex/ harvest time were exposed to H# 14,555 in corn oil ( assumed 100% a. i.) at doses of 100, 300 and 1000 mg/ kg by oral gavage. Bone marrow cells were harvested at 6, 12, 24 and 48 hours posttreatment The highest dose tested (1000 mg/ kg) was lethal. A major limitation of this study was the number of animals treated and the number of cells analyzed per animal. At most, three rats/ sex/ dose/ harvest time were treated with, at most, 50 cells per rat analyzed. Few or no analyzable cell were available from many rats. Positive control values were significantly (p= 0.03) increased. There was no evidence that H# 14, 14,555 induced an increase in the incidence of chromosomal aberrations in the bone marrow cells of treated animals. 17 This study is classified as Unacceptable. The number of cells analyzed and the number of rats treated was insufficient. The study does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5385 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. Guideline 870.5550 Other Genotoxic Effects Assay; In an unscheduled DNA synthesis assay (MRID 00130708), primary rat hepatocyte cultures were exposed to INA­ 3674­ 112 (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol for 18 hours at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 10.0 and 30.0 mM in Trial 1 and at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 5.0, 10.0 and 30.0 mM in Trial 2. INA­ 3674­ 112 was tested up to the highest achievable concentration in the solvent. Two slides per dose, 25 cells per slide were evaluated for UDS induction in Trial 1. One slide per dose, 25 cells per slide were evaluated in Trial 2. The author did not report that the slides were coded prior to analysis. The average net nuclear grain counts of test material treated cells in Trial 1 were all less than zero with the exception of one slide at 1 x 10 ­5 mM (0.1 ± 9.6) and one slide at 1.0 mM (1.6 ± 5.2). The average net nuclear grain count was below zero for all test material concentrations in Trial 2 with the exception of 0.1 mM where the average net nuclear grain count was 0.0 ± 2.9. The criterion for a positive response was an average net nuclear grain count of at least five in two experiments at any tested concentration. The results were thus negative. The number of cells in repair was not reported. The solvent and positive (DMBA) controls induced the appropriate responses. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline; OPPTS 870.5550 [§ 84­ 2] for other genotoxic mutagenicity data. 5. FQPA CONSIDERATIONS 5.1 Adequacy of the Data Base The toxicity data base for FQPA considerations is incomplete. The rabbit developmental toxicity study is unacceptable/ upgradable because doses were not analyzed and some required maternal and fetal data were missing, such that developmental effects seen in the study could not be discounted or confirmed. The study was otherwise acceptably conducted. Another rabbit developmental toxicity study is currently in progress. A rat developmental toxicity study is acceptable and the 2­ generation reproduction study is acceptable. The remaining toxicity data base is adequate. 5.2 Neurotoxicity Data: No neurotoxicity studies have been conducted. The chronic dog study showed a statistically 18 significant absolute brain weight decrement of 12­ 13% in the female dogs, however, these dogs showed severe malnutrition. The individual animal dog data showed that the two dogs showing the largest decreased body weight from the initial body weight also showed the lowest brain weight. This severe body weight decrement in females may have resulted in nutritional deficiencies indirectly affecting the brain weight. The brain weight decrement was not considered to be a direct effect of hexazinone. No significant changes in brain weight were seen in the rat studies. 5.3 Developmental Toxicity 5.3.1 Developmental toxicity in rats Executive Summary: In a developmental toxicity study (MRID 40397501), hexazinone (99.26% a. i.; Lot# S30306A, Batch# 2/ 36) in 0.5% methylcellulose was administered orally via gavage to 25 Crl: CD ® BR female rats/ group at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day (GD) 7 through 16. The dosing volume was 10 mL/ kg (calculated by reviewers). All dams were sacrificed on GD 22 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in clinical signs, gross pathology, pregnancy rate, live fetuses, resorptions, pre­ or post­ implantation loss, corpora lutea, or implantations were noted at any dose level tested. No treatment­ related findings were noted in the 100, or 40 mg/ kg groups. In the 900 mg/ kg dams, one treatment­ related death occurred; alopecia and an enlarged stomach containing fluid and food were noted at necropsy. Decreased (p< 0.05) body weight gains were noted during GDs 15­ 17 (937%) and 17­ 22 (917%). In addition, body weight gains were decreased (p< 0.05) for the overall (GDs 7­ 17) treatment interval (930%). Gravid uterine weights were not reported; however, adjusted (for gravid uterine weight) terminal body weights were slightly decreased (96%; p#0.05). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 9­ 11, 15­ 17, 7­ 17, and 17­ 22. Decreased (p#0.05) food consumption was observed throughout treatment (GDs 7­ 17; 916­ 22%) and post­ treatment (GDs 17­ 22; 99%). A significant (p#0.05) trend by linear combination of dose ranks from analysis of variance (ANOVA) was noted for GDs 7­ 9, 9­ 11, 11­ 13, 13­ 15, 15­ 17, 7­ 17, and 17­ 22. Also a significantly decreased food consumption was seen at 400 mg/ kg/ day (GD9­ 11; 91%) and (GD 7­ 17; 98%). In addition, relative (to body) liver weights were increased (p#0.05) in the 400 (5.2%) and 900 (5.6%) mg/ kg dams compared to concurrent controls (4.9%). Decreased (p#0.05) terminal body weights were noted at 900 mg/ kg (96%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for relative liver weights and adjusted terminal body weights. In addition, a significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for absolute liver weights. Despite this trend, the observed 19 increases in absolute liver weights at 100, 400, and 900 mg/ kg (81­ 8%) were not statistically significant. Liver weight findings are considered equivocal. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. The maternal NOAEL is 100 mg/ kg/ day. In the 900 mg/ kg/ day group, male and female fetal weights were decreased (921%; p#0.05); a significant (p#0.05) trend by Jonckheere's test was noted for this parameter. At 400 mg/ kg/ day, the female fetal weights that were significantly decreased were not considered to be biologically significant. At necropsy, an increased (p#0.05) incidence of misaligned sternebra (1), a variation, was observed (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0066; litter incidence: 0.09). In addition, an increased (p#0.05) incidence of misaligned sternebrae (2+), a variation, was noted (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0033; litter incidence: 0.04). Furthermore, an increased incidence of kidneys with no papilla was observed (fetal incidence: 0.0347; litter incidence: 0.25) relative to concurrent controls (fetal incidence: 0.0062; litter incidence: 0.04). Although the incidence was not statistically significant, a doserelated trend (p#0.05) was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day, based on decreased male and female fetal weight, increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The developmental toxicity NOAEL is 400 mg/ kg/ day. The developmental toxicity study in the rat is classified acceptable/ guideline (OPPTS 870.3700; §83­ 3 a) and satisfies the guideline requirement for a developmental toxicity study in the rat. An unacceptable developmental feeding study in the rat shows (MRID# 00114486) a maternal body weight decrement at 482 mg/ kg/ day with a NOAEL of 94.5 mg/ kg/ day with a developmental NOAEL of 482mg/ kg/ day. This study tends to add support the acceptable rat developmental (by gavage) toxicity study. 5.3.2 Developmental Toxicity in the rabbit Executive Summary: In a developmental toxicity study (MRID 00028863), hexazinone (100% a. i.; Lot/ batch # E21216A) was administered orally via gavage in a dosing volume of 1 mL/ kg) to 17 female New Zealand White rabbits/ group at dose levels of 0, 20, 50, or 125 mg/ kg on GD 6 through 19. All does (except those that died or delivered prematurely) were sacrificed on GD 29, and their fetuses removed by cesarean and examined. 20 When compared to concurrent controls, no treatment­ related changes in mortality, clinical signs, body weights, gross pathology, fetal weights, sex ratios, pre­ implantation or postimplantation losses, or the number of corpora lutea, implantations, resorptions, live fetuses, or dead fetuses were observed. At 125 mg/ kg, food consumption was decreased (p#0.05), relative to concurrent controls, at the beginning of treatment from GD 7 through 11 (961­ 89%). Decreases in food consumption, that were not statistically significant, continued throughout treatment (GDs 12­ 19; 92­ 37%). Diminished food consumption resulted in decreased (not statistically significant) body weight gains in the does (­ 241.5 g) relative to concurrent controls (­ 7.2 g) during GDs 6­ 11. However, weight gain in these animals recovered quickly and was higher than control animals during subsequent treatment intervals (GDs 11­ 15 and 15­ 19). The maternal LOAEL is 125 mg/ kg/ day based on transient decreases in food consumption and body weight gains. The maternal NOAEL is 50 mg/ kg/ day. At 125 mg/ kg/ day, the following skeletal variations were noted (data presented as fetal incidence vs. 0 controls): (i) lagging ossification in extremities (0.0882); (ii) malaligned thoracic vertebrae (0.0294); and (iii) flexed wrist( s) (0.0294). In addition, non­ ossified thumb, an anomaly, was noted at an increased incidence (0.0294) relative to concurrent controls (0). In the absence of historical control data, these findings are considered treatment­ related. In addition, it could not be determined how many of these nominally increased incidences were from different litters, which would have increased concern for developmental toxicity. The developmental toxicity LOAEL is 125 mg/ kg/ day, based on possible skeletal abnormalities and total abnormalies. The developmental toxicity NOAEL is 50 mg/ kg/ day. The developmental toxicity study in the rabbit is classified unacceptable/ upgradable, pending submission of acceptable purity, concentration, stability and litter data and historical control data. A letter dated 9/ 26/ 01 from the registrant provided no additional information about this rabbit developmental toxicity study other than that the doses were not analyzed and that a repeat rabbit developmental toxicity was currently being conducted. 5.4 Reproductive Toxicity 5.4.1 Executive Summary: In a two­ generation reproduction study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 30 male and 30 female Sprague­ Dawley rats in the diet at concentrations of 0, 200, 2000, or 5000 ppm (MRID 42066501). One litter was produced in the first generation and two litters were produced in the second generation. Test substance intake for the treated F0 groups was 11.8, 117, and 294 mg/ kg/ day, respectively, for 21 males and 14.3, 143, and 383 mg/ kg/ day, respectively, for females. Test substance intake for the treated F1 groups was 15.3, 154, and 399 mg/ kg/ day, respectively, for males and 17.7, 180, and 484 mg/ kg/ day, respectively, for females. F0 and F1 parental animals were administered test or control diet for 73 or 105 days, respectively, prior to mating, throughout mating, gestation, and lactation, and until necropsy. Deaths of several F0 and F1 parental animals were considered incidental to treatment. No treatment­ related clinical signs of toxicity were observed in the adult animals of either generation. Gross necropsy was unremarkable and no microscopic lesions were observed in selected tissues from the reproductive tracts of male and female parental animals. Body weights and body weight gains of the F0 males were not affected by treatment. Premating body weight gains by the mid­ and high­ dose F0 females were 76% and 62% (p # 0.05 for both), respectively, of the control level resulting in final premating body weights 93% and 87% (p # 0.05), respectively, of the controls. Body weights of the high­ dose F1 males and females were significantly reduced (p # 0.05) during the premating interval with overall weight gains 87% and 82%, respectively, of the control group amounts. Reductions in body weights and body weight gains during premating for the mid­ and high­ dose F0 and high­ dose F1 dams continued during gestation and lactation. Food consumption during premating was similar between the treated and control groups for males and females of both generations. However, during gestation significantly (p # 0.05) lower food consumption was noted for the high­ dose F1 dams during production of both litters and for the mid­ dose F1 dams during production of the second litter. There was a statistically significant increase in absolute P0 testes weight that appeared to be dose related, but a nominally decrease absolute F1 adult testes weight in the 5000 ppm dose groups. The F1 testes weight change did not appear to dose related. The testes weight changes in males would appear to be incidental. Therefore, the systemic toxicity LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced body weight and body weight gains by F1 males and F0 and F1 females. The systemic toxicity NOAEL is 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). No reproductive effects were seen in the study except for the weight effects on offspring. Live birth and viability indices and litter survival were similar between the treated and control groups. The lactation index for the F2b high­ dose litters was 85.8% (p # 0.05) compared to 97.5% for the control group. Pup body weights were decreased throughout lactation in the mid­ and high­ dose groups of all litters as compared with the control groups with statistical significance (p # 0.05) attained at most time points. The lower pup body weights were more pronounced in females than in males. F1 and F2a female pup weights were statistically significantly decreased at birth, day 7 and 14 of lactation at $2000 ppm. There were no obvious reproductive effects other than the pup weight decrement. 22 Therefore, the offspring LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced female pup body weights at birth and during lactation. The reproductive toxicity NOAEL was 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a reproductive toxicity study [OPPTS 870.3800 (§ 83­ 4)] in rats. 5.5 Additional Information from Literature Sources (if available) The published literature found on hexazinone were the papers on the same studies submitted to the Agency [ Kennedy, GL and Kaplan, AM (1984) Chronic Toxicity, Reproductive, and Teratogenic Studies of Hexazinone. Fundemental and applied Toxicology 4, 960­ 971.]. No other relevant literature on the toxicity was found. 5.6 Determination of Susceptibility No quantitative or qualitative evidence of increased susceptibility was seen following in utero or pre/ post natal exposure to rats. The rabbit developmental study is classified as unacceptable because of technical deficiencies. On April 2, 2002, the HIARC concluded that susceptibility in this species could not be assessed. Since the unacceptable study indicates that a lower NOAEL/ LOAEL may be demonstrated in the rabbit, the committee concluded that an additional database uncertainty factor is warranted in the absence of this study. Additionally, the Committee concluded that the hazard­ based special FQPA safety factor is 1x is adequate because there is not evidence of susceptibility in rats and a database uncertainty factor is applied to the acute RfD for the lack of a rabbit developmental toxicity study. 5.7 Determination of the Need for Developmental Neurotoxicity Study The weight of evidence does not suggest the need for a Developmental Neurotoxicity study. 5.7.1 Evidence that suggest requiring a Developmental Neurotoxicity study: 1. The structurally related pesticide, Atrazine, causes CNS related changes in prolactin secretion, which is related to reproductive senescence in Sprague Dawley rats through continuous estrus from decreasing LH release, but this effect would require a special study and would not be detected by a neurotoxicity study. 5.7.2 Evidence that do not support the need for a Developmental Neurotoxicity study 1. No evidence of neurotoxicity or neuropathology was seen in the database. 23 2. A 12­ 13% absolute female brain decrement was seen in the chronic dog study, but the brain weight decrement was associated with severe body weight decrement. The brain weight decrement may have been secondary to the malnutrition in these animals and not directly due to neurotoxic effects of hexazinone 6. HAZARD CHARACTERIZATION Hexazinone is a herbicide used to control a broad spectrum of weeds including woody plants in alfalfa, rangeland, pastures, woodlands, pineapple, sugarcane and blue berries. Non­ crop areas include ornamental plants and forests. Hexazinone is used as a pre­ emergent, post emergence herbicide as well as by direct spray and soil applications. There are no non­ occupational (residential) uses. Hexazinone has low acute toxicity by the oral (Category III), dermal (Category IV ) and inhalation routes (Category III). Primary eye irritation is severe, causing corneal opacity and moderate irritation in unwashed eyes (Category I). It causes mild skin irritation and is classified Category IV for skin irritation. It is not a skin sensitizer in the Guinea pig. Body weight decrement and liver toxicity were the most frequent effects shown in studies with hexazinone. Liver toxicity was seen in the chronic dog and mouse studies. Body weight decrement was seen in the chronic rat studies and the studies on reproduction. In a reproduction study, pup weight decrement occurred at the same dose as parental body weight decrement. No reproductive effects were seen in the study other than pup weight decrement. The rat prenatal study showed fetal weight decrement and possibly renal malformations but no increased susceptibility. The rabbit study possibly showed skeletal anomalies and delayed ossifications at the highest dose tested, however it is classified as unacceptable and susceptibility in this species could not be assessed. The 21­ day dermal study in the rabbit showed no systemic toxicity and mild dermal irritation at the limit dose. The chronic study in dogs showed severe body weight decrement, changes in liver related clinical chemistry values, and microscopic lesions. Body weight decrement was seen in a chronic carcinogenicity studies in rats and mice. Liver toxicity was seen in mice. The mouse carcinogenicity study showed an increased trend for liver carcinomas, but no pair wise significant increases. The rat study showed no carcinogenic potential. Based on these studies in rats and mice, hexazinone was classified in a group D, not classifiable as a carcinogen. Rat metabolism studies showed that hexazinone was rapidly absorbed and excreted and essentially no difference in the metabolism of males and females at high or low dose levels. Almost no parent hexazinone was recovered in urine or feces. Two major metabolites were recovered from feces and urine, in addition to lesser amounts of a third metabolite and small amounts conjugated products from urine. 24 7. Data Gaps The HIARC requested a 28­ day inhalation study with hexazinone because of the concern for potential inhalation exposure based on the use pattern.. The rabbit developmental toxicity study is classified as unacceptable. Another study in the rabbit, requested by Cal EPA, is expected to be submitted to OPP as well. 8. ACUTE TOXICITY Acute Toxicity of Hexazinone Guideline No. Study Type MRIDs # Results Toxicity Category 81­ 1 Acute Oral/ Rat 41235004 (1989) LD50 = 1200 mg/ kg III 81­ 2 Acute Dermal/ Rabbit 00104974 LD50 >5278 mg/ kg IV 81­ 3 Acute Inhalation 00104975 (1973) LC50 > 7.50 mg/ L( 1 hour) LC50 >1.9 mg/ L 1 Equivalent to 340 mg/ kg 2 III 81­ 4 Primary Eye Irritation 00106003 (1982) Irreversible corneal opacity, Severe 3 I 81­ 5 Primary Skin Irritation 00106004 (1982) Mild IV 81­ 6 Dermal Sensitization 41235005 (1989) NA Not a skin sensitizer 81­ 8 Acute Neurotoxicity Not conducted 1 One hour inhalation study on technical converted to probable no effects at 4 hours. Consistent with an unreviewed three week inhalation study (MRID# 00063972) showing no significant toxic effects. The effects seen were consistent with dust inhalation at 2.5 mg/ mL, the only dose tested. Another acute 4 hour inhalation study in rats showed no effects at 3.9 mg/ L using a 25% a. i. granular product (MRID# 41756701). 2 Calculated by the reviewer from the following information from Whalan (1998). This conversion generally is not considered valid, especially for irritating substances. {[( 1.9 mg/ L x 1 x 9.13 x 4 x 1)/( 0.204 kg)] = 340 mg/ kg} 3 The toxicity category was based on the corneal opacity. Irritation not counting opacity was tox category III. 25 9. SUMMARY OF TOXICOLOGY ENDPOINT SELECTION Summary of Toxicology Endpoint Selection for Hexazinone Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Dietary Risk Assessments Acute Dietary females 13­ 50 years of age NOAEL = 400 UF = 100 Acute RfD = 0.40 mg/ kg/ day UFdb = 10 Developmental Toxicity ­ Rat Decreased male and female fetal weight, kidneys with no papilla (malformation) and misaligned sternebrae (variation) Acute Dietary general population including infants and children An appropriate endpoint attributable to a single dose was not identified in the oral studies, including the rat and rabbit developmental studies. Chronic Dietary all populations NOAEL= 5.0 UF = 100 Chronic RfD = 0.05 mg/ kg/ day N/ A Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Incidental Oral Short­ Term (1 ­ 30 Days) Residential Only There are no residential uses at the present time and therefore, endpoints were not selected. Incidental Oral Intermediate­ Term (1 ­ 6 Months) Residential Only There are no residential uses at the present time and therefore, endpoints were not selected. Non­ Dietary Risk Assessments Dermal Short­ Term (1 ­ 30 days) No hazard was identified, therefore quantification of risk is not required. No systemic toxicity was seen at the limit dose following repeat dermal application, and there were no concerns for developmental or reproductive toxicity. Residential Occupational Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment 26 Dermal Intermediate­ Term 1 (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day N/ A Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential N/ A Occupational MOE= 100 Dermal Long­ Term 1 (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day N/ A Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential N/ A Occupational MOE= 100 Inhalation Short­ Term 2 (1 ­ 30 days) Oral NOAEL= 100 mg/ kg/ day Developmental Toxicity ­ Rat LOAEL= 400 mg/ kg/ day based on decreases in maternal food consumption and dose related body weight decrement. Residential N/ A Occupational MOE= 100 Inhalation Intermediate­ Term (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day N/ A Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential N/ A Occupational MOE= 100 Inhalation Long­ Term (> 6 Months) Oral NOAEL= 5.0 mg/ kg/ day N/ A Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential N/ A Occupational MOE= 100 Cancer Classification: D ­ Not Classifiable as to human carcinogenicity 1 Since an oral NOAEL was selected 25% dermal absorption factor should be used for route to route exposures. 27 2 Since an oral NOAEL was selected 100% inhalation absorption factor should be used for route to route exposures.

epa

2024-06-07T20:31:42.882273

regulations

EPA-HQ-OPP-2002-0188-0014

Supporting & Related Material

TXR# DATE: 1/ 16/ 02 MEMORANDUM SUBJECT: Hexazinone ­ Report of the Hazard Identification Assessment Review Committee. FROM: David G Anderson Toxicologist. Reregistration Branch­ 2 Health Effects Division (7509C) THROUGH: Jess Rowland, Co­ Chair and Elizabeth Doyle, Co­ Chair Hazard Identification Assessment Review Committee Health Effects Division (7509C) TO: Diana Locke, Risk Assessor Reregistration Branch­ 2 Health Effects Division (7509C) PC Code: 107201 On Dec 4, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for HEXAZINONE with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to HEXAZINONE was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. The conclusions drawn at this meeting are presented in this report. 2 Committee Members in Attendance Members present were: LIST NAMES Member( s) in absentia: LIST NAMES Data evaluation prepared by: TOXICOLOGIST, BRANCH Also in attendance were: LIST NAMES and DIVISION Data Evaluation/ Report presentation David G Anderson Toxicologist 3 1. INTRODUCTION On December 4, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for HEXAZINONE with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to HEXAZINONE was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. The last review of the hexazinone toxicity data base was February 11, 1993, by the RfD/ Peer Review Committee. A Reregistration Eligibility Document was issued September, 1994 (EPA­ 738­ F­ 94­ 019). 2. HAZARD IDENTIFICATION 2.1 Acute Reference Dose (RfD)( Population Subgroup: Females 13­ 50) Study Selected: Developmental toxicity Study in Rats § 870.3700 MRID No.: 40397501 Executive Summary: In a developmental toxicity study (MRID 40397501), hexazinone (99.26% a. i.; Lot# S30306A, Batch# 2/ 36) in 0.5% methylcellulose was administered orally via gavage to 25 Crl: CD ® BR female rats/ group at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day (GD) 7 through 16. The dosing volume was 10 mL/ kg (calculated by reviewers). All dams were sacrificed on GD 22 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in clinical signs, gross pathology, pregnancy rate, live fetuses, resorptions, pre­ or post­ implantation loss, corpora lutea, or implantations were noted at any dose level tested. No treatment­ related findings were noted in the 100, or 40 mg/ kg groups. In the 900 mg/ kg dams, one treatment­ related death occurred; alopecia and an enlarged stomach containing fluid and food were noted at necropsy. Decreased (p< 0.05) body weight gains were noted during GDs 15­ 17 (937%) and 17­ 22 (917%). In addition, body weight gains were decreased (p< 0.05) for the overall (GDs 7­ 17) treatment interval (930%). Gravid uterine weights were not reported; however, adjusted (for gravid uterine weight) terminal body weights were slightly decreased (96%; p#0.05). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 9­ 11, 15­ 17, 7­ 17, and 17­ 22. Decreased (p#0.05) food consumption was observed throughout treatment (GDs 7­ 17; 916­ 22%) and post­ treatment (GDs 17­ 22; 99%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 7­ 9, 9­ 11, 11­ 13, 13­ 15, 15­ 17, 7­ 17, and 17­ 22. Also a significantly decreased food consumption was seen at 400 mg/ kg/ day (GD9­ 11; 91%) and (GD 7­ 17; 98%). In addition, relative (to body) liver weights were increased (p#0.05) in the 400 (5.2%) and 900 (5.6%) mg/ kg dams compared to concurrent controls (4.9%). Decreased (p#0.05) terminal body weights were noted at 900 mg/ kg (96%). A significant (p#0.05) trend by linear combination of dose ranks from 4 ANOVA was noted for relative liver weights and adjusted terminal body weights. In addition, a significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for absolute liver weights. Despite this trend, the observed increases in absolute liver weights at 100, 400, and 900 mg/ kg (81­ 8%) were not statistically significant. Liver weight findings are considered equivocal. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. The maternal NOAEL is 100 mg/ kg/ day. In the 900 mg/ kg/ day group, male and female fetal weights were decreased (921%; p#0.05); a significant (p#0.05) trend by Jonckheere's test was noted for this parameter. At 400 mg/ kg/ day, only female fetal weights were significantly decreased (2%) but were not considered to biologically significantly depressed. At 900 mg/ kg/ day, an increased (p#0.05) incidence of misaligned sternebra (1), a variation, was observed (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0066; litter incidence: 0.09). In addition, an increased (p#0.05) incidence of misaligned sternebrae (2+), a variation, was noted (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0033; litter incidence: 0.04). Furthermore, an increased incidence of kidneys with no papilla was observed (fetal incidence: 0.0347; litter incidence: 0.25) relative to concurrent controls (fetal incidence: 0.0062; litter incidence: 0.04). Although the incidence was not statistically significant, a dose­ related trend (p#0.05) was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day, based on decreased male and female fetal weight and increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The developmental toxicity NOAEL is 400 mg/ kg/ day. The developmental toxicity study in the rat is classified acceptable/ guideline (OPPTS 870.3700; §83­ 3 a) and satisfies the guideline requirement for a developmental toxicity study in the rat. Dose and Endpoint for Establishing RfD: Developmental NOAEL is 400 mg/ kg/ day. The LOAEL is 900 mg/ kg/ day based on increased kidneys with no papillae and misaligned sternebrae. Uncertainty Factor (UF): 100 Comments about Study/ Endpoint/ Uncertainty Factor: The malformations (kidneys with no papillae) are presumed to occur after a single and thus appropriate for acute risk assessment. The rabbit developmental toxicity study showed a lower NOAEL of 50 mg/ kg/ day and LOAEL of 125 mg/ kg/ day based possible skeletal and total abnormalities. The HIARC did not select this study because of uncertainties in the effects at the LOAEL. The technical accuracy and overall confidence in this study was low and the study is classified unacceptable. Acute RfD( Females 13­ 50) = 400 mg/ kg = 4.0 mg/ kg 100 (UF) 5 2.2 Acute Reference Dose (RfD)( General Population) An appropriate endpoint attributable to a single dose was not identified in the oral studies, including the rat and rabbit developmental studies. 2.3 Chronic Reference Dose (RfD) Study Selected: One­ Year Chronic Dog Study Guideline #: 870.4100 MRID No.: 42162301 Executive Summary: In a one­ year chronic toxicity study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 5 male and 5 female beagle dogs in the diet at concentrations of 0, 200, 1500, or 6000 ppm (MRID 42162301). Time­ weighted average doses for the treated groups were 5.00, 41.24, and 161.48 mg/ kg/ day, respectively, for males and 4.97, 37.57, and 166.99 mg/ kg/ day, respectively, for females. All animals survived to scheduled necropsy. Treatment­ related clinical signs of toxicity included the observation of thinness in 1/ 5 mid­ dose males, 3/ 5 high­ dose males, and 1/ 5 high­ dose females. Body weights of the high­ dose groups were significantly (p # 0.05) less than those of the control throughout most of the study. Final body weights of the high­ dose males and females were 78% and 67%, respectively, of the control levels. Food consumption by the high­ dose groups was slightly (n. s.) less than that of the controls throughout the study with statistical significance (p # 0.05) attained for females at week 52. Overall food consumption (weeks 1­ 52) for high­ dose males and females was 85% (n. s.) and 74% (p # 0.05), respectively, of the control group levels. Body weights and food consumption for the low­ and mid­ dose groups were not affected by treatment. No treatment­ related ophthalmological lesions, changes in urinalysis parameters, or gross necropsy findings were noted. A moderate macrocytic anemia was observed in the high­ dose groups as evidenced by slight or significant (p # 0.05) decreases in RBC counts, hemoglobin, and hematocrit and increases in MCV and MCH in one or both sexes throughout the study. Cholesterol levels were significantly (p # 0.05) decreased in the high­ dose groups beginning at week 13 for males (52­ 64% of controls) and at week 26 for females (45­ 51% of controls). Albumin levels were significantly (p # 0.05) decreased in the mid­ dose males (93% of controls) at week 13 only, and in the highdose males (74­ 78% of controls) and females (75­ 82% of controls) throughout the study. Beginning on week 13 or 26, the high­ dose groups had aspartate aminotransferase levels 140­ 203% (p # 0.05) of the control values and alanine aminotransferase levels 206­ 276% (p # 0.05) of the control values. Alkaline phosphatase levels were significantly (p # 0.05) increased in the mid­ dose males (259­ 409% of controls) and females (163­ 194% of controls; n. s.) beginning at week 26 and in the high­ dose males (346­ 1363% of controls) and females (307­ 559% of controls) beginning at week 13. For the high­ dose animals, decreases in absolute testes weights in males and kidney, heart, and brain weights in females (­ 12%) and increases in relative liver weights in males and females were considered due to lower final body weights of these animals as compared with controls. 6 Microscopic lesions in the liver of high­ dose animals included concentric membranous bodies in 4 males and 5 females, centrilobular single cell necrosis in 3 males and 3 females, hepatocellular pigment in 3 males and 3 females, and vacuolation in 3 males and 4 females. In addition vacuolation was observed in one mid­ dose male and pigment and membranous bodies were each observed in one mid­ dose female. These lesions were not seen in control or low­ dose animals. Therefore, the LOAEL for hexazinone in male and female beagle dogs is 1500 ppm (41.24 and 37.57 mg/ kg/ day, respectively) based on thinness in one male and hepatotoxicity as evidenced by changes in clinical chemistry parameters and microscopic lesions. The NOAEL is 200 ppm (5.00 and 4.97 mg/ kg/ day, respectively). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a chronic toxicity study [OPPTS 870.4100 (§ 83­ 1b)] in dogs. Proposed Dose and Endpoint for Establishing RfD: NOAEL of 5.0 mg/ kg/ day. The LOAEL is 38 mg/ kg/ day based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and clinical observation of thinnest in one male (4 of 10 males and females at the next higher dose). Proposed Uncertainty Factor( s): 100 Comments about Study/ Endpoint/ Uncertainty Factor( s): The study is of the appropriate duration. The RfD/ peer Review Committee chose the same value in 1994, which formed the basis of the Chronic RfD for the 1994 RED. 2.4 Occupational/ Residential Exposure 2.4.1 Short­ Term (1 Day ­ 1 Month) and Intermediate­ Term (1 Month ­6 Months) Incidental Oral Exposure Toxicity endpoints for incidental oral exposure were not selected since there are no residential exposure based on the current use pattern and none is anticipated in the future. 2.4.2 Dermal Absorption No dermal absorption study is available. For dermal absorption, the NOAEL from the 21­ day Chronic RfD = 5.0 mg/ kg/ day (NOAEL) = 0.05 mg/ kg/ day 100 (UF) 7 dermal toxicity study at the limit dose of 1000 mg/ kg/ day was considered a lower bound for the LOAEL, which was compared with LOAEL of 250 mg/ kg/ day from the range­ finding rabbit study (MRID# 00028863). The ratio of these two numbers was used to estimate a dermal absorption factor of 25%. The range­ finding study was chosen instead of the main rabbit developmental toxicity study (MRID# 00028863) for comparison because the main study was considered to be unacceptable for regulatory purposes. Dermal Absorption Factor: 25% Comments about Study/ Endpoint: The use of a 25% dermal absorption factor for route to route extrapolation of oral studies to occupational dermal exposure would be protective of the developmental effects seen in the rat study. 2.4.3 Short­ Term Dermal (1 Day ­ 1 Month) Exposure Study Selected: None § MRID No.: None Executive Summary: None Dose and Endpoint for Risk Assessment: Not applicable Comments about Study/ Endpoint: No hazard and no quantification required. There were no systemic effects at 1000 mg/ kg/ day, limit dose, in the 21­ day dermal study in rabbits (MRID# 41309005). The oral developmental NOAEL (400 mg/ kg/ day) in conjunction with the use of 25% dermal absorption factor yields a dermal equivalent dose of 1600 mg/ kg/ day [( 400/ 0.25)= 1600 mg/ kg/ day], which is higher than the limit dose in the rabbit 21­ day dermal study and will adequately protect pesticide handlers from developmental toxicity. 2.4.4 Intermediate­ Term Dermal (1­ 6 Months) and Long­ Term Dermal (longer than 6 Months) Exposure Study Selected: Chronic Feeding Study in Dogs § 870.4100 MRID No.: 42162301 Executive Summary: [See Section 2.3 on the Chronic Reference Dose (RfD).] 8 Dose/ Endpoint for Risk Assessment: NOAEL is 5.0 mg/ kg/ day. The LOAEL is 38 mg/ kg/ day based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and the clinical observation of thinnest in one male. Comments about Study/ Endpoint: The elevation in clinical chemistry parameters were seen at 3 and 6 months and thus appropriate fro the exposure period. Since an oral NOAEL was selected, a 25% dermal absorption factor should be used for route to route exposure. 2.4.5 Short­ Term Inhalation Exposure (1 day to 1 Month) Study Selected: Developmental Toxicity in the Rat § 870.3700 MRID No.: 40397501 Executive Summary: [See Section 2.1 Acute Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: The maternal NOAEL is 100 mg/ kg/ day. The LOAEL is 400 mg/ kg/ day based on based on maternal body weight and food consumption decrement. Comments about Study/ Endpoint: In the absence of a inhalation study, the maternal NOAEL was selected. The dosing period was appropriate for this exposure and is protective of developmental effects. For the route to route exposures assume 100% absorption. 2.4.6 Intermediate­ Term inhalation (1 Month to 6 Months) and Long­ Term Inhalation (longer than 6 Months) Exposure. Study Selected: Chronic Feeding Study in Dogs § 870.4100 MRID No.: 42162301 Executive Summary: [See Section 2.3 on the Chronic Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: NOAEL is 5.0 mg/ kg/ day. The LOAEL is 38 mg/ kg/ day based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and clinical observation of thinnest in one male (4 of 10 males and females at the next higher dose). 9 Comments about Study/ Endpoint: The affects seen in clinical chemistry values at 3, 6 and 12 months are appropriate for these exposure periods. Assume 100% absorption in route to route assessment. 2.5 Margins of Exposure for Occupational/ Residential Risk Assessment A margin of exposure of 100 is adequate for occupational dermal and inhalation exposure. There is no non­ occupational (residential) exposures identified at this time. 2.6 Recommendation for Aggregate Exposure Risk Assessments Aggregate exposure risk assessment is not required since there are no non­ occupational (residential) uses at the present time. 3. CLASSIFICATION OF CARCINOGENIC POTENTIAL 3.1 Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No. 00108638 Executive Summary: In this combined chronic/ oncogenicity study (MRID 00108638), hexazinone (94­ 96% a. i.; Lot/ Batch #: 6897­ 40 and 74.25) was administered in the diet to ChR­ CD rats (36/ sex/ group) for up to 25 months at nominal doses of 0, 0, 200, 1000, or 2500 ppm (equivalent to 0, 0, 10.2, 53.4, and 138.3 mg/ kg/ day in males and 0, 0, 12.5, 67.5, and 178.6 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, clinical signs, food consumption, hematology, clinical chemistry, organ weights, and gross or microscopic pathology. No adverse effects were observed in the 200 ppm animals. There were several signs of general toxicity, but a target organ could not be clearly identified at any dose. Terminal body weights were decreased 8% in1000 ppm and 20%, p#0.05, in the 2500 ppm females. A decrease in overall body weight gain (Days 0­ 728; calculated by the reviewers) was also observed in the 1000 (­ 10%) and 2500 ppm (­ 25%) females. Nominal decreases in body weight and body weight gain (­ 3 to ­5%) occurred in males at 1000 ppm during the study, which may have been biologically significant at the end of the study (­ 12% body weight and ­14% for body weight gain). Decreases (p­ values not calculated) in total food efficiency were observed in females at 1000 (­ 10%) and 2500 ppm (­ 25%) and in males at 1000 ppm during the study with overall decrement in food efficiency in 1000 ppm males (­ 10%). In males at 2500 ppm, food efficiency was depressed for the first 6 months of the study 25 but from 6 months to the end of the study, it was increased 139%. The reviewer noted problems interpreting the body weights and food efficiency in males at the top dose level, which were not consistent with the mid­ dose level. For the first 6 months of the study in males, a body 10 weight decrement due to probable toxicity was seen at 1000 and 2500 ppm. After 6 months food efficiency in males at the 1000 ppm remained less than controls (­ 56%) while food efficiency at 2500 ppm in males was higher than controls (+ 139%)( Table 4). By the end of the study, male body weight at 1000 ppm was ­12% and body weight gain ­14%, where as body weight and body weight gain in males at 2500 ppm was +3% for both weight and gain. The reason for this recovery in male body weight decrement at 2500 ppm is unknown, but it appears to be real. [Since absolute and relative liver weights were decreased in males at 2500 ppm, liver enzyme induction allowing the recovery seems unproven.] The body weight decrement at 1000 and 2500 ppm with recovery in body weight at 2500 ppm indicates the an adequate dose level to test for carcinogenicity in males was approached, but probably not attained. Other treatment groups were similar to the average of concurrent controls. Dosing was considered adequate based on decreased body weights, body weight gains, and food efficiency in the 2500 and 1000 ppm females and food efficiency and body weights in the 2500 ppm males for the first 6 months. Body weight (­ 12%) and body weight gain (­ 14%) in males at 1000 ppm were decreased at the end of the study, in addition overall food efficiency (­ 14%) was decreased by the end of the study. Thus female body weight and body weight gain was decreased sufficiently to adequately test for carcinogenicity. Male body weight and body weight gain at1000 ppm appeared to be adequate to test for carcinogenicity by the end of the study, but the lack of dose response in male body weight and body weight gain at 2500 ppm (showing recovery after 6 months such that body weight and body weight gain were higher than control values) may indicate problems with the interpretation of the body weights and body weight gains at 1000 ppm. In the 2500 ppm males, creatinine was increased (NS) in the urine at months 18 and 24 and bilirubin was detected at month 18 and 24. The Sponsor reported that the urine was more alkaline in the 2500 ppm treatment groups (data not reported). Also at 2500 ppm, decreased (p#0.05) absolute and relative liver and kidney organ weights were observed in the males and increased (p#0.05) relative (to body) stomach and kidney organ weights were observed in the females. However, histopathological data did not corroborate these findings. The LOAEL is 1000 ppm for males and females (equivalent to 53.3 for males and 67.5 mg/ kg/ day for females) based on decreased body weight and food efficiency in males and females. In males at 2500 ppm the body weight decrement and food efficiency decrement occurred only for the first 6 months of the study. The NOAEL is 200 ppm for males and females (10.2 for males and 12.5 mg/ kg/ day for females). Neoplasm data were evaluated by two pathologists. An increase incidence of thyroid C­ cell adenomas was observed in the 2500 ppm males, but when analyzed by the Fisher's exact test (p> 0.10) or life­ table methods (p> 0.20) no significant differences were observed between controls and treated groups. Using life­ table analyses a significant (p< 0.05) dose­ response trend was observed in thyroid C­ cell tumors in only one of the two pathology reports. Female rats did not show any potential for C­ cell thyroid adenomas. The incidence, malignancy and latency of tumors were comparable among control and treated rats of both sexes. Under the conditions of this study, carcinogenic potential of hexazinone is considered negative. The submitted study is classified as acceptable for guideline 870.4300 combined 11 chronic/ carcinogenicity study in rats. Discussion of Tumor Data: Neoplasm data were evaluated by two pathologists. An increase incidence of thyroid C­ cell adenomas was observed in the 2500 ppm males, but when analyzed by the Fisher's exact test (p> 0.10) or life­ table methods (p> 0.20) no significant differences were observed between controls and treated groups. Using life­ table analyses a significant (p< 0.05) dose­ response trend was observed in thyroid C­ cell tumors in only one of the two pathology reports. Female rats did not show any potential for C­ cell thyroid adenomas. The incidence, malignancy and latency of tumors were comparable among control and treated rats of both sexes. The study in rats does not support a carcinogenic potential for hexazinone. Adequacy of the Dose Levels Tested: The dose levels in female rats was adequate to test for the carcinogenic potential hexazinone. There was an adequate body weight decrement and body weight gain decrement at the two top dose levels. The dose levels in male rats approached an adequate dose level to test for carcinogenic potential of hexazinone. There may have been an adequate body weight and body weight gain at the mid­ dose level at the end of the study to test for carcinogenic potential of hexazinone, however body weights of males at the top dose level behaved atypically. At the top dose level, males showed a adequate body weight decrement only for the first 6 months of the study and by the end of the study, body weights were higher than the average of the two controls. The reason for this reversible body weight decrement is unknown, but the top dose level in males was one­ half the top dose level of 5000 ppm in the 90­ day subchronic study in males where liver toxicity was seen. These body weight decrements in males and females are supported by a corresponding decrements in food efficiency. 3.2 Carcinogenicity Study in Mice MRID No. 41359301,42509301 and 43202901 § 870.4200 Executive Summary: In this mouse oncogenicity study (MRIDs 00079203, 41359301, 42509301 and 43202901), hexazinone ($95% a. i.; Lot/ Batch #: H­ 11, 265 and 265­ 2) was administered in the diet to CD­ 1 mice (80/ sex/ group) for up to 104 weeks at nominal doses of 0, 200, 2500 or 10,000 ppm (equivalent to 28, 366 and 1635 mg/ kg/ day in males and 0, 34, 450 and 1915 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, food consumption, food efficiency or hematology. Hepatotoxicity was evident at the terminal sacrifice. Macroscopic liver nodule/ mass (% treated vs % controls; n = 28­ 55) was observed in males at 2500 (39% vs 7%) and 10,000 ppm (33%). Increased incidences (% treated vs 0% controls; n = 38­ 55) in the following microscopic liver lesions were observed: hyperplastic nodule( s) (includes both foci of cellular alteration and adenoma) in males at 2500 (39% vs 20%) and 10,000 ppm (36%) and in females at 10,000 ppm (15% vs 3%); and necrosis (severity and type 12 unspecified) in the 10,000 ppm males (36% vs 7%). Centrilobular hepatocyte hypertrophy was observed (% treated vs % controls) at the terminal sacrifice (n = 38­ 55) in males at 2500 (18% vs 0%) and 10,000 ppm (98%) and in females at 10,000 ppm (46% vs 0%) and in the dead and moribund males (n = 25­ 40) at 2500 (44% vs 0%) and 10,000 ppm (60%). Increased (p#0.05 or 0.01) liver/ gall bladder weights were observed at 10,000 ppm in males in both absolute and relative to body weights and in females in relative to body weight. Other signs of toxicity were evident. Distal tail tip sloughing and/ or discoloration was observed at 10,000 ppm in males at Weeks 13­ 104 and in females at Weeks 5 and 13­ 104. Macroscopically, tip of tail missing/ sloughed was observed at the terminal sacrifice in the 10,000 ppm males (31% vs 5%) and females (61% vs 11%) and in the dead and moribund 10,000 ppm females (46% vs 2%). The toxicological significance of these findings was unclear. Minor decreases (p#0.05 or 0.01) in body weights were observed in the 10,000 ppm treatment groups at Weeks 13­ 104 in both sexes. Overall body weight gains (calculated by the reviewers) were decreased in the 10,000 ppm males (925%) and females (931%). The LOAEL is 2500 ppm for males (equivalent to 366 mg/ kg/ day) based on gross liver nodules/ masses, hyperplastic nodules in the liver and centrilobular hepatocyte hypertrophy and 10,000 ppm for females (equivalent to 1915 mg/ kg/ day [limit dose]) based on decreased body weights, increased relative liver/ gall bladder weights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. The NOAEL is 200 ppm (equivalent to 28 mg/ kg/ day) for males and 2500 ppm (equivalent to 450 mg/ kg/ day) for females. Liver samples were first evaluated using the term hyperplastic nodule which did not clearly distinguish neoplasia from non­ neoplasia. Reevaluation was conducted to make this distinction, and no significant differences were observed between the treatment groups and the concurrent controls. However positive trends (p< 0.05) were observed (% treated vs % controls) in focus/ foci of cellular alteration in males, hepatocellular neoplasm( s) (including adenoma, sarcoma, carcinoma, leukemia, and lymphoma) in females, and singular hepatocellular adenoma in females. Focus/ foci of cellular alteration were observed in males at 2500 (11.3% vs 5.0%) and 10,000 ppm (24.1%) and females at 10,000 ppm (12.5% vs 3.8%) beginning at Week 57. Singular hepatocellular adenoma was observed in the 10,000 ppm females (7.5% vs 2.5%) beginning at Week 77. Hepatocellular neoplasm( s) were observed in the 10,000 ppm females (8.8% vs 2.5%). A carcinoma in the 10,000 ppm treatment groups was first observed at Week 65. The incidence of carcinomas were within historical control ranges for each sex, while the incidence of adenomas were increased by 3.21% in the 10,000 ppm females. A dose­ dependent increase in adenomas was not observed in males. The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) concluded that hexazinone should be classified as a Group D (not classifiable as to human carcinogenicity)( 7/ 27/ 94). Under the conditions of this study, evidence of carcinogenic potential was equivocal: a positive trend test for neoplasia was observed in female mice, but no significant difference was determined by pair­ wise comparison. The submitted study is classified as acceptable for guideline 870­ 4200 carcinogenicity study in mice. Discussion of Tumor Data: A dose­ dependent increase in adenomas was not observed in males. The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) concluded that hexazinone should be classified as a Group D (not classifiable as to human carcinogenicity)( 7/ 27/ 94). 13 Under the conditions of this study, evidence of carcinogenic potential was equivocal: a positive trend test for neoplasia was observed in female mice, but no significant difference was determined by pairwise comparison. Adequacy of the Dose Levels Tested: Adequate dose levels were used in male and female mice to test for the carcinogenic potential of hexazinone. Liver toxicity was seen at the top dose level in males and females. 3.3 Classification of Carcinogenic Potential The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) concluded that hexazinone should be classified as a Group D (not classifiable as to human carcinogenicity)( 7/ 27/ 94). In rats, females showed no evidence of carcinogenic potential and males showed a significant trend only in thyroid adenomas. In mice, the evidence of carcinogenic potential was equivocal: a positive trend test for neoplasia was observed in female mice, but no significant difference was seen by pair­ wise comparison. The top doses in rats and mice were adequate to test for carcinogenicity. 4. MUTAGENICITY The required mutagenicity testing is complete. This section was copied from the 1994 RED for Hexazinone and the updated DERs. One mutagenicity study was submitted since the 1994 RED was written; a negative in vivo mammalian micronucleus test in mouse bone marrow cells (MRID# 45124401). Hexazinone was found to be positive for mutagenicity in one chromosomal aberration assay (in vitro cytogenics) (MRID# 00130709), but negative in the remaining studies. It is concluded that the test material was clastogenic in both of the nonactivated trials and was also clastogenic in the one adequate S9­ activated trials. Under both test conditions, concentrations providing evidence of clastogenicity induced an acceptable level of cytotoxicity (> 50% relative cell survival). Thus, the findings can not be considered to be a secondary effect of cytotoxicity. Nevertheless, the outcome of the induced structural damage (i. e., primarily chromatid and chromosome breaks) is unclear since these types of structural aberrations would not likely be passed on to daughter cells. Because unambiguous positive results were achieved, it was concluded that the study provided adequate evidence that INA­ 3674­ 112 (hexazinone, technical) is clastogenic in an acceptable study. 4.1 Guideline 870.5100 Gene Mutation Assay in Ames Test: Hexazinone was tested with metabolic activation (rat liver microsomal fraction commonly known as S­ 9 fraction, plus cofactors) at concentrations ranging from 400 to 2000 ug/ plate and without metabolic activation 14 at concentrations ranging from 200 to 1000 ug/ plate. The strains of Salmonella typhimurium used were TA1535, TA1537, TA1538, TA98 and TA100. No increases in reverse mutations were observed at any concentration. Positive results were obtained with standard reference mutagens (positive controls)( MRID 00098982). 4.2 Guideline 870.5100 Reverse mutation assay: In a reverse gene mutation assay in bacteria (MRID 40826201), strains TA98, TA100, TA1535, TA1537 and TA1538 of S. typhimurium were exposed to S­ triazine­ 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino1 methyl­ (95% a. i.) in ethanol at concentrations of 200, 400, 600, 800 and 1000 :g/ plate without mammalian metabolic activation (S9­ mix) and at concentrations of 400, 800, 1200, 1600 and 2000 :g/ mL with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Crl: CD( SD) BR rat liver. The maximum concentrations of S­ triazine­ 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ tested produced little or no cytotoxicity, were not limited by solubility and were not a limit dose for the assay. No statistically significant increases in the number of revertants per plate or positive linear dose­ response were seen. The solvent and positive controls induced acceptable responses in the corresponding strains. There was no evidence of induced mutant colonies over background. This study is classified as Unacceptable. It does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5100 (§ 84­ 2)] for in vitro mutagenicity [bacterial reverse gene mutation] data and should be repeated using higher doses. 4.3 Guideline 870.5300: Gene Mutation Assay in Mammalian Cells: In a mammalian cell gene mutation assay at the HGPRT locus (MRID No. 00076956), Chinese hamster CHO­ K1­ BH4 cells cultured in vitro were exposed to INA­ 3674­ 112, (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol in two trials. Concentrations used in Trial 1 were 2.0, 11.1, 13.1, 13.9 and 14.3 mM under nonactivated conditions and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM under activated conditions (S9­ mix). Concentrations used in Trial 2 were 2.0, 5.9, 11.1, 13.1 and 13.9 mM without S9­ mix and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Charles River CD® rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. In Trial 1, the cultures treated at 14.3 mM ­S9 were not plated for mutation determination due to cytotoxicity in both Trials 1 and 2. Cytotoxicity was also noted at 9.9 mM +S9. No statistically significant increases in mutant frequency over solvent control values were seen with or without S9­ mix in either Trial 1 or 2. The expected marked increase in the mutation were seen with the positive controls. There was, however, no indication that INA­ 3674­ 112 induced a mutagenic effect either in the presence or the absence of S9 activation. This study is classified as acceptable. It satisfies the requirement for FIFRA Test Guideline OPPTS [870.5300 (§ 84­ 2)] for in vitro mutagenicity (mammalian forward gene mutation) data. 15 4.4 Guideline: 870.5395 Mouse bone marrow micronucleus assay: In a Crl: CD­ 1 (ICR) BR mouse bone marrow micronucleus assay (MRID 45124401), 5 mice/ sex/ dose/ harvest time were treated orally with Hexazinone 25L (Lot No. 9912033, 25% Hexazinone a. i. (24.5% by analysis) and 75% inert ingredients) at doses of 1000, 2000 and 3000 mg/ kg. Bone marrow cells were harvested at 24 and 48 hours post­ treatment and examined for micronucleated polychromatic erythrocytes (MPCEs). The vehicle was Milli­ Q ® water. Signs of toxicity noted at 3000 mg/ kg included: death, convulsions, half­ shut eyes, head­ tilt, irregular respiration, lethargy, low carriage, pallor, prostration, uncontrollable spinning, shovel­ nosing, straining up on toes and tremors. Micronuclei were scored in bone marrow from mice treated at 3000 mg/ kg and from the solvent and positive controls. Mice from the two lower dose groups were not evaluated for micronuclei induction. No statistically significant increases in the frequency of MPCEs or in the PCE/ NCE ratio over the solvent control values were seen in either sex at either the 24 or 48 hour harvest time. The solvent and positive control values were appropriate and within the testing laboratory's historical control ranges. There was no evidence that Hexazinone 25L induced a clastogenic or aneugenic effect in bone marrow at any harvest time. This study is classified as Acceptable/ Guideline. It satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5395 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. 4.5 Guideline 870.5375 Structural Chromosome Aberration Assay; In vitro Cytogenetic Assay: In a mammalian cell cytogenetics assay (MRID No. 00130709), Chinese hamster ovary CHO­ K1 ­BH4 cell cultures were exposed to INA­ 3674­ 112 (Hexazinone, 95% a. i.) in ethanol in two separate trials. Exposure was for two hours with activation and for 10 hours without activation. Cells were harvested 10 hours after the start of treatment. In Trial 1, cells were treated at concentrations of 1.58, 3.94, 15.85 and 19.82 mM without metabolic activation (S9­ mix) and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. In Trial 2, cells were treated at concentrations of 1.58, 3.94, 7.93 and 15.85 without S9­ mix and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced CD rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. Based on the results of a preliminary cytotoxicity test, upper concentrations of 23.78 mM without S9­ mix and 47.56 mM with S9­ mix were selected for the first cytogenetic assay but these concentrations proved excessively cytotoxic and were not scored for chromosomal aberrations. Without S9 activation, statistically significant increases (p< 0.01) in structural aberrations per cell (excluding gaps), lesions per cell and percent abnormal cells were seen at 15.85 mM (Trials 1 and 2) and 19.82 mM (tested in Trial 1 only). Relative percent survival (RPS) at this level was .50%. The percent abnormal cells averaged over all cultures from both trials was 28.0% and 21.5% at 19.82 and 15.85 mM, respectively, compared to the solvent control values of 2.0% (0.5% ethanol in Trial 2) and 7.0% (0.75% ethanol in Trial 1). The percent abnormal cells in positive control cultures was 18% in both Trial 1 (4.83 mM EMS) and Trial 2 (6.44 mM EMS). In the presence of S9­ mix, no statistically significant increases in chromosomal aberration induction 16 were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix. Statistically significant increases were seen at 15.85 mM in Trial 2; RPS at 15.85 mM was 75%. There was a statistically significant dose­ related trend for all three parameters. The statistically significant (p <0.01) increases at 15.85 mM remained when the data from Trial 1 and 2 were combined (average of 20% abnormal cells compared to 10% for the solvent control). The predominant aberrations with or without S9­ mix were chromatid and isochromatid breaks. Solvent and positive controls (except the positive control in Trial 1 with S9­ mix) induced the appropriate responses. INA­ 3674­ 112 was positive for the induction of structural chromosomal aberrations in both the presence and absence of S9­ mix. This study is classified as Acceptable/ guideline and satisfies the requirement for FIFRA Test Guideline [OPPTS 870.5375 (§ 84­ 2)] for in vitro cytogenetic mutagenicity data. 4.6 Guideline 870.5385 Structural Chromosome Aberration Assay; In vivo Cytogenetic Assay: In a mammalian cell cytogenetics assay (MRID 00131355), in bone marrow cells of Sprague­ Dawley CD rats, three rats/ dose/ sex/ harvest time were exposed to H# 14,555 in corn oil ( assumed 100% a. i.) at doses of 100, 300 and 1000 mg/ kg by oral gavage. Bone marrow cells were harvested at 6, 12, 24 and 48 hours post­ treatment. The highest dose tested (1000 mg/ kg) was lethal. A major limitation of this study was the number of animals treated and the number of cells analyzed per animal. At most, three rats/ sex/ dose/ harvest time were treated with, at most, 50 cells per rat analyzed. Few or no analyzable cell were available from many rats. Positive control values were significantly (p= 0.03) increased. There was no evidence that H# 14, 14,555 induced an increase in the incidence of chromosomal aberrations in the bone marrow cells of treated animals. This study is classified as Unacceptable. The number of cells analyzed and the number of rats treated was insufficient. The study does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5385 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. 4.7 Guideline 870.5550 Other Genotoxic Effects Assay; In an unscheduled DNA synthesis assay (MRID 00130708), primary rat hepatocyte cultures were exposed to INA­ 3674­ 112 (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol for 18 hours at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 10.0 and 30.0 mM in Trial 1 and at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 5.0, 10.0 and 30.0 mM in Trial 2. INA­ 3674­ 112 was tested up to the highest achievable concentration in the solvent. Two slides per dose, 25 cells per slide were evaluated for UDS induction in Trial 1. One slide per dose, 25 cells per slide were evaluated in Trial 2. The author did not report that the slides were coded prior to analysis. The average net nuclear grain counts of test material treated cells in Trial 1 were all less than zero with the exception of one slide at 1 x 10 ­5 mM (0.1 ± 9.6) and one slide at 1.0 mM (1.6 ± 5.2). The average net nuclear grain count was below zero for all test material concentrations in Trial 2 with the exception of 0.1 mM where the average net nuclear grain count was 0.0 ± 2.9. The criterion for a positive response was an average net nuclear grain count of at least five in two experiments at any tested concentration. The results 17 were thus negative. The number of cells in repair was not reported. The solvent and positive (DMBA) controls induced the appropriate responses. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline; OPPTS 870.5550 [§ 84­ 2] for other genotoxic mutagenicity data. 5. FQPA CONSIDERATIONS 5.1 Adequacy of the Data Base The toxicity data base for FQPA considerations is incomplete. The rabbit developmental toxicity study is unacceptable/ upgradable because doses were not analyzed and some required maternal and fetal data were missing, such that developmental effects seen in the study could not be discounted or confirmed. The study was otherwise acceptably conducted. Another rabbit developmental toxicity study is currently in progress. A rat developmental toxicity study is acceptable and the 2­ generation reproduction study is acceptable. The remaining toxicity data base is adequate. 5.2 Neurotoxicity Data: No neurotoxicity studies have been conducted. The chronic dog study showed a statistically significant absolute brain weight decrement of 12­ 13% in the female dogs, however, these dogs showed severe malnutrition. The individual animal dog data showed that the two dogs showing the largest decreased body weight from the initial body weight also showed the lowest brain weight. This severe body weight decrement in females may have resulted in nutritional deficiencies indirectly affecting the brain weight. The brain weight decrement was not considered to be a direct effect of hexazinone. No significant changes in brain weight were seen in the rat studies. 5.3 Developmental Toxicity 5.3.1 Developmental toxicity in rats Executive Summary: In a developmental toxicity study (MRID 40397501), hexazinone (99.26% a. i.; Lot# S30306A, Batch# 2/ 36) in 0.5% methylcellulose was administered orally via gavage to 25 Crl: CD ® BR female rats/ group at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day (GD) 7 through 16. The dosing volume was 10 mL/ kg (calculated by reviewers). All dams were sacrificed on GD 22 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in clinical signs, gross pathology, pregnancy rate, live fetuses, resorptions, pre­ or post­ implantation loss, corpora lutea, or implantations were 18 noted at any dose level tested. No treatment­ related findings were noted in the 100, or 40 mg/ kg groups. In the 900 mg/ kg dams, one treatment­ related death occurred; alopecia and an enlarged stomach containing fluid and food were noted at necropsy. Decreased (p< 0.05) body weight gains were noted during GDs 15­ 17 (937%) and 17­ 22 (917%). In addition, body weight gains were decreased (p< 0.05) for the overall (GDs 7­ 17) treatment interval (930%). Gravid uterine weights were not reported; however, adjusted (for gravid uterine weight) terminal body weights were slightly decreased (96%; p#0.05). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 9­ 11, 15­ 17, 7­ 17, and 17­ 22. Decreased (p#0.05) food consumption was observed throughout treatment (GDs 7­ 17; 916­ 22%) and post­ treatment (GDs 17­ 22; 99%). A significant (p#0.05) trend by linear combination of dose ranks from analysis of variance (ANOVA) was noted for GDs 7­ 9, 9­ 11, 11­ 13, 13­ 15, 15­ 17, 7­ 17, and 17­ 22. Also a significantly decreased food consumption was seen at 400 mg/ kg/ day (GD9­ 11; 91%) and (GD 7­ 17; 98%). In addition, relative (to body) liver weights were increased (p#0.05) in the 400 (5.2%) and 900 (5.6%) mg/ kg dams compared to concurrent controls (4.9%). Decreased (p#0.05) terminal body weights were noted at 900 mg/ kg (96%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for relative liver weights and adjusted terminal body weights. In addition, a significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for absolute liver weights. Despite this trend, the observed increases in absolute liver weights at 100, 400, and 900 mg/ kg (81­ 8%) were not statistically significant. Liver weight findings are considered equivocal. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. The maternal NOAEL is 100 mg/ kg/ day. In the 900 mg/ kg/ day group, male and female fetal weights were decreased (921%; p#0.05); a significant (p#0.05) trend by Jonckheere's test was noted for this parameter. At 400 mg/ kg/ day, the female fetal weights that were significantly decreased were not considered to be biologically significant. At necropsy, an increased (p#0.05) incidence of misaligned sternebra (1), a variation, was observed (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0066; litter incidence: 0.09). In addition, an increased (p#0.05) incidence of misaligned sternebrae (2+), a variation, was noted (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0033; litter incidence: 0.04). Furthermore, an increased incidence of kidneys with no papilla was observed (fetal incidence: 0.0347; litter incidence: 0.25) relative to concurrent controls (fetal incidence: 0.0062; litter incidence: 0.04). Although the incidence was not statistically significant, a dose­ related trend (p#0.05) was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day, based on decreased male and female fetal weight, increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The developmental toxicity NOAEL is 400 mg/ kg/ day. The developmental toxicity study in the rat is classified acceptable/ guideline (OPPTS 870.3700; §83­ 3 a) and satisfies the guideline requirement for a developmental toxicity study in the rat. An unacceptable developmental feeding study in the rat shows (MRID# 00114486) a maternal body weight decrement at 482 mg/ kg/ day with a NOAEL of 94.5 mg/ kg/ day with a developmental NOAEL of 19 482mg/ kg/ day. This study tends to add support the acceptable rat developmental (by gavage) toxicity study. 5.3.2 Developmental Toxicity in the rabbit Executive Summary: In a developmental toxicity study (MRID 00028863), hexazinone (100% a. i.; Lot/ batch # E21216A) was administered orally via gavage in a dosing volume of 1 mL/ kg) to 17 female New Zealand White rabbits/ group at dose levels of 0, 20, 50, or 125 mg/ kg on GD 6 through 19. All does (except those that died or delivered prematurely) were sacrificed on GD 29, and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in mortality, clinical signs, body weights, gross pathology, fetal weights, sex ratios, pre­ implantation or post­ implantation losses, or the number of corpora lutea, implantations, resorptions, live fetuses, or dead fetuses were observed. At 125 mg/ kg, food consumption was decreased (p#0.05), relative to concurrent controls, at the beginning of treatment from GD 7 through 11 (961­ 89%). Decreases in food consumption, that were not statistically significant, continued throughout treatment (GDs 12­ 19; 92­ 37%). Diminished food consumption resulted in decreased (not statistically significant) body weight gains in the does (­ 241.5 g) relative to concurrent controls (­ 7.2 g) during GDs 6­ 11. However, weight gain in these animals recovered quickly and was higher than control animals during subsequent treatment intervals (GDs 11­ 15 and 15­ 19). The maternal LOAEL is 125 mg/ kg/ day based on transient decreases in food consumption and body weight gains. The maternal NOAEL is 50 mg/ kg/ day. At 125 mg/ kg/ day, the following skeletal variations were noted (data presented as fetal incidence vs. 0 controls): (i) lagging ossification in extremities (0.0882); (ii) malaligned thoracic vertebrae (0.0294); and (iii) flexed wrist( s) (0.0294). In addition, non­ ossified thumb, an anomaly, was noted at an increased incidence (0.0294) relative to concurrent controls (0). In the absence of historical control data, these findings are considered treatment­ related. In addition, it could not be determined how many of these nominally increased incidences were from different litters, which would have increased concern for developmental toxicity. The developmental toxicity LOAEL is 125 mg/ kg/ day, based on possible skeletal abnormalities and total abnormalies. The developmental toxicity NOAEL is 50 mg/ kg/ day. The developmental toxicity study in the rabbit is classified unacceptable/ upgradable, pending submission of acceptable purity, concentration, stability and litter data and historical control data. A letter dated 9/ 26/ 01 from the registrant provided no additional information about this rabbit developmental toxicity study other than that the doses were not analyzed and that a repeat rabbit developmental toxicity was currently being conducted. 5.4 Reproductive Toxicity 5.4.1 Executive Summary: In a two­ generation reproduction study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 30 male and 30 female Sprague­ Dawley rats in the diet at concentrations of 0, 200, 2000, or 5000 ppm (MRID 42066501). One litter was produced in the first generation and two litters were produced in the second generation. Test substance intake for the treated F0 20 groups was 11.8, 117, and 294 mg/ kg/ day, respectively, for males and 14.3, 143, and 383 mg/ kg/ day, respectively, for females. Test substance intake for the treated F1 groups was 15.3, 154, and 399 mg/ kg/ day, respectively, for males and 17.7, 180, and 484 mg/ kg/ day, respectively, for females. F0 and F1 parental animals were administered test or control diet for 73 or 105 days, respectively, prior to mating, throughout mating, gestation, and lactation, and until necropsy. Deaths of several F0 and F1 parental animals were considered incidental to treatment. No treatmentrelated clinical signs of toxicity were observed in the adult animals of either generation. Gross necropsy was unremarkable and no microscopic lesions were observed in selected tissues from the reproductive tracts of male and female parental animals. Body weights and body weight gains of the F0 males were not affected by treatment. Premating body weight gains by the mid­ and high­ dose F0 females were 76% and 62% (p # 0.05 for both), respectively, of the control level resulting in final premating body weights 93% and 87% (p # 0.05), respectively, of the controls. Body weights of the high­ dose F1 males and females were significantly reduced (p # 0.05) during the premating interval with overall weight gains 87% and 82%, respectively, of the control group amounts. Reductions in body weights and body weight gains during premating for the mid­ and high­ dose F0 and highdose F1 dams continued during gestation and lactation. Food consumption during premating was similar between the treated and control groups for males and females of both generations. However, during gestation significantly (p # 0.05) lower food consumption was noted for the high­ dose F1 dams during production of both litters and for the mid­ dose F1 dams during production of the second litter. There was a statistically significant increase in absolute P0 testes weight that appeared to be dose related, but a nominally decrease absolute F1 adult testes weight in the 5000 ppm dose groups. The F1 testes weight change did not appear to dose related. The testes weight changes in males would appear to be incidental. Therefore, the systemic toxicity LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced body weight and body weight gains by F1 males and F0 and F1 females. The systemic toxicity NOAEL is 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). No reproductive effects were seen in the study except for the weight effects on offspring. Live birth and viability indices and litter survival were similar between the treated and control groups. The lactation index for the F2b high­ dose litters was 85.8% (p # 0.05) compared to 97.5% for the control group. Pup body weights were decreased throughout lactation in the mid­ and high­ dose groups of all litters as compared with the control groups with statistical significance (p # 0.05) attained at most time points. The lower pup body weights were more pronounced in females than in males. F1 and F2a female pup weights were statistically significantly decreased at birth, day 7 and 14 of lactation at $2000 ppm. There were no obvious reproductive effects other than the pup weight decrement. Therefore, the offspring LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced female pup body weights at birth and during lactation. The reproductive toxicity NOAEL was 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a reproductive toxicity study [OPPTS 870.3800 (§ 83­ 4)] in rats. 21 5.5 Additional Information from Literature Sources (if available) The published literature found on hexazinone were the papers on the same studies submitted to the Agency [ Kennedy, GL and Kaplan, AM (1984) Chronic Toxicity, Reproductive, and Teratogenic Studies of Hexazinone. Fundemental and applied Toxicology 4, 960­ 971.]. No other relevant literature on the toxicity was found. 5.6 Determination of Susceptibility No quantitative or qualitative evidence of increased susceptibility was seen following in utero exposure to rats or rabbits, and following pre/ post natal exposure to rats. The rabbit study, even though classified as unacceptable because of technical deficiencies, did not show evidence of increased susceptibility. Never­ theless the HIARC noted that the lack of an acceptable non­ rodent study is a data gap for FQPA assessment. 5.7 Determination of the Need for Developmental Neurotoxicity Study The weight of evidence does not suggest the need for a Developmental Neurotoxicity study. 5.7.1 Evidence that suggest requiring a Developmental Neurotoxicity study: 1. The structurally related pesticide, Atrazine, causes CNS related changes in prolactin secretion, which is related to reproductive senescence in Sprague Dawley rats through continuous estrus from decreasing LH release, but this effect would require a special study and would not be detected by a neurotoxicity study. 5.7.2 Evidence that do not support the need for a Developmental Neurotoxicity study 1. No evidence of neurotoxicity was seen in either developmental toxicity study in the rat or rabbit. 2. A 12­ 13% absolute female brain decrement was seen in the chronic dog study, but the brain weight decrement was associated with severe body weight decrement. The brain weight decrement may have been secondary to the malnutrition in these animals and not directly due to neurotoxic effects of hexazinone 3. No neurotoxic signs were seen in any of the other toxicity studies with hexazinone 6. HAZARD CHARACTERIZATION 22 Hexazinone is a herbicide used to control a broad spectrum of weeds including woody plants in alfalfa, rangeland, pastures, woodlands, pineapple, sugarcane and blue berries. Non­ crop areas include ornamental plants and forests. Hexazinone is used as a pre­ emergent, post emergence herbicide as well as by direct spray and soil applications. There are no non­ occupational (residential) uses. The pesticide is classified with the triazine herbicides. The selectivity of triazine herbicides depends on the plant's ability to degrade or metabolize the parent compound. Sensitive plants have limited ability to metabolize hexazinone. Hexazinone acts through inhibition of photosynthesis. Hexazinone has low acute toxicity by the oral (Category III), dermal (Category IV ) and inhalation routes (Category III). Primary eye irritation is severe, causing corneal opacity and moderate irritation in unwashed eyes (Category I). It causes mild skin irritation and is classified Category IV for skin irritation. It is not a skin sensitizer in the Guinea pig. Body weight decrement and liver toxicity were the most frequent effects shown in studies with hexazinone. Liver toxicity was seen in the chronic dog and mouse studies. Body weight decrement was seen in the chronic rat studies and the studies on reproduction. In a reproduction study, pup weight decrement occurred at the same dose as parental body weight decrement. No reproductive effects were seen in the study other than pup weight decrement. Prenatal studies in the rat and rabbit showed no increased fetal susceptibility. The rat prenatal study showed fetal weight decrement and possibly renal malformations. The rabbit study possibly showed skeletal anomalies and delayed ossifications at the highest dose tested. Thus, there is no increased quantitative or qualitative susceptibility in reproduction study or prenatal developmental toxicity studies. The 21­ day dermal study in the rabbit showed no systemic toxicity and mild dermal irritation at the limit dose. The chronic study in dogs showed severe body weight decrement, changes in liver related clinical chemistry values, and microscopic lesions. Body weight decrement was seen in a chronic carcinogenicity studies in rats and mice. Liver toxicity was seen in mice. The mouse carcinogenicity study showed an increased trend for liver carcinomas, but no pair wise significant increases. The rat study showed no carcinogenic potential. Based on these studies in rats and mice, hexazinone was classified in a group D, not classifiable as a carcinogen. Rat metabolism studies showed that hexazinone was rapidly absorbed and excreted and essentially no difference in the metabolism of males and females at high or low dose levels. Almost no parent hexazinone was recovered in urine or feces. Two major metabolites were recovered from feces and urine, in addition to lesser amounts of a third metabolite and small amounts conjugated products from urine. 6.0 Data Gaps The HIARC requested a 28­ day inhalation study with hexazinone because of the concern for potential inhalation exposure based on the use pattern.. The rabbit developmental toxicity study is classified as unacceptable. Another study in the rabbit, requested by Cal EPA, is expected to be submitted to OPP as well. 23 7.0 ACUTE TOXICITY Acute Toxicity of Hexazinone Guideline No. Study Type MRIDs # Results Toxicity Category 81­ 1 Acute Oral/ Rat 41235004 (1989) LD50 = 1200 mg/ kg III 81­ 2 Acute Dermal/ Rabbit 00104974 LD50 >5278 mg/ kg IV 81­ 3 Acute Inhalation 00104975 (1973) LC50 > 7.50 mg/ L( 1 hour) LC50 >1.9 mg/ L 1 Equivalent to 340 mg/ kg 2 III 81­ 4 Primary Eye Irritation 00106003 (1982) Irreversible corneal opacity, Severe 3 I 81­ 5 Primary Skin Irritation 00106004 (1982) Mild IV 81­ 6 Dermal Sensitization 41235005 (1989) NA Not a skin sensitizer 81­ 8 Acute Neurotoxicity Not conducted 1 One hour inhalation study on technical converted to probable no effects at 4 hours. Consistent with an unreviewed three week inhalation study (MRID# 00063972) showing no significant toxic effects. The effects seen were consistent with dust inhalation at 2.5 mg/ mL, the only dose tested. Another acute 4 hour inhalation study in rats showed no effects at 3.9 mg/ L using a 25% a. i. granular product (MRID# 41756701). 2 Calculated by the reviewer from the following information from Whalan (1998). This conversion generally is not considered valid, especially for irritating substances. {[( 1.9 mg/ L x 1 x 9.13 x 4 x 1)/( 0.204 kg)] = 340 mg/ kg} 3 The toxicity category was based on the corneal opacity. Irritation not counting opacity was tox category III. 24 25 8.0 SUMMARY OF TOXICOLOGY ENDPOINT SELECTION The doses and toxicological endpoints selected for various exposure scenarios are summarized below. EXPOSURE SCENARIO DOSE (mg/ kg/ day) ENDPOINT STUDY Acute Dietary NOAEL= 400 mg/ kg/ day UF = 100 LOAEL= 900 mg/ kg/ day based on decreased male and female fetal weight, kidneys with no papilla (malformation) and misaligned sternebrae (variation) Developmental Toxicity Study in rats MRID# 40397501 Acute RfD = 4.0 mg/ kg Chronic Dietary NOAEL =5.0 mg/ kg/ day UF = 100 LOAEL= 37.6 mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Chronic One Year Feeding study in dogs MRID# 42162301 Chronic RfD = 0.05 mg/ kg/ day Incidental Oral, Short­ and Intermediate­ Term No residential uses; endpoints not selected Dermal, ShortTerm NOAEL= No hazard was identified, therefore quantification of risk is not required. No systemic toxicity was seen at the limit dose following repeat dermal application. Dermal, Intermediate Term 1 Oral NOAEL= 5.0 mg/ kg/ day UF= 100 LOAEL= 37.6 mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase Chronic One Year Feeding study in dogs MRID# 42162301 Dermal, Long Term 1 Oral NOAEL= 5.0 Mg/ kg/ day UF= 100 LOAEL= 37.6 mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase Chronic One Year Feeding study in dogs MRID# 42162301 26 Inhalation, ShortTerm 2 Oral NOAEL= 100 mg/ kg/ day UF= 100 LOAEL= 400 mg/ kg/ day based on decrease maternal food consumption and dose related body weight decrement. Developmental Toxicity Study in rats MRID# 40397501 Inhalation, Intermediate­ Term & Long­ Term 2 Oral NOAEL= 5.0 mg/ kg/ day UF= 100 LOAEL= 37.6 mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Chronic One Year Feeding study in dogs MRID# 42162301 1 Since the endpoint was chosen from an oral study, assume 25% dermal absorption factor should be used for route to route exposures. 3 Since the endpoint was chosen from an oral study, 100% inhalation absorption factor should be used for route to route exposures. On the dermal absorption factor for hexazinone: December 12, 2001 It does not make sense to chose the range­ finding study over the main study. The main study was unacceptable primarily because of the inability to determine the number of affected litters while the range­ finding and main study both suffer from a lack of dosage analysis. In addition, choosing a LOAEL which includes a dose causing 50% maternal mortality (2/ 4) is problematic. At least the main study was conducted on 16 pregnant females at the 27 LOAEL and the LOAEL was more comparable with lower bound of the LOAEL of 1000 mg/ kg/ day in the 21­ day dermal study. Thus, if 12.5% dermal absorption factor had been used (125/ 1000x100), adequate protection of workers from the developmental effects seen in rats would still be apparent. Rabbit maternal LOAEL/ dermal lower bound LOAEL= 125/ 1000 = 12.5% . Developmental NOAEL of 400 mg/ kg/ day/ 0.125 =3200 mg/ kg/ day which is also higher than 1000 mg/ kg/ day, which is the objective, I think.

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EPA-HQ-OPP-2002-0188-0015

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES May 1, 2002 MEMORANDUM SUBJECT: Review of Hexazinone Incident Reports DP Barcode D282798, Chemical #107201 FROM: Jerome Blondell, Ph. D., Health Statistician Chemistry and Exposure Branch 1 Health Effects Division (7509C) Monica F. Spann, M. P. H., Environmental Health Scientist Chemistry and Exposure Branch 1 Health Effects Division (7509C) THRU: Francis B. Suhre, Senior Scientist Chemistry and Exposure Branch 1 Health Effects Division (7509C) TO: Carol Christensen, Environmental Protection Specialist Reregistration Branch 2 Health Effects Division (7509C) BACKGROUND The following data bases have been consulted for the poisoning incident data on the active ingredient Hexazinone (PC Code: 107201): 1) OPP Incident Data System (IDS) ­ reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. Reports submitted to the Incident Data System represent anecdotal reports or allegations only, unless otherwise stated. Typically no conclusions can be drawn implicating the pesticide as a cause of any of the reported health effects. Nevertheless, sometimes with enough cases and/ or enough documentation risk mitigation measures may be suggested. 2 2) Poison Control Centers ­ as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1998 for all pesticides. Most of the national Poison Control Centers (PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System which obtains data from about 65­ 70 centers at hospitals and universities. PCCs provide telephone consultation for individuals and health care providers on suspected poisonings, involving drugs, household products, pesticides, etc. 3) California Department of Pesticide Regulation ­ California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required, by statute, to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides. The majority of the incidents involve workers. Information on exposure (worker activity), type of illness (systemic, eye, skin, eye/ skin and respiratory), likelihood of a causal relationship, and number of days off work and in the hospital are provided. 4) National Pesticide Telecommunications Network (NPTN) ­ NPTN is a toll­ free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984­ 1991, inclusive has been prepared. The total number of calls was tabulated for the categories human incidents, animal incidents, calls for information, and others. HEXAZINONE REVIEW I. Incident Data System Please note that the following cases from the IDS do not have documentation confirming exposure or health effects unless otherwise noted. Incident# 956­ 1 A pesticide incident occurred in 1994, when an individual reported burning and red welts on their legs after using a backpack sprayer that was leaking on his hip while applying the product. No further information on the disposition of the case was reported. Incident# 3172­ 1 A pesticide incident occurred in 1996, when utility workers were exposed to the product for about one to one and a half hours after a tank mixture was sprayed in the area close to where they were working. The workers reported temporary eye irritation. No further information on the disposition of the case was reported. Incident# 3645­ 1 A pesticide incident occurred in 1996, when a worker, who was not wearing gloves but was wearing boots, reported peeling skin on their hands and feet. The worker was applying the product that got onto their hands and feet. No further information on the disposition of the case was reported. 3 Incident# 9945­ 6 A pesticide incident occurred in 1999, when a field was sprayed with the product within a half mile of a couple's home. Specific symptoms were not mentioned. No further information on the disposition of the case was reported. II. Poison Control Center Data ­ 1993 through 1998 Results for the years 1993 through 1998 were acquired for 17 exposures to hexazinone reported to Poison Control Centers. Cases involving exposures to multiple products are excluded. No cases were reported among children under six years of age and 4 cases among older children and adults exposed at their workplace. One of the four cases reported a moderate outcome with eye effects that resulted in being seen in a health care facility. This was too few cases to warrant detailed analysis. There were 13 non­ occupationally exposed cases among older children and adults. Of these cases, 5 had outcome determined of which none reported a serious or even a moderate outcome. One should be cautious about drawing conclusions from such a small number of cases. III. California Data ­ 1982 through 1999 Detailed descriptions of 1 case submitted to the California Pesticide Illness Surveillance Program (1982­ 1999) were reviewed. In the case, a worker reported breathing difficulties and was diagnosed with bronchitis and slight asthma after hexazinone was applied to the ground. Hexazinone ranked 208 th as a cause of systemic poisoning in California based on data for 1982 through 1999. IV. National Pesticide Telecommunications Network On the list of the top 200 chemicals for which NPTN received calls from 1984­ 1991 inclusively, hexazinone was ranked 159 th with 17 incidents in humans reported and 2 in animals (mostly pets). V. Conclusions Relatively few incidents of illness have been reported due to hexazinone. VI. Recommendations No recommendations can be made based on the few incident reports available. 4 cc: Correspondence Hexazinone file (chemical no. 107201) Dirk Helder, SRRD ­ (7508C)

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EPA-HQ-OPP-2002-0188-0016

Supporting & Related Material

OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 DATE: April 25, 2002 SUBJECT: Hexazinone. The Outcome of the HED Metabolism Assessment Review Committee for Water. PC code 107201; Rereg. Case 0266; DP Barcode: D282111; TXR No. 0050425. FROM: Sherrie L. Kinard, Chemist Reregistration Branch II Health Effects Division (7509C) THROUGH: Al Nielsen, Branch Senior Scientist Reregistration Branch II Health Effects Division (7509C) TO: Christine Olinger, Chair Metabolism Assessment Review Committee (MARC) Health Effects Division (7509C) MATERIAL REVIEWED The MARC met on January 29, 2002 and then again on March 12, 2002 to consider residues of hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione] and metabolites in/ on plant and animal comodities and in water. Specifically, MARC determined which metabolites should be included in the tolerance expression and risk assessment. MARC CONCLUSIONS The Committee concluded that hexazinone plus metabolites A, B, C, D, and E (calculated as hexazinone) are the residues of concern to be included in tolerance expression and risk assessment for plants and rotational crops. The residues of concern to be included in the tolerance expression for ruminants are hexazinone plus metabolites B, C, C­ 2, and F in milk, and hexazinone plus metabolites B and F in tissue. For purposes of risk assessment, the residues of concern in/ on ruminants are hexazinone plus metabolites B, C, C­ 1, C­ 2, and F. The Agency has previously determined that tolerances in poultry commodities and a poultry feeding study are not required for reregistration based on results of reviewed poultry metabolism data. For water, the Committee concluded that for risk assessment purposes, hexazinone, G3170, and all metabolites with conjoined cyclohexyl and triazine rings should be included. Hexazinone HED MARC Meeting Summary Chart: Chemical: Hexazinone Date: 29­ Jan­ 2002 Residues of Concern Matrix For Risk Assessment For Tolerance Expression Plants Parent, metabolites A, B, C, D, and E Parent, metabolites A, B, C, D, and E Rotational crop Parent, metabolites A, B, C, D, and E Parent, metabolites A, B, C, D, and E Poultry Not Required Not Required Ruminant Parent, metabolites B, C, C­ 1, C­ 2, and F For milk: Parent, B, C, C­ 2 and F For tissue: Parent, B, and F Water Not discussed N/ A Chemical: Hexazinone Date: 12­ March­ 2002 Residues of Concern Matrix For Risk Assessment For Tolerance Expression Water Parent, G3170, and all metabolites with conjoined cyclohexyl and triazine rings. N/ A RATIONALE Plant: Hexazinone and metabolites A, B, C, D, and E are detected in plant metabolism studies. Toxicity data are not available for these metabolites, and MARC assumed they have potentially similar toxicity to the parent due to the similarities in structure. These metabolites are also measured by the enforcement method; in addition, metabolites A­ D and F were observed in the rat metabolism study. MARC concluded that for risk assessment and tolerance expression, hexazinone plus metabolites A, B, C, D, and E are the residues of concern. Rotational crop: Hexazinone and metabolites F, G, H, G3170, G3170­ NG, A­ 1, 1, and C­ 1 were also found in field rotational crop studies, in addition to the parent, A, B, C, D, and E; however, metabolites F, G, H, G3170, G3170­ NG, A­ 1, 1, and C­ 1 were below the LOQ in the field studies. The MARC concluded that these low level metabolites are not likely to be significantly more toxic than the parent and can therefore be excluded. Ruminant: Metabolites B, C­ 1, C­ 2, and F are the major metabolites (> 10% TRR) found in milk and tissue in the goat metabolism study; therefore, the MARC concluded that hexazinone plus these metabolites need to be included in the risk assessment. Since the enforcement method detects only parent, B, C, C­ 2, and F in milk, and parent, B, and F in tissues, MARC recommended that for milk tolerance expression, the residues of concern are hexazinone plus metabolites B, C, C­ 2, and F, and for livestock tissues tolerance expression, the residues of concern are hexazinone plus metabolites B, and F. Although the Committee previously (5/ 19/ 94) recommended inclusion of metabolites A, D and E in animal commodities, these moieties each represented <1 to 4% of the total residues in goat milk and tissues. Poultry: No decision is needed at this time (40CFR180.6( a) (3)). Water: Environmental fate data suggest that the parent and degradates are likely to be persistent and mobile in the environment. Leaching and runoff are expected to be primary dissipation routes. Metabolites A, B, D, 1 (JS472), and 2 (JT677) are major metabolites (> 10% TRR) found in soil/ aquatic studies. Metabolites A­ 1, C and G3170 are detected in ground water analysis. Due to lack of toxicity data for these metabolites, MARC assumes they have similar toxicity as the parent because of the structure similarities (except G3170). G3170 was detected at the highest level in the California prospective groundwater study (PGW) and there are no toxicity information available to indicated that it is of less toxicological concern than the parent. Therefore, MARC concludes that parent, G3170, and all degradates with conjoined cyclohexyl and triazine rings (specifically, A, A­ 1, B, C, D, 1 (JS472), and 2 (JT677)) are residues of concern for risk assessment in water. ATTENDEES Members in Attendance (January 29, 2002): Abdallah Khasawinah, Yan Donovan, David Nixon, Rick Loranger, Leung Cheng, John Doherty, Sheila Piper, Bill Wassell, William Dykstra (alternate). Members Not Present: Alberto Protzel, Christine Olinger, Norman Birchfield. Non­ Members in Attendance: David Anderson, Sherrie Kinard, Diana Locke, Dirk Helder, Pauline Wagner, Larry Liu. Members in Attendance (March 12, 2002): Abdallah Khasawinah, Christine Olinger, Norman Birchfield, Yan Donovan, David Nixon, Rick Loranger, Leung Cheng, John Doherty, Sheila Piper. Members Not Present: Bill Wassell, Alberto Protzel, Leonard Keifer. Non­ Members in Attendance: Dirk Helder, Sherrie Kinard, Larry Liu. cc: SF, RF, List A File, S. Kinard (RRB2), D. Anderson (RRB2), Diana Locke (RRB2), L. Liu (EFED) RDI: C. Olinger: 04/ 25/ 02; A. Nielson: 04/ 25/ 02. 7509C: RRB2: S. Kinard: CM# 2: Rm 722B: 703­ 305­ 0563: 04/ 25/ 02.

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Supporting & Related Material

N N N N O O 2­ 15­ 02 MEMORANDUM SUBJECT: Hexazinone. List A Reregistration Case 0266. PC Code 107201. Product Chemistry Chapter for the Tolerance Reassessment Eligibility Decision [TRED] Document. DP Barcode D279324. FROM: K. Dockter, Chemist Reregistration Branch 2 Health Effects Division [7509C] THRU: Alan Nielsen, Branch Senior Scientist Reregistration Branch 2 Health Effects Division [7509C] TO: Diana Locke, Ph. D., Risk Assessor Reregistration Branch 2 Health Effects Division [7509C] Hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione] is a contact and residual herbicide. "Apply when plants are actively growing for control of many annual, biennial and perennial weeds and woody plants on noncropland areas. Gives contact and residual control. Rainfall is needed for soil activation. Controls woody plants in reforestation areas (site preparation or conifer release); selective weed control in conifers, sugarcane, pineapple, rubber trees, alfalfa, blueberries." Farm Chemicals Handbook, 1999 Empirical formula: C12H20N4O2 Molecular weight: 252.3 CAS Registry No.: 51235­ 04­ 2 PC Code: 107201 Chemical structure by J. Punzi A search of REFS conducted 12/ 07/ 01 identified a single hexazinone technical [T] registered 2 under PC Code 107201, the Dupont 98.7 % T; EPA Reg. No. 352­ 399. It is subject to a TRED. The pre­ FQPA Reregistration Eligibility Decision Document issued 9/ 94. The Registration Standard + FRSTR issued 6/ 88; the Update issued 5/ 10/ 91. The product chemistry data base is essentially complete. There are no reported impurities of toxicological concern in hexazinone. The Series 830 physical and chemical properties are given in the table below. GLN MRID Data 6302 Color 41203201 white 6303 Physical state " crystalline solid 6304 Odor " mildly pungent 7200 MP " 113.5 C 7300 Bulk density " 0.61 g/ mL 7840 Water solubility " 2.98 g/ 100g @ 25 C 7950 vp " 1.9 x 10 ­7 mm Hg @ 25 C 7550 Pow " 15 at pH 7.0 6313 Stability " stable in slightly acidic or alkaline media at elevated temperatures, slowly degrades under artificial sunlight. ~1% decomposition when stored 2 yrs under ambient conditions. 7370 Dissociation constants in water " a very weak base 7000 pH " 8.0 6320 Corrosion characteristics " 0.18­ 34 mils/ yr @ 50 C in various metals; no change in packaging materials. 3 cc: Reg. Std. file, RF, Dockter, S. Kinard, D. Anderson. RD\ I Hexazinone TRED Team. 7509C: RRB2: Rm712G: 57886: KD/ kd Hexazinone. TRED [992f8] = D279324. mem.

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EPA-HQ-OPP-2002-0188-0018

Supporting & Related Material

N N N N O O R E V I S E D 4­ 23­ 02 MEMORANDUM SUBJECT: Hexazinone. List A Reregistration Case 0266. PC Code 107201. Product Chemistry Chapter for the Tolerance Reassessment Eligibility Decision [TRED] Document. DP Barcode D279324. FROM: K. Dockter, Chemist Reregistration Branch 2 Health Effects Division [7509C] THRU: Alan Nielsen, Branch Senior Scientist Reregistration Branch 2 Health Effects Division [7509C] TO: Carol Christensen, Risk Assessor Reregistration Branch 2 Health Effects Division [7509C] Hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione] is a contact and residual herbicide. "Apply when plants are actively growing for control of many annual, biennial and perennial weeds and woody plants on noncropland areas. Gives contact and residual control. Rainfall is needed for soil activation. Controls woody plants in reforestation areas (site preparation or conifer release); selective weed control in conifers, sugarcane, pineapple, rubber trees, alfalfa, blueberries." Farm Chemicals Handbook, 1999 Empirical formula: C12H20N4O2 Molecular weight: 252.3 CAS Registry No.: 51235­ 04­ 2 PC Code: 107201 2 Chemical structure by J. Punzi A search of REFS conducted 12/ 07/ 01 identified a single hexazinone technical [T] registered under PC Code 107201, the Dupont 98.7 % T; EPA Reg. No. 352­ 399. It is subject to a TRED. The pre­ FQPA Reregistration Eligibility Decision Document issued 9/ 94. The Registration Standard + FRSTR issued 6/ 88; the Update issued 5/ 10/ 91. The product chemistry data base is essentially complete. There are no reported impurities of toxicological concern in hexazinone. The Series 830 physical and chemical properties are given in the table below. GLN MRID Data 6302 Color 41203201 white 6303 Physical state " crystalline solid 6304 Odor " mildly pungent 7200 MP " 113.5 C 7300 Bulk density " 0.61 g/ mL 7840 Water solubility " 2.98 g/ 100g @ 25 C 7950 vp " 1.9 x 10 ­7 mm Hg @ 25 C 7550 Pow " 15 at pH 7.0 6313 Stability " stable in slightly acidic or alkaline media at elevated temperatures, slowly degrades under artificial sunlight. ~1% decomposition when stored 2 yrs under ambient conditions. 7370 Dissociation constants in water " a very weak base 7000 pH " 8.0 3 6320 Corrosion characteristics " 0.18­ 34 mils/ yr @ 50 C in various metals; no change in packaging materials. cc: Reg. Std. file, RF, Dockter, S. Kinard, D. Anderson. RD\ I Hexazinone TRED Team. 7509C: RRB2: Rm712G: 57886: KD/ kd Hexazinone. TRED [26] = D279324. mem.

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EPA-HQ-OPP-2002-0188-0019

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM 05/ 20/ 2002 SUBJECT: Hexazinone Residue Chemistry Chapter for the Tolerance Reassessment Eligibility Decision (TRED); PC Code 107201; DP Barcode D279899; Rereg. Case 0266. FROM: John S. Punzi, Ph. D., Chemist Reregistration Branch II Health Effects Division (7509C) THROUGH: Alan Nielsen, Branch Senior Scientist Reregistration Branch II Health Effects Division (7509C) and Chemistry Science Advisory Council (Chem SAC) 05/ 15/ 2002 Health Effects Division (7509C) TO: Carol Christensen, Risk Assessor Reregistration Branch II Special Review and Reregistration Division (7509C) and Dirk Helder, Chemical Review Manager Reregistration Branch II Special Review and Reregistration Division (7508W) cc: JSPunzi (RRB2), Hexazinone Reg. Std. File, Hexazinone SF, RF, LAN. RD/ I: RRB2 Chem Review Team (05/ 12/ 2002), Alan Nielsen (05/ 25/ 2002). 7509C: RRB2: John S. Punzi: CM2: Rm 712M: 703­ 305­ 7727: 05/ 08/ 2002. INTRODUCTION Hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H) dione is a triazine­ dione herbicide registered for use on alfalfa, blueberries, pasture and range grasses, pineapple, and sugarcane. It is also registered for use on ornamental plants, forest trees, and noncrop areas. Hexazinone is a proprietary chemical of E. I. du Pont de Nemours and Company, Inc. which is the sole producer and primary registrant of this broad spectrum herbicide. The dry flowable (DF), emulsifiable concentrate (EC), and soluble concentrate (SC) are the formulation classes registered to du Pont with food/ feed uses. These formulations, sold under the trade name Velpar®, may be applied for preemergence, postemergence, layby, directed spray, or basal soil treatments using ground or aerial equipment. EXECUTIVE SUMMARY OF RESIDUE CHEMISTRY DATA REQUIREMENTS The 10/ 8/ 93 Residue Chemistry Chapter required label amendments for: (1) alfalfa to specify a 30­ day preharvest interval (PHI) for the feeding of forage and cutting of hay; (2) blueberries to specify PHIs of 90 and 450 days for highbush and lowbush varieties, respectively. These label revisions remain outstanding. Details of the required label amendments are presented in the respective endnote for GLN 860.1500 (Crop Field Trials) in Table B. Data depicting magnitude of the residues of hexazinone and metabolites A, B, C, D, and E in/ on grass forage and hay harvested 0 day following a single broadcast application of representative formulations at 1.125 lb ai/ A are required. GLN 860.1300: Nature of the Residue ­ Plants The qualitative nature of the residue in plants is adequately understood. Studies indicate that root uptake is the principal mechanism for the absorption of hexazinone by plants from soils. Hexazinone is translocated through the xylem to the foliage where it blocks the photosynthetic process. The HED Metabolism Assessment Review Committee (MARC) concluded that the hexazinone tolerance expression for plants and rotational crops should include hexazinone and metabolites A, B, C, D, and E (see Figure 1 for structures and proper nomenclature). Toxicity data for the metabolites is not available; but, based on the structural similarity of the metabolites, it is assumed they will exhibit similar toxicity to the parent hexazinone. The current tolerance expression for hexazinone in 40 CFR §180.396 is for "combined residues of the herbicide hexazinone (3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine2,4 1H, 3H)­ dione) and its metabolites, calculated as hexazinone." The tolerance expression should be modified to include specific metabolites A, B, C, D, and E, identified by the appropriate name. GLN 860.1300: Nature of the Residue ­ Livestock The qualitative nature of the residue in livestock is adequately understood based on acceptable ruminant and poultry metabolism studies. The HED MARC concluded that the hexazinone tolerance expression for ruminants should include hexazinone plus metabolites B, C, C­ 2, and F for milk. The Committee concluded that the hexazinone tolerance expression for ruminant tissue should include hexazinone plus metabolites B and F. The Committee concluded that residues of hexazinone and metabolites B, C, C1 C­ 2, and F should be taken into account when risk assessments are done. GLN 860.1340: Residue Analytical Methods Plant Commodities Adequate methods are available for purposes of data collection and enforcement of tolerances for residues of hexazinone and metabolites A, B, C, D, and E in/ on plant commodities. Livestock Commodities The registrant has proposed an LC/ MS method (designated as du Pont AMR 3783­ 96) as an enforcement method for livestock commodities. The method has been subjected to a successful ILV and a radiovalidation study and will be forwarded to the Analytical Chemistry Branch for a tolerance method validation by Agency chemists. If the results of method validation by Agency chemists are successful, then Method AMR 3783­ 96 will be proposed for inclusion in PAM Volume II, and no additional data concerning this GLN topic will be required for reregistration. GLN 860.1360: Multiresidue Methods The reregistration requirements for multiresidue methods data are fulfilled. GLN 860.1380: Storage Stability Plant Commodities No additional storage stability data for plant and processed commodities are required for reregistration. Livestock Commodities Adequate storage stability data are available to support the existing ruminant feeding study. GLN 860.1500: Crop Field Trials Berries Group Blueberry The 10/ 8/ 93 Residue Chemistry Chapter concluded that no additional data are required for blueberries provided all pertinent product labels are amended to specify PHIs of 90 and 450 days for application to highbush and lowbush blueberries, respectively. Based on the combined LOQs (0.55 ppm) of the enforcement method for parent plus metabolites, HED recommends that the RAC tolerance be increased from 0.2 ppm to 0.60 ppm. Grass Forage, Fodder, and Hay Group Grass (pasture and rangeland) forage An examination of registered uses of hexazinone on pasture and rangeland grasses (see Table A2) reveal that there two distinct use patterns, a basal soil application and a broadcast application. It is noted that the 10­ ppm tolerance for grass forage (listed as "grasses, pasture" and "grasses, range" under 40 CFR §180.396) was established based on residue data reflecting basal soil application only. In the absence of residue data reflecting broadcast application, HED is requiring the following additional data for grass forage before the RAC tolerance can be reassessed: Data depicting magnitude of the residues of hexazinone and metabolites A, B, C, D, and E in/ on grass forage harvested 0 day following a single broadcast application of representative formulations at 1.125 lb ai/ A. It is HED policy to require 0­ day crop field residue data for grass forage unless it is not feasible (e. g., preplant/ preemergence pesticide uses). The formulations to be tested may be applied in side­ by­ side plots. The location and number of trials should be in compliance with the current OPPTS GLN for adequate geographic representation of data. Grass (pasture and rangeland) hay The reregistration requirements for residue data on grass hay have not been fulfilled. The registrant has submitted a petition (PP# 1F3967), for the establishment of a tolerance for residues of hexazinone and its metabolites in/ on grass hay. The petition is currently in reject status because grass hay data, from field trials with adequate geographical representation, remain outstanding. Since 1991 HED has reviewed two proposals to amend the original petition requesting that the Agency establish tolerances for grass hay based on theoretical grass drying factors. HED recommended against the establishment of grass hay tolerances each time. In addition, HED reviewed two registrant responses to the petition amendment reviews and concluded in each case that the recommendation to require actual field trial data for grass hay is appropriate. Non­ Grass Animal Feeds (Forage, Fodder, Straw, and Hay) Group Alfalfa forage and hay The Updated Table A for Residue Chemistry RED Chapter dated 9/ 8/ 94 concluded that adequate residue data are available for alfalfa forage and hay. However, label amendments were required on all product labels for alfalfa, including supplemental labels, to establish a 30­ day PHI for the feeding of forage and the cutting of hay. The available residue data indicate that the combined residues of hexazinone and its metabolites A, B, C, D, and E in/ on treated samples were <1.87 ppm and <3.33 ppm for alfalfa forage and hay, respectively. Based on these data, the established tolerance for alfalfa forage is reassessed at its existing level of 2.0 ppm; however, the tolerance for alfalfa hay should be lowered from 8.0 ppm to 4.0 ppm. Table A2 shows that product labels for the 90% SC (EPA Reg. No. 352­ 378) and 75% DF (EPA Reg. No. 352­ 58) formulations have been revised in compliance with previously requested label amendment. However, the product label for the 2 lb/ gal EC (EPA Reg. No. 352­ 392) formulation does not specify any PHI; this label must be amended to establish a 30­ day PHI (or pregrazing interval) for the feeding of forage and the cutting of hay. Alfalfa seed The available residue data indicate that the combined residues of hexazinone and its regulated metabolites ranged from <1.30 ppm to <1.46 ppm in/ on alfalfa seed following a single broadcast dormant application of the 2 lb/ gal EC or 90% SC formulation at 0.75 lb ai/ A (1.5x the maximum registered rate on alfalfa grown for seed); no data were submitted reflecting 1.0x. HED is requesting the registrant to propose a tolerance for hexazinone residues of concern in/ on alfalfa seed of 2.0 ppm. Miscellaneous Pineapple The available data indicate that the combined residues of hexazinone and its regulated metabolites were <0.35 ppm in/ on pineapple fruits harvested at a minimum PHI of 181 days following five ground applications of a representative hexazinone formulation at 0.45­ 0.9 lb ai/ A for a total rate of 3.6 lb ai/ A. Based on the combined LOQs (0.55 ppm) of the enforcement method, HED is now recommending that the RAC tolerance be increased from 0.5 ppm to 0.60 ppm. Sugarcane The available data indicate that the combined residues of hexazinone and its regulated metabolites were <0.35 ppm in/ on samples of sugarcane treated with the 90% SC formulation of hexazinone from the following test locations: (i) in Puerto Rico where sugarcane was harvested 288 days following a single postemergence application at 0.45 lb ai/ A (0.5x the maximum registered seasonal rate for this area); (ii) in TX where sugarcane was harvested 234 days following one preemergence application followed by one postemergence application at 0.675 lb ai/ A/ application (0.75x the maximum seasonal rate in TX); and (iii) in HI where sugarcane was harvested 179­ 181 days following a total of four applications (one preemergence application at 1.35 or 1.47 lb ai/ A, a postemergence application at 0.45 lb ai/ A/ application, followed by two postemergence applications at 1.8 lb ai/ A/ application) for a total rate of 5.4­ 5.5 lb ai/ A/ season (1.5x the maximum seasonal rate in HI). Based on the combined LOQs (0.55 ppm) of the enforcement method, HED is now recommending that the RAC tolerance be increased from 0.20 ppm to 0.60 ppm. GLN 860.1520: Processed Food/ Feed Pineapple process residue and juice Residues of hexazinone and its regulated metabolites did not concentrate in pineapple process residue and juice except for Metabolite B in process residue. The registrant calculated a concentration factor of 3.0x for Metabolite B in pineapple process residue based on quantified residues of 0.06 ppm in pineapple process residue and 0.02 ppm in/ on pineapple RAC after treatment with hexazinone at a 1.0x rate. When this concentration factor of 3.0x is multiplied by the highest average field trial (HAFT) residue of <0.05 ppm, the maximum expected residues of metabolite B in pineapple process residue is 0.15 ppm which is less than the reassessed RAC tolerance of 0.60 ppm. Therefore, no tolerance for pineapple process residues is warranted. Sugarcane molasses and refined sugar An acceptable sugarcane processing study is available. Following processing of the RAC according to simulated commercial practices, residues of hexazinone and/ or metabolites A through E concentrated in "A molasses" (4.0x). However, residues declined in raw sugar (reduction factor of 0.2x) and processed sugar (reduction factor of 0.2x). Adjusting for the degree of exaggeration (2.0x) used in the processing study, the residue for blackstrap molasses is 3.83 ppm. The available data suggest that the established tolerance for sugarcane molasses should be decreased from 5.0 ppm to 4.0 ppm. GLN 860.1480: Meat, Milk, Poultry, and Eggs The results of ruminant metabolism study suggest significant transfer of hexazinone residues of concern to meat and milk. The registrant has submitted a dairy cattle feeding study (MRID 43703501) which was deemed acceptable. HED is recommending that; in order to reassess the established hexazinone tolerances for milk and the fat, meat, and meat byproducts of livestock and to compute a maximum theoretical dietary burden (MTDB) of hexazinone to livestock, uses on pasture and rangeland grasses be cancelled. A MTDB could not be calculated including grass and grass hay since additional residue data are required for use patterns for which significant residues are expected in/ on the RACs. HED recognizes that the estimated 100,000 acres of pasture and rangeland treated with hexazinone is relatively low. However, since grass and grass hay are considered major dietary components of ruminants (up to 60% of the diet per current OPPTS GLN), a MTDB for livestock could not be developed when grasses are included. HED has determined that a MTDB could be constructed from potential feed items for livestock and subsequently tolerances for meats and milk can be reassessed. HED has previously determined that tolerances in poultry commodities and a poultry feeding study are not required for reregistration based on results of reviewed poultry metabolism data. A brief summary of the reviewed dairy cattle feeding study (MRID 43703501) is presented below. Three groups of dairy cows (3 animals/ dose group) were dosed with hexazinone at 29, 87, and 290 ppm in the diet for 28 consecutive days; three additional cows served as control animals. These dose levels are equivalent to 6.25x, 18.75x, and 62.5x, respectively, the MTDB for beef and dairy cattle. These dose levels are equivalent to 64x, 190x, and 640x the MTDB for hogs. The maximum total hexazinone residues in milk were 0.78 ppm at the 6.25x feeding level (29 ppm in the diet) and 11.09 ppm at the 62.5x level. On day­ 14, after total residues had reached plateaus, milk was separated into skim milk and cream. Total residues in skim milk were comparable to those in whole milk; total residues in cream were approximately half those in skim milk. In tissues, the maximum total hexazinone residues at the 62.5x feeding level were 3.85 ppm in liver, 2.19 ppm in kidney, 0.32 ppm in muscle, and nondetectable ( # 0.10 ppm) in fat. The maximum total residues at the 6.25x feeding level were 0.24 ppm in liver, 0.47 ppm in kidney, and nondetectable ( # 0.15 ppm) in muscle. Because total residues were nondetectable in all fat samples from the 18.75x and 62.5x levels, fat samples were not analyzed at lower feeding levels. A tolerance of 0.5 ppm is presently established for the combined residues of hexazinone and its metabolites (calculated as hexazinone) in milk. Based on the MTDB for beef and dairy cattle without grass or grass hay as a potential feed item, it is possible to reassess the animal commodity tolerances. The HED Metabolism Assessment Review Committee has concluded that the hexazinone tolerance expression for ruminants should include hexazinone plus metabolites B, C, C­ 2, and F for milk. Residue levels of hexazinone and metabolites in whole milk from the feeding study corrected for exaggeration levels ranged from 0.110 ppm to 0.164 ppm. Based on the enforcement method, the sum of the LOQ's for hexazinone and metabolites B, C, C­ 2, and F is 0.20 ppm ; therefore it is appropriate that the tolerance for milk be reduced from 0.5 to 0.20 ppm. Tolerances of 0.1 ppm are presently established for the combined residues of hexazinone and its metabolites (calculated as hexazinone) in meat. Residue levels of hexazinone and metabolites in muscle from the feeding study corrected for exaggeration levels ranged from 0.003 ppm to 0.039 ppm. Based on the enforcement method, the sum of the LOQ's for hexazinone and metabolites B and F is 0.10 ppm therefore it is appropriate that the tolerance for meat byproducts of cattle, goats, horses, and sheep be reassessed at 0.10 ppm. Residue levels of hexazinone and metabolites in muscle from the feeding study corrected for exaggeration levels ranged from 0.0004 ppm to 0.002 ppm therefore tolerances for hog meat are not required. Tolerances of 0.1 ppm are presently established for the combined residues of hexazinone and its metabolites (calculated as hexazinone) in meat byproducts of cattle, goats, hogs, horses, and sheep. Residue levels of hexazinone and metabolites in kidney from the feeding study corrected for exaggeration levels ranged from 0.046 ppm to 0.090 ppm. Based on the enforcement method, the sum of the LOQ's for hexazinone and metabolites B and F is 0.10 ppm; therefore, it is appropriate that the tolerance for meat byproducts of cattle, goats, horses, and sheep be reassessed at 0.10 ppm. Residue levels of hexazinone and metabolites in kidney from the feeding study corrected for exaggeration levels ranged from 0.003 ppm to 0.007 ppm therefore tolerances for hog meat byproducts are not required and should be revoked. Tolerances of 0.1 ppm are presently established for the combined residues of hexazinone and its metabolites (calculated as hexazinone) in fat. Residue levels of hexazinone and metabolites in fat from the feeding study were nondetectable <0.1 ppm at the 62.5x exaggerated rate. HED has determined that tolerances for hexazinone residues in fat of cattle, goats, hogs, horses, and sheep are not required. Tolerances for fat of cattle, goats, hogs, horses, and sheep are not required and should be revoked. GLN 860.1850: Confined Accumulation in Rotational Crops The data requirements for confined rotational crops are satisfied. GLN 860.1900: Field Accumulation in Rotational Crops The data requirements for field accumulation in rotational crops are only partially satisfied. This conclusion is based on a recent review of a limited field crop rotation study wherein the 75% DF formulation of hexazinone was applied as a single postemergence broadcast application to mowed alfalfa at 1.5 lb ai/ A (1x the maximum seasonal rate for alfalfa). Approximately one year following application, the remaining alfalfa crop residue was plowed up and returned to the soil, and head lettuce, field corn, and wheat were planted. Residues were below the respective method LOQs for hexazinone and metabolites A, B, C, D, E, F, G, H, G3170, G3170­ NG, A­ 1, and C­ 1 in/ on head lettuce, wheat forage and grain, and field corn forage and grain. In wheat straw, residues of metabolite B were <0.02­ 0.021 ppm; residues of hexazinone and the remaining metabolites were below the LOQ. In field corn stover, residues of hexazinone were 0.02­ 0.081 ppm, residues of metabolite B were 0.038­ 0.053 ppm, and residues of the remaining metabolites were below the LOQ. These data indicate that extended field rotational crop studies and rotational crop tolerances will not be required for residues of hexazinone residues of concern in/ on leafy vegetables provided that labels are amended to specify a rotational crop restriction of at least 12 months. A previous review of a confined rotational crop study concluded that rotational crop tolerances were not needed for root crops provided that a 12­ month plantback interval was established; an examination of the basic registrant's labels shows that the 12­ month plantback interval for root crops has been established. Because the data from the limited field trials indicate that quantifiable residues occur in field corn stover and wheat straw, extended field rotational crop trials for corn stover, sorghum stover, and wheat straw to support a 12­ month rotational interval and a tolerance for inadvertent hexazinone residues are required. HEXAZINONE TRED: RESIDUE CHEMISTRY CONSIDERATIONS PC Code 107201; Case 0266 (DP Barcode 279899) TABLE OF CONTENTS page INTRODUCTION ......................................................... 1 REGULATORY BACKGROUND ............................................ 1 SUMMARY OF SCIENCE FINDINGS........................................ 2 GLN 860.1200: Directions for Use ...................................... 2 Product List .................................................... 2 Food/ Feed Use Pattern Table ....................................... 3 Rotational Crop Restrictions ....................................... 4 GLN 860.1300: Nature of the Residue ­ Plants ............................ 12 GLN 860.1300: Nature of the Residue ­ Livestock ......................... 16 GLN 860.1340: Residue Analytical Methods ............................. 18 Plant Commodities .............................................. 18 Animal Commodities ............................................ 19 GLN 860.1360: Multiresidue Methods .................................. 20 GLN 860.1380: Storage Stability Data .................................. 20 Plant Commodities .............................................. 20 Animal Commodities ............................................ 21 GLN 860.1500: Crop Field Trials ...................................... 21 Berries Group.................................................. 21 Blueberry ................................................ 21 Grass Forage, Fodder, and Hay Group .............................. 22 Grass (pasture and rangeland) forage........................... 22 Grass (pasture and rangeland) hay............................. 22 Non­ Grass Animal Feeds (Forage, Fodder, Straw, and Hay) Group ........ 23 Alfalfa forage and hay ...................................... 23 Alfalfa seed .............................................. 23 Miscellaneous Commodities ...................................... 24 Pineapple ................................................ 24 Sugarcane ................................................ 24 GLN 860.1520: Processed Food/ Feed ................................... 25 Pineapple process residue and juice............................ 25 Sugarcane molasses and refined sugar.......................... 25 GLN 860.1480: Meat, Milk, Poultry, and Eggs ............................ 26 Maximum theoretical dietary burden (tentative) .................. 26 Table of Contents (continued) page ix Dairy cattle feeding study ................................... 27 GLN 860.1400: Water, Fish, and Irrigated Crops .......................... 28 GLN 860.1460: Food Handling ........................................ 28 GLN 860.1850: Confined Accumulation in Rotational Crops ................. 28 GLN 860.1900: Field Accumulation in Rotational Crops .................... 28 TOLERANCE REASSESSMENT SUMMARY ................................ 35 Tolerances Listed Under 40 CFR §180.396 (a) ............................. 36 Tolerances Needed Under 40 CFR §180.396 (a) ........................... 36 Tolerances Listed Under 40 CFR §180.396 (c) ............................. 36 CODEX HARMONIZATION .............................................. 38 AGENCY MEMORANDA CITATIONS ..................................... 39 STUDY CITATIONS ..................................................... 45 N N N O O CH 3 N CH 3 CH 3 HEXAZINONE TRED ­ REPORT ON FQPA TOLERANCE REASSESSMENT PROGRESS AND INTERIM RISK MANAGEMENT DECISION: RESIDUE CHEMISTRY CONSIDERATIONS PC Code 107201; Case 0266 INTRODUCTION Hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)dione is a triazine­ dione herbicide registered for use on alfalfa, blueberries, pasture and range grasses, pineapple, and sugarcane. It is also registered for use on ornamental plants, forest trees, and noncrop areas. Hexazinone is a proprietary chemical of E. I. du Pont de Nemours and Company, Inc. (Dupont) which is the sole producer and primary registrant of this broad spectrum herbicide. The dry flowable (DF), emulsifiable concentrate (EC), and soluble concentrate (SC) are the formulation classes registered to du Pont with food/ feed uses. These formulations, sold under the trade name Velpar®, may be applied as preemergence, postemergence, layby, directed spray, or basal soil treatments using ground or aerial equipment. REGULATORY BACKGROUND Hexazinone was first registered by the Agency in November 1975 for general weed control in non­ cropland areas. Uses on Christmas trees and forest trees were added in 1977. Use patterns for the culture of sugarcane and alfalfa were conditionally registered in 1980 and 1981, respectively. The Agency has issued several regulatory documents summarizing the reregistration status of hexazinone. In February 1982, the Agency issued a Pesticide Registration Standard for hexazinone which identified data gaps according to guidelines then in place. After issuance of the 1982 Standard, new uses for hexazinone were established on blueberries, rangeland and pasture grasses, and pineapple. A second Registration 2 Standard was issued in September, 1988 (NTIS# PB89­ 126080). The 1988 Standard summarized available data supporting the registration of products containing hexazinone as the active ingredients and required additional residue chemistry data among other requirements. Hexazinone was also the subject of a Final Registration Standard and Tolerance Reassessment (FRSTR) Residue Chemistry Chapter dated 5/ 25/ 88, a Reregistration Standard Update to the Residue Chemistry Chapter dated 9/ 5/ 91, and Product and Residue Chemistry Chapters for Hexazinone Reregistration Eligibility Decision (RED) document in 10/ 8/ 93. An Updated Table A for Hexazinone Residue Chemistry Chapter RED was issued in 9/ 8/ 94 in order to reflect the conclusions of reviews completed since the RED Chapter was completed. The 10/ 8/ 93 Residue Chemistry Chapter to the Hexazinone RED required label revisions for alfalfa, blueberry, pineapple, and sugarcane in order to reflect use pattern parameters for which residue data are available. In addition, the 10/ 8/ 93 Residue Chapter required additional residue chemistry data pertaining to: animal metabolism (additional data were required to upgrade an existing ruminant study); residue analytical methods (an enforcement method is required for determination of hexazinone residues of concern in milk, meat, and meat byproducts of ruminants); storage stability (alfalfa and certain metabolites for grass); magnitude of the residue in/ on grass hay, sugarcane, and in the processed commodities of pineapple and sugarcane; and rotational crops. The basic registrant, DuPont, has submitted most of the requested residue chemistry data which have been evaluated by HED. This document is a comprehensive update to the 10/ 8/ 93 Residue Chapter, and the information contained herein incorporates HED's conclusions of recently reviewed residue chemistry studies as well as a reassessment of hexazinone tolerances, as mandated by the Food Quality Protection Act (FQPA) of 1996. Hexazinone tolerances are established under 40 CFR §180.396 (a) and (b). The tolerance expression, for plant and animal commodities, is in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). An adequate enforcement method is available for determination of regulated hexazinone residues in/ on plants. The registrant has proposed an LC/ MS method (designated as du Pont method AMR 3783­ 96) as an enforcement method for livestock commodities. The method has been subjected to a successful ILV and a radiovalidation study and will be forwarded to the Analytical Chemistry Branch for a tolerance method validation by Agency chemists. If the results of method validation by Agency chemists are successful, then Method AMR 3783­ 96 will be proposed for inclusion in PAM Volume II, and no additional data concerning this GLN topic will be required for reregistration. SUMMARY OF SCIENCE FINDINGS 3 GLN 860.1200: Directions for Use Product List A search of the Agency's Reference Files System (REFS) database, conducted on 7/ 26/ 01, identified three active hexazinone end­ use products (EPs) registered to the basic registrant (DuPont) under FIFRA Section 3 for use on food and feed crops. There are also eight products registered under Section 24 (c). These products are listed below in Table A1. Table A1. Hexazinone EPs with Uses on Feed/ Food Crops Registered to E. I. du Pont de Nemours and Company. EPA Reg No. Label Acceptance Date Formulation Class Product Name 352­ 378 1 3/ 27/ 98 90% SC DuPont Velpar ® Herbicide 352­ 392 2 5/ 22/ 01 2 lb/ gal EC DuPont Velpar ® L Herbicide 352­ 581 3 5/ 22/ 01 75% DF DuPont Velpar ® DF Herbicide 1 Including SLN TX940008. 2 Including SLN ME980002, MT940001, NC830012, and WY920001. 3 Including SLN ME980003, ND970002, and SD970001. Food/ Feed Use Pattern Table A summary of hexazinone food/ feed use patterns, based on the product labels registered to E. I. duPont de Nemours and Company, is presented in Table A2. The application rates listed in Table A2 depend on soil texture (coarse, medium, and fine) and percent organic matter (OM) in the soil; a higher rate is recommended for soil with organic matter greater than 5%. Use on gravelly or rocky soils, exposed subsoils, hardpan, sand, poorly drained soil, or alkali soils is prohibited. Unless otherwise specified, applications may be made in a minimum of 5 gal/ A by air or in a minimum of 20 gal/ A using ground equipment. A tabular summary of the residue chemistry science assessments for reregistration of hexazinone is presented in Table B. The status of reregistration requirements for each guideline topic listed in Table B is based on the use patterns registered to the basic registrant. When end­ use product DCIs are developed (e. g., at issuance of the RED), RD should require that all end­ use product labels (e. g., MAI labels, SLNs, and products subject to the generic data exemption) be amended such that they are consistent with the label of the basic registrant. The 10/ 8/ 93 Residue Chapter required label amendments for: (1) alfalfa to specify a 30­ day preharvest interval (PHI) for the feeding of forage and cutting of hay; (2) blueberries to specify PHIs of 90 and 450 days for highbush and lowbush varieties, respectively; (3) pineapple to specify a maximum application rate of 3.6 lb 4 ai/ A/ cropping cycle and a minimum PHI of 181 days; (4) pineapple forage to include a pineapple forage feeding restriction; and (5) sugarcane to specify use rates if hexazinone were to be registered in the state of FL. The registrant has complied with some of the previously requested label amendments; however, label revisions remain outstanding for alfalfa and blueberries; details of the required label amendments are presented in the respective endnote for GLN 860.1500 (Crop Field Trials) in Table B. Rotational Crop Restrictions The following rotational crop restrictions have been established for the 90% SC (EPA Reg. No. 352­ 378), 2 lb/ gal EC (EPA Reg. No. 352­ 378), and 75% DF (EPA Reg. No. 352­ 581) following use of hexazinone on alfalfa: (i) do not replant treated areas to any crop except corn, root crops or sugarcane within two years after treatment, as crop injury may result; (ii) corn may be planted 12 months after the last treatment, provided the use rate did not exceed 0.75 lb per acre, except in areas of low rainfall (20" or less); (iii) root crops such as potatoes, sugar beets, radish and carrots may be planted 12 months after the last treatment, provided the use rate did not exceed 0.5 lb/ A. Sites with use rates higher than 0.5 lb/ A should not be replanted to any crop within 2 years of application, or unacceptable crop injury may result; (iv) sugarcane may be planted any time following treatment; (v) in CA, do not replant seed alfalfa areas to any crop within two years after treatment, as crop injury may result. Based on the results of a recently reviewed field accumulation study (MRID 45084101) in rotational crops, the registrant is required to amend product labels to establish a 12­ month plantback interval for leafy vegetables. HED previously recommended the establishment of a 12­ month plantback interval for root crops based on the results of a confined rotational crop study (MRID 42824001). Except for the recommendation to establish a plantback interval of 12 months for leafy vegetables, the existing rotational crop restrictions appear adequate. HED notes that the current labels bear certain plantback intervals of two years for some crops which apparently is largely or wholly based on phytotoxicity considerations. HED further notes that the established plantback intervals are dependent on application rates which are about 0.5x or less the maximum seasonal rate for alfalfa. Because the data from the limited field trials indicate that quantifiable residues occur in field corn stover and wheat straw, extended field rotational crop trials for corn stover, sorghum stover, and wheat straw to support a 12­ month rotational interval and a tolerance for inadvertent hexazinone residues are required. 5 (continued; footnotes follow) Table A2. Food/ Feed Use Patterns Subject To Reregistration for Hexazinone (PC Code 107201). Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single Application Rate (lb ai/ A) Max. # Apps./ Season Maximum Seasonal Rate (lb ai/ A) Preharvest or Pregrazing Interval (Days) Use Directions and Limitations 1 Alfalfa (grown for hay) Broadcast application Dormant, non­ dormant, and semi­ dormant Ground or aerial 90% SC [352­ 378] 1.35 0.675 (for alfalfa less than one year old) 1 1. 35/ year 30 Use prohibited in ND and SD. Broadcast application Dormant, non­ dormant, and semi­ dormant Ground or aerial 2 lb/ gal EC [352­ 392] 75% DF [352­ 581] 1.5 For the EC formulation only: 0.75 (for alfalfa <1 year old) 1 1. 5/ year 30 (75% DF only) Alfalfa (grown for seed) Broadcast application Dormant, non­ dormant, and semi­ dormant Ground or aerial 90% SC [352­ 378] 2 lb/ gal EC [352­ 392] 75% DF [352­ 581] 0.5 1 0.5 Not specified (NS) Use limited to CA. A maximum rate of 0.5 lb ai/ A is specified for fields with sandy loam or loamy sand soils having 1­ 2% OM and on seed alfalfa that has been established for only one growing season. Table A2. (continued). Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single Application Rate (lb ai/ A) Max. # Apps./ Season Maximum Seasonal Rate (lb ai/ A) Preharvest or Pregrazing Interval (Days) Use Directions and Limitations 1 6 (continued; footnotes follow) Alfalfa (grown for forage) Broadcast application Dormant Ground 2 lb/ gal EC [MT940001] [WY920001] 75% DF [ND970002] [SD970001] 1.0 1 1.0 30 (75% DF) Use limited to MT, ND, SD, and WY for established stands of forage alfalfa. Application to soils with <1.5% OM is prohibited for the EC formulation. Blueberry 2 Broadcast application Spring of fruiting year (prior to budbreak) Ground 2 lb/ gal EC [ME980002] 75% DF [ME980003] 2.0 NS 2. 0 450 Use limited to ME for established lowbush blueberries. Do not exceed 2.0 or 1.8 lb ai/ A if soil has been respectively treated with the EC or DF formulations of hexazinone within the past 8 years. Broadcast application Dormant (prior to budbreak) Ground 2 lb/ gal EC [NC830012] 2.0 NS NS 50 Use limited to NC. Application may be made in sufficient water to provide thorough and uniform coverage, usually 20 gal/ A. Table A2. (continued). Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single Application Rate (lb ai/ A) Max. # Apps./ Season Maximum Seasonal Rate (lb ai/ A) Preharvest or Pregrazing Interval (Days) Use Directions and Limitations 1 7 (continued; footnotes follow) Pineapple Broadcast or directed spray application Ground or aerial 90% SC [352­ 378] 2 lb/ gal EC [352­ 392] 75% DF [352­ 581] 1.8 NS 3. 6/ crop cycle 181 Broadcast applications may be made between successive pineapple crops, preplant after rows have been mulched, and postplant prior to active growth. Three to ten months after planting, directed spray applications may be made to the soil between crop rows. Broadcast applications may be made in 100­ 400 gallons of water/ A using ground equipment, or in at least 10 gal/ A using aerial equipment. Directed sprays may be applied at 50­ 200 gal/ A using ground equipment. Directed spot treatments are also permitted at 0.9­ 1.8 lb ai/ 100 gal prior to floral induction. Table A2. (continued). Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single Application Rate (lb ai/ A) Max. # Apps./ Season Maximum Seasonal Rate (lb ai/ A) Preharvest or Pregrazing Interval (Days) Use Directions and Limitations 1 8 (continued; footnotes follow) Pasture Broadcast application Ground 90% SC [352­ 378] 2 lb/ gal EC [352­ 392] 75% DF [352­ 581] 1.125 1 1. 125 (implied) 60 Use limited to Bermuda grass/ Bahia grass pastures. Applications may be made in a minimum of 25 gal/ A using ground equipment. Basal soil application (undiluted) Ground 2 lb/ gal EC [352­ 392] 2­ 4 mL of product for each inch of stem diameter NS 0.67/ year NS Use limited to brush control in pastures and rangelands. No restrictions on grazing by domestic animals nor on cutting surrounding vegetation for forage and hay when product is applied as a basal soil treatment. Basal soil application Ground 75% DF [352­ 581] 2 lb/ 1 gal [2­ 4 mL of suspension for each inch of stem diameter] NS 0.67/ year NS Table A2. (continued). Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single Application Rate (lb ai/ A) Max. # Apps./ Season Maximum Seasonal Rate (lb ai/ A) Preharvest or Pregrazing Interval (Days) Use Directions and Limitations 1 9 (continued; footnotes follow) Rangeland Basal soil application (undiluted) Ground 2 lb/ gal EC [352­ 392] 2­ 4 mL of product for each inch of stem diameter NS 0.67/ year NS Use limited to brush control in pastures and rangelands. No restrictions on grazing by domestic animals nor on cutting surrounding vegetation for forage and hay when product is applied as a basal soil treatment. Basal soil application Ground 75% DF [352­ 581] 2 lb/ 1 gal [2­ 4 mL of suspension for each inch of stem diameter] NS 0.67/ year NS Sugarcane Broadcast application Preemergence and postemergence Ground or aerial 90% SC [352­ 378] 2 lb/ gal EC [352­ 392] 75% DF [352­ 581] 3.6 1 3.6/ crop cycle (18­ 24 months) 180 Use limited to HI. Application may be made with a nonionic surfactant at 0.25% v/ v. Table A2. (continued). Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single Application Rate (lb ai/ A) Max. # Apps./ Season Maximum Seasonal Rate (lb ai/ A) Preharvest or Pregrazing Interval (Days) Use Directions and Limitations 1 10 (continued; footnotes follow) Sugarcane (continued) Broadcast application Preemergence (in fall) and postemergence (in spring before active cane tillering begins) Ground or aerial 90% SC [352­ 378] 2 lb/ gal EC [352­ 392] 75% DF [352­ 581] 0.9 NS 0. 45/ year for the 90% SC 1.5/ year for the 2 lb/ gal EC and 75% DF 234 Use limited to LA. Broadcast application Preemergence and postemergence Ground or aerial 90% SC [352­ 378] 2 lb/ gal EC [352­ 392] 75% DF [352­ 581] 0.45­ 0.5 NS 0. 9/ crop cycle 288 Use limited to PR. Preemergence, early postemergence, and/ or directed layby Ground or aerial 90% SC [352­ 378] 2 lb/ gal EC [352­ 392] 75% DF [352­ 581] 0.9 NS 1. 8/ crop cycle 234 Use limited to TX. Two treatments are allowed (one early treatment plus one directed treatment at layby), provided 60 days have elapsed and at least 3" of rainfall have occurred. Table A2. (continued). Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single Application Rate (lb ai/ A) Max. # Apps./ Season Maximum Seasonal Rate (lb ai/ A) Preharvest or Pregrazing Interval (Days) Use Directions and Limitations 1 11 Sugarcane (continued) Preemergence, early postemergence, or directed layby Ground or aerial 90% SC [TX940008] 0.45 1 0. 45 NS Tank mix use with diuron (Karmex DF Herbicide) limited to TX. Application may be made in a minimum of 5 gal/ A by air or in a minimum of 25 gal/ A using ground equipment. The feeding of sugarcane forage to livestock is prohibited. Use on gravelly or rocky soils, thinly­ covered subsoils, coarse­ textured soils with <2% OM, or on any soil with <1% OM is prohibited. The planting of any crop other than sugarcane within 18 months of the last application is prohibited. 1 The restricted entry interval (REI) for the 90% SC (EPA Reg. No. 352­ 378), 2 lb/ gal EC (EPA Reg. No. 352­ 378), and 75% DF (EPA Reg. No. 352­ 581) formulations is 24 hours. 2 A REFS search, conducted 7/ 26/ 01, listed blueberries as a use site for the Federal labels of the 2 lb/ gal EC (EPA Reg. No. 352­ 392) and the 90% SC (EPA Reg. No. 352­ 378). However, upon label examination of these products, it was determined that there are no Section 3 registrations of hexazinone on blueberries; only Section 24( c) registrations exist. 12 GLN 860.1300: Nature of the Residue ­ Plants The qualitative nature of the residue in plants is adequately understood. The 10/ 8/ 93 Residue Chemistry Chapter reported that acceptable metabolism studies had been conducted on alfalfa, pineapple, and sugarcane. These studies indicate that root uptake is the principal mechanism for the absorption of hexazinone by plants from soils. Hexazinone is translocated through the xylem to the foliage where it blocks the photosynthetic process. Hexazinone is metabolized by hydroxylation to metabolite A which is then metabolized to metabolite C by demethylation and to metabolite E after oxidation. The available plant metabolism data for hexazinone were presented to the HED Metabolism Assessment Review Committee (MARC) in a meeting held January 29, 2002 for a determination of hexazinone residues to be regulated (DP Barcode D279897, 02/ 05/ 2002, S. Kinard). The Committee concluded that the hexazinone tolerance expression for plants and rotational crops should include hexazinone and metabolites A, B, C, D, and E. Toxicity data for the metabolites are not available but based on the structural similarity of the metabolites it is assumed they will exhibit similar toxicity to the parent hexazinone. The current tolerance expression for hexazinone in 40 CFR §180.396 is for "combined residues of the herbicide hexazinone (3­ cyclohexyl­ 6­ (dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione) and its metabolites, calculated as hexazinone." Hexazinone metabolites which are currently regulated (because they are measured by the enforcement analytical method) include the parent and metabolites A, B, C, D, and E. The hexazinone enforcement method involves extraction and several cleanup steps, followed by analysis by GLC with nitrogen phosphorus detection. Hexazinone and each of the five metabolites are quantitated as individual peaks. The chemical names and structures of the hexazinone residues of concern in plants and livestock are presented in Figure 1. Brief summaries of the available plant metabolism data, initially reported in the Hexazinone Registration Standard dated 2/ 82 and then in the Hexazinone FRSTR Residue Chemistry Chapter dated 5/ 25/ 88, are presented below. Alfalfa (MRID 00104846) In a study conducted at the University of Kentucky Research Farm, a 12 ft 2 area of alfalfa was isolated and fenced for this study. In mid­ March, the test plot was sprayed using a hand­ held sprayer, with 125 mg of [ 14 C] hexazinone dissolved in water; the application rate was equivalent to 1.0 lb ai/ 100 gal/ A. Alfalfa samples were collected at two, three, and six months after treatment. Total radioactive residues (TRR), calculated as hexazinone, declined at each sampling interval, and respectively were 0.6, 0.5, and 0.1 ppm. The extractable percentages of TRR were 95, 84, and 80% for the two­, three and six­ month harvests, respectively. Analysis of the two­ month alfalfa cutting identified hexazinone (2.7% TRR), free metabolite A (7.1% TRR), free metabolite B 13 N N N O O CH 3 N CH 3 CH 3 (0.7% TRR), and conjugated metabolites A, B, and C (4.5% TRR). The remaining radioactive residues were found in water­ soluble, polar materials which were subsequently found to be comprised of amino acids, sugars, polybasic acids, and smaller amounts of natural products. Pineapple (MRID 00126127) A pineapple metabolism study was submitted by the basic registrant in conjunction with PP# 3F2846. The Hexazinone FRSTR Residue Chemistry Chapter dated 5/ 25/ 88 reported the salient features of this study with respect to residue characterization/ identification only. The fruit (pulp and rind) were extracted with methanol, and 94­ 99% of TRR was extractable. The following components were identified in the pulp: hexazinone (0.8­ 1.8% TRR), metabolite A (23­ 28% TRR), metabolite C (13­ 15% TRR), metabolite D (16­ 21% TRR), and metabolite F (1­ 2% TRR). Sugarcane (MRID 00078047) Greenhouse­ grown dwarf sugarcane were grown in large tubs (2 canes/ tub) and when the canes reached 5.5 to 6.0 feet in height, they were treated with a soil drench application of [ 14 C] hexazinone at rates of 0.54 and 1.0 kg/ ha (0.48 and 0.89 lb ai/ A); a third tub was maintained as a control. About six months after treatment, sugarcane samples were collected. The TRRs, calculated as hexazinone, were 0.07­ 0.08 and 0.05 ppm in sugarcane treated at 0.89 and 0.48 lb ai/ A, respectively. Following organic solvent extraction, 76% of TRR was recovered. The following components were identified by GC/ MS in sugarcane: metabolite E (30% TRR), metabolite C (23% TRR), metabolite A (14% TRR), metabolite B (1% TRR), metabolite D (3% TRR), and hexazinone (< 1% TRR). Figure 1. Chemical Structures of Hexazinone and its Regulated Metabolites (Metabolites A through F). Common Name/ Code Chemical name Structure Hexazinone 3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione Figure A (continued). Common Name/ Code Chemical name Structure 14 (continued next page) N N N O O CH 3 N CH 3 CH 3 HO N N N O O CH 3 N H CH 3 N N N O O CH 3 N H CH 3 HO N N NH O O CH 3 O Metabolite A 3­( 4­ hydroxycyclohexyl)­ 6­ (dimethylamino)­ 1­ methyl­ 1,3,5­ triazine 2,4­( 1H, 3H)­ dione Metabolite A­ 1 is hydroxylated at the 2­ position of the cyclohexyl ring; Metabolite A­ 2 is hydroxylated at the 3­ position of the cyclohexyl ring. Metabolite B 3­ cyclohexyl­ 6­( methylamino)­ 1­ methyl 1,3,5­ triazine­ 2,4­( 1H, 3H)­ dione Metabolite C 3­( 4­ hydroxycyclohexyl)­ 6­ methylamino 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H dione Metabolite C­ 1 is hydroxylated at the 2­ position of the cyclohexyl ring; Metabolite C­ 2 is hydroxylated at the 3­ position of the cyclohexyl ring. Metabolite D 3­ cyclohexyl­ 1­ methyl­ 1,3,5­ 2,4,6 1H, 3H, 5H)­ trione Figure A (continued). Common Name/ Code Chemical name Structure 15 N N NH O O CH 3 O HO N N N O O CH 3 NH 2 Metabolite E 3­( 4­ hydroxycyclohexyl)­ 1­ methyl 1,3,5­ triazine­ 2,4,6­( 1H, 3H, 5H)­ trione Metabolite F 3­ cyclohexyl­ 6­ amino­ 1­ methyl 1,3,5­ triazine­ 2,4­( 1H, 3H)­ dione 16 GLN 860.1300: Nature of the Residue ­ Livestock The qualitative nature of the residue in livestock is adequately understood based on acceptable ruminant and poultry metabolism studies. The requirement to confirm the identities of metabolites in goat tissues and milk by a second method, specified in the 10/ 8/ 93 Residue Chemistry Chapter, has been fulfilled. The requirement to radiovalidate the proposed enforcement method using samples collected from the ruminant metabolism study has also been fulfilled. No additional livestock metabolism data are required for reregistration. The available livestock metabolism data were presented to the HED MARC in a meeting held January 29, 2002 for a determination of hexazinone residues to be regulated (D279897, 02/ 05/ 2002, S. Kinard). The Committee concluded that the hexazinone tolerance expression for ruminants should include hexazinone plus metabolites B, C, C­ 2, and F for milk. The Committee concluded that the hexazinone tolerance expression for ruminant tissue should include hexazinone plus metabolites B and F. The Committee concluded that residues of hexazinone and metabolites B, C, C1 C­ 2, and F should be taken into account when risk assessments are done. The above determination was partially based on the assumption that the current enforcement method listed in the PAM, Volume II for plant commodities could be used for livestock commodities provided additional method validation data are submitted; there is presently no enforcement method listed in PAM Volume II for livestock commodities. HED has determined that tolerances for hexazinone residues in eggs and poultry tissues are not required (Category 3, 40 CFR §180.6a) based on the results of the reviewed poultry metabolism study. In the poultry study, the liver contained the highest TRR, 0.19 ppm. Considering that the feeding level was about 38x the maximum theoretical dietary burden, the maximum residue in poultry tissue would be 0.005 ppm, an order of magnitude below the limit of detection for hexazinone metabolites. Brief summaries of available goat and hen metabolism studies are presented below. Goat (MRIDs 42187901, 43074201, and 43488901) A lactating goat was dosed orally with [ 14 C] hexazinone radiolabeled in the triazine ring at a dose rate of 136.4 mg/ day, equivalent to 2.2 mg/ kg body weight for five consecutive days. This dose represents a level of approximately 90 ppm in the feed, which is 19.4x the maximum theoretical dietary burden for ruminants. TRRs, expressed as hexazinone equivalents, were 6.74 ppm in milk, 3.03 ppm in liver, 2.54 ppm in kidney, 0.27 ppm in muscle, and 0.03 ppm in fat. Residues were adequately extracted with organic solvents. A list of characterized/ identified residues in goat matrices is presented below. 17 Table 1. Characterization/ identification of residues from goat milk and tissues dosed with 90 ppm of [ 14 C] hexazinone for 5 consecutive days. (Reproduced from DP Barcode D198348, 5/ 25/ 94, S. Hummel). Metabolite Liver TRR = 3.03 ppm Kidney TRR = 2.54 ppm Muscle TRR = 0.27 ppm Milk TRR = 6.74 ppm %TRR PPM %TRR PPM %TRR PPM %TRR PPM Hexazinone 0.1 0. 04 ­­ <0.01 ­­ <0.01 1. 2 0.08 B 56.7 1. 70 28.3 0. 72 40.7 0. 11 48.1 3. 24 A­ 2 ­­ <0.01 0.4 0. 01 ­­ <0.01 0.4 0. 03 A, A­ 1 0. 1 0.04 2.0 0. 05 ­­ <0.01 3.9 0. 26 C ­­ <0.01 3.1 0. 08 ­­ <0.01 3.4 0. 23 C­ 1, C­ 2 11.9 0. 36 18.5 0. 47 7. 4 0.02 16.6 1. 12 E ­­ <0.01 1.2 0. 03 ­­ <0.01 ­­ <0.01 F 11.6 0. 35 37.4 0. 95 25.9 0. 07 17.1 1. 15 Others* 5. 8 0.19 5.1 0. 13 14.8 0. 04 4. 0 0.27 Total Identified 86.2 2. 68 96.0 2. 44 88.9 0. 24 94.7 6. 38 Unknown ­­ <0.01 ­­ <0.01 ­­ <0.01 5.2 0. 35 Unextracted 11.9 0. 36 4. 7 0.12 11.1 0.03 0.1 0. 01 Total 98.1 3. 03 101 2.56 100 0.27 100 6.74 *Others identified at <0.01 ppm each Poultry (MRIDs 41524801, 42690601, 43074201) Five ISA Brown laying hens were dosed orally at 6.9 mg/ day with carbonyl­ labeled [ 14 C] hexazinone for six consecutive days. The daily dose rate was equivalent to 57 ppm in the feed, which is 38x the maximum theoretical dietary burden. Mean TRR levels, expressed as hexazinone equivalents, were 0.189 ppm in liver, 0.02 ppm in fat, 0.078 and 0.106 ppm in thigh and breast muscle, respectively, and 0.059 ppm in skin. TRR level in eggs (day 6) was 0.12 ppm. Residues were adequately extracted with organic solvents. No single metabolite in edible poultry tissue was greater than 0.04 ppm, and unidentified metabolites represented less than 0.05 ppm in all edible tissues. A list of characterized and identified residues in poultry muscle and eggs is presented below. 18 Table 2. Characterization/ identification of residues from hen eggs and muscle tissues dosed with 57 ppm of [ 14 C] hexazinone for six consecutive days. (DP Barcode D198348, 5/ 25/ 94, S. Hummel). Metabolite Muscle TRR = 0.12 ppm Eggs TRR = 0.13 ppm %TRR PPM %TRR PPM Hexazinone – <0.01 ­­ <0.01 A, A­ 1, A­ 2 16.7 0. 02 23.1 0. 03 C 16.7 0.02 23.1 0. 03 A­ OH, C­ OH 16.7 0. 02 7. 7 0.01 E ­­ <0.01 ­­ <0.01 Others* 33.3 0. 04 15.4 0. 02 Total Identified 83.5 0. 10 69.3 0. 09 Unknown 16.7 0. 02 23.1 0. 03 Unextracted 8.4 0.01 7.7 0. 01 Total 109 0.13 100 0.13 *Others identified at <0.01 ppm. GLN 860.1340: Residue Analytical Methods Plant Commodities The 10/ 8/ 93 Residue Chapter concluded that adequate methods are available for purposes of data collection and enforcement of tolerances for residues of hexazinone and metabolites A, B, C, D, and E in/ on plant commodities. No additional data on residue analytical methods for plant commodities are required for reregistration. For tolerance enforcement, the PAM, Volume II lists Method I as available for the determination of hexazinone residues of concern in/ on plant commodities. Using this method, residues of hexazinone and metabolites A, B, D, and E are extracted with chloroform and cleaned up by liquid­ liquid partitioning. Residues of Metabolite C, a highly polar metabolite, are extracted from samples with methanol in a separate isolation scheme. Both schemes use derivatization of residues with trifluoroacetic anhydride and determination of the derivatives by nitrogen­ selective GLC. Some samples (e. g., alfalfa and grasses) require additional cleanup on a gel permeation column, before derivatization, or on a deactivated Florisil column, either before or after derivatization. The combined limit of quantitation (LOQ) for hexazinone residues by Method I in PAM, Volume II, is 0.55 ppm. For data collection, the registrant utilized Method Nos. 92013­ V2 and 92013­ V3 during analyses of samples collected from field trials on alfalfa. These methods are similar to the PAM, Volume II method but were modified to include additional clean up steps. They have been deemed adequate for data collection based on acceptable method 19 validation and concurrent recovery data. Livestock Commodities The 10/ 8/ 93 Residue Chapter required data collection and tolerance enforcement methodology for determination of hexazinone residues of concern in livestock commodities. In an attempt to fulfill this requirement, the registrant requested a meeting with HED to report progress of their work in developing a new method prior to submitting it for an independent laboratory validation (ILV). In a meeting held 8/ 31/ 94, the registrant advised that the current method in PAM, Volume II for plant commodities did not appear appropriate for livestock commodities because of complications with matrix effects and the inability to detect metabolite F, among other problems. The registrant instead proposed an LC/ MS method (designated as du Pont AMR 3783­ 96) as an enforcement method. The proposed method would determine residues of parent hexazinone, metabolite B, metabolite C and its isomer (C­ 2), and metabolite F in milk. In livestock tissues, Method AMR 3783­ 96 would determine residues of parent hexazinone, metabolite B, and metabolite F. Briefly, residues in milk and animal tissues are extracted three times with acetone: aqueous 0.1 M potassium phosphate/ 0.5 M sodium chloride solution (1: 1, v: v). The extract is concentrated to remove the acetone, and purified using solid phase extraction (SPE) cartridges. A combination of reverse­ (C8) and normal­ (silica) phase SPE sorbents is used to remove most substances that may interfere with the instrument analysis. Residues of hexazinone and metabolites B and F are quantitated in tissue samples and residues of hexazinone and metabolites B, C, C­ 2, and F are quantitated in milk using LC/ MS with an electrospray interface and selected ion monitoring (SIM). The reported LOQs were 0.02 ppm for hexazinone and metabolite B and 0.05 ppm for metabolites C, C­ 2, and F. The proposal to develop DuPont Method AMR 3783­ 96 as an enforcement method was based on a cattle feeding study which had been reviewed by HED and deemed acceptable. Data from the cattle feeding study indicate that in milk, the metabolites determined by the proposed method represent nearly 95% of total hexazinone residues. In tissues, parent and metabolite B represent at least 85% of total residues in liver and 63% of total residues in kidney; metabolite B is the only residue detected in muscle, even at the 10x feeding level; and all residues are nondetectable in fat at the 10x level. DuPont Method AMR 3783­ 96 has been subjected to a successful ILV and a radiovalidation study. The ILV data did support the reliability of and reproducibility of the method for the determination of residues of hexazinone, metabolite B, metabolite C and its isomer (C­ 2), and metabolite F in milk; the ILV data also showed that Method AMR 3783­ 96 can adequately recover residues of hexazinone, metabolite B, and metabolite F in livestock tissues. Method AMR 3783­ 96 will be forwarded to the Analytical Chemistry Branch (ACL; Beltsville, MD) for a tolerance method validation 20 by Agency chemists. If the results of method validation by Agency chemists are successful, then Method AMR 3783­ 96 will be proposed for inclusion in PAM, Volume II, and no additional data concerning this GLN topic will be required for reregistration. GLN 860.1360: Multiresidue Methods The reregistration requirements for multiresidue methods data are fulfilled. The 10/ 99 FDA PESTDATA database (PAM, Volume I, Appendix I) indicates that hexazinone is only partially recovered (50­ 80%) using Multiresidue Method Sections 302 (Luke Method; Protocol D) and is not recovered using Sections 303 (Mills, Onley, Gaither; Protocol E ­ nonfatty foods) and 304 (Mills; Protocol E ­ fatty foods). There is a small recovery (< 50%) of metabolite A (IN­ T3937) and metabolite C INT3935 using Multiresidue Method Section 302 (Luke Method; Protocol D). There is also a small recovery (< 50%) of metabolite B (IN­ T3928) and metabolite E (IN­ T3936) using Multiresidue Method Section 302 (Luke Method; Protocol D) but the metabolites are not recovered using Sections 303 (Mills, Onley, Gaither; Protocol E ­ nonfatty foods) and 304 (Mills; Protocol E ­ fatty foods). Metabolite D (IN­ B2838) is partially recovered (50­ 80%) using Multiresidue Method Sections 302 (Luke Method; Protocol D) and is not recovered using Sections 303 (Mills, Onley, Gaither; Protocol E ­ nonfatty foods) and 304 (Mills; Protocol E ­ fatty foods). GLN 860.1380: Storage Stability Data Plant Commodities The Updated Table A for Residue Chemistry RED Chapter dated 9/ 8/ 94 required additional storage stability data for: (1) hexazinone and metabolites in alfalfa, and (2) metabolite C in grass. The registrant has submitted the requested data which were deemed adequate to support the storage conditions and intervals of samples used for tolerance reassessment. No additional storage stability data for plant and processed commodities are required for reregistration. A summary of the available storage stability data is presented below. Residues of hexazinone and its metabolites A, B, C, D, and E are relatively stable under frozen (­ 20 to ­10 °C) storage conditions in/ on blueberries for up to 13 months, in/ on pineapple for up to 8 months, in pineapple juice for up to 6 months, in/ on sugarcane for up to 12 months, and in sugarcane processed commodities for up to 6 months. Hexazinone and metabolites A, B, D, and E are also stable in grass samples during frozen (­ 20 °C) storage for up to 24 months, and metabolite C is stable in grass samples during frozen (­ 20 ± 10 °C) storage for up to 36 months. Livestock Commodities 21 Adequate storage stability data are available to support the existing ruminant feeding study. Samples of milk, liver, kidney, muscle, and fat samples were stored under freezer storage conditions for maximums of 8, 10, 14, 2, and 2 months, respectively, prior to residue analysis. In a fortification study, hexazinone residues of concern were found to be stable during maximum storage times for samples collected and analyzed from the feeding study. GLN 860.1500: Crop Field Trials Pending label revisions for certain crops, the reregistration requirements for data depicting magnitude of the residue in/ on the following raw agricultural commodities (RACs) are satisfied: alfalfa forage, alfalfa hay, alfalfa seed, blueberries, pineapple, and sugarcane. An adequate number of field trials have been conducted for these RACs, and the trials were conducted using registered hexazinone formulation( s) at the maximum registered rate. Brief summaries of available hexazinone residue data, deemed useful for tolerance reassessment, are presented below. It is noted that product labels of registrants other than du Pont were not examined in the preparation of this document. Berries Group Blueberry The 10/ 8/ 93 Residue Chapter concluded that no additional data are required for blueberries provided all pertinent product labels are amended to specify PHIs of 90 and 450 days for application to highbush and lowbush blueberries, respectively. Data (MRIDs 41964101 and 41964102) reviewed in the Hexazinone Update indicate that the combined residues of hexazinone and its regulated metabolites, as measured by the data­ collection method, were <0.3 ppm (nondetectable; <0.05 ppm for each compound) in/ on: (1) 12 samples of lowbush blueberries harvested 433­ 446 days following a single application of the 2 lb/ gal EC or 90% SC formulation at 3 or 6 lb ai/ A (1.5 or 3.0x the maximum registered rate) using ground or aerial equipment; and (2) 12 samples of highbush blueberries harvested 68­ 97 days following a single application of the 2 lb/ gal EC or 90% SC formulation at 2 or 4 lb ai/ A (0.8 or 1.3x the maximum registered rate). Based on the combined LOQs (0.55 ppm) of the enforcement method, HED is now recommending that the RAC tolerance be reassessed from 0.2 ppm to 0.60 ppm. Although uses of hexazinone on blueberries (see Table A2) are limited to Section 24( c) registration, label revisions remain a requirement. The product labels for ME980002 22 and ME980003, which are limited for use on lowbush blueberries, should be amended to specify a PHI of 450 days. The product label for NC830012 should also be amended to specify PHIs of 90 and 450 days for application to highbush and lowbush blueberries, respectively. Grass Forage, Fodder, and Hay Group Grass (pasture and rangeland) forage An examination of registered uses of hexazinone on pasture and rangeland grasses (see Table A2) reveal that there two distinct use patterns, a basal soil application and a broadcast application. It is noted that the 10­ ppm tolerance for grass forage (listed as "grasses, pasture" and "grasses, range" under 40 CFR §180.396) was established based on residue data reflecting basal soil application only. Data reflecting basal­ soil application were submitted under PP# 1F2513 and summarized in the Hexazinone FRSTR Residue Chemistry Chapter dated 5/ 25/ 88. Samples of range and pasture grasses were harvested at various intervals following application of the 2 lb/ gal EC formulation at 3 or 6 mL per one inch of diameter at breast height (0.75 or 1.5x the maximum registered rate for directed spray basal soil application). Samples were taken 2", 12", and 24" in radius from the treatment point on days 0­ 56 after application. The FRSTR Residue Chemistry Chapter did not report specific residues; however, it was concluded that the combined residues of hexazinone and its metabolites (calculated as hexazinone) did not exceed the established tolerances of 10 ppm in/ on treated samples of pasture and range grass forage. In the absence of residue data reflecting broadcast application, HED is requiring the following additional data for grass forage before the RAC tolerance can be reassessed: "Data depicting magnitude of the residues of hexazinone and metabolites A, B, C, D, and E in/ on grass forage harvested 0 day following a single broadcast application of representative formulations at 1.125 lb ai/ A. It is the Agency policy to require 0­ day crop field residue data for grass forage unless it is not feasible (e. g., preplant/ preemergence pesticide uses). The formulations to be tested may be applied in side­ by­ side plots. The location and number of trial should be in compliance with the current OPPTS GLN for adequate geographic representation of data. Grass (pasture and rangeland) hay The reregistration requirements for residue data on grass hay have not been fulfilled. The registrant has submitted a petition (PP# 1F3967) for the establishment of a tolerance for residues of hexazinone and its metabolites in/ on grass hay. The petition is currently in reject status because additional grass hay data, from field trials with adequate 23 geographical representation, remain outstanding. Since 1991 HED has reviewed two proposals to amend the original petition requesting that the Agency establish tolerances for grass hay based on theoretical grass drying factors. HED recommended against the establishment of grass hay tolerances each time. In addition, HED reviewed two registrant responses to the petition amendment reviews and concluded in each case that the recommendation to require actual field trial data for grass hay is appropriate (D162863, D181318, D172408, D201738). Non­ Grass Animal Feeds (Forage, Fodder, Straw, and Hay) Group Alfalfa forage and hay The Updated Table A for Residue Chemistry RED Chapter dated 9/ 8/ 94 concluded that adequate residue data are available for alfalfa forage and hay. However, label amendments were required on all product labels for alfalfa, including supplemental labels, to establish a 30­ day PHI for the feeding of forage and the cutting of hay. The available residue data (MRIDs 43074401 and 43074402) indicate that the combined residues of hexazinone and its metabolites A, B, C, D, and E did not exceed the established tolerances of 2.0 ppm in/ on alfalfa forage and 8.0 ppm in/ on alfalfa hay harvested 29­ 31 days following a single broadcast dormant or non­ dormant application of the 2 lb/ gal EC or 90% SC formulation at 1.5 lb ai/ A (~ 1x). The maximum combined residues in/ on treated samples were <1.87 ppm and <3.33 ppm for alfalfa forage and hay, respectively. Based on these data, the established tolerance for alfalfa forage is reassessed at its existing level of 2.0 ppm; however, the tolerance for alfalfa hay should be lowered from 8.0 ppm to 4.0 ppm. Table A2 shows that product labels for the 90% SC (EPA Reg. No. 352­ 378) and 75% DF (EPA Reg. No. 352­ 58) formulations have been revised in compliance with the requested label amendment. However, the product label for the 2 lb/ gal EC (EPA Reg. No. 352­ 392) formulation does not specify any PHI; this label must be amended to establish a 30­ day PHI (or pregrazing interval) for the feeding of forage and the cutting of hay. Alfalfa seed The Updated Table A for the Residue Chemistry RED Chapter dated 9/ 8/ 94 concluded that adequate residue data have been submitted for alfalfa seed; the Chapter, however, required the registrant to propose a tolerance for this commodity in order to support registered uses of hexazinone on alfalfa grown for seed. The available residue data (MRIDs 43074401 and 43074402) indicate that the combined residues of hexazinone and its regulated metabolites ranged from <1.30 ppm 24 (sum of the LOQs) to <1.46 ppm in/ on alfalfa seed following a single broadcast dormant application of the 2 lb/ gal EC or 90% SC formulation at 0.75 lb ai/ A (1.5x the maximum registered rate on alfalfa grown for seed); no data were submitted reflecting 1.0x. HED is requesting the registrant to propose a tolerance for hexazinone residues of concern in/ on alfalfa seed; the available data suggest that a tolerance level of 2.0 ppm is appropriate. Residue data and a tolerance proposal for alfalfa seed screenings, previously requested in the Updated Table A for the Residue Chemistry RED Chapter dated 9/ 8/ 94, are no longer required because this item has been deleted from Table 1 of OPPTS 860.1000 as a significant livestock feed item. Miscellaneous Commodities Pineapple The 10/ 8/ 93 Residue Chapter concluded that no additional residue data are required for pineapple provided all pertinent product labels are amended to specify a maximum application rate of 3.6 lb ai/ A/ cropping cycle and a minimum PHI of 181 days. The basic registrant has complied with this requirement as shown in Table A2. The available data (MRID 42535601) indicate that the combined residues of hexazinone and its regulated metabolites, as measured by the data­ collection method, were <0.35 ppm (or <0.05 ppm for each compound) in/ on pineapple fruits harvested at a minimum PHI of 181 days following five ground applications of a representative hexazinone formulation at 0.45­ 0.9 lb ai/ A for a total rate of 3.6 lb ai/ A. Based on the combined LOQs (0.55 ppm) of the enforcement method, HED is now recommending that the RAC tolerance be reassessed from 0.5 ppm to 0.60 ppm. HED's request to impose a feeding restriction on pineapple forage, previously specified in the Updated Table A for the Residue Chemistry RED Chapter dated 9/ 8/ 94, is no longer required because this item has been deleted from Table 1 of OPPTS 860.1000 as a significant livestock feed item. Sugarcane The Updated Table A for Residue Chemistry RED Chapter dated 9/ 8/ 94 concluded that no additional residue data are required for sugarcane provided all pertinent product labels are amended to prohibit use of hexazinone on sugarcane grown in FL. The basic registrant has complied with the requested label amendment (see Table A2). Presently, registered uses of hexazinone on sugarcane are limited to those grown in the states of HI, LA, TX, and in Puerto Rico. 25 The available data (MRID 42322701) indicate that the combined residues of hexazinone and its regulated metabolites, as measured by the data­ collection method, were <0.35 (or <0.05 ppm for each compound) in/ on samples of sugarcane treated with the 90% SC formulation of hexazinone from the following test locations: (i) in Puerto Rico where sugarcane was harvested 288 days following a single postemergence application at 0.45 lb ai/ A (0.5x the maximum registered seasonal rate for this area); (ii) in TX where sugarcane was harvested 234 days following one preemergence application followed by one postemergence application at 0.675 lb ai/ A/ application (0.75x the maximum seasonal rate in TX); and (iii) in HI where sugarcane was harvested 179­ 181 days following a total of four applications (one preemergence application at 1.35 or 1.47 lb ai/ A, a postemergence application at 0.45 lb ai/ A/ application, followed by two postemergence applications at 1.8 lb ai/ A/ application) for a total rate of 5.4­ 5.5 lb ai/ A/ season (1.5x the maximum seasonal rate in HI). Based on the combined LOQs (0.55 ppm) of the enforcement method, HED is now recommending that the RAC tolerance be reassessed from 0.20 ppm to 0.60 ppm. GLN 860.1520: Processed Food/ Feed Pineapple process residue and juice The registrant has submitted a pineapple processing study (MRIDs 42492101 and 43401901) which was first deemed inadequate but later upgraded as acceptable. Residues of hexazinone and its regulated metabolites did not concentrate in pineapple process residue and juice except for Metabolite B in process residue. The registrant calculated a concentration factor of 3.0x for Metabolite B in pineapple process residue based on quantified residues of 0.06 ppm in pineapple process residue and 0.02 ppm in/ on pineapple RAC after treatment with hexazinone at a 1.0x rate. When this concentration factor of 3.0 x is multiplied by the highest average field trial (HAFT) residue of <0.05 ppm, the maximum expected residues of metabolite B in pineapple process residue is 0.15 ppm which is less than the reassessed RAC tolerance of 0.60 ppm. Therefore, no tolerance for pineapple process residues is warranted. Sugarcane molasses and refined sugar An acceptable sugarcane processing study (MRIDs 42276001 and 42417901) is available. The reviewed study indicate that residues of the parent hexazinone were 0.23 ppm in/ on the RAC (sugarcane) following application of the 90% SC formulation at a total rate of 7.2 lb ai/ A (2.0x the maximum seasonal application rate for sugarcane grown in HI). Residues of metabolites A, B, C, D, and E were each nondetectable (< 0.05 ppm) in/ on treated RAC samples. Following processing of the RAC according to simulated commercial practices, residues of hexazinone and/ or metabolites A through E concentrated in bagasse (1.6x) and "A molasses" (4.0x). However, residues 26 declined in raw sugar (reduction factor of 0.2x) and processed sugar (reduction factor of 0.2x). The presently regulated processed commodities of sugarcane are molasses and refined sugar; bagasse has been removed from Table 1 of OPPTS 860.1000. Samples of treated "A molasses" from the above study were re­ analyzed to confirm results. The average total residues of hexazinone and its regulated metabolites, from duplicate analysis, were 1.915 ppm for "A molasses". Based on this re­ analysis, residues of hexazinone and metabolites concentrated about 8.0x in "A molasses". The registrant reported that a 4.0x concentration factor should be considered when "A molasses" is further processed to final (blackstrap) molasses, the form of molasses typically fed to livestock. To reassess the adequacy of the established 0.5 ppm tolerance for sugarcane molasses, HED will consider the HAFT residue reported from the field study as well as the concentration factors observed from the processing study. Data from the sugarcane field trials indicate that residues of hexazinone and its regulated metabolites, as measured by the data­ collection method, were <0.35 ppm (or <0.05 ppm for each compound) in/ on samples of sugarcane treated according to the maximum registered use pattern. According to OPPTS GDLN 860.1520, if no quantifiable residues are found in the RAC from the maximum registered rate, but the exaggerated rate does produce quantifiable residues, the latter samples should be adjusted for the degree of exaggeration. These adjusted residues should then be compared to the LOQ for the RAC. If the adjusted residues are greater than or equal to twice the LOQ, then a tolerance is needed. The maximum average combined residue of hexazinone and its regulated metabolites was 1.915 ppm for "A molasses". To correct concentrations in "A molasses" to blackstrap molasses, residues in "A molasses" are multiplied by a concentration factor of 4.0x, resulting in 7.66 ppm. Adjusting for the degree of exaggeration (2.0x) used in the processing study, the residue for blackstrap molasses is 3.83 ppm. Because this result is greater than twice the LOQ for the RAC (sugarcane), the available data suggest that the established tolerance for sugarcane molasses should be decreased from 5.0 ppm to 4.0 ppm. GLN 860.1480: Meat, Milk, Poultry, and Eggs The Agency changed the data requirement status for this GLN topic from "Reserved" to "Required" because the results of ruminant metabolism study suggested a very significant transfer of hexazinone residues of concern to meat and milk (Memo, 2/ 4/ 93, R. Perfetti). The registrant has since submitted an acceptable dairy cattle feeding study (MRID 43703501) which was deemed acceptable. HED is recommending that in order to reassess the established hexazinone tolerances for milk and the fat, meat, and meat byproducts of livestock and to compute a maximum theoretical dietary burden (MTDB) 27 of hexazinone to livestock, uses on pasture and rangeland grasses must be revoked. A MTDB could not be calculated including grass and grass hay since additional residue data are required for use patterns in which significant residues are expected in/ on the RACs. HED recognizes that the estimated 100,000 acres of pasture and rangeland treated with hexazinone is relatively low. Since grass and grass hay are considered major dietary components of ruminants (up to 60% of the diet per current OPPTS GLN) a MTDB for livestock could not be developed when grasses are included in the registered uses. HED has determined that a MTDB could be constructed from other potential feed items for livestock and subsequently tolerances for meats and milk can be reassessed. HED has previously determined that tolerances in poultry commodities and a poultry feeding study are not required for reregistration based on results of reviewed poultry metabolism data. Maximum theoretical dietary burden (tentative, pending revocation of uses on pasture and rangeland grasses and hay) There are no registered direct livestock treatments for hexazinone on cattle, goats, hogs, horses, or sheep. However, hexazinone residues of concern may transfer to milk and edible tissues of livestock as a result of ingestion of feed items such as: alfalfa forage, hay, meal, and silage; grass forage, hay, and silage; pineapple process residue; and sugarcane molasses. The maximum theoretical dietary burdens of hexazinone to beef and dairy cattle are tentatively calculated to be 4.64 ppm (see Table 3 below). The dietary burden calculations are tentative because it assumes use on pasture and rangland grasses will be canceled and tolerances revoked Table 3. Tentative calculation of maximum ruminant dietary burden for hexazinone. Feed Commodity Reassessed Tolerance (ppm) % Dry Matter 1 Beef Cattle Dairy Cattle % of Diet 1 Burden (ppm) 2 % of Diet 1 Burden (ppm) 2 Alfalfa, forage 2 35 60 3. 43 60 3. 43 Alfalfa, hay (as meal) 4 89 15 0.68 15 0.68 Sugarcane molasses 4 75 10 0.53 10 0.53 TOTAL 85 3 4.64 85 3 4.64 1 Table 1 (OPPTS Guideline 860.1000). 2 Contribution = [tolerance / % DM (if cattle)] X % diet). 3 All beef and dairy cattle in the U. S. should have in their diet 15% cottonseed meal, peanut meal, soybean meal, canola meal, or flax seed meal. Hexazinone is not registered for use on any of these commodities. Therefore, to account for these commodities in the diet of beef and dairy cattle, the percentage has been reduced by 15% to 85%. Dairy cattle feeding study 28 A brief summary of the reviewed dairy cattle feeding study (MRID 43703501) is presented below. Three groups of dairy cows (3 animals/ dose group) were dosed with hexazinone at 29, 87, and 290 ppm in the diet for 28 consecutive days; three additional cows served as control animals. The registrant indicated that these dose levels represent feeding level of 1.0x, 3.0x, and 10.0x based on a diet of grass forage. These dose levels are equivalent to 6.25x, 18.75x, and 62.5x, respectively, the maximum theoretical dietary burden for beef and dairy cattle when grass or grass hay is not included. An additional treatment group, fed at 17.4 ppm (3.88x), was added later, and one animal was held over from the control group for this phase of the study. These dose levels are equivalent to 64x, 190x, and 640x the MTDB for hogs. Hexazinone was placed into gelatin capsules and administered by balling gun, twice daily after each milking. Milk was collected twice daily. The cattle were sacrificed 13­ 21 hours after administration of the final dose, and samples of liver, kidney, muscle, and fat were collected. The collected milk and tissue samples were analyzed for residues of hexazinone and its metabolites using two analytical methods. One method was used for milk, muscle, and fat, and another method for liver and kidney. Although cumbersome and complicated, the method was deemed adequate for data collection. Based on the data­ collection method used in this study, the registrant is now proposing an LC/ MS method (designated as du Pont AMR 3783­ 96) as an enforcement method for milk and animal tissues. Refer to "GLN 860.1340: Residue Analytical Methods ­ Animal Commodities" for a discussion of this method and a list of specific hexazinone residues that the method can determine. Assuming Method AMR 3783­ 96 passes a successful tolerance method validation, the tolerance expression for milk and tissues will be changed. The maximum total hexazinone residues in milk were 0.78 ppm at the 6.25x feeding level (29 ppm in the diet) and 11.09 ppm at the 62.5x level. On day­ 14, after total residues had reached plateaus, milk was separated into skim milk and cream. Total residues in skim milk were comparable to those in whole milk; total residues in cream were approximately half those in skim milk. In tissues, the maximum total hexazinone residues at the 62.5x feeding level were 3.85 ppm in liver, 2.19 ppm in kidney, 0.32 ppm in muscle, and nondetectable ( # 0.10 ppm) in fat. The maximum total residues at the 6.25x feeding level were 0.24 ppm in liver, 0.47 ppm in kidney, and nondetectable ( # 0.15 ppm) in muscle. Because total residues were nondetectable in all fat samples from the 18.75x and 62.5x levels, fat samples were not analyzed at lower feeding levels. A tolerances of 0.5 ppm is presently established for the combined residues of hexazinone and its metabolites (calculated as hexazinone) in milk. Based on the MTDB for beef and dairy cattle without grass or grass hay as a potential feed item, it is possible to re­ assess the animal commodity tolerances. The HED MARC has concluded that the hexazinone tolerance expression for ruminants should include 29 hexazinone plus metabolites B, C, C­ 2, and F for milk. Residue levels of hexazinone and metabolites in whole milk from the feeding study corrected for exaggeration levels ranged from 0.110 ppm to 0.164 ppm. Based on the enforcement method, the sum of the LOQ's for hexazinone and metabolites B, C, C­ 2, and F is 0.20 ppm; therefore, it is appropriate that the tolerance for milk be reduced from 0.5 to 0.20 ppm. Tolerances of 0.1 ppm are presently established for the combined residues of hexazinone and its metabolites (calculated as hexazinone) in fat, meat, and meat byproducts of cattle, goats, hogs, horses, and sheep. The Committee concluded that the hexazinone tolerance expression for ruminant tissue should include hexazinone plus metabolites B and F. Residue levels of hexazinone and metabolites in kidney from the feeding study corrected for exaggeration levels ranged from 0.046 ppm to 0.090 ppm. Based on the enforcement method, the sum of the LOQ's for hexazinone and metabolites B and F is 0.10 ppm therefore it is appropriate that the tolerance for meat byproducts of cattle, goats, horses, and sheep be reassessed at 0.10 ppm. Residue levels of hexazinone and metabolites from the feeding study corrected for exaggeration levels ranged from 0.003 ppm to 0.007 ppm therefore tolerances for hog meat are not required. Residue levels of hexazinone and metabolites in muscle from the feeding study corrected for exaggeration levels ranged from 0.003 ppm to 0.039 ppm. Based on the enforcement method, the sum of the LOQ's for hexazinone and metabolites B and F is 0.10 ppm; therefore, it is appropriate that the tolerance for meat byproducts of cattle, goats, horses, and sheep be reassessed at 0.10 ppm. Residue levels of hexazinone and metabolites in muscle from the feeding study corrected for exaggeration levels ranged from 0.0004 ppm to 0.002 ppm therefore tolerances for hog meat are not required. Tolerances of 0.1 ppm are presently established for the combined residues of hexazinone and its metabolites (calculated as hexazinone) in fat. Residue levels of hexazinone and metabolites in fat from the feeding study were nondetectable (< 0.1 ppm) at the 62.5x exaggerated rate. The Agency has determined that tolerances for hexazinone residues in fat of cattle, goats, hogs, horses, and sheep are not required (Category 3, 40 CFR §180.6a). Tolerances for fat of cattle, goats, hogs, horses, and sheep are not required and should be revoked. GLN 860.1400: Water, Fish, and Irrigated Crops Hexazinone is presently not registered for direct use on water and aquatic food and feed crops; therefore, no residue chemistry data are required under these guideline topics. GLN 860.1460: Food Handling 30 Hexazinone is presently not registered for use in food­ handling establishments; therefore, no residue chemistry data are required under this guideline topic. GLN 860.1850: Confined Accumulation in Rotational Crops The data requirements for confined rotational crops are satisfied. The basic registrant has submitted acceptable studies (MRIDs 41008401, 42824001, 43892401) which indicate that [ 14 C] hexazinone residues accumulate at 0.01 ppm in/ on tested rotational crop commodities at certain plantback intervals. Based on these data, the registrant was required to conduct a limited field rotational crop study in order to assess the adequacy of existing rotational crop restrictions on the registrant's end­ use product labels and to determine whether rotational crop tolerances are needed. The major residue components that were identified from the confined rotational crop study were either the glucose conjugate of G3170 or hexazinone or both. The remaining ten identified metabolites all contain the triazinone ring structure, and four of these compounds (metabolites A, B, C, and F) have been determined to be residues of concern in/ on primary crops. GLN 860.1900: Field Accumulation in Rotational Crops The data requirements for field accumulation in rotational crops are only partially satisfied. This conclusion is based on a recent review of a limited field crop rotation study (MRID 45084101) wherein the 75% DF formulation of hexazinone was applied as a single postemergence broadcast application to mowed alfalfa at test sites in MN and CA at 1.5 lb ai/ A (1x the maximum seasonal rate for alfalfa). Approximately one year following application, the remaining alfalfa crop residue was plowed up and returned to the soil, and head lettuce, field corn, and wheat were planted (350 days after treatment, DAT, for the MN test site and 358 DAT for the CA test site). Residues were below the respective method LOQs for hexazinone and metabolites A, B, C, D, E, F, G, H, G3170, G3170­ NG, A­ 1, and C­ 1 in/ on head lettuce, wheat forage and grain, and field corn forage and grain. In wheat straw, residues of metabolite B were <0.02­ 0.021 ppm; residues of hexazinone and the remaining metabolites were below the LOQ. In field corn stover, residues of hexazinone were 0.02­ 0.081 ppm, residues of metabolite B were 0.038­ 0.053 ppm, and residues of the remaining metabolites were below the LOQ. These data indicate that extended field rotational crop studies and rotational crop tolerances will not be required for residues of hexazinone residues of concern in/ on leafy vegetables provided that labels are amended to specify a rotational crop restriction of at least 12 months. A previous review of a confined rotational crop study concluded 31 that rotational crop tolerances were not needed for root crops provided that a 12­ month plantback interval was established; an examination of the basic registrant's labels shows that the 12­ month plantback interval for root crops has been established. Because the data from the limited field trials indicate that quantifiable residues occur in field corn stover and wheat straw, extended field rotational crop trials for corn stover, sorghum stover, and wheat straw to support a 12­ month rotational interval and a tolerance for inadvertent hexazinone residues are required. The data for the application rate used in this study are sufficient to support rotation from alfalfa and pasture and rangeland grass only. The registrant has stated previously that they intend to modify product labels to restrict rotation from sugarcane to sugarcane only (HED memorandum, 10/ 31/ 96, J. Abbotts). 32 Table B. Residue Chemistry Science Assessments for Reregistration of Hexazinone. GLN: Data Requirements Tolerances [40 CFR] (ppm) Must Additional Data Be Submitted? References 1 860.1200: Directions for Use N/ A = Not Applicable Yes 2 See Table A 860.1300: Plant Metabolism N/ A No 00078047, 00104846, 00126127 860.1300: Animal Metabolism N/ A No 00104843, 41524801, 42187901 3 , 42219301 4 , 42248901 5 , 42690601 6 , 43488901 7 860.1340: Residue Analytical Methods ­ Plant commodities N/ A No 00038868, 00101574, 00126127, 41964101, 41964102, 42987201 8 , 430025401 9 ­ Animal commodities N/ A Reserved 10 00038868, 43074201 11 , 44259101 12 , 44259102 12 860.1360: Multiresidue Methods N/ A No 41572101, 41572102, 41572103, 41572104, 41572105, 41572106 860.1380: Storage Stability Data ­ Plant commodities N/ A No 42276001 13 , 42322701 14 , 42418001 15 , 42423001 16 , 42492101 17 , 42535601 18 , 42867501 19 , 43524301 20 , 43936501 21 , 44133501 22 ­ Animal commodities N/ A No 43703501 23 860.1500: Crop Field Trials Berries Group ­ Blueberries 0.2 [§ 180.396( a)] No 24 00101574, 41964101, 41964102 Grass Forage, Fodder, Hay Group GLN: Data Requirements Tolerances [40 CFR] (ppm) Must Additional Data Be Submitted? References 1 33 ­ Grasses (pastures and rangeland), forage and hay 10, grasses, pasture and rangeland [§ 180.396( a)] Yes 25, 26 00138226, 41898301 27 , 42419101 15 , 42867501 19 Table B (continued). GLN: Data Requirements Tolerances [40 CFR] (ppm) Must Additional Data Be Submitted? References 1 34 Non­ grass Animal Feeds (forage, fodder, straw, and hay) Group ­ Alfalfa, forage, hay, and seed 2.0, forage 8.0, hay [§ 180.396( a)] No 28 , 29 00118050, 43074401 30 , 43074402 30 Miscellaneous Commodities ­ Pineapple 0. 5, whole fruit [§ 180.396( a)] No 00126127, 42535601 18 ­ Sugarcane 0. 2 [§ 180.396( c)] No 00028733, 00114039, 42322701 14 860.1520: Processed Food/ Feed ­ Pineapple None No 42492101 17 , 43401901 31 ­ Sugarcane 5. 0, molasses [§ 180.396( c)] No 42276001 13 , 42417901 32 , PP# 8F2119/ FAP# 4H5683 33 860.1480: Meat, Milk, Poultry, Eggs ­ Milk, Fat, Meat, and Meat Byproducts of Cattle, Goats, Hogs, Horses, and Sheep 0.1, milk, fat, meat, and meat byproducts [§ 180.396( a)] No 34 00028866, 00140161, 43703501 23 ­ Eggs and the Fat, Meat, and Meat Byproducts of Poultry None No 35 00104845 860.1400: Water, Fish, and Irrigated Crops NA No 860.1460: Food Handling NA No 860.1850: Confined Rotational Crops NA No 41008401 36 , 42824001 37 , 43892401 38 860.1900: Field Rotational Crops None Yes 39 45084101 40 Table B (continued). 35 1. Bolded references were reviewed in the Reregistration Update of 9/ 5/ 91. Unbolded references were reviewed in the Residue Chemistry Science Chapter of the Final Registration Standard and Tolerance Reassessment (FRSTR) dated 5/ 25/ 88. All other references were reviewed as noted. 2. Label amendments are required for alfalfa and blueberries, and details of the required label amendments are presented in the respective endnote for GLN 860.1500 (Crop Field Trials) of this table. Label amendments are also required to establish a 12­ month plantback interval for leafy vegetables. 3. DP Barcode D174764, CBRS No. 9418, 5/ 22/ 92, J. Abbotts. 4. DP Barcode D175243, CBRS No. 9510, 7/ 14/ 92, J. Abbotts. 5. DP Barcode D176715, CBRS No. 9697, 9/ 15/ 92, J. Abbotts. 6. DP Barcode D189285, CBRS No. 11656, 6/ 25/ 93, J. Abbotts. 7. DP Barcode D210574, CBRS No. 14889, 1/ 19/ 95, J. Abbotts. 8. DP Barcode D196446, CBRS No. 12815, 1/ 6/ 94, J. Abbotts. 9. DP Barcode D197342, CBRS No. 12932, 1/ 6/ 94, J. Abbotts. 10. The registrant has proposed an LC/ MS method (designated as du Pont AMR 3783­ 96) as an enforcement method for animal commodities. Method AMR 3783­ 96 has been subjected to a successful ILV and a radiovalidation study. Method AMR 3783­ 96 will be forwarded to the Analytical Chemistry Branch (ACL; Beltsville, MD) for a tolerance method validation by Agency chemists. If the results of method validation are successful, then Method AMR 3783­ 96 will be proposed for inclusion in PAM Volume II, and no additional enforcement methodology for animal commodities will be required for reregistration. 11. DP Barcode D198348, CBRS No. 13076, 5/ 25/ 94, S. Hummel. 12. DP Barcode D282683, 05/ 15/ 02, J. S. Punzi. 13. DP Barcode D177572, CBRS No. 9808, 6/ 18/ 92, S. Funk. 14. DP Barcode D178771, CBRS No. 9985, 9/ 22/ 92, J. Abbotts. 15. DP Barcode D181318, CBTS No. 10354, 1/ 28/ 93, R. Lascola. 16. DP Barcode D181480, CBRS No. 10365, 11/ 9/ 92, J. Abbotts. 17. DP Barcode D183296, CBRS No. 10702, 2/ 23/ 93, J. Abbotts. 18. DP Barcode D184852, CBRS No. 10924, 2/ 25/ 93, J. Abbotts. 19. DP Barcode D195426, CBRS No. 12617, 10/ 25/ 93, J. Abbotts. 20. DP Barcode D211642, CBRS No. 15101, 3/ 14/ 95, J. Abbotts. 21. DP Barcode D282685, 05/ 15/ 02, J. S. Punzi. Table B (continued). 36 22. DP Barcode D282682, 05/ 15/ 02, J. Punzi. 23. DP Barcode D217257, CBRS No. 15881, 9/ 25/ 95, J. Abbotts. 24. No additional data are required for blueberries. However, label revisions remain a requirement. The product labels for ME980002 and ME980003, which are limited for use on lowbush blueberries, should be amended to specify a PHI of 450 days. The product label for NC830012 should also be amended to specify PHIs of 90 and 450 days for application to highbush and lowbush blueberries, respectively. 25. Uses on grass should be cancelled and tolerances revoked. The following grass forage would be required for grass: "Data depicting magnitude of the residues of hexazinone and metabolites A, B, C, D, and E in/ on grass forage harvested 0 day following a single broadcast application of representative formulations at 1.125 lb ai/ A. It is the Agency policy to require 0­ day crop field residue data for grass forage unless it is not feasible (e. g., preplant/ preemergence pesticide uses). The formulations to be tested may be applied in side­ by­ side plots. The location and number of trials should be in compliance with the current OPPTS GLN for adequate geographic representation of data. 26. Uses on grass should be cancelled and tolerances revoked. Additional grass hay data would be required. The registrant has submitted a petition (PP# 1F3967) for the establishment of a tolerance for residues of hexazinone and its metabolites in/ on grass hay. The petition is currently in reject status because additional grass hay data, from field trials with adequate geographical representation, remain outstanding. 27. DP Barcodes D165324, D165303, and D165277, CBRS Nos. 8147, 8148, 8149, 8134, 8152, and 8153, 11/ 14/ 91, J. Smith. 28. No additional data are required for alfalfa forage and hay. However, the product label for the 2 lb/ gal EC (EPA Reg. No. 352­ 392) formulation must be amended to establish a 30­ day PHI (or pregrazing interval) for the feeding of forage and the cutting of hay. 29. No additional data are required for alfalfa seed. However, the registrant is required to propose a tolerance for hexazinone residues of concern in/ on alfalfa seed; the available data suggest that a tolerance level of 2.0 ppm is appropriate. 30. DP Barcode D198336, CBRS No. 13075, 6/ 22/ 94, S. Hummel. 31. DP Barcode D208605, CBRS No. 14591, 1/ 20/ 95, C. Eiden and DP Barcode D215057, 11/ 28/ 95, C. Eiden. 32. DP Barcode D181308, CBRS No. 10333, 10/ 26/ 92, B. Cropp­ Kohlligian. 33. DP Barcode D196510, CB No. 12796, 9/ 1/ 94, S. Hummel. 34. An acceptable dairy cattle feeding study is available. HED is able, at this time, to reassess the established hexazinone tolerances for milk and the fat, meat, and meat byproducts of livestock using maximum theoretical dietary burdens of hexazinone to livestock, calculated without grass or grass hay. Since additional residue data are required for grass forage and hay, for which significant residues are expected in/ on the RACs and are considered major dietary components of ruminants, HED recommends that the uses be canceled and tolerances revoked. 35. HED has determined that tolerances for hexazinone residues in eggs and poultry tissues are not required (Category 3, 40 CFR §180.6) based on the results of the reviewed poultry metabolism study. 36. DP Barcode D188349, CBRS No. 11458, 5/ 14/ 93, L. Cheng. Table B (continued). 37 37. DP Barcode D192877, CBRS No. 12222, 3/ 3/ 94, F. Fort. 38. DP Barcode D222455, CBRS No. 16791, 7/ 1/ 96, L. Cheng. 39. Because the data from the limited field trials indicate that quantifiable residues occur in field corn stover and wheat straw, extended field rotational crop trials for corn stover, sorghum stover, and wheat straw to support a 12­ month rotational interval and a tolerance for inadvertent hexazinone residues are required. 40. DP Barcode D282684, 05/ 15/ 02, J. S. Punzi. 38 TOLERANCE REASSESSMENT SUMMARY Tolerances for residues of hexazinone in/ on plant, livestock, and processed commodities are currently expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). Permanent tolerances are established for several raw agricultural commodities and livestock commodities under 40 CFR §180.396( a). Tolerances with regional registrations which exclude use of hexazinone on sugarcane in Florida are established under 40 CFR §180.396( c). The qualitative nature of the residue in plants and livestock is adequately understood. The HED MARC concluded that the hexazinone tolerance expression for plants and rotational crops should include hexazinone and metabolites A, B, C, D, and E. The qualitative nature of the residue in livestock is adequately understood based on acceptable ruminant and poultry metabolism studies. The HED MARC concluded that the hexazinone tolerance expression for ruminants should include hexazinone plus metabolites B, C, C­ 2, and F for milk. The Committee concluded that the hexazinone tolerance expression for ruminant tissue should include hexazinone plus metabolites B and F. The Committee concluded that residues of hexazinone and metabolites B, C, C1 C­ 2, and F should be taken into account when risk assessments are done. HED has determined that tolerances for hexazinone residues in eggs and poultry tissues, hog meat and meat by products, and fat of livestock are not required (Category 3, 40 CFR §180.6) based on the results of the respective metabolism and feeding studies. An adequate enforcement method is available for plant commodities. Method I of PAM, Volume II is a nitrogen­ selective GLC method capable of determining residues of hexazinone and metabolites A, B, C, D, and E. The combined limit of quantitation (LOQ) for hexazinone residues by Method I is 0.55 ppm. An enforcement method, Method AMR 3783­ 96, has been proposed for milk and livestock tissues. Method AMR 3783­ 96 has been subjected to a successful ILV and a radiovalidation study. It will be forwarded to the Analytical Chemistry Branch for a tolerance method validation by Agency chemists. HED is recommending that the hexazinone tolerances listed under 40 CFR §180.396 (a) and (c) be reorganized, as listed below, to indicate the specific residues of concern that can be quantitated by the existing plant enforcement method and the proposed livestock enforcement method. This proposal to reorganize hexazinone tolerances is contingent upon successful validation of Method AMR 3783­ 96. Note that for simplicity the tolerence expression is shown as "Hexazinone and its metabolites A, B, C, D, and E (calculated as hexazinone)" however the metabolites must be identified by the appropriate chemical name. Table 4. 39 40 CFR Reserved for Tolerance Expression §180.396 (a) (1) Permanent tolerances for plant and processed commodities Hexazinone and its metabolites A, B, C, D, and E (calculated as hexazinone) §180.396 (a) (2) Milk Hexazinone and its metabolite B, metabolite C and its isomer (C­ 2), and metabolite F (calculated as hexazinone) §180.396 (a) (3) Ruminant tissues Hexazinone and its metabolite B and metabolite F (calculated as hexazinone) §180.396 (c) Tolerances for plant and processed commodities with regional registration Hexazinone and its metabolites A, B, C, D, and E (calculated as hexazinone) NOTE: See Figure 1 for full chemical names of regulated hexazinone metabolites. A summary of hexazinone tolerance reassessments is presented in Table C. Discussions of residue data used for tolerance reassessment are presented in the "Summary of Science Findings" section for GLNs 860.1500 (Crop Field Trials) and 860.1480 (Meat, Milk, Poultry, and Eggs). Certain commodity definitions need to be corrected. Tolerances Listed Under 40 CFR §180.396 (a): Sufficient data are available to ascertain the adequacy of tolerances listed in 40 CFR §180.96 (a) for alfalfa forage, alfalfa hay, blueberries, and pineapple. Tolerances for pasture and rangeland grasses should be revoked and uses cancelled. An acceptable ruminant feeding study is available; HED is able to reassess the established hexazinone tolerances for milk and the fat, meat, and meat byproducts of livestock using a maximum theoretical dietary burden of hexazinone to livestock assuming revocation of tolerances for grasses and hay. The established tolerances for blueberries and pineapple should be increased to 0.60 ppm to reflect the combined LOQs of the enforcement method. The available field trial data indicate that residues of hexazinone and its regulated metabolites, as measured by the data­ collection method, were nondetectable in/ on these RACs following treatment at 1.0x. Tolerances Needed Under 40 CFR §180.396 (a): The registrant is required to propose a tolerance for hexazinone residues of concern in/ on alfalfa seed; the available data suggest that a tolerance level of 2.0 ppm is appropriate. Tolerances Listed Under 40 CFR §180.396 (c): 40 Adequate data are available for sugarcane and sugarcane molasses. The tolerance for sugarcane molasses should be reduced from 5.0 ppm to 4.0 ppm based on re­ calculation of expected residues. 41 (continued; endnotes follow) Table C. Tolerance Reassessment Summary for Hexazinone. Commodity Current Tolerance (ppm) a Range of residues (ppm) b Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition Tolerances listed under 40 CFR §180.396( a): Alfalfa green forage 2 <1.87 2.0 Alfalfa, forage Alfalfa hay 8 <3.33 4. 0 Alfalfa, hay Blueberries 0.2 <0.3 ppm (nondetectable; <0.05 ppm for each compound) 0.60 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Blueberry Cattle, fat 0. 1 Revoke c Cattle, mbyp 0.1 0. 10 Cattle, meat 0.1 0. 10 Goat, fat 0. 1 Revoke c Goat, mbyp 0.1 0. 10 Goats, meat 0.1 0. 10 Grasses, pasture 10 Revoke d Grass, forage Grass, hay Grasses, rangeland 10 Revoke d Hog, fat 0.1 Revoke c Hog, mbyp 0.1 Revoke c Hog, meat 0.1 Revoke c Horses, fat 0. 1 Revoke c Horses, mbyp 0.1 0. 10 Horses, meat 0.1 0. 10 Milk 0.5 0. 20 Pineapple 0. 5 <0.35 (or <0.05 ppm for each compound) 0.60 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Sheep, fat 0. 1 Revoke c Sheep, mbyp 0.1 0. 10 Sheep, meat 0.1 0. 10 Tolerances needed under 40 CFR §180.396( a): Alfalfa, seed ­­ <1.30­< 1.46 2. 0 Table C (continued). Commodity Current Tolerance (ppm) a Range of residues (ppm) b Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition 42 Tolerances listed under 40 CFR §180.396( c): Sugarcane 0. 2 <0.05 ppm (nondetectable) each for hexazinone and its metabolites 0.60 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Sugarcane molasses 5 (1.915 x 4x) ÷ 2x = 3.83 4.0 a Expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). b Refer to section on Magnitude of Residues in Crop Plant for detailed discussion of residues in crops. c Tolerances for fat are not required (Category 3, 40 CFR §180.6). d HED is recommending revocation of these tolerances and cancellation of uses, since grasses are a major feed item and required data are not available for reassessment. CODEX HARMONIZATION No maximum residue limits (MRLs) for hexazinone and its metabolites have been established or proposed by Codex for any agricultural commodity. Therefore, no compatibility questions exist with respect to U. S. tolerances.. 43 AGENCY MEMORANDA CITATIONS Agency Memoranda Citations Relevant to Hexazinone Reregistration. Date DP Barcode CB No. From To MRID Nos. Subject 7/ 18/ 91 D162863 7835 R. Lascola J. Miller/ D. Wilson None PP# 1F3967. Hexazinone (Velpar L) in/ on Pasture and Rangeland Hay. 11/ 14/ 91 D165277, D165303, D165324 8134, 8147, 8148, 8149, 8152, 8153 J. Smith J. Miller 41898301 Hexazinone. Amendment of label reflecting a new pregrazing interval for forestry use, new replanting instructions following alfalfa, reduced use on sugarcane, and overall clarifications. 3/ 11/ 92 D174869 9463 D. McNeilly A. Ertman None Hexazinone reregistration; question concerning pineapple forage feeding restriction from DuPont Agricultural Products. 5/ 22/ 92 D174764 9418 J. Abbotts L. Rossi 42187901 Hexazinone. Du Pont Company Response to the Reregistration Standard: Animal Metabolism Data for Goat. 6/ 18/ 92 D177572 9808 S. Funk A. Ertman 42276001 Reregistration of Hexazinone (Velpar). 171­ 4( l): Sugarcane Processing Study. 171­ 4( K): Sugarcane Field Trial Time Extension Request. 6/ 24/ 92 D172408 9127 R. Lascola E. Wilson/ J. Miller None PP# 1F3967. Hexazinone (Velpar L) in/ on Pasture and Rangeland Hay. Amended Response to Registration Standard Data Gap. 7/ 14/ 92 D175243 9510 J. Abbotts L. Rossi 42219301 Hexazinone. Du Pont Company Response to the Reregistration Standard: Storage Stability Data for Animal Metabolism in Poultry. 8/ 21/ 92 D178781 9961 J. Abbotts A. Ertman None Hexazinone. Du Pont Company Response to the Reregistration Update to the Residue Chemistry Chapter. Agency Memo Citations for Hexazinone (continued). Date DP Barcode CB No. From To MRID Nos. Subject 44 8/ 25/ 92 D174070 9366 M. Bradley J. Miller None Hexazinone. Label Amendment to Add Pregrazing Intervals for Forestry and Non Crop Land Use. 9/ 15/ 92 D176715 9697 J. Abbotts L. Rossi 42248901 Hexazinone. Du Pont Company Response to the Reregistration Standard: Storage Stability Data for Animal Metabolism in Goat. 9/ 22/ 92 D178771 9985 J. Abbotts L. Rossi 42322701 Hexazinone. Du Pont Company Response to the Reregistration Standard: Residue Data for Sugarcane. 10/ 26/ 92 D181308 10333 B. Cropp Kohlligian L. Rossi 42417901 Hexazinone: Supplemental Data Submitted to Address Sugarcane Processing Study Deficiencies. 11/ 9/ 92 D181480 10365 J. Abbotts L. Rossi 42423001 Hexazinone. Du Pont Company Response to the Reregistration Standard: Storage Stability Data for Blueberry. 1/ 28/ 93 D181318 10354 R. Lascola E. Wilson/ J. Miller 42418001 and 42419101 PP 1F3967. Hexazinone (Velpar L) in/ on Pasture and Rangeland Hay. 2/ 4/ 93 None None R. Perfetti L. Rossi and E. Saito None Animal Feeding Studies: Requirement Status Modification. 2/ 23/ 93 D183296 10702 J. Abbotts L. Rossi 42492101 Hexazinone. Du Pont Company Response to the Reregistration Standard: Processing Data for Pineapple. 2/ 25/ 93 D184852 10924 J. Abbotts L. Rossi 42535601 Hexazinone. Du Pont Company Response to the Reregistration Standard: Residue Data for Pineapple. 5/ 14/ 93 D188349 11458 L. Cheng A. Ertman/ W. Waldrop 41008401 Hexazinone. Rotational Crop Data Requirement. 6/ 25/ 93 D189285 11656 J. Abbotts A. Ertman 42690601 Hexazinone, Reregistration. Supplemental Data on Poultry Metabolism. Agency Memo Citations for Hexazinone (continued). Date DP Barcode CB No. From To MRID Nos. Subject 45 7/ 22/ 93 None None R. Perfetti L. Rossi and A. Rathman None Animal Feeding Studies. Requirement Status Modification: Reconsideration. 9/ 9/ 93 None None M. Metzger L. Rossi None Animal Feeding Studies (171­ 4( j)); Requirement Status Modification. 10/ 5/ 93 D194489 12425 J. Abbotts A. Ertman None Hexazinone, Reregistration. Animal Feeding Study Protocol. 10/ 5/ 93 D194395 12427 J. Abbotts A. Ertman None Hexazinone, Reregistration. Pineapple Residue Data. 10/ 8/ 93 None None J. Abbotts L. Rossi and F. Chow/ C. Frick None Hexazinone. Reregistration Eligibility Document Chapters for Product Chemistry and Residue Chemistry, Current Status. 10/ 8/ 93 None None J. Abbotts Hexazinone Reregistration File None Hexazinone. Anticipated Residues for Reregistration Eligibility Document. 10/ 25/ 93 D195426 12617 J. Abbotts A. Ertman 42867501 Hexazinone, Reregistration. Storage Stability Data in Grass. 1/ 6/ 94 D196446 12815 J. Abbotts A. Ertman 42987201 Hexazinone, Reregistration. Analytical Method for Sugarcane Commodities. 1/ 6/ 94 D197342 12932 J. Abbotts A. Ertman 43025401 Hexazinone, Reregistration. Independent Laboratory Validation of an Analytical Method for Sugar Commodities. 3/ 3/ 94 D192877 12222 F. Fort L. Rossi/ W. Waldrop 42824001 Hexazinone. Supplemental Information Pertaining to Rotational Crop Requirements. List A Case No. 0266. Chemical I. D. No. 107201. 3/ 16/ 94 D199887 13301 S. Hummel A. Ertman None Hexazinone (107201), Reregistration Case No. 0266. Storage Intervals and Conditions in Grass Time Extension Request for Livestock Feeding Study. Agency Memo Citations for Hexazinone (continued). Date DP Barcode CB No. From To MRID Nos. Subject 46 4/ 20/ 94 D201203 13492 F. Suhre A. Ertman None Hexazinone (ID 107201). Magnitude of the Residue, Cattle Feeding Study [171­ 4( j)]; Protocol Amendment. 4/ 29/ 94 D201738 13527 G. Kramer E. Wilson/ J. Miller None PP# 1F3967. Hexazinone (Velpar L) in/ on Pasture and Rangeland Hay. Amendment of 3/ 28/ 94. 5/ 16/ 94 None None S. Hummel Metabolism Committee None Hexazinone (107201), Reregistration Case No. 0266. Issues to be Presented to the Metabolism Committee. 5/ 25/ 94 D198348 13076 S. Hummel A. Ertman 43074201 Hexazinone (107201), Reregistration Case No. 266. Livestock Metabolism ­ Confirmatory Analyses Hexazinone Tolerance Expression. 5/ 25/ 94 D203472 None S. Hummel HED Metabolism Committee None Hexazinone (107201) Plant and Animal Metabolism: Results of HED Metabolism Committee Meeting Held May 19, 1994. 6/ 1/ 94 D202919 13649 F. Suhre W. Waldrop None Hexazinone (107201). Pineapple Processing Study 171­ 4( l). 6/ 22/ 94 D198336 13075 S. Hummel A. Ertman 43074401 and 43074402 Hexazinone (107201) Residue Data on Alfalfa. 9/ 1/ 94 D196510 12796 S. Hummel E. Wilson/ J. Miller/ A. Ertman None PP# 8F2119/ FAP# 4H5683 Hexazinone (107201) Residue Data on Sugarcane Reregistration Case No. 0266. 9/ 8/ 94 D207225 14319 S. Hummel A. Ertman None Hexazinone (107201) ­ Reregistration Case No. 0266. Updated Table A for Residue Chemistry RED Chapter. 9/ 22/ 94 D207493 14363 S. Hummel E. Wilson/ J. Miller/ A. Ertman None PP# 8F2119/ FAP# 4H5683 Hexazinone (107201) on Sugarcane Reregistration Case No. 0266. Clarification of CB 12796, DP Barcode D196510. Agency Memo Citations for Hexazinone (continued). Date DP Barcode CB No. From To MRID Nos. Subject 47 10/ 12/ 94 D207995 14455 S. Hummel E. Wilson/ J. Miller/ A. Ertman None PP# 8F2119/ FAP# 4H5683 Hexazinone (107201) on Sugarcane Amendment of 9/ 21/ 94 EPA Reg. No. 352­ 378 DuPont Velpar Herbicide Reregistration Case No. 0266 Amended Registration, Deletion of Use in FL. 11/ 30/ 94 D209648 14740 S. Hummel E. Wilson/ A. Ertman None PP# 8F2119/ FAP# 4H5683 Hexazinone (107201) on Sugarcane Amendment of 11/ 2/ 94, Draft FR Notice EPA Reg. No. 352­ 378 DuPont Velpar Herbicide Reregistration Case No. 0266 Justification for Disallowing Use in FL. 1/ 19/ 95 D210574 14899 J. Abbotts A. Ertman 43488901 Hexazinone (107201), Reregistration Case 0266. Ruminant Metabolism, Supplemental Data. 1/ 20/ 95 D208605 14591 C. Eiden W. Waldrop 43401901 Hexazinone. Pineapple Processing Study. 3/ 14/ 95 D211642 15101 J. Abbotts A. Ertman 43524301 Hexazinone (107201), Reregistration Case 0266. Storage Stability of Metabolite C in Grass, Interim Report. 9/ 25/ 95 D217257 15881 J. Abbotts A. Ertman 43703501 Hexazinone (107201), Reregistration Case 0266. Cattle Feeding Study. 11/ 28/ 95 D215057 15974 C. Eiden W. Waldrop/ A. Ertman None Hexazinone. Pineapple Processing Study Follow­ Up: Response from Registrant. 4/ 15/ 96 None None J. Abbotts A. Ertman None Hexazinone (107201), Reregistration Case 0266. Meeting with Registrant DuPont, 4/ 9/ 96, on Progress Toward Analytical Method, Animal Commodities. 7/ 1/ 96 D222455 16791 L. Cheng P. Deschamp 43892401 Hexazinone. Case 0266. Confined Rotational Crop Studies (GLN 165­ 1). 9/ 27/ 96 D228808 17552 J. Abbotts M. Metzger None Hexazinone (107201), Reregistration Case 0266. Registrant DuPont Agricultural Products. Guideline 860.1900. Field Rotational Crops, Limited. Agency Memo Citations for Hexazinone (continued). Date DP Barcode CB No. From To MRID Nos. Subject 48 10/ 31/ 96 None None J. Abbotts P. Deschamp None Hexazinone (107201), Reregistration Case 0266. Meeting with Registrant DuPont, 10/ 30/ 96, on Requirements for Limited Field Rotational Trials. 02/ 05/ 02 D279897 None S. Kinard C. Olinger None Hexazinone. The Outcome of the HED Metabolism Assessment Review Committee. 05/ 15/ 02 D282685 None J. Punzi D. Helder 43936501 Hexazinone (107201), Reregistration Case 0266. Storage Stability Study for Hexazinone and Metabolites A, B, C, D, and E in Pasture and Range Grasses. 05/ 15/ 02 D282682 None J. Punzi D. Helder 44133501 Hexazinone (107201), Reregistration Case 0266. Storage Stability Study for Hexazinone and Metabolites A, B, C, D, and E in Alfalfa Forage, Hay, and Seed. 05/ 15/ 02 D282683 None J. Punzi D. Helder 44259101 Hexazinone (107201), Reregistration Case 0266. Enforcement Method For the Determination of Hexazinone and its Metabolites in Animal Tissue and Milk Using ESI­ LC/ MS 05/ 15/ 02 D282683 None J. Punzi D. Helder 44259102 Hexazinone (107201), Reregistration Case 0266. Independent Laboratory Validation of Proposed Enforcement Method For the Determination of Hexazinone and its Metabolites in Animal Tissue and Milk Using ESI­ LC/ MS 05/ 15/ 02 D282684 None J. Punzi D. Helder 45084101 Hexazinone (107201), Reregistration Case 0266. Field Accumulation in Rotational Crops 49 STUDY CITATIONS 00028733 E. I. du Pont de Nemours & Company (1976) Determination of Hexazinone Metabolite C. Undated method. (Unpublished study received Jan 21, 1980 under 352­ 378; CDL: 099225­ A) 00028866 Holt, R. F.; Baude, F. J.; More, D. W. (1979) Hexazinone Livestock Feeding Studies: Milk and Meat. (Unpublished study received Mar 14, 1980 under 352­ 378; submitted by E. I. du Pont de Nemours & Co., Wilmington, Del.; CDL: 099298­ F) 00038868 Holt, R. F. (1980) Determination of Hexazinone and Metabolite Residues Using Nitrogen Selective Gas Chromatography. Undated method. (Unpublished study received Jul 1, 1980 under 352­ 378; submitted by E. I. du Pont de Nemours & Co., Wilmington, Del.; CDL: 099514­ E) 00038869 Rapisarda, C. (1978) Metabolism of 14C­ Labeled Hexazinone in the Goat. (Unpublished study received Jul 1, 1980 under 352­ 378; submitted by E. I. du Pont de Nemours & Co., Wilmington, Del.; CDL: 099514­ F) 00078047 Rhodes, R. C. (1975) Letter sent to 324 File dated Aug 12, 1975: Uptake and metabolism studies with 14 C­ DPX­ 3674 on sugarcane in the greenhouse. (Unpublished study received Mar 22, 1976 under 352­ EX­ 91; submitted by E. I. du Pont de Nemours & Co., Wilmington, Del.; CDL: 095980­ E) 00101574 Interregional Research Project No. 4 (1982) Residue Studies of Hexazinone on Blueberries and Methomyl on Sugarcane. (Compilation; unpublished study received May 17, 1982 under 2E2687; CDL: 070861­ A) 00104843 Study ADP record deleted. Study is a duplicate of MRID 38869 00104845 E. I. du Pont de Nemours & Co., Inc. (1979) Results of Tests on the Amount of Residue Remaining on Treated Crop: Hexazinone plus Metabolites. (Compilation; unpublished study received May 24, 1979 under 9G2214; CDL: 098309­ C) 00104846 Rapisarda, C. Metabolism of 14C­ labeled Hexazinone in Alfalfa: Doc. No. HME 12­ 79. (Unpublished study received May 24, 1979 under 9G2214; submitted by E. I. du Pont de Nemours & Co., Inc., Wilmington, DE; CDL: 098309­ D) 00114039 E. I. du Pont de Nemours & Co., Inc. (1978) Investigations Made with Respect to Residue Chemistry: [Velpar]. (Compilation; unpublished 50 study received Aug 29, 1978 under 352­ 378; CDL: 097321­ E) 00118050 E. I. du Pont de Nemours & Co., Inc. (1982) Data Supporting Amendment of Velpar Weed Killer Use on Alfalfa and Adding Velpar L Weed Killer Use on Alfalfa. (Unpublished study received Nov 15, 1982 under 352­ 378; CDL: 248831­ A) 00126127 E. I. du Pont de Nemours & Co., Inc. (1983) Results of Tests on the Amount of Residue Remaining on Treated Crop: Hexazinone. (Compilation; unpublished study received Feb 28, 1983 under 352­ 378; CDL: 071438­ A) 00138226 E. I. du Pont de Nemours & Co., Inc. (1984) Residue Chemistry Data Supporting the Use of Velpar L Weed Killer for Control of Undesirable Woody Plants in Rangeland. (Compilation; unpublished study received Apr 4, 1984 under 352­ 392; CDL: 252954­ A) 00140161 Magnitude of the Residue in Animals 41008401 Rapisarda, C. (1980) Rotational Crop Studies with 14C­ LabeledHexazinone Laboratory Project AMR­ 26­ 80. Unpublished study prepared by E. I. du Pont de Nemours & Co. 25 p. 41524801 Hawkins, W.; Elsom, L.; Gray, S., et al. (1990) The Metabolism of Carbon 14­ Hexazinone in Laying Hens: Lab Project Number: 203/ 90454: AMR­ 1517­ 89. Unpublished study prepared by Huntingdon Research Centre, Ltd. 80 p. 41572101 Fomenko, J. (1990) Testing of DPX­ A3674 through FDA Multi­ Residue Protocols A­ E: Lab Project Number: AMR­ 1489­ 89: DP001­ 01. Unpublished study prepared by Spectralytix. 67 p. 41572102 Fomenko, J. (1990) Testing of IN­ T3937 through FDA Multi­ Residue Protocols A­ E: Lab Project Number: AMR­ 1490­ 89: DP001­ 02. Unpublished study prepared by Sprectalytix Inc. 57 p. 41572103 Fomenko, J. (1990) Testing of IN­ A3928 through FDA Multi­ Residue Protocols A­ E: Lab Project Number: AMR­ 1491­ 89: DP001­ 03. Unpublished study prepared by Spectralytix, Inc. 67 p. 41572104 Fomenko, J. (1990) Testing of IN­ T3935 through FDA Multi­ Residue Protocols A­ E: Lab Project Number: AMR­ 1492­ 89: DP001­ 04. Unpublished study prepared by Spectralytix Inc. 57 p. 51 41572105 Fomenko, J. (1990) Testing of IN­ B2838 through FDA Multi­ Residue Protocols A­ E: Lab Project Number: AMR­ 1493­ 89: DP001­ 05. Unpublished study prepared by Spectralytix Inc. 67 p. 41572106 Fomenko, J. (1990) Testing of IN­ B3936 through FDA Multi­ Residue Protocols A­ E: Lab Project Number: AMR­ 1494­ 89: DP001­ 06. Unpublished study prepared by Spectralytix Inc. 67 p. 41898301 Bollin, E. (1991) Magnitude of Residues of Velpar Herbicide in Pasture and Range Grasses: Lab Project Number: AMR­ 1429­ 89. Unpublished study prepared by E. I. du Pont de Nemours and Co. 241 p. 41964101 Bollin, E.; Hay, R. (1991) Magnitude of Residues of Velpar and Velpar L Herbicide in Lowbush Blueberries: Lab Project Number: AMR­ 1431­ 89. Unpublished study prepared by E. I. du Pont de Nemours and Co. 46 p. 41964102 Bollin, E.; Hay, R. (1991) Magnitude of Residues of Velpar and Velpar L Herbicide in Highbush Blueberries: Lab Project Number: AMR­ 1434­ 89. Unpublished study prepared by E. I. du Pont de Nemours and Co. 46 p. 42187901 Hawkins, D.; Elsom, L.; Dighton, M.; et al. (1992) The Metabolism of Carbon 14­ Hexazinone in the Goat: Lab Project Number: 245/ 91718: AMR­ 1906­ 90. Unpublished study prepared by Huntingdon Research Centre Ltd. 105 p. 42219301 Hawkins, D.; Elsom, L.; Dighton, M.; (1992) The Metabolism of Carbon 14­ Hexazinone in Laying Hens: The Freezer Storage Stability of Tissues, Eggs and Excreta from Laying Hens Dosed with Carbon 14­ Hexazinone: Supplement to: Lab Project Number: HRC/ 203/ 90454; AMR­ 1517­ 89. Unpublished study prepared by Huntingdon Research Centre Ltd. 33 p. 42248901 Hawkins, D.; Elsom, L.; Dighton, M. (1992) The Metabolism of Carbon­ 14 Hexazinone in the Goat, Supplement 1: The Freezer Storage Stability of Carbon­ 14 Residues in Tissues and Milk from a Lactating Goat Dosed with Carbon 14 Hexazinone: Lab Project Number: HRC/ DPT 245/ 91718: AMR­ 1906­ 90. Unpublished study prepared by Huntingdon Research Centre. 36 p. 42276001 Powley, C.; Tomic, D. (1992) Magnitude of the Residue of Velpar Herbicide in Sugarcane and its Processed Fractions: Lab Project Number: AMR 1473­ 89: 35­ 5300: 14­ 5308. Unpublished study prepared by Dupont and Hawaiian Sugar Planters Association. 151 p. 52 42322701 Powley, C.; Tomic, D. (1992) Magnitude of Residues of Velpar Herbicide in Sugarcane: Lab Project Number: AMR 1472­ 89: 14­ 5308. Unpublished study prepared by E. I. DuPont de Nemours and Co. and Hawaiian Sugar Planters Assoc. 180 p. 42417901 Mulcahey, L. (1992) Magnitude of the Residues of Velpar Herbicide in Sugarcane and its Processed Fractions (Supplemental): Lab Project Number: AMR 1473­ 89 (SUPP 1): 35­ 5300: 14­ 5308. Unpublished study prepared by E. I. DuPont de Nemours and Co. in coop with the Hawaiian Sugar Planters' Assoc. 40 p. 42418001 Klemens, A.; Tomic, D. (1992) Freezer Storage Stability of Hexazinone and Metabolites in Pasture and Range Grasses. Lab Project Number: AMR 1582­ 90: A022.005. Unpublished study prepared by E. I. DuPont de Nemours and Co. in coop with Huntingdon Analytical Services. 54 p. 42419101 Mulcahey, L. (1992) Magnitude of Residues of Velpar Herbicide in Pasture and Range Grasses: A Supplement: Lab Project Number: AMR 1429­ 89: 1022.004: 91012. Unpublished study prepared by E. I. du Pont de Nemours and Co. 89 p. 42423001 Klemens, A.; Devine, P. (1992) Freezer Storage Stability of Velpar Herbicide and Metabolites on Blueberries: Lab Project Number: AMR 1911­ 90. Unpublished study prepared by E. I. DuPont de Nemours and Co. 47 p. 42492101 Powley, C.; Tomic, D. (1992) Magnitude of Residues of Velpar Herbicide in the Processed Fractions of Pineapples: Lab Project Number: AMR 1471­ 89: MP 90­ 03.01: 36­ 5309. Unpublished study prepared by E. I. du Pont de Nemours & Co. 114 p. 42535601 Powley, C.; Tomic, D. (1992) Magnitude of Residues of Velpar Herbicide in Pineapples: Lab Project Number: AMR 1570­ 89: 36­ 5309. Unpublished study prepared by E. I. du Pont de Nemours and Co.; Hawaiian Sugar Planters' Association. 81 p. 42690601 Hawkins, D. R.; Elsom, L. F.; Gray, S. P., et al. (1990) The Metabolism of 14C­ Hexazinone in Laying Hens, Supplement 2. Du Pont AMR­ 1517­ 89, Supplement 2. Unpublished study prepared by E. I. du Pont de Nemours & Co., Inc. 42824001 Rapisarda, C. (1993) Rotational Crop Studies with (carbon 14)­ Labeled Hexazinone: Supplement No. 1: Lab Project Number: AMR 26­ 80. Unpublished study prepared by E. I. du Pont de Nemours and Co. 11 p. 53 42867501 Klemens, A.; Devine, P. (1993) Freezer Storage Stability of Hexazinone and Metabolites in Pasture and Range Grasses: Supplement No. 1: Lab Project Number: AMR 1582­ 90: A022.005. Unpublished study prepared by E. I. du Pont de Nemours and Co. and Huntingdon Analytical Services. 72 p. 42987201 Powley, C.; Zhou, M.; DeBernard, P. (1993) Method for the Determination of Hexazinone in Sugarcane and Processed Fractions: Lab Project Number: AMR 2654­ 93. Unpublished study prepared by DuPont Agricultural Products. 30 p. 43025401 Bruns, G. (1993) Independent Laboratory Validation of the Analytical Enforcement Method for the Determination of Hexazinone in Sugarcane, Molasses, and Bagasse by Gas Chromatography: Lab Project Number: DUP69/ REP: AMR/ 2804/ 93. Unpublished study prepared by Enviro­ Test Labs. 34 p. 43074201 Hawkins, D.; Elsom, L.; Dighton, M.; et al. (1993) A Comparison of (carbon 14)­ Hexazinone Metabolites in Hen Tissues and Eggs and Goat Tissues and Milk Synthesised Metabolite Standards: Lab Project Number: 294/ 932331: DPT/ 294/ 932331: HRC/ DPT/ 294/ 932331. Unpublished study prepared by Huntingdon Research Centre Ltd. 110 p. 43074401 Djanegara, T.; Devine, P. (1993) Magnitude of Residues of Hexazinone in Alfalfa Forage, Hay, and Seed Grown in the Western United States Following Application of Velpar Herbicide: Lab Project Number: AMR 1924­ 91: 92013. Unpublished study prepared by E. I. du Pont de Nemours & Co. and Spectralytix, Inc. 330 p. 43074402 Djanegara, T.; Devine, P. (1993) Magnitude of Residues of Hexazinone in Alfalfa Forage and Hay Grown in the Eastern United States Following Application of Velpar Herbicide: Lab Project Number: AMR 2010­ 91: 92025. Unpublished study prepared by E. I. du Pont de Nemours & Co. and Spectralytix, Inc. 316 p. 43401901 Powley, C.; Devine, P. (1994) Magnitude of Residues of Velpar Herbicide in the Processed Fractions of Pineapples: Supplement No. 1: Lab Project Number: MP/ 90/ 03/ 01: 5309: AMR/ 1471/ 89. Unpublished study prepared by E. I. du Pont de Nemours and Co.; Maui Pineapple Co., Ltd.; and Hawaiian Sugar Planters' Association. 74 p. 43488901 Hawkins, D.; Elsom, L.; Dighton, M. et al. (1994) A Comparison of (carbon 14)­ Hexazinone Metabolites in Hen Tissues and Eggs and Goat Tissues and Milk With Synthesised Metabolite Standards: Supplement 1: 54 Examples of Calculations and Chromatographic Raw Data: Lab Project Number: DPT 294/ 932331: AMR 2633­ 93. Unpublished study prepared by Huntingdon Research Centre, Ltd. 94 p. 43524301 Mulcahey, L.; Orescan, D. (1995) Freezer Storage Stability of Hexazinone and Metabolites in Pasture and Range Grasses: Supplement No. 2: Lab Project Number: AMR 1582­ 90: HAS­ A022.005: SPX­ 92020. Unpublished study prepared by DuPont Agricultural Products; Huntingdon Analytical Services; and Spectralytix. 76 p. 43703501 Mulcahey, L.; George, S.; Brisbin, J. et al. (1995) Magnitude of Residues of Hexazinone in Edible Tissues and Milk of Lactating Dairy Cows: Lab Project Number: . 43892401 Djanegara, T.; Reardon­ Green, L. (1996) Confined Accumulation Study of (4­ Carbonyl­( carbon 14))­ Hexazinone (DPX­ A3674) in Rotational Crops: Lab Project Number: AMR 2800­ 93. Unpublished study prepared by DuPont Agricultural Products. 115 p. Relatesto letter L0000071. 43936501 Mulcahey, L. (1996) Freezer Storage Stability of Hexazinone and Metabolites in Pasture and Range Grasses: Supplement No. 3 (Final): Lab Project Number: AMR 1582­ 90: HAS­ A022.005: SPX­ 92020. Unpublished study prepared by DuPont Agricultural Products; Huntingdon Analytical Services and Environmental Analytical Services. 63 p. 44133501 Bollin, E. (1996) Magnitude of the Residue of Hexazinone in Alfalfa Forage, Hay, and Seed Grown in the Western United States Following Application of Velpar Herbicide: Supplement No. 1 to MRID 43074401: Lab Project Number: AMR 1924­ 91: 92013. Unpublished study prepared by DuPont Agricultural Products and Environmental Analytical Services, Inc. 40 p. 44259101 Brill, F.; Bramble, F.; Norwood, G.; et al. (1997) Enforcement Analytical Method for the Determination of Hexazinone and Metabolites of Interest in Animal Tissues and Milk Using ESI­ LC/ MS: Lab Project Number: AMR 3783­ 96. Unpublished study prepared by E. I. du Pont de Nemours and Co. 100 p. 44259102 Xu, B. (1997) Independent Laboratory Validation of a Proposed Enforcement Analytical Method for the Determination of Hexazinone and Metabolites of Interest in Animal Tissue and Milk Using ESI­ LC/ MS: Lab Project Number: AMR 4366­ 97: 008­ 07. Unpublished study prepared by Centre Analytical Laboratories, Inc. 117 p. 55 45084101 Brill, F. (2000) Magnitude of Residues of Hexazinone in Rotational Crops Following Application of Velpar Herbicide at Maximum Label Rates to Alfalfa: Lab Project Number: AMR 4336­ 97. Unpublished study prepared by E. I. du Pont de Nemours and Co. 253 p.

epa

2024-06-07T20:31:42.914317

regulations

EPA-HQ-OPP-2002-0188-0020

Supporting & Related Material

[Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 1 of 13 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: 05/ 14/ 2002 SUBJECT: Hexazinone Acute and Chronic Dietary Exposure Assessments for the TRED. PC Code: 107201 DP Barcode: D279898 REVIEWER: John S. Punzi, Ph. D., Chemist Reregistration Branch II Health Effects Division (7509C) THROUGH: Richard Griffin, DESAC Reviewer Branch/ Health Effects Division (7509C) Alan Nielsen, Branch Senior Scientist Branch/ Health Effects Division (7509C) TO: Dirk Helder, Chemical Review Manager Reregistration Branch II Special Review and Reregistration Division (7509C) and Carol Christensen, Risk Assessor Reregistration Branch II Health Effects Division (7509C) Executive Summary The purpose of this memorandum is to report the results of a Tier 1 dietary exposure analysis for hexazinone. In this analysis the acute and chronic dietary exposure and risk estimates resulting from food intake were determined for the U. S. population and various population subgroups. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 2 of 13 Acute and chronic dietary exposure assessments were performed in order to determine the exposure and risk estimates which result from the use of hexazinone on the crops included in the reregistration eligibility decision. Hexazinone residues of concern for plants are parent plus metabolites A, B, C, D, E (see D279897, S. Kinard 02/ 05/ 2002) for structures and metabolite discussion). The tolerance values for hexazinone in/ on blueberry, pineapple, and sugarcane are based on the analytical method's limit of quantitation (LOQ) and all non detectable residues were found in residue studies (see D279899, J. Punzi, 05/ 15/ 2002). This analysis used a single residue estimate based on the reassessed tolerance for blueberry, pineapple, and sugarcane. Default processing factors and 100% crop treated were used for residue input into DEEM. Hexazinone residues of concern in ruminant milk are hexazinone plus metabolites B, C, C­ 2, and F. Hexazinone residues of concern in ruminant tissue are hexazinone plus metabolites B and F. For purposes of risk assessment however, the residues of concern in livestock milk and tissue are hexazinone plus metabolites B, C, C­ 1, C­ 2, and F. The livestock feeding study indicates significant residues in milk at all feeding levels and quantifiable residues in kidney. When the residue levels are corrected for exaggerated rates the values are less than the sum of the LOQ's for the residues of concern. Based on the analytical method's LOQ the reside estimate for meats and milk are 0.24 ppm. Default processing factors and 100% crop treated were used for residue input into DEEM. The chronic dietary risk estimates are provided for the U. S. population (total) and various population subgroups. This assessment concludes that the exposure is below HED's level of concern for all population subgroups examined. Exposures, as a percentage of the RfD, ranged from approximately 3% for females aged 13 through 50 years to 15% for children aged 1 through 6 years. The acute dietary risk estimates are provided for the population subgroup consisting of females aged 13 through 50 years only. This assessment concludes that the exposure is below HED's level of concern for this subgroup. Exposures as a percentage of the RfD are calculated to be less than 1% at the 95 th percentile. I. Introduction Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic assessments, the risk is expressed as a percentage of a maximum acceptable dose. This dose is the highest daily dose which HED has deemed will pose no unreasonable adverse health effects and is called the population adjusted dose (PAD). The PAD is equivalent to the Reference Dose (RfD) divided by the FQPA Safety Factor. Dietary risk is expressed as a percentage of the PAD. HED's level of concern is exceeded when the dietary risk exceeds 100% of the PAD. References which discuss the acute and chronic risk assessments in more detail are available on the EPA/ pesticides web site: "Available Information on Assessing Exposure from Pesticides, A User's Guide", 6/ 21/ 2000, web link: [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 3 of 13 http:// www. epa. gov/ fedrgstr/ EPA­ PEST/ 2000/ July/ Day­ 12/ 6061. pdf ; or see SOP 99.6 (8/ 20/ 99). II. Residue Information Hexazinone tolerances are established under 40 CFR §180.396 (a) and (b). The tolerance for plant and animal commodities, is currently expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). Tolerances are currently established for; alfalfa; alfalfa hay; blueberries; cattle, goat, hog, and horse fat, meat, and meat by products; range grasses, pasture grasses, milk, pineapple and sugarcane. Current tolerances range from 0.1 ppm in/ on meats and milk to 10 ppm on grasses. Reassessed tolerances range from 0.1 ppm to 4 ppm. Tolerances are not currently needed for livestock fat, hog meat, and hog meat by products. HED is recommending that in order to reassess the established hexazinone tolerances for milk and the fat, meat, and meat byproducts of livestock and to compute a maximum theoretical dietary burden (MTDB) of hexazinone to livestock, uses on pasture and rangland grasses must be revoked. A MTDB could not be calculated including grass and grass hay since additional residue data are required for use patterns in which significant residues are expected in/ on the RACs. HED recognizes that the estimated 100,000 acres of pasture and rangeland treated with hexazinone is relatively low. Since grass and grass hay are considered major dietary components of ruminants (up to 60% of the diet per current OPPTS GLN) a MTDB for livestock could not be developed when grasses are included in the registered uses. HED has determined that a MTDB could be constructed from other potential feed items for livestock and subsequently tolerances for meats and milk can be reassessed. Hexazinone residues of concern for plants are parent plus metabolites A, B, C, D, E (see D279897, S. Kinard 02/ 05/ 2002, for structures and metabolite discussion). The tolerance values for hexazinone in/ on blueberry, pineapple, and sugarcane are based on the analytical method's limit of quantitation (LOQ) and all non detectable residues were found in residue studies (see D279899, J. Punzi, 05/ 05/ 2002). This analysis used a single residue estimate based on the reassessed tolerance for blueberry, pineapple, and sugarcane. Default processing factors and 100% crop treated were used for residue input into DEEM. Hexazinone residues of concern in ruminant milk are hexazinone plus metabolites B, C, C­ 2, and F. Hexazinone residues of concern in ruminant tissue are hexazinone plus metabolites B and F. For purposes of risk assessment however, the residues of concern in livestock milk and tissue are hexazinone plus metabolites B, C, C­ 1, C­ 2, and F. The livestock feeding study indicates significant residues in milk at all feeding levels and quantifiable residues in kidney. When the residue levels are corrected for exaggerated rates the values are less than the sum of the LOQ's for the residues of concern. Based on the analytical method's LOQ the reside estimate for meats and milk are 0.24 ppm. Default processing factors and 100% crop treated were used for residue input into DEEM. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 4 of 13 Residue Data used for Acute and Chronic Assessments: This TIER 1 analysis used a single residue estimate based on the reassessed tolerance for blueberry, pineapple, and sugarcane. Default processing factors and 100% crop treated were used for residue input into DEEM. For purposes of risk assessment however, the residues of concern in livestock milk and tissue are hexazinone plus metabolites B, C, C­ 1, C­ 2, and F. The same data are being used in both acute and chronic analysis. III. DEEM™ Program and Consumption Information Hexazinone acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model (DEEM™) software, Version [7.76], which incorporates consumption data from USDA's Continuing Surveys of Food Intake by Individuals (CSFII), 1989­ 1992. The 1989­ 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive days, and therefore represent more than 30,000 unique "person days" of data. Foods "as consumed" (e. g., apple pie) are linked to raw agricultural commodities and their food forms (e. g., apples­ cooked/ canned or wheat­ flour) by recipe translation files internal to the DEEM software. Consumption data are averaged for the entire U. S. population and within population subgroups for chronic exposure assessment, but are retained as individual consumption events for acute exposure assessment. For chronic exposure and risk assessment, an estimate of the residue level in each food or foodform (e. g., orange or orange­ juice) on the commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms on the commodity residue list to arrive at the total average estimated exposure. Exposure is expressed in mg/ kg body weight/ day and as a percent of the cPAD. This procedure is performed for each population subgroup. For acute exposure assessments, individual one­ day food consumption data are used on an individual­ by­ individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic (Tier 1 or Tier 2) exposure assessment, or "matched" in multiple random pairings with residue values and then summed in a probabilistic (Tier 3/ 4) assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user (i. e., those who reported eating relevant commodities/ food forms) and a per­ capita (i. e., those who reported eating the relevant commodities as well as those who did not) basis. In accordance with HED policy, per capita exposure and risk are reported for all tiers of analysis. However, for tiers 1 and 2, significant differences in user vs. per capita exposure and risk are identified and noted in the risk assessment. HED notes that there is a degree of uncertainty in extrapolating exposures for certain population subgroups which may not be sufficiently represented in the consumption surveys, (e. g., nursing and non­ nursing infants or Hispanic females). Therefore, risks estimated for these subpopulations were included in representative populations having sufficient numbers of survey [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 5 of 13 respondents (e. g., all infants, or females 13­ 50 years). IV. Toxicological Information The toxicological endpoint summary table below is from the HIARC document (01/ 16/ 2002, TXR# 0050371). The FQPA SF was obtained from the committee report (05/ 15/ 2002, TXR# 0050750). Table 1. Summary of Toxicological Doses and Endpoints for [CHEMICAL] for Use in Dietary Exposure Assessment Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF* and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary [Female 13­ 50] NOAEL = [400] mg/ kg/ day UF = [100] Acute RfD = [4.0] mg/ kg/ day FQPA SF = [10] aPAD =[ 0.40] mg/ kg/ day [Developmental Toxicity­ Rat] LOAEL = [ 900] mg/ kg/ day based on [decreased fetal weight, malformation of kidneys] Chronic Dietary all populations NOAEL= [5] mg/ kg/ day UF = [100] Chronic RfD = [0.05] mg/ kg/ day FQPA SF = [1] cPAD =[ ] = [0.05] mg/ kg/ day [Chronic One Year Feeding­ Dog] LOAEL = [ ~40] mg/ kg/ day based on [hepatotoxicity] V. Results/ Discussion As stated above, for acute and chronic assessments, HED's level of concern is exceeded when the dietary risk exceeds 100% of the PAD. The DEEM analyses can estimate the dietary exposure of the U. S. population and 26 population subgroups. The results reported in Table 2 are for the appropriate subpopulation, females aged 13 to 50 years. The results reported in Table 3 are for the U. S. Population (total), all infants (< 1 year old), children 1­ 6, children 7­ 12, females 13­ 50, males 13­ 19, males 20+, and seniors 55+. The results for the other population subgroups are included in the appendices. They are not included in the tables because the numbers of respondents in the other subgroups were not sufficient; and therefore, the exposure estimates for these subgroups contained higher levels of uncertainty. However, the respondents in these subgroups were also part of larger subgroups which are listed in the Tables. For example, nursing and non­ nursing infants are included in all infants. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 6 of 13 Results of Acute Dietary Exposure Analysis Results are reported at the 95th percentile of exposure because the assessment incorporated 100% CT. The acute dietary risk estimates are provided for the population subgroup consisting of females aged 13 through 50 years only. This assessment concludes that the exposure is below HED's level of concern for this subgroup. Exposures as a percentage of the RfD are calculated to be less than 1% at the 95 th percentile. Table 2. Results of Acute Dietary Exposure Analysis at the 95 th Percentile of Exposure Population Subgroup aPAD (mg/ kg/ day) Exposure (mg/ kg/ day) % aPAD Females 13­ 50 years old 0. 40 0. 003475 <1 Results of Chronic Dietary Exposure Analysis Table 3. Results of Chronic Dietary Exposure Analysis Population Subgroup cPAD (mg/ kg/ day) Exposure (mg/ kg/ day) % cPAD U. S. Population (total) 0. 05 0. 002118 4 All Infants (< 1 year) 0. 05 0. 003629 7 Children 1­ 6 years 0. 05 0. 007304 15 Children 7­ 12 years 0. 05 0. 003899 8 Females 13­ 50 0.05 0.001265 3 Males 13­ 19 0.05 0.002315 5 Males 20+ years 0. 05 0. 001183 2 Seniors 55+ 0.05 0.001123 2 The chronic dietary risk estimates are provided for the U. S. population (total) and various population subgroups. This assessment concludes that the exposure is below HED's level of concern for all population subgroups examined. Exposures, as a percentage of the RfD, ranged from approximately 3% for females aged 13 through 50 years to 15% for children aged 1 through 6 years. VII. Conclusions [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 7 of 13 The Tier 1 acute and chronic dietary risk assessments were conducted for all supported hexazinone food uses. Dietary risk estimates are provided for the U. S. population (total) and various population subgroups. This assessment concludes that for all supported registered commodities, the acute risk estimates are below the Agency's level of concern at the 95 th exposure percentile for the population subgroup consisting of females aged 13 to 50 years. The acute dietary exposure estimate for this group is <1% of the aPAD. This assessment also concludes that for all commodities, the chronic risk estimates are below the Agency's level of concern for the U. S. population (total) (4% of the cPAD) and all population subgroups. The most highly exposed population subgroup is children aged 1 to 6 years. The chronic dietary exposure estimate for the highest exposed population subgroup is 15% of the cPAD. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 8 of 13 Apendix U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for HEXAZINONE (1989­ 92 data) Residue file name: C:\ deem\ hexazinone_ nopork. RS7 Adjustment factor #2 used. Analysis Date 05­ 15­ 2002/ 12: 57: 29 Residue file dated: 05­ 15­ 2002/ 12: 12: 42/ 8 Reference dose (RfD, Chronic) = .05 mg/ kg bw/ day =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Percent of Subgroup body wt/ day Rfd ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­­­­ U. S. Population (total) 0.002118 4.2% U. S. Population (spring season) 0.002129 4.3% U. S. Population (summer season) 0.002075 4.2% U. S. Population (autumn season) 0.002208 4.4% U. S. Population (winter season) 0.002060 4.1% Northeast region 0.002098 4.2% Midwest region 0.002360 4.7% Southern region 0.001942 3.9% Western region 0.002147 4.3% Hispanics 0.002297 4.6% Non­ hispanic whites 0.002126 4.3% Non­ hispanic blacks 0.001914 3.8% Non­ hisp/ non­ white/ non­ black 0.002242 4.5% All infants (< 1 year) 0.003629 7.3% Nursing infants 0.000963 1.9% Non­ nursing infants 0.004751 9.5% Children 1­ 6 yrs 0.007304 14.6% Children 7­ 12 yrs 0.003899 7.8% Females 13­ 19 (not preg or nursing) 0.001791 3.6% Females 20+ (not preg or nursing) 0.001104 2.2% Females 13­ 50 yrs 0.001265 2.5% Females 13+ (preg/ not nursing) 0.001947 3.9% Females 13+ (nursing) 0.001973 3.9% Males 13­ 19 yrs 0.002315 4.6% Males 20+ yrs 0.001183 2.4% Seniors 55+ 0.001123 2.2% Pacific Region 0.002128 4.3% ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 9 of 13 Attachment (electronic file id 107201accr. rs7). cc: JSPunzi (RRB2), Hexazinone Reg. Std. File, Hexazinone SF, RF, LAN. 7509C: RRB2: John S. Punzi: CM2: Rm 712M: 703­ 305­ 7727: 05/ 15/ 2002. "hexazinone" 0.05 NEWD, 0.04 NOEL, 0 0 0 05­ 15­ 2002/ 12: 12: 42 999 0 7 "01009AA"," 13B", 0.3 1 1 7 "Blueberries", "" 11 Uncooked, 0.3 1 1 "" 12 Cooked: NFS, 0.3 1 1 "" 13 Baked, 0.3 1 1 "" 14 Boiled, 0.3 1 1 "" 15 Fried, 0.3 1 1 "" 31 Canned: NFS, 0.3 1 1 "" 41 Frozen: NFS, 0.3 1 1 "" 89 "06013AA"," O", 0.3 1 1 7 "Pineapples­ peeled fruit", "" 11 Uncooked, 0.3 1 1 "" 12 Cooked: NFS, 0.3 1 1 "" 13 Baked, 0.3 1 1 "" 14 Boiled, 0.3 1 1 "" 31 Canned: NFS, 0.3 1 1 "" 33 Canned: Baked, 0.3 1 1 "" 41 Frozen: NFS, 0.3 1 1 "" 90 "06013DA"," O", 0.3 5 1 1 "Pineapples­ dried", "" 18 Dried, 0.3 5 1 "" 91 "06013JA"," O", 0.3 1.7 1 5 "Pineapples­ juice", "" 11 Uncooked, 0.3 1.7 1 "" 12 Cooked: NFS, 0.3 1.7 1 "" 14 Boiled, 0.3 1.7 1 "" 31 Canned: NFS, 0.3 1.7 1 "" 42 Frozen: Cooked, 0.3 1.7 1 "" 283 "25003SA"," O", 0.6 1 1 0 "Sugar­ cane", "" 284 "25003SB"," O", 4 1 1 0 "Sugar­ cane/ molasses", "" 318 "50000DB"," D", 0.24 1 1 0 "Milk­ nonfat solids", "" 319 "50000FA"," D", 0.24 1 1 14 "Milk­ fat solids", "" 12 Cooked: NFS, 0.24 1 1 "" 13 Baked, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 16 Pasteurized, 0.24 1 1 "" 18 Dried, 0.24 1 1 "" 31 Canned: NFS, 0.24 1 1 "" 32 Canned: Cooked, 0.24 1 1 "" 34 Canned: Boiled, 0.24 1 1 "" 41 Frozen: NFS, 0.24 1 1 "" 42 Frozen: Cooked, 0.24 1 1 "" 45 Frozen: Fried, 0.24 1 1 "" 51 Cured: NFS (smoked/ p, 0.24 1 1 "" 52 Cured: Cooked( smokd/, 0.24 1 1 "" 320 "50000SA"," D", 0.24 1 1 14 "Milk sugar (lactose)", "" 12 Cooked: NFS, 0.24 1 1 "" 13 Baked, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 16 Pasteurized, 0.24 1 1 "" 18 Dried, 0.24 1 1 "" 31 Canned: NFS, 0.24 1 1 "" 32 Canned: Cooked, 0.24 1 1 "" 34 Canned: Boiled, 0.24 1 1 "" 41 Frozen: NFS, 0.24 1 1 "" 42 Frozen: Cooked, 0.24 1 1 "" 45 Frozen: Fried, 0.24 1 1 "" 51 Cured: NFS (smoked/ p, 0.24 1 1 "" 52 Cured: Cooked( smokd/, 0.24 1 1 "" 321 "53001BA"," M", 0.24 1 1 8 "Beef­ meat byproducts", "" 12 Cooked: NFS, 0.24 1 1 "" 13 Baked, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 31 Canned: NFS, 0.24 1 1 "" 41 Frozen: NFS, 0.24 1 1 "" 42 Frozen: Cooked, 0.24 1 1 "" 52 Cured: Cooked( smokd/, 0.24 1 1 "" 322 "53001BB"," M", 0.24 1 1 3 "Beef­ other organ meats", "" 12 Cooked: NFS, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 52 Cured: Cooked( smokd/, 0.24 1 1 "" 323 "53001DA"," M", 0.24 1.92 1 0 "Beef­ dried", "" 325 "53001KA"," M", 0.24 1 1 2 "Beef­ kidney", "" 12 Cooked: NFS, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 326 "53001LA"," M", 0.24 1 1 3 "Beef­ liver", "" 12 Cooked: NFS, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 327 "53001MA"," M", 0.24 1 1 13 "Beef­ lean (fat/ free) w/ o bones", "" 11 Uncooked, 0.24 1 1 "" 12 Cooked: NFS, 0.24 1 1 "" 13 Baked, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 31 Canned: NFS, 0.24 1 1 "" 32 Canned: Cooked, 0.24 1 1 "" 33 Canned: Baked, 0.24 1 1 "" 34 Canned: Boiled, 0.24 1 1 "" 42 Frozen: Cooked, 0.24 1 1 "" 51 Cured: NFS (smoked/ p, 0.24 1 1 "" 52 Cured: Cooked( smokd/, 0.24 1 1 "" 59 Cured: Dried (smokd/, 0.24 1 1 "" 328 "53002BA"," M", 0.24 1 1 0 "Goat­ meat byproducts", "" 329 "53002BB"," M", 0.24 1 1 0 "Goat­ other organ meats", "" 331 "53002KA"," M", 0.24 1 1 0 "Goat­ kidney", "" 332 "53002LA"," M", 0.24 1 1 0 "Goat­ liver", "" 333 "53002MA"," M", 0.24 1 1 3 "Goat­ lean (fat/ free) w/ o bone", "" 12 Cooked: NFS, 0.24 1 1 "" 13 Baked, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 334 "53003AA"," M", 0.24 1 1 0 "Horsemeat", "" 336 "53005BA"," M", 0.24 1 1 2 "Sheep­ meat byproducts", "" 12 Cooked: NFS, 0.24 1 1 "" 31 Canned: NFS, 0.24 1 1 "" 337 "53005BB"," M", 0.24 1 1 0 "Sheep­ other organ meats", "" 339 "53005KA"," M", 0.24 1 1 0 "Sheep­ kidney", "" 340 "53005LA"," M", 0.24 1 1 0 "Sheep­ liver", "" 341 "53005MA"," M", 0.24 1 1 4 "Sheep­ lean (fat free) w/ o bone", "" 12 Cooked: NFS, 0.24 1 1 "" 13 Baked, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 398 "50000WA"," D", 0.24 1 1 15 "Milk­ based water", "" 12 Cooked: NFS, 0.24 1 1 "" 13 Baked, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 16 Pasteurized, 0.24 1 1 "" 18 Dried, 0.24 1 1 "" 31 Canned: NFS, 0.24 1 1 "" 32 Canned: Cooked, 0.24 1 1 "" 33 Canned: Baked, 0.24 1 1 "" 34 Canned: Boiled, 0.24 1 1 "" 41 Frozen: NFS, 0.24 1 1 "" 42 Frozen: Cooked, 0.24 1 1 "" 43 Frozen: Baked, 0.24 1 1 "" 45 Frozen: Fried, 0.24 1 1 "" 52 Cured: Cooked( smokd/, 0.24 1 1 "" 406 "06013JC"," O", 0.3 6.3 1 4 "Pineapples­ juice­ concentrate", "" 12 Cooked: NFS, 0.3 6.3 1 "" 31 Canned: NFS, 0.3 6.3 1 "" 33 Canned: Baked, 0.3 6.3 1 "" 41 Frozen: NFS, 0.3 6.3 1 "" 425 "56000MA"," M", 0.24 1 1 5 "Veal­ lean (fat free) w/ o bones", "" 12 Cooked: NFS, 0.24 1 1 "" 13 Baked, 0.24 1 1 "" 14 Boiled, 0.24 1 1 "" 15 Fried, 0.24 1 1 "" 31 Canned: NFS, 0.24 1 1 "" 426 "56000KA"," M", 0.24 1 1 0 "Veal­ kidney", "" 427 "56000LA"," M", 0.24 1 1 0 "Veal­ liver", "" 428 "56000BB"," M", 0.24 1 1 0 "Veal­ other organ meats", "" 429 "56000DA"," M", 0.24 1.92 1 0 "Veal­ dried", "" 430 "56000BA"," M", 0.24 1 1 0 "Veal­ meat byproducts", ""

epa

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regulations

EPA-HQ-OPP-2002-0188-0021

Supporting & Related Material

Quantitative Usage Analysis for Hexazinone Case Number: 0266 PC Code: 107201 Date: August 7, 2002 Analyst: Frank Hernandez Based on available pesticide usage information for the years of 1992 through 2001, total annual domestic usage of hexazinone averaged approximately one million pounds of active ingredient (a. i.) on about one million acres treated. Hexazinone is a herbicide with its largest markets, in terms of total pounds active ingredient, allocated to forestry (55%), alfalfa (35%), and pasture/ rangeland (7%). Crops with a high percentage of total U. S. planted acres treated include nurseries (4%), and alfalfa (2%). Crops with less than 1 percent of the site treated include berries, other hay, landscape, pasture/ rangeland, and sugarcane. Acres Pounds A. I. Application Rate Planted Treated 1,000 % 1,000 lbs. a. i./ A Alfalfa 25,000 500 2 350 0.7 Berries 100,000 11 <1 10 0.9 Forestry 50,000 400 1 550 1.4 Hay, Other 33,000 24 <1 8 0.3 Landscape 30,000 5 <1 10 2.0 Nurseries 400 15 4 10 0.7 Pasture/ Rangeland 90,000 77 <1 70 0.9 Sugarcane 1,000 2 <1 1 0.5 1,034 1,009 SOURCES: EPA data, USDA, and National Center for Food and Agricultural Policy

epa

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regulations

EPA-HQ-OPP-2002-0188-0022

Supporting & Related Material

TXR# 0051040 TXR# 0051040 August 12, 2002 August 12, 2002 OFFICE OF PREVENTION, PESTICIDES AND MEMORANDUM: TOXIC SUBSTANCES Subject: 107201: The Revised Toxicology Chapter for the TRED for Hexazinone. DP Barcode: D275620 Submission: S598837 ReReg Case# 0266 CAS#: 51235­ 04­ 02 From: David G Anderson RRB­ 2 HED (7509C) To: Carol Christensen, Risk Assessor RRB­ 2 HED (7509C) Thru: Alan Nielsen, BSS RRB­ 2, HED (7509C) cc Pauline Wagner The Revised Toxicology Chapter for the Tolerance Reassessment Evaluation Decision (TRED) for Hexazinone is attached. The old developmental toxicity in rabbits, which was considered a data gap has been replaced by a new acceptable developmental toxicity study in rabbits. The results from a new 3 rd HIARC report and a new 2 nd FQPA Safety Committee report have been included. ­1­ Hexazinone PC Code: 107201 Toxicology Disciplinary Chapter for the Tolerance Reassessment Evaluation Decision Document Date completed: August 12, 2002 Prepared for: Health Effects Division Office of Pesticide Programs U. S. Environmental Protection Agency Arlington, VA 22202 Prepared by: David G Anderson form: FINAL June 21, 2000 ­2­ TABLE OF CONTENTS 1.0 HAZARD CHARACTERIZATION ........................................ ­3­ 2.0 REQUIREMENTS ..................................................... ­4­ 3.0 DATA GAP( S)/ REQUIREMENT( S) ....................................... ­5­ 4.0 HAZARD ASSESSMENT ............................................... ­5­ 4.1 Acute Toxicity ................................................... ­5­ 4.2 Subchronic Toxicity ............................................... ­5­ 4.3 Prenatal Developmental Toxicity ...................................... ­8­ 4.4 Reproductive Toxicity ............................................ ­12­ 4.5 Chronic Toxicity ................................................. ­14­ 4.6 Carcinogenicity ................................................. ­15­ 4.7 Mutagenicity ................................................... ­18­ 4.8 Neurotoxicity ................................................... ­22­ 4.9 Metabolism .................................................... ­23­ 4.10 Special/ Other Studies ............................................. ­24­ 5.0 TOXICITY ENDPOINT SELECTION .................................... ­24­ 5.1 See Section 9.2 for Endpoint Selection Table. ........................... ­24­ 5.2 Dermal Absorption ............................................... ­24­ 5.3 Classification of Carcinogenic Potential ................................ ­24­ 6.0 FQPA CONSIDERATIONS ............................................ ­25­ 6.1 Special Sensitivity to Infants and Children .............................. ­25­ 6.2 Recommendation for a Developmental Neurotoxicity Study ................. ­25­ 7.0 OTHER ISSUES ...................................................... ­25­ 8.0 REFERENCES ....................................................... ­25­ Other references ...................................................... ­29­ 9.0 APPENDICES ..................................................... ­30­ 9.1 Toxicity Profile Summary Tables ..................................... ­31­ 9.1.1 Acute Toxicity Table ....................................... ­31­ 9.1.2 Subchronic, Chronic and Other Toxicity Tables ................... ­31­ 9.2 Summary of Toxicological Dose and Endpoints .......................... ­36­ HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 3 of 38 1.0 HAZARD CHARACTERIZATION Hexazinone is a herbicide used to control a broad spectrum of weeds including woody plants in alfalfa, rangeland, pastures, woodlands, pineapple, sugarcane and blueberries. Non­ crop areas include ornamental plants and forests. Hexazinone is used as a pre­ emergent, post emergence herbicide. It is applied by direct spray to plants and to soils. There are no non­ occupational (residential) uses. Hexazinone is a triazine herbicide, which structurally dissimilar and toxicology different from other triazines, such as atrazine. The selectivity of triazine herbicides depends on the plant's ability to degrade or metabolize the parent compound. Sensitive plants have limited ability to metabolize hexazinone. Hexazinone acts through inhibition of photosynthesis. Rat metabolism studies showed that hexazinone was rapidly absorbed and excreted and essentially no difference in the metabolism of males and females at high or low dose levels. Almost no parent hexazinone was recovered in urine or feces. Two major metabolites were recovered from feces and urine, in addition to lesser amounts of a third metabolite and individually small amounts of conjugated products from urine. Hexazinone has low acute toxicity by the oral (Category III), dermal (Category IV ) and inhalation routes (Category III). Primary eye irritation is severe, causing corneal opacity and moderate irritation in unwashed eyes (Category I). It causes mild skin irritation and is classified Category IV for skin irritation. It is not a skin sensitizer in the Guinea pig. The 21­ day dermal study in the rabbit showed no systemic toxicity and mild dermal irritation at the limit dose. Body weight decrement and liver toxicity were the most frequent effects shown in studies with hexazinone. Liver toxicity was seen in the chronic dog and mouse studies. Body weight decrement was seen in the chronic rat studies and the studies on reproduction. No quantitative or qualitative susceptibility was shown in the prenatal or reproduction studies. In a reproduction study, pup weight decrement occurred at the same dose as parental body weight decrement. No reproductive effects were seen in the study other than pup weight decrement. The rat prenatal study showed fetal weight decrement and possibly renal malformations but no increased susceptibility. The rabbit study possibly showed maternal and fetal weight decrement at the same dose levels. The chronic study in dogs showed severe body weight decrement, changes in liver related clinical chemistry values, and microscopic lesions. Body weight decrement was seen in a chronic carcinogenicity studies in rats and mice. Liver toxicity was seen in mice. The mouse carcinogenicity study showed an increased trend for liver carcinomas, but no pair wise significant increases. The rat study showed no carcinogenic potential. Based on these studies in rats and mice, hexazinone was classified in a group D, not classifiable as a carcinogen. Hexazinone is clastogenic in one in vitro test for chromosomal aberrations, but negative in the remaining six other mutagenicity studies including an in vivo micronucleus test in mouse bone marrow. The HIARC requested a 28­ day inhalation study with hexazinone because of the concern for potential inhalation exposure based on the use pattern. 2.0 REQUIREMENTS HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 4 of 38 The requirements (40 CFR 158.340) for food and non food use for HEXAZINONE are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Table 1. Test Technical Required Satisfied 870.1100 Acute Oral Toxicity .............................. 870.1200 Acute Dermal Toxicity ............................ 870.1300 Acute Inhalation Toxicity ......................... 870.2400 Primary Eye Irritation ............................. 870.2500 Primary Dermal Irritation .......................... 870.2600 Dermal Sensitization .............................. Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 870.3100 Oral Subchronic (rodent) .......................... 870.3150 Oral Subchronic (nonrodent) ...................... 870.3200 21­ Day Dermal ................................... 870.3250 90­ Day Dermal ................................... 870.3465 90­ Day Inhalation ................................ Yes Yes Yes No 1 No 2 Yes Yes Yes Yes No 870.3700a Developmental Toxicity (rodent) ................... 870.3700b Developmental Toxicity (nonrodent) ............... 870.3800 Reproduction ................................... Yes Yes Yes Yes Yes Yes 870.4100a Chronic Toxicity (rodent) ......................... 870.4100b Chronic Toxicity (nonrodent) ...................... 870.4200a Oncogenicity (rat) ............................... 870.4200b Oncogenicity (mouse) ............................ 870.4300 Chronic/ Oncogenicity ........................... Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 870.5100 Mutagenicity— Gene Mutation ­ bacterial ........... 870.5300 Mutagenicity— Gene Mutation ­ mammalian ......... 870.5375 Mutagenicity— Structural Chromosomal Aberrations . 870. 5395 Mutagenicity— Structural Chromosomal Aberrations. 870.5550 Mutagenicity— Other Genotoxic Effects ............ Yes Yes Yes Yes Yes No 3 Yes Yes Yes Yes 870.6100a Acute Delayed Neurotox. (hen) .................... 870.6100b 90­ Day Neurotoxicity (hen) ........................ 870.6200a Acute Neurotox. Screening Battery (rat) ............ 870.6200b 90 Day Neuro. Screening Battery (rat) .............. 870.6300 Develop. Neuro .................................. No 4 No 4 No 5 No 5 No 5 870.7485 General Metabolism .............................. 870.7600 Dermal Penetration .............................. Yes No 6 Yes No Special Studies for Ocular Effects 7 Acute Oral (rat) .................................. Subchronic Oral (rat) ............................. Six­ month Oral (dog) ............................. 1 Study not required by use pattern. 2 A 28­ day inhalation study was recommended by the HIARC and is required. 3 Another study is not required. 4 Required of organophosphates only. 5 Not required by toxicity pattern. 6 Study is optional. 7 Not required for this class of pesticides. 3.0 DATA GAP( S)/ REQUIREMENT( S) HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 5 of 38 1. 28­ Day Inhalation Study (Confirmatory study) (Contact Agency before conducting test). 4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of data base for acute toxicity: The data base for acute toxicity is considered complete. No additional studies are required at this time. The acute toxicity data on HEXAZINONE technical is summarized below. Acute Toxicity of Hexazinone Guideline No. Study Type MRIDs # Results Toxicity Category 81­ 1 Acute Oral/ Rat 41235004 (1989) LD50 = 1200 mg/ kg III 81­ 2 Acute Dermal/ Rabbit 00104974 LD50 >5278 mg/ kg IV 81­ 3 Acute Inhalation 41756701 (1991) LC50 > 3.94 mg/ L( 4 hour) III 81­ 4 Primary Eye Irritation 00106003 (1982) Irreversible corneal opacity, Severe I 81­ 5 Primary Skin Irritation 00106004 (1982) Mild IV 81­ 6 Dermal Sensitization 41235005 (1989) NA Not a skin sensitizer 4.2 Subchronic Toxicity Adequacy of data base for subchronic toxicity: The data base for subchronic toxicity is considered adequate for reregistration. Only a 28­ day inhalation study is required for confirmation at this time. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 6 of 38 870.3100 90­ Day Oral Toxicity ­ Rat EXECUTIVE SUMMARY: In this subchronic oral toxicity study (MRID 00104977), hexazinone (INA­ 3674; purity not provided; Lot/ Batch # not provided) was administered in the diet to 16 ChRCD rats/ sex/ group at nominal doses of 0, 200, 1000, or 5000 ppm (equivalent to 0/ 0, 16.0/ 16.4, 81.0/ 87.3, or 440.4/ 450.7 mg/ kg for males/ females) for 13 weeks. After 4, 8, and 13 weeks on the test diet, 10 of the 16 rats/ sex/ dose were subjected to hematology, clinical chemistry, and urinalysis tests. After 13 weeks, 10 rats/ sex/ group were sacrificed for necropsy and histopathological examination. The remaining 6 rats/ sex/ group continued on the test diet for at least 3 weeks in a onegeneration one­ litter reproduction study. There were no treatment­ related effects on mortality, clinical signs, food consumption, hematology, urinalysis, organ weights, or histopathology. No data were provided for gross pathology. In the 200 and 1000 ppm animals, all parameters examined were comparable to controls. Body weights were decreased in the 5000 ppm animals (94­ 15%) throughout the study. Likewise, overall body weight gains (calculated by the reviewers) were decreased in this group (98­ 20%). Although food consumption was comparable among treated animals and controls, overall (Days 0­ 91) mean food efficiency was decreased (statistics not performed) in the 5000 ppm males (911%) and females (915%) compared to controls. Food efficiency in males and females was unchanged for the first 28 days of the study. Males showed a 6% and 9% decrement for days 28­ 56 and days 56­ 91, respectively at 5000 ppm. Females showed a 25% and 64% decrement in food efficiency for the same respective days. The progressive nature of the reduced food efficiency, especially in females, supports a body weight decrement at 5000 ppm from toxicity. Alanine aminotransferase (ALT) was increased (statistics not performed) in the 5000 ppm females at 1 (863%), 2 (863%), and 3 (825%) months. However, because there were no treatmentrelated changes in liver weights or histology, increases in ALT were considered of equivocal toxicological significance. For all other clinical chemistry parameters examined, treatment groups were either comparable to controls, sporadic, or differences were not dose­ related. Additionally, in the one­ generation, one­ litter reproduction study, there were no treatmentrelated differences in pregnancy rate (fertility), gestation, number of pups born, pup viability, or lactation. However, the mean pup weight was lower (924%; statistics not performed) in the 5000 ppm group than in controls. The LOAEL for this study is 5000 ppm (equivalent to 440.4/ 450.7 mg/ kg/ day for male/ females) based on decreased body weights and food efficiency. The NOAEL is 1000 ppm (equivalent to 81.0/ 87.3 mg/ kg/ day for males/ females). The submitted study is classified as acceptable does satisfy the guideline (§ 82­ 1a; OPPTS 870.3100) requirements for a subchronic oral toxicity study in the rat. 870.3100 90­ Day Oral Toxicity ­ Mouse HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 7 of 38 No study is required or available. 870.3150 90­ Day Oral Toxicity ­ Dog EXECUTIVE SUMMARY: In this subchronic oral study (MRID 00114484), hexazinone INA3674 97.5% a. i.; Lot/ Batch# not provided) was administered in the diet to 4 beagle dogs/ sex/ group at doses of 0, 200, 1000, or 5000 ppm (equivalent to 0/ 0, 5.1/ 7.0, 25.9/ 31.6, 122.5/ 137.3 mg/ kg/ day for males/ females) for 13 weeks. Homogeneity, concentration, and stability analyses were not performed on the test diets. No mortalities occurred during the study. Clinical signs and hematology were unaffected by the test substance. At 5000 ppm, the negative overall (Weeks 0­ 13) body weight gains show that these animals were unable to maintain body weight (­ 0.9 kg in males, ­0.3 kg in females). Food consumption was decreased in the females in this dose group at Weeks 1 (941%) and 2 (915%). In the males, food consumption was comparable among treated and control groups throughout the study. Findings in organ weights and clinical chemistry at 5000 ppm indicate liver toxicity as an effect of treatment. Absolute liver weights were increased in the males at 200 (810%), 1000 (821%), and 5000 (826%) ppm and in the females at 5000 (833%) ppm. However, relative liver weights were only increased at 5000 ppm in the males (827%) and females (840%), indicating the increases in absolute liver weights at 200 and 1000 ppm were most likely due to increased body weights in these animals compared to controls. Alkaline phosphatase levels were increased in the males and females in this dose group at 1 (846­ 75%), 2 (886­ 125%), and 3 (8124­ 214%) months. Serum levels of this enzyme increased as the study progressed. In the 5000 ppm males, proteinuria was observed at Months 2 and 3 (1/ 4 each treated vs 0/ 4 in any other dose group). Vacuolation of the cytoplasm of the cells lining the Loop of Henle was observed in the males (1/ 4 treated vs 0/ 4 controls) and females (1/ 4 treated vs 0/ 4 controls) in this dose group. The LOAEL was 5000 ppm (equivalent to 122.5/ 137.3 mg/ kg/ day in males/ females) based on decreased body weight gains, increased relative liver weights, and increased alkaline phosphatase levels in both sexes and transiently decreased food consumption in the females. The NOAEL for this study is 1000 ppm (equivalent to 25.9/ 31.6 mg/ kg/ day for males/ females). The submitted study is classified as acceptable and does satisfy the guideline (§ 82­ 1b; OPPTS 870.3150) requirement for a subchronic oral toxicity study in the dog. The deficiencies in the parameters reported did not appear to compromise the study results. 870.3200 21/ 28­ Day Dermal Toxicity – Rabbit EXECUTIVE SUMMARY: In a repeated dose dermal toxicity study (MRID 41309005), groups of five male and five female New Zealand White rabbits received applications of 0, 50, 400, or 1000 mg/ kg/ day Hexazinone technical (> 98%, Lot No. T02118994) in distilled water, 6 hours/ day for 21 HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 8 of 38 consecutive days. There were no treatment­ related deaths, clinical signs, hematological or clinical chemistry effects, organ weight effects or gross or histopathological effects attributable to treatment. No treatment­ related body weight, food consumption, or food efficiency effects were observed. Treatment­ related dermal irritation was observed on rabbits in all treatment groups, including controls. Slight erythema was noted on 3/ 5 control females, 4/ 5 low­ dose males, 4/ 5 low­ dose females, and all mid­ and high­ dose males and females. Slight edema was noted on 1/ 5 control female, 1/ 5 high­ dose male, and 1/ 5 high­ dose female. These dermal effects were not considered toxicologically significant. The systemic and dermal NOAEL for Hexazinone technical in male and female rabbits is the limit dose of 1000 mg/ kg/ day. The systemic and dermal LOAEL were not identified. This study is classified as Acceptable/ Guideline and does satisfy the guideline requirements for a repeated­ dose dermal study [OPPTS 870.3200 (§ 82­ 2)] in rabbits. 870.3465 90­ Day Inhalation – Rat No study is available. The HIARC determined that a 28­ day inhalation study is required to address the concern for inhalation exposure due in part to the irritating properties of hexazinone. The Agency should be contacted prior to conducting this study. A two page summary of a 21­ day inhalation study has been submitted (MRID# 00063972), which is unacceptable due to failure to submitted a complete report of the study and probable unacceptable particle sizes. 4.3 Prenatal Developmental Toxicity Adequacy of data base for Prenatal Developmental Toxicity: The data base for prenatal developmental toxicity is complete. There was no quantitative or qualitative evidence of increased susceptibility following in utero exposure to the acceptable rat study or the unacceptable rabbit study. In rats, maternal toxicity was seen at a lower dose than developmental toxicity, and in rabbits, developmental effects occurred at the same dose level as maternal toxicity. 870.3700a Prenatal Developmental Toxicity Study ­ Rat EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 40397501), hexazinone (99.26% a. i.; Lot# S30306A, Batch# 2/ 36) in 0.5% methylcellulose was administered orally via gavage to 25 Crl: CD ® BR female rats/ group at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day (GD) 7 through 16. The dosing volume was 10 mL/ kg (calculated by reviewers). All dams were sacrificed on GD 22 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in clinical signs, gross HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 9 of 38 pathology, pregnancy rate, live fetuses, resorptions, pre­ or post­ implantation loss, corpora lutea, or implantations were noted at any dose level tested. No treatment­ related findings were noted in the 100, or 40 mg/ kg groups. In the 900 mg/ kg dams, one treatment­ related death occurred; alopecia and an enlarged stomach containing fluid and food were noted at necropsy. Decreased (p< 0.05) body weight gains were noted during GDs 15­ 17 (937%) and 17­ 22 (917%). In addition, body weight gains were decreased (p< 0.05) for the overall (GDs 7­ 17) treatment interval (930%). Gravid uterine weights were not reported; however, adjusted (for gravid uterine weight) terminal body weights were slightly decreased (96%; p#0.05). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 9­ 11, 15­ 17, 7­ 17, and 17­ 22. Decreased (p#0.05) food consumption was observed throughout treatment (GDs 7­ 17; 916­ 22%) and post­ treatment (GDs 17­ 22; 99%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 7­ 9, 9­ 11, 11­ 13, 13­ 15, 15­ 17, 7­ 17, and 17­ 22. Also a significantly decreased food consumption was seen at 400 mg/ kg/ day (GD9­ 11; 91%) and (GD 7­ 17; 98%). In addition, relative (to body) liver weights were increased (p#0.05) in the 400 (5.2%) and 900 (5.6%) mg/ kg dams compared to concurrent controls (4.9%). Decreased (p#0.05) terminal body weights were noted at 900 mg/ kg (96%). A significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for relative liver weights and adjusted terminal body weights. In addition, a significant (p#0.05) trend by linear combination of dose ranks from ANOVA was noted for absolute liver weights. Despite this trend, the observed increases in absolute liver weights at 100, 400, and 900 mg/ kg (81­ 8%) were not statistically significant. Liver weight findings are considered equivocal. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. The maternal NOAEL is 100 mg/ kg/ day. In the 900 mg/ kg/ day group, male and female fetal weights were decreased (921%; p#0.05); a significant (p#0.05) trend by Jonckheere's test was noted for this parameter. At 400 mg/ kg/ day, only female fetal weights were significantly decreased by 2% (insufficient to be considered an effect). At necropsy, an increased (p#0.05) incidence of misaligned sternebrae (1), a variation, was observed (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0066; litter incidence: 0.09). In addition, an increased (p#0.05) incidence of misaligned sternebrae (2+), a variation, was noted (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0033; litter incidence: 0.04). Furthermore, an increased incidence of kidneys with no papilla was observed (fetal incidence: 0.0347; litter incidence: 0.25) relative to concurrent controls (fetal incidence: 0.0062; litter incidence: 0.04). Although the incidence was not statistically significant, a dose­ related trend (p#0.05) was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day based on decreased male and female fetal weight, increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The developmental toxicity NOAEL is 400 mg/ kg/ day. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 10 of 38 The developmental toxicity study in the rat is classified acceptable/ guideline (OPPTS 870.3700; §83­ 3 a) and satisfies the guideline requirement for a developmental toxicity study in the rat. 870.3700a Prenatal Developmental Toxicity Study ­ Rat EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 00114486), hexazinone (97.5% a. i.; Code# INA­ 3674­ 19, Lot/ Batch# N. B. 6849­ 30 [6842­ 29]; no further information provided) was administered orally in the diet to 25­ 27 ChR­ CD female rats/ group at dose levels of 0, 200, 1000, or 5000 ppm (equivalent to 0, 18.9, 94.5, and 482.0 mg/ kg) on GD 6 through 15. All dams were sacrificed on GD 21 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in food consumption, or number of implantations, live fetuses, dead fetuses, or premature deliveries were noted. It was stated that no treatment­ related changes in mortality, clinical signs, or gross pathology were observed; however no data were provided. Gravid uterine weights were not reported. Sex ratios, the number of corpora lutea, pre­ implantation loss, and post­ implantation loss were not reported and could not be calculated without individual data (not provided). Throughout the study, standard deviations were not calculated, individual data were not provided, and statistical analyses were not performed. Mean body weight gains and food efficiency were decreased during treatment (GDs 6­ 16). At 5000 ppm, mean body weight gains were decreased by 74% compared to concurrent controls. In addition, food efficiency during the treatment interval was 0.84 (vs. 3.0 in controls). At 5000 ppm, markedly decreased body weights were observed at GDs 16 (919%) and 21 (912%). Additionally at 5000 ppm, the number of females showing partial resorption (excluding complete resorptions) was 56.5%. This incidence exceeded the concurrent control incidence (39.1%); however, it was within the range of historical controls (mean was 40.6%, range was10.5­ 77.8%). The maternal LOAEL is 5000 ppm (equivalent to 482 mg/ kg/ day) based on decreased body weights, body weight gains, and food efficiency. The maternal NOAEL is 1000 ppm (equivalent to 94.5 mg/ kg/ day). No treatment­ related findings were noted in the fetuses at 200, 1000, or 5000 ppm. The developmental toxicity LOAEL was not observed. The developmental toxicity NOAEL is 5000 ppm (equivalent to 482.0 mg/ kg/ day). This developmental toxicity study in the rat is classified unacceptable/ upgradable pending submission of the following information: ­ Individual maternal and fetal data ­ Statistical analyses of the data ­ Environmental conditions of the testing laboratory ­ Gross pathology data. ­ Sex ratios, the number of corpora lutea, pre­ implantation loss, and post­ implantation loss ­ Litter incidence for fetal necropsy findings ­ Clinical signs and mortality data HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 11 of 38 870.3700b Prenatal Developmental Toxicity Study ­ Rabbit EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 45677801) [DXP­ A3674] hexazinone (98.78 % a. i., batch/ lot# DXP­ A3694­ 329) was administered to 22 female [Hra:( NZW) SPF strain] rabbits/ group by gavage] at dose levels of 0, 20, 50, 125 or 175 mg/ kg bw/ day from days 7 through 28 of gestation. Maternal toxicity was demonstrated by statistically significant findings at 125 mg/ kg/ day of a body weight gain decrement of ­102 g between gd 7­ 9 and ­57 g between gd 9­ 11, food consumption decrement of 18%, abortions, death and clinical signs such as diarrhea, stained cageboard and tail. Only 1 dam and 1 litter survived to termination at 175 mg/ kg/ day. The maternal LOAEL is 125 mg/ kg bw/ day, based on body weight gain decrement, decreased food consumption, abortions, death and clinical signs including abnormal gait at 175 mg/ kg/ day. The maternal NOAEL is 50 mg/ kg bw/ day. No dose related external, visceral or skeletal findings were noted. Since only 1 dam with 1 litter survived to termination at the 175 mg/ kg/ day dose, evaluation of embryo/ fetal effects at this dose are meaningless. Random malformations were seen in control and the highest dose group with no dose relationship. Mean male and female fetal weight was reduced by 5% and female fetal weight was reduced by 10% at 125 mg/ kg/ day. Although this weight reduction was not list as being statistically significant, the author stated that this slight weight reduction at 125 mg/ kg/ day was a developmental effect level and this reviewer agrees. The developmental LOAEL is 125 mg/ kg bw/ day, based on mean male and female fetal weight decrement and female fetal weight decrement. The developmental NOAEL is 50 mg/ kg bw/ day. The developmental toxicity study in the rabbit is classified acceptable (guideline) and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rabbit. 870.3700b Prenatal Developmental Toxicity Study ­ Rabbit EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 00028863), hexazinone (100% a. i.; Lot/ batch # E21216A) was administered orally via gavage in a dosing volume of 1 mL/ kg) to 17 female New Zealand White rabbits/ group at dose levels of 0, 20, 50, or 125 mg/ kg on GD 6 through 19. All does (except those that died or delivered prematurely) were sacrificed on GD 29, and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in mortality, clinical signs, body weights, gross pathology, fetal weights, sex ratios, pre­ implantation or post­ implantation losses, or the number of corpora lutea, implantations, resorptions, live fetuses, or dead fetuses were observed. At 125 mg/ kg, food consumption was decreased (p#0.05), relative to concurrent controls, at the beginning of treatment from GD 7 through 11 (961­ 89%). Decreases in food consumption, that were not statistically significant, continued throughout treatment (GDs 12­ 19; 92­ 37%). Diminished HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 12 of 38 food consumption resulted in decreased (not statistically significant) body weight gains in the does 241.5 g) relative to concurrent controls (­ 7.2 g) during GDs 6­ 11. However, weight gain in these animals recovered quickly and was higher than control animals during subsequent treatment intervals (GDs 11­ 15 and 15­ 19). The maternal LOAEL is 125 mg/ kg/ day based on transient decreases in food consumption and body weight gains. The maternal NOAEL is 50 mg/ kg/ day. At 125 mg/ kg/ day, the following skeletal variations were noted (data presented as fetal incidence vs. 0 controls): (i) lagging ossification in extremities (0.0882); (ii) malaligned thoracic vertebrae (0.0294); and (iii) flexed wrist( s) (0.0294). In addition, non­ ossified thumb, an anomaly, was noted at an increased incidence (0.0294) relative to concurrent controls (0). In the absence of historical control data, these findings are considered treatment­ related. In addition, it could not be determined how many of these nominally increased incidences were from different litters, which would have increased concern for developmental toxicity. The developmental toxicity LOAEL is 125 mg/ kg/ day, based on possible skeletal abnormalities and total abnormalies. The developmental toxicity NOAEL is 50 mg/ kg/ day. The developmental toxicity study in rabbits is classified unacceptable/ upgradable, pending submission of acceptable purity, concentration, stability and litter data and historical control data. A letter dated 9/ 26/ 01 from the registrant provided no additional information about this rabbit developmental toxicity study other than the doses were not analyzed and that a repeat rabbit developmental toxicity was currently being conducted. 4.4 Reproductive Toxicity Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered complete. No additional studies are required at this time. There was no evidence of qualitative or quantitative susceptibility in a two­ generation study of reproduction. 870.3800 Reproduction and Fertility Effects ­ Rat Executive Summary: In a two­ generation reproduction study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 30 male and 30 female Sprague­ Dawley rats in the diet at concentrations of 0, 200, 2000, or 5000 ppm (MRID 42066501). One litter was produced in the first generation and two litters were produced in the second generation. Test substance intake for the treated F0 groups was 11.8, 117, and 294 mg/ kg/ day, respectively, for males and 14.3, 143, and 383 mg/ kg/ day, respectively, for females. Test substance intake for the treated F1 groups was 15.3, 154, and 399 mg/ kg/ day, respectively, for males and 17.7, 180, and 484 mg/ kg/ day, respectively, for females. F0 and F1 parental animals were administered test or control diet for 73 or 105 days, respectively, prior to mating, throughout mating, gestation, and lactation, and until necropsy. Deaths of several F0 and F1 parental animals were considered incidental to treatment. No HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 13 of 38 treatment­ related clinical signs of toxicity were observed in the adult animals of either generation. Gross necropsy was unremarkable and no microscopic lesions were observed in selected tissues from the reproductive tracts of male and female parental animals. Body weights and body weight gains of the F0 males were not affected by treatment. Premating body weight gains by the mid­ and high­ dose F0 females were 76% and 62% (p # 0.05 for both), respectively, of the control level resulting in final premating body weights 93% and 87% (p # 0.05), respectively, of the controls. Body weights of the high­ dose F1 males and females were significantly reduced (p # 0.05) during the premating interval with overall weight gains 87% and 82%, respectively, of the control group amounts. Reductions in body weights and body weight gains during premating for the mid­ and high­ dose F0 and high­ dose F1 dams continued during gestation and lactation. Food consumption during premating was similar between the treated and control groups for males and females of both generations. However, during gestation significantly (p # 0.05) lower food consumption was noted for the high­ dose F1 dams during production of both litters and for the middose F1 dams during production of the second litter. There was a statistically significant increase in absolute P0 testes weight that appeared to be dose related, but a nominally decrease absolute F1 adult testes weight in the 5000 ppm dose groups. The F1 testes weight change did not appear to dose related. The testes weight changes in males would appear to be incidental. Therefore, the systemic toxicity LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced body weight and body weight gains by F1 males and F0 and F1 females. The systemic toxicity NOAEL is 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). No reproductive effects were seen in the study except for the weight effects on offspring. Live birth and viability indices and litter survival were similar between the treated and control groups. The lactation index for the F2b high­ dose litters was 85.8% (p # 0.05) compared to 97.5% for the control group. Pup body weights were decreased throughout lactation in the mid­ and high­ dose groups of all litters as compared with the control groups with statistical significance (p # 0.05) attained at most time points. The lower pup body weights were more pronounced in females than in males. F1 and F2a female pup weights were statistically significantly decreased at birth, day 7 and 14 of lactation at $2000 ppm. There were no obvious reproductive effects other than the pup weight decrement. Therefore, the offspring LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced female pup body weights at birth and during lactation. The reproductive toxicity NOAEL was 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a reproductive toxicity study [OPPTS 870.3800 (§ 83­ 4)] in rats. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 14 of 38 4.5 Chronic Toxicity Adequacy of data base for chronic toxicity: The data base for chronic toxicity is considered complete. No additional studies are required at this time. The chronic study in dogs showed severe body weight decrement, changes in liver related clinical chemistry values, and microscopic lesions. Body weight decrement was seen in a chronic carcinogenicity studies in rats and mice. Liver toxicity was seen in mice. 870.4100a Chronic/ Carcinogenic Toxicity ­ Rat See Section below on Carcinogenicity study in rats (870.4300 Chronic/ Carcinogenicity in rats). 870.4100b Chronic Toxicity ­ Dog EXECUTIVE SUMMARY: In a one­ year chronic toxicity study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 5 male and 5 female beagle dogs in the diet at concentrations of 0, 200, 1500, or 6000 ppm (MRID 42162301). Time­ weighted average doses for the treated groups were 5.00, 41.24, and 161.48 mg/ kg/ day, respectively, for males and 4.97, 37.57, and 166.99 mg/ kg/ day, respectively, for females. All animals survived to scheduled necropsy. Treatment­ related clinical signs of toxicity included the observation of thinness in 1/ 5 mid­ dose males, 3/ 5 high­ dose males, and 1/ 5 high­ dose females. Body weights of the high­ dose groups were significantly (p # 0.05) less than those of the control throughout most of the study. Final body weights of the high­ dose males and females were 78% and 67%, respectively, of the control levels. Food consumption by the high­ dose groups was slightly (n. s.) less than that of the controls throughout the study with statistical significance (p # 0.05) attained for females at week 52. Overall food consumption (weeks 1­ 52) for high­ dose males and females was 85% (n. s.) and 74% (p # 0.05), respectively, of the control group levels. Body weights and food consumption for the low­ and mid­ dose groups were not affected by treatment. No treatment­ related ophthalmological lesions, changes in urinalysis parameters, or gross necropsy findings were noted. A moderate macrocytic anemia was observed in the high­ dose groups as evidenced by slight or significant (p # 0.05) decreases in RBC counts, hemoglobin, and hematocrit and increases in MCV and MCH in one or both sexes throughout the study. Cholesterol levels were significantly (p # 0.05) decreased in the high­ dose groups beginning at week 13 for males (52­ 64% of controls) and at week 26 for females (45­ 51% of controls). Albumin levels were significantly (p # 0.05) decreased in the mid­ dose males (93% of controls) at week 13 only, and in the high­ dose males (74­ 78% of controls) and females (75­ 82% of controls) throughout the study. Beginning on week 13 or 26, the high­ dose groups had aspartate aminotransferase levels 140­ 203% (p # 0.05) of the control values and alanine aminotransferase levels 206­ 276% (p # 0.05) of the control values. Alkaline phosphatase levels were significantly (p # 0.05) HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 15 of 38 increased in the mid­ dose males (259­ 409% of controls) and females (163­ 194% of controls; n. s.) beginning at week 26 and in the high­ dose males (346­ 1363% of controls) and females (307­ 559% of controls) beginning at week 13. For the high­ dose animals, decreases in absolute testes weights in males and kidney, heart, and brain weights in females (­ 12%) and increases in relative liver weights in males and females were considered due to lower final body weights of these animals as compared with controls. Microscopic lesions in the liver of high­ dose animals included concentric membranous bodies in 4 males and 5 females, centrilobular single cell necrosis in 3 males and 3 females, hepatocellular pigment in 3 males and 3 females, and vacuolation in 3 males and 4 females. In addition vacuolation was observed in one mid­ dose male and pigment and membranous bodies were each observed in one mid­ dose female. These lesions were not seen in control or low­ dose animals. Therefore, the LOAEL for hexazinone in male and female beagle dogs is 1500 ppm (41.24 and 37.57 mg/ kg/ day, respectively) based on thinness in one male and hepatotoxicity as evidenced by changes in clinical chemistry parameters and microscopic lesions. The NOAEL is 200 ppm (5.00 and 4.97 mg/ kg/ day, respectively). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a chronic toxicity study [OPPTS 870.4100 (§ 83­ 1b)] in dogs. 4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The data base for carcinogenicity is considered complete. No additional studies are required at this time. HED's Carcinogenicity Peer Review Committee classified hexazinone as a Group D chemical (not classifiable as to human carcinogenicity) (7/ 27/ 94). This classification was based on the following weight of evidence considerations. In rats, females showed no evidence for carcinogenicity; males showed a significant trend only for thyroid adenomas. In mice, the evidence of carcinogenicity was equivocal: a positive trend test for liver tumors was observed only in female mice, but no significant difference was seen by pair­ wise comparison (CPRC Report dated July 27, 1994). 870.4200b Carcinogenicity (feeding) ­ Mouse EXECUTIVE SUMMARY: In this mouse oncogenicity study (MRIDs 00079203, 41359301, 42509301 and 43202901), hexazinone ($95% a. i.; Lot/ Batch #: H­ 11, 265 and 265­ 2) was administered in the diet to CD­ 1 mice (80/ sex/ group) for up to 104 weeks at nominal doses of 0, 200, 2500 or 10,000 ppm (equivalent to 28, 366 and 1635 mg/ kg/ day in males and 0, 34, 450 and 1915 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, food consumption, food efficiency or hematology. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 16 of 38 Hepatotoxicity was evident at the terminal sacrifice. Macroscopic liver nodule/ mass (% treated vs % controls; n = 28­ 55) was observed in males at 2500 (39% vs 7%) and 10,000 ppm (33%). Increased incidences (% treated vs 0% controls; n = 38­ 55) in the following microscopic liver lesions were observed: hyperplastic nodule( s) (includes both foci of cellular alteration and adenoma) in males at 2500 (39% vs 20%) and 10,000 ppm (36%) and in females at 10,000 ppm (15% vs 3%); and necrosis (severity and type unspecified) in the 10,000 ppm males (36% vs 7%). Centrilobular hepatocyte hypertrophy was observed (% treated vs % controls) at the terminal sacrifice (n = 38­ 55) in males at 2500 (18% vs 0%) and 10,000 ppm (98%) and in females at 10,000 ppm (46% vs 0%) and in the dead and moribund males (n = 25­ 40) at 2500 (44% vs 0%) and 10,000 ppm (60%). Increased (p#0.05 or 0.01) liver/ gall bladder weights were observed at 10,000 ppm in males in both absolute and relative to body weights and in females in relative to body weight. Other signs of toxicity were evident. Distal tail tip sloughing and/ or discoloration was observed at 10,000 ppm in males at Weeks 13­ 104 and in females at Weeks 5 and 13­ 104. Macroscopically, tip of tail missing/ sloughed was observed at the terminal sacrifice in the 10,000 ppm males (31% vs 5%) and females (61% vs 11%) and in the dead and moribund 10,000 ppm females (46% vs 2%). The toxicological significance of these findings was unclear. Minor decreases (p#0.05 or 0.01) in body weights were observed in the 10,000 ppm treatment groups at Weeks 13­ 104 in both sexes. Overall body weight gains (calculated by the reviewers) were decreased in the 10,000 ppm males (925%) and females (931%). The LOAEL is 2500 ppm for males (equivalent to 366 mg/ kg/ day) based on gross liver nodules/ masses, hyperplastic nodules in the liver and centrilobular hepatocyte hypertrophy and 10,000 ppm for females (equivalent to 1915 mg/ kg/ day [limit dose]) based on decreased body weights, increased relative liver/ gall bladder weights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. The NOAEL is 200 ppm (equivalent to 28 mg/ kg/ day) for males and 2500 ppm (equivalent to 450 mg/ kg/ day) for females. Liver samples were first evaluated using the term hyperplastic nodule which did not clearly distinguish neoplasia from non­ neoplasia. Re­ evaluation was conducted to make this distinction, and no significant differences were observed between the treatment groups and the concurrent controls. However positive trends (p< 0.05) were observed (% treated vs % controls) in focus/ foci of cellular alteration in males, hepatocellular neoplasm( s) (including adenoma, sarcoma, carcinoma, leukemia, and lymphoma) in females, and singular hepatocellular adenoma in females. Focus/ foci of cellular alteration were observed in males at 2500 (11.3% vs 5.0%) and 10,000 ppm (24.1%) and females at 10,000 ppm (12.5% vs 3.8%) beginning at Week 57. Singular hepatocellular adenoma was observed in the 10,000 ppm females (7.5% vs 2.5%) beginning at Week 77. Hepatocellular neoplasm( s) were observed in the 10,000 ppm females (8.8% vs 2.5%). A carcinoma in the 10,000 ppm treatment groups was first observed at Week 65. The incidence of carcinomas were within historical control ranges for each sex, while the incidence of adenomas were increased by 3.21% in the 10,000 ppm females. A dose­ dependent increase in adenomas was not observed in males. The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) concluded that hexazinone should be classified as a Group D (not classifiable as to human carcinogenicity)( 7/ 27/ 94). Under the conditions of this study, evidence of carcinogenic potential was equivocal: HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 17 of 38 a positive trend test for neoplasia was observed in female mice, but no significant difference was determined by pair­ wise comparison. The submitted study is classified as acceptable for guideline 870­ 4200 carcinogenicity study in mice. 870.4300 Chronic/ Carcinogenicity Study ­ rat EXECUTIVE SUMMARY: In this combined chronic/ oncogenicity study (MRID 00108638), hexazinone (94­ 96% a. i.; Lot/ Batch #: 6897­ 40 and 74.25) was administered in the diet to ChR­ CD rats (36/ sex/ group) for up to 25 months at nominal doses of 0, 0, 200, 1000, or 2500 ppm (equivalent to 0, 0, 10.2, 53.4, and 138.3 mg/ kg/ day in males and 0, 0, 12.5, 67.5, and 178.6 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, clinical signs, food consumption, hematology, clinical chemistry, organ weights, and gross or microscopic pathology. No adverse effects were observed in the 200 ppm animals. There were several signs of general toxicity, but a target organ could not be clearly identified at any dose. Terminal body weights were decreased 8% in1000 ppm and 20%, p#0.05, in the 2500 ppm females. A decrease in overall body weight gain (Days 0­ 728; calculated by the reviewers) was also observed in the 1000 (­ 10%) and 2500 ppm (­ 25%) females. Nominal decreases in body weight and body weight gain (­ 3 to ­5%) occurred in males at 1000 ppm during the study, which may have been biologically significant at the end of the study (­ 12% body weight and ­14% for body weight gain). Decreases (p­ values not calculated) in total food efficiency were observed in females at 1000 (­ 10%) and 2500 ppm (­ 25%) and in males at 1000 ppm during the study with overall decrement in food efficiency in 1000 ppm males (­ 10%). In males at 2500 ppm, food efficiency was depressed for the first 6 months of the study (­ 25%), but from 6 months to the end of the study, it was increased 139%. The reviewer noted problems interpreting the body weights and food efficiency in males at the top dose level, which were not consistent with the mid­ dose level. For the first 6 months of the study in males, a body weight decrement due to probable toxicity was seen at 1000 and 2500 ppm. After 6 months food efficiency in males at the 1000 ppm remained less than controls (­ 56%) while food efficiency at 2500 ppm in males was higher than controls (+ 139%)( Table 4). By the end of the study, male body weight at 1000 ppm was ­12% and body weight gain ­14%, where as body weight and body weight gain in males at 2500 ppm was +3% for both weight and gain. The reason for this recovery in male body weight decrement at 2500 ppm is unknown, but it appears to be real. [Since absolute and relative liver weights were decreased in males at 2500 ppm, liver enzyme induction allowing the recovery seems unproven.] The body weight decrement at 1000 and 2500 ppm with recovery in body weight at 2500 ppm indicates the an adequate dose level to test for carcinogenicity in males was approached, but probably not attained. Other treatment groups were similar to the average of concurrent controls. Dosing was considered adequate based on decreased body weights, body weight gains, and food efficiency in the 2500 and 1000 ppm females and food efficiency and body HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 18 of 38 weights in the 2500 ppm males for the first 6 months. Body weight (­ 12%) and body weight gain 14 in males at 1000 ppm were decreased at the end of the study, in addition overall food efficiency (­ 14%) was decreased by the end of the study. Thus female body weight and body weight gain was decreased sufficiently to adequately test for carcinogenicity. Male body weight and body weight gain at 1000 ppm appeared to be adequate to test for carcinogenicity by the end of the study, but the lack of dose response in male body weight and body weight gain at 2500 ppm (showing recovery after 6 months such that body weight and body weight gain were higher than control values) may indicate problems with the interpretation of the body weights and body weight gains at 1000 ppm. In the 2500 ppm males, creatinine was increased (NS) in the urine at months 18 and 24 and bilirubin was detected at month 18 and 24. The Sponsor reported that the urine was more alkaline in the 2500 ppm treatment groups (data not reported). Also at 2500 ppm, decreased (p#0.05) absolute and relative liver and kidney organ weights were observed in the males and increased (p#0.05) relative (to body) stomach and kidney organ weights were observed in the females. However, histopathological data did not corroborate these findings. The LOAEL is 1000 ppm for males and females (equivalent to 53.3 for males and 67.5 mg/ kg/ day for females) based on decreased body weight and food efficiency in males and females. In males at 2500 ppm the body weight decrement and food efficiency decrement occurred only for the first 6 months of the study. The NOAEL is 200 ppm for males and females (10.2 for males and 12.5 mg/ kg/ day for females). Neoplasm data were evaluated by two pathologists. An increase incidence of thyroid Ccell adenomas was observed in the 2500 ppm males, but when analyzed by the Fisher's exact test (p> 0.10) or life­ table methods (p> 0.20) no significant differences were observed between controls and treated groups. Using life­ table analyses a significant (p< 0.05) dose­ response trend was observed in thyroid C­ cell tumors in only one of the two pathology reports. Female rats did not show any potential for C­ cell thyroid adenomas. The incidence, malignancy and latency of tumors were comparable among control and treated rats of both sexes. Under the conditions of this study, carcinogenic potential of hexazinone is considered negative. The submitted study is classified as acceptable for guideline 870.4300 combined chronic/ carcinogenicity study in rats. 4.7 Mutagenicity Adequacy of data base for Mutagenicity: The data base for Mutagenicity is considered adequate based on pre­ 1991 mutagenicity guidelines. The lack of an acceptable in vitro reverse mutation study is mitigated by an acceptable in vivo mutation study, and adequate carcinogenicity studies. Hexazinone was found to be positive for mutagenicity in one chromosomal aberration assay HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 19 of 38 (in vitro cytogenics) (MRID# 00130709), but negative in the remaining studies. It is concluded that the test material was clastogenic in both of the non­ activated trials and was also clastogenic in the one adequate S9­ activated trials. Under both test conditions, concentrations providing evidence of clastogenicity induced an acceptable level of cytotoxicity (> 50% relative cell survival). Thus, the findings can not be considered to be a secondary effect of cytotoxicity. Nevertheless, the outcome of the induced structural damage (i. e., primarily chromatid and chromosome breaks) is unclear since these types of structural aberrations would not likely be passed on to daughter cells. Because unambiguous positive results were achieved, it was concluded that the study provided adequate evidence that INA3674 112 (hexazinone, technical) is clastogenic in an acceptable study. Gene Mutation 4.7.1 Guideline 870.5100, Reverse mutation in Salmonella EXECUTIVE SUMMARY: In a reverse gene mutation assay in bacteria (MRID 40826201), strains TA98, TA100, TA1535, TA1537 and TA1538 of S. typhimurium were exposed to S­ triazine2,4 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ (95% a. i.) in ethanol at concentrations of 200, 400, 600, 800 and 1000 :g/ plate without mammalian metabolic activation (S9­ mix) and at concentrations of 400, 800, 1200, 1600 and 2000 :g/ mL with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Crl: CD( SD) BR rat liver. The maximum concentrations of S­ triazine­ 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ tested produced little or no cytotoxicity, were not limited by solubility and were not a limit dose for the assay. No statistically significant increases in the number of revertants per plate or positive linear dose­ response were seen. The solvent and positive controls induced acceptable responses in the corresponding strains. There was no evidence of induced mutant colonies over background. This study is classified as Unacceptable. It does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5100 (§ 84­ 2)] for in vitro mutagenicity [bacterial reverse gene mutation] data and should have used higher doses. 4.7.2 Guideline 870.5300, Gene mutation at HGPRT locus EXECUTIVE SUMMARY: In a mammalian cell gene mutation assay at the HGPRT locus (MRID No. 00076956), Chinese hamster CHO­ K1­ BH4 cells cultured in vitro were exposed to INA­ 3674­ 112, (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol in two trials. Concentrations used in Trial 1 were 2.0, 11.1, 13.1, 13.9 and 14.3 mM under nonactivated conditions and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM under activated conditions (S9­ mix). Concentrations used in Trial 2 were 2.0, 5.9, 11.1, 13.1 and 13.9 mM without S9­ mix and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM with S9­ mix. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 20 of 38 The S9­ fraction was obtained from Aroclor 1254 induced male Charles River CD® rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. In Trial 1, the cultures treated at 14.3 mM were not plated for mutation determination due to cytotoxicity and in both Trials 1 and 2, those cultures treated at 13.9 mM were excluded from analysis because no mutants were seen. No statistically significant increases in mutant frequency over solvent control values were seen with or without S9­ mix in either Trial 1 or 2. The expected marked increase in the mutation were seen with the positive controls. There was, however, no indication that INA­ 3674­ 112 induced a mutagenic effect either in the presence or the absence of S9 activation. This study is classified as acceptable. It satisfies the requirement for FIFRA Test Guideline OPPTS [870.5300 (§ 84­ 2)] for in vitro mutagenicity (mammalian forward gene mutation) data. 4.7.3 Guideline: 870.5375: In vitro mammalian cytogenics (chromosomal aberrations) in Chinese hamster CHO cells. EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (MRID No. 00130709), Chinese hamster ovary CHO­ K1 ­BH4 cell cultures were exposed to INA­ 3674­ 112 (Hexazinone, 95% a. i.) in ethanol in two separate trials. Exposure was for two hours with activation and for 10 hours without activation. Cells were harvested 10 hours after the start of treatment. In Trial 1, cells were treated at concentrations of 1.58, 3.94, 15.85 and 19.82 mM without metabolic activation (S9­ mix) and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. In Trial 2, cells were treated at concentrations of 1.58, 3.94, 7.93 and 15.85 without S9­ mix and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced CD rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. Based on the results of a preliminary cytotoxicity test, upper concentrations of 23.78 mM without S9­ mix and 47.56 mM with S9­ mix were selected for the first cytogenetic assay but these concentrations proved excessively cytotoxic and were not scored for chromosomal aberrations. Without S9 activation, statistically significant increases (p< 0.01) in structural aberrations per cell (excluding gaps), lesions per cell and percent abnormal cells were seen at 15.85 mM (Trials 1 and 2) and 19.82 mM (tested in Trial 1 only). Relative percent survival (RPS) at this level was .50%. The percent abnormal cells averaged over all cultures from both trials was 28.0% and 21.5% at 19.82 and 15.85 mM, respectively, compared to the solvent control values of 2.0% (0.5% ethanol in Trial 2) and 7.0% (0.75% ethanol in Trial 1). The percent abnormal cells in positive control cultures was 18% in both Trial 1 (4.83 mM EMS) and Trial 2 (6.44 mM EMS). In the presence of S9­ mix, no statistically significant increases in chromosomal aberration induction were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix. Statistically significant increases were seen at 15.85 mM in Trial 2; RPS at 15.85 mM was 75%. There was a statistically significant dose­ related trend for all three parameters. The statistically significant (p <0.01) increases at 15.85 mM remained when the data from Trial 1 and 2 were combined (average of 20% abnormal cells compared to 10% for the solvent control). The predominant aberrations with or without S9­ mix were chromatid and isochromatid breaks. Solvent and positive controls (except the positive control in Trial 1 with S9­ mix) induced the appropriate responses. INA­ 3674­ 112 was positive for the induction of structural chromosomal aberrations in both the HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 21 of 38 presence and absence of S9­ mix. This study is classified as Acceptable/ guideline and satisfies the requirement for FIFRA Test 4.7.4 Guideline 870.5385: In vivo cytogenics assay in rat bone marrow cells EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (MRID 00131355), in bone marrow cells of Sprague­ Dawley CD rats, three rats/ dose/ sex/ harvest time were exposed to H# 14,555 in corn oil ( assumed 100% a. i.) at doses of 100, 300 and 1000 mg/ kg by oral gavage. Bone marrow cells were harvested at 6, 12, 24 and 48 hours post­ treatment. The highest dose tested (1000 mg/ kg) was lethal. A major limitation of this study was the number of animals treated and the number of cells analyzed per animal. At most, three rats/ sex/ dose/ harvest time were treated with, at most, 50 cells per rat analyzed. Few or no analyzable cell were available from many rats. Positive control values were significantly (p= 0.03) increased. There was no evidence that H# 14, 14,555 induced an increase in the incidence of chromosomal aberrations in the bone marrow cells of treated animals. This study is classified as Unacceptable. The number of cells analyzed and the number of rats treated was insufficient. The study does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5385 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. 4.7.5 Guideline 870.5395: Micronucleus assay in mouse bone marrow EXECUTIVE SUMMARY: In a Crl: CD­ 1 (ICR) BR mouse bone marrow micronucleus assay (MRID 45124401), 5 mice/ sex/ dose/ harvest time were treated orally with Hexazinone 25L (Lot No. 9912033, 25% Hexazinone a. i. (24.5% by analysis) and 75% inert ingredients) at doses of 1000, 2000 and 3000 mg/ kg. Bone marrow cells were harvested at 24 and 48 hours post­ treatment and examined for micronucleated polychromatic erythrocytes (MPCEs). The vehicle was Milli­ Q ® water. Signs of toxicity noted at 3000 mg/ kg included: death, convulsions, half­ shut eyes, head­ tilt, irregular respiration, lethargy, low carriage, pallor, prostration, uncontrollable spinning, shovel­ nosing, straining up on toes and tremors. Micronuclei were scored in bone marrow from mice treated at 3000 mg/ kg and from the solvent and positive controls. Mice from the two lower dose groups were not evaluated for micronuclei induction. No statistically significant increases in the frequency of MPCEs or in the PCE/ NCE ratio over the solvent control values were seen in either sex at either the 24 or 48 hour harvest time. The solvent and positive control values were appropriate and within the testing laboratory's historical control ranges. There was no evidence that Hexazinone 25L induced a clastogenic or aneugenic effect in bone marrow at any harvest time. This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline [OPPTS 870.5395 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 22 of 38 4.7.6 Guideline 8760.5550: Unscheduled DNA synthesis assay in rat hepatocytes EXECUTIVE SUMMARY: In an unscheduled DNA synthesis assay (MRID 00130708), primary rat hepatocyte cultures were exposed to INA­ 3674­ 112 (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol for 18 hours at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 10.0 and 30.0 mM in Trial 1 and at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 5.0, 10.0 and 30.0 mM in Trial 2. INA­ 3674­ 112 was tested up to the highest achievable concentration in the solvent. Two slides per dose, 25 cells per slide were evaluated for UDS induction in Trial 1. One slide per dose, 25 cells per slide were evaluated in Trial 2. The author did not report that the slides were coded prior to analysis. The average net nuclear grain counts of test material treated cells in Trial 1 were all less than zero with the exception of one slide at 1 x 10 ­5 mM (0.1 ± 9.6) and one slide at 1.0 mM (1.6 ± 5.2). The average net nuclear grain count was below zero for all test material concentrations in Trial 2 with the exception of 0.1 mM where the average net nuclear grain count was 0.0 ± 2.9. The criterion for a positive response was an average net nuclear grain count of at least five in two experiments at any tested concentration. The results were thus negative. The number of cells in repair was not reported. The solvent and positive (DMBA) controls induced the appropriate responses. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline; OPPTS 870.5550 [§ 84­ 2] for other genotoxic mutagenicity data. Compliance statements were not provided. 4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: No neurotoxicity data are required. 870.6100 Delayed Neurotoxicity Study ­ Hen Study is not required of hexazinone, which is not an organophosphate. 870.6200 Acute Neurotoxicity Screening Battery Study not required 870.6200 Subchronic Neurotoxicity Screening Battery Study not required. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 23 of 38 870.6300 Developmental Neurotoxicity Study Study not required. 4.9 Metabolism Adequacy of data base for metabolism: The data base for metabolism is considered to be complete. No additional studies are required at this time. 870.7485 Metabolism ­ Rat EXECUTIVE SUMMARY: A metabolism study (MRID 00109237 & 00140162) was conducted to evaluate the absorption, distribution, metabolism, and excretion of hexazinone in male and female CD rats. Radiolabeled ( 14 C at position 2 or 4 on the cyclohexyl ring) hexazinone, (Lot # not reported, purity >95%, radiochemical purity >99%) was administered by gavage to groups of one male and one female rat at concentrations of 14 mg/ kg or 1000 mg/ kg. A third group of two male and two female rats received unlabeled hexazinone (~ 5 mg/ kg/ day) in the diet for three weeks before being given a single 14 mg/ kg radiolabeled gavage dose. Mass balance was excellent and ranged from 95­ 102% recovery for all treatment groups. Based on the amount of radiolabel recovered in the urine and cage wash, absorption of the test material was at least 83% with no dose­ or sex­ dependent differences noted. By 72 hours after treatment, essentially none of the radiolabeled test material was present in the tissues. Urine was the primary route of elimination accounting for ~83% of the administered dose. Urinary elimination was rapid and ~96% complete within 48 hours of treatment. No apparent sex or dose­ related differences were found. Fecal excretion was a minor route of elimination, accounting for ~16% of the dose and was rapid with ~95% occurring within 72 hours of treatment. Once again, no apparent sex or dose­ related differences were found. Essentially none of the parent compound was found in the urine (-83% of dose) or feces (-16% of dose) of male and female rats following multiple low­ dose or a single high­ dose treatment with hexazinone. (Molecular structures of the parent and metabolites can be found in Section IV, Appendix.) 3­( 4­ hydroxycyclohexyl)­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione (metabolite A) and 3­( 4­ hydroxycyclohexyl)­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H) dione (metabolite C) comprised ~66 and 28%, respectively, of the identified fecal metabolites in males and females. These two metabolites resulted from hydroxylation of the cyclohexyl ring and differed only by the metabolic conversion of the 6­ dimethyl amine to a secondary methyl amine. No sex­, or dose­ related differences in the formation and excretion of these metabolites were found. Three metabolites were identified in the urine of males and females (metabolite A and C, -57% and -28% of identified metabolites, respectively) . Two of the metabolites were identical to those found in the feces . The third metabolite (3­( cyclohexyl)­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione) (metabolite B, -9% of urinary metabolites) resulted from demethylation of HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 24 of 38 the 6­ dimethyl amine group to form a secondary amine without hydroxylation of the 4­ position on the cyclohexyl ring. Approximately 3% of the urine metabolites were unidentified polar compounds and 5% were isolated from the hydrolyzed urine, suggesting they had undergone glucuronide or sulfate conjugation. No differences between the sexes or dose groups in the metabolic conversion of hexazinone were found. This metabolism and disposition study with rats is considered Acceptable/ Nonguideline and does satisfy the requirements for a Metabolism and Pharmacokinetics Study [OPPTS 870.7485 (§ 85­ 1)]. Major deficiencies include the use of 1­ 2 male and female rats/ group; no submission of test material lot numbers, stability, or dose confirmation data; and study dates. 4.10 Special/ Other Studies None available. 5.0 TOXICITY ENDPOINT SELECTION 5.1 See Section 9.2 for Endpoint Selection Table. 5.2 Dermal Absorption No dermal absorption study is available. For dermal absorption, the NOAEL from the 21­ day dermal toxicity study (MRID 41309005) at the limit dose of 1000 mg/ kg/ day was considered a lower bound for the LOAEL, which was compared with the LOAEL of 125 mg/ kg/ day from the rabbit developmental toxicity study (MRID 45677801). The ratio of these two numbers was used to estimate a dermal absorption factor of 12.5%. Dermal Absorption Factor: 12.5 % 5.3 Classification of Carcinogenic Potential 5.3.1 Conclusions There was no evidence of treatment related tumors in chronic rat studies and insufficient evidence in mouse studies. 5.3.2 Classification of Carcinogenic Potential The RfD/ Peer Review Committee has classified hexazinone as a group D chemical; no evidence of carcinogenicity in rats and in mice insufficient evidence of human carcinogenic potential. 5.3.3 Quantification of Carcinogenic Potential HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 25 of 38 Not required. 6.0 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children There was no evidence of quantitative or qualitative postnatal susceptibility in a twogeneration study of reproduction. There was no quantitative or qualitative evidence of increased susceptibility following in utero exposure to rats or rabbits in developmental toxicity studies. In rats, developmental toxicity was seen at the highest dose level tested, and in rabbits, developmental effects were seen at the same dose showing maternal toxicity. 6.2 Recommendation for a Developmental Neurotoxicity Study No neurotoxic potential was seen in any of the studies. A developmental neurotoxicity study is not required. 7.0 OTHER ISSUES None 8.0 REFERENCES: MRID 00028863. Unknown (1980) Teratology Study in Rabbits. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 201­ 522, February 14, 1980. Unpublished. MRID 00063972. Sarver, J. W. (1976) Three­ Week Inhalation Hazard Study on Vel­ par( R) Dust: Haskell Laboratory Report No. 477­ 76. Rev. (Un­ published study received Jun 9, 1978 under 352­ 388; submitted by E. I. du Pont de Nemours & Co., Wilmington, Del. MRID 00076956. McCooey, K. T., and Krahn, D. F. (1980). Chinese Hamster Ovary Cell Assay for Mutagenicity. E. I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, Newark, DE 19711. Haskell Laboratory Report No.: 56­ 81, MR No.: 0581­ 865, HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 26 of 38 December 1, 1980. Unpublished. MRID 00079203. Unknown (1981) Two­ Year Feeding Study in Mice. International Research and Development Corporation, Mattawan, MI. Laboratory Project Id.: HLO414 81, June 23, 1981. Unpublished. MRID 00104974 Morrow, R. (1973) Skin Absorption Toxicity ALD and Skin Irritancy Test: Haskell Laboratory Report No. 503­ 73. (Unpublished study received Dec 5, 1973 under 352­ EX­ 85; submitted by E. I. du Pont de Nemours & Co., Inc., Wilmington, DE MRID 00104977. Sherman, H. et. al. (1973) Ninety­ Day feeding Study in Rats with INA­ 3674. Haskell Laboratory. Laboratory Study Id.: 235­ 73, May 21, 1973. Unpublished. MRID 00106003 Dashiell, O.; Henry, J. (1982) Eye Irritation Test in Rabbits­­ EPA Pesticide Registration [INA­ 3674­ 122]: Haskell Laboratory Report No. 251­ 82. (Unpublished study received Jul 7, 1982 under 352­ 399; submitted by E. I. du Pont de Nemours & Co., Inc., Wilmington, DE. MRID 00106004 Dashiell, O.; Hinckle, L. (1982) Skin Irritation Test on Rabbits for EPA Pesticide Registration: Haskell Laboratory Report No. 203­ 82. (Unpublished study received Jul 7, 1982 under 352­ 399; submitted by E. I. du Pont de Nemours & Co., Inc., Wilmington, DE MRID 00108638. Kaplan, A. M., Frazier, C. V., et al. (1977) Long­ Term Feeding Study in Rats with INA­ 3674. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 353­ 77, May 13, 1977. Unpublished MRID 00109237. Repisarda, C. (1982). Metabolism of 14 C­ labeled hexazinone in the rat. E. I. duPont de Nemours and Co., Biochemicals Dept., Research Div., Experimental Station, Wilmington, DE 19898. Document No. AMR­ 79­ 82. Unpublished. MRID 00114484. Sherman, H. et al. (1973) Three­ Month Feeding Study in Dogs with INA3674 E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 408­ 73, September 12, 1973. Unpublished. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 27 of 38 MRID 00114486. Culik, R., et al. (1974) Teratogenic Study in Rats with INA­ 3674. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 265­ 74, April 9, 1974. Unpublished. MRID 00130708. Summers, J. C. (1983) Unscheduled DNA Synthesis/ Rat Hepatocytes In Vitro. E. I. du Pont de Nemours and Co., Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, P. O. Box 50, Newark, Delaware 19711. Laboratory Report No.: 766­ 82, MR No.: 4508­ 001, Date Issued: January 4, 1983. Unpublished. MRID 00130709. Valachos, D., Irr, J. and Krahn, D. F.( 1982) In Vitro Assay for Chromosome Aberrations in Chinese Hamster Ovary (CHO) Cells. E. I. du Pont Nemours and Co., Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, P. O. Box 50, Newark, Delaware 19711. Laboratory Report No. 768­ 82, MR No. 4508­ 001, December 3, 1982. Unpublished. MRID 00131355. Farrow, M. G., Cortina, T. and Zito, M. (1982). In Vivo Bone Marrow Cytogenetic Assay in Rats with H# 14,555: Final Report. Hazleton Laboratories America, Inc., 9200 Leesburg Turnpike, Vienna, Virginia 22180. HLA Project number: 201­ 573, December 9, 1982. Unpublished. MRID 00140162. Rhodes, R. C., Jewell, R. A., Sherman, H. (No date). Metabolism of "Velpar" weed killer in the rat. E. I. duPont de Nemours and Co., Biochemicals Dept., Experimental Station and Haskell Laboratory for Toxicology and Industrial Medicine, Wilmington, DE 19898. No document or report number. Results published in J. Agric. and Food Chem., 28, 303 (1980) MRID 40397501. Mullin, L. S. (1987) Teratogenicity Study of INA­ 3674 in Rats. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE. Laboratory Project Id.: Haskell Laboratory Report No. 748­ 86, January 30, 1987. Unpublished. MRID 40826201. J. F. Russell Jr. and D. F. Krahn (1977). Mutagenicity Evaluation of Striazine 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ in Salmonella typhimurium. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Elkton Road, P. O. Box 50, Newark, Delaware 19714. Haskell Laboratory Report No. 588­ 77, MR No. 0581­ 693; Date Issued: July 29, 1977. Unpublished. MRID 41235004 Hutton, J. (1989) Acute Oral Toxicity Study with IN A3674­ 207 in HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 28 of 38 Male and Female Rats: Project ID 347­ 89. Unpublished study prepared by E. I. du Pont de Nemours and Co. 34 p. MRID 41235005 Pharmakon Research International, Inc. (1989) Closed Patch Repeated Insult Dermal Sensitization Study (Buehler Method) with IN A3674 ­207 in Guinea Pigs: Project ID 446­ 89. Unpublished study pre­ pared by E. I. du Pont de Nemours and Co., Inc. 35 p. MRID 41309005. Malek, D. (1989). Repeated Dose Dermal Toxicity: 21­ Day Study with DPXA3674 207 (Hexazinone) in Rabbits. E. I. du Pont de Nemours and Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, P. O. Box 50, Elkton Road, Newark, DE 19714. Study No. HLA 673­ 89. November 22, 1989. Unpublished. MRID 41359301. Goldenthal, E. I. (1989) Supplement 1 to: Two­ Year Feeding Study in Mice with Hexazinone. International Research and Development Corporation, Mattawan, MI. Laboratory Project Id.: HLO­ 414­ 81, November 22, 1989. Unpublished. MRID 41756701 Shapiro, R. (1990) Acute Inhalation­ Limit Test: Hexazinone, Batch # GG1­ 15: Lab Project Number: T­ 452. Unpublished study prepared by Product Safety Labs. 24 p. MRID 42066501. Mebus, C. A. (1991). Reproductive and fertility effects with IN­ A3674­ 207; multigeneration reproduction study in rats. Haskell Laboratory, Newark, Delaware. Study No. HLA­ 404­ 91. September 11, 1991. Unpublished. MRID 42162301. Dalgard, D. W. (1991) Chronic toxicology study in dogs with DPX­ A3674­ 207 (Hexazinone). Hazleton Washington, Inc., 9200 Leesburg Turnpike, Vienna, VA 22182. Laboratory Study No. 201­ 905. November 5, 1991. Unpublished. MRID 42509301. Slone, Jr., T. W. (1992) Supplement 1 to: Two­ Year Feeding Study in Mice with Hexazinone. E. I. du Pont de Nemours and Company, Newark, DE. Laboratory Project Id.: HLO­ 414­ 81, October 2, 1992. Unpublished. MRID 43202901. Slone, Jr., T. W., (1994) Supplement No. 3: Two­ Year Feeding Study in Mice with Hexazinone. E. I. du Pont de Nemours and Company, Newark, DE. Laboratory Project Id.: HLO­ 414­ 81, April 11, 1994. Unpublished. MRID 45124401. Ford, L. S. (2000) Hexazinone 25L: Mouse Bone Marrow Micronucleus HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 29 of 38 Assay. DuPont Pharmaceuticals Company, Safety Assessment Section, Stine Haskell Research Center, P. O. Box 30, Elkton Road, Newark, Delaware 19714­ 3507. Laboratory Project ID: DuPont 3852; Company Study Number: THA­ 00­ 02­ 47, April 12, 2000. Unpublished. MRID 45677801. Munley, SM (2002) Hexazinone (DPX­ A3674) Technical: Developmental Toxicity Study in Rabbits. EI du Pont de Nemours and Co. Laboratory report number DuPont­ 7405, May 3, 2002. Unpublished Other references: U. S. EPA Report: Peer Review of Hexazinone (August 12, 1992). U. S. EPA Report: RfD/ Peer Review Report of Hexazinone (March 24, 1993). U. S. EPA Report: Carcinogenicity Peer Review of Hexazinone. (July 27, 1994). U. S. EPA Report: Hexazinone­ 3 rd Report of the Hazard Identification Assessment Review Committee (TXR# 0051033). U. S. EPA Report: Hexazinone ­ 2 nd Report of the FQPA Safety Factor Committee (TXR# 0051049). HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 30 of 38 9.0 APPENDICES Tables for Use in Risk Assessment HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Page 31 of 38 9.1 Toxicity Profile Summary Tables 9.1.1 Acute Toxicity Table Acute Toxicity Data on HEXAZINONE Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity 41235004 LD50 = 1200 mg/ kg III 870.1200 Acute dermal toxicity 00104974 LD50 > 5278 mg/ kg IV 870.1300 Acute inhalation toxicity 41756701 (1990) LC50 > 3.94 mg/ L( 4 hour) III 870.2400 Acute eye irritation 00106003 Irreversible corneal opacity I 870.2500 Acute dermal irritation 00106004 Mild IV 870.2600 Skin sensitization 41235005 Not a dermal sensitizer in the Buehler test in Guinea pigs NA 9.1.2 Subchronic, Chronic and Other Toxicity Tables Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90­ Day oral toxicity rats 0010977 (1973) Dose: 0, 200, 1000, 5000 ppm (equivalent to 0, 16.0/ 16.4, 81.0/ 87.3, 440/ 451 mg/ kg/ day, male/ female) Acceptable NOAEL = 1000 ppm (81.0/ 87.3 mg/ kg/ day male/ female) LOAEL = 5000 ppm (440/ 451 mg/ kg/ day male/ female) based decreased body weight and food efficiency. 870.3150 90­ Day oral toxicity in dogs 00114484 (1973) Doses of 0, 200, 1000, or 5000 ppm (equivalent to 0/ 0, 5.1/ 7.0, 25.9/ 31.6, 122.5/ 137.3 mg/ kg/ day, males/ females) Acceptable NOAEL = 1000 ppm (equivalent to 25.9/ 31.6 mg/ kg/ day for males/ females). LOAEL = 5000 ppm (equivalent to 122.5/ 137.3 mg/ kg/ day in males/ females) based on decreased body weight gains, increased relative liver weights, and increased alkaline phosphatase levels in both sexes and transiently decreased food consumption in the females. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Page 32 of 38 870.3200 21/ 28­ Day dermal toxicity in rabbits 41309005 (1989) Doses: 0, 50, 400, or 1000 mg/ kg/ day Acceptable NOAEL = 1000 mg/ kg/ day. LOAEL = was not identified for systemic and dermal toxicity. 870.3250 90­ Day dermal toxicity Not required 870.3465 21­ Day inhalation toxicity in the rat 00063972 (1976) Dose: 0, 2.5 mg/ L Unacceptable/ upgradable No documentation was submitted with a summary of an inhalation study. 870.3465 90­ Day inhalation toxicity The 90­ day inhalation study is not required, however a 28­ Day inhalation study is required (contact Agency prior to conducting study) 870.3700a Prenatal developmental in rats 40397501 (1980) Doses: 0, 40, 100, 400, or 900 mg/ kg Acceptable Maternal NOAEL = 100 mg/ kg/ day LOAEL = 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. Developmental NOAEL = 400 mg/ kg/ day LOAEL = 900 mg/ kg/ day based on decreased female fetal weight, and increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). 870.3700a Prenatal developmental in rats 00114486 (1974) Doses: 0, 200, 1000, or 5000 ppm (equivalent to 0, 18.9, 94.5, and 482.0 mg/ kg) Unacceptable/ Upgradable Maternal: NOAEL is 1000 ppm (equivalent to 94.5 mg/ kg/ day). LOAEL = 5000 ppm (equivalent to 482 mg/ kg/ day) based on decreased body weights, body weight gains, and food efficiency. Developmental: NOAEL = 5000 ppm (equivalent to 482.0 mg/ kg/ day). LOAEL was not observed. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Page 33 of 38 870.3700b Prenatal developmental in rabbits 45677801 (2002) Doses: 0, 50, 125, 175 mg/ kg/ day Acceptable Maternal: NOAEL = 50 mg/ kg/ day. LOAEL = 125 mg/ kg/ day based body weight and food consumption decrement. Developmental: NOAEL = 50 mg/ kg/ day. LOAEL = 125 mg/ kg/ day based on 5% decrement in male and female fetal weight and a 10% decrement in female fetal weight. 870.3700b Prenatal developmental in rabbits 00028863 (1980) Doses: 0, 20, 50, or 125 mg/ kg Unacceptable/ Upgradable Maternal NOAEL = 50 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on transient decreases in food consumption and body weight gains. Developmental NOAEL = 50 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on possible skeletal abnormalities and total abnormalies. 870.3800 Reproduction and fertility effects in rats 42066501 (1991) Doses: 0, 200, 2000 or 5000 ppm M: 0, 11.8, 117 or 294 mg/ kg/ day F: 0, 14.3, 143 or 383 mg/ kg/ day Acceptable Parental/ Systemic NOAEL = 14.3 mg/ kg/ day LOAEL = 143 mg/ kg/ day based on male body weight decrement. Reproductive NOAEL = 383 mg/ kg/ day LOAEL = None based on no effects on or organs of reproduction. Offspring NOAEL = 14.3 mg/ kg/ day LOAEL = 143 mg/ kg/ day based on reduced female pup weight at birth and during lactation. 870.4100a Chronic toxicity in rats See 870.4300 NOAEL = LOAEL = 870.4100b Chronic toxicity dogs 42162301 (1991) Doses: 0, 200, 1500, or 6000 ppm (equivalent to 5.00/ 4.97, 41.24/ 37.6 and 161/ 167 mg/ kg/ day, male/ female. Acceptable NOAEL = 200 ppm (5.0/ 5.0 mg/ kg/ day, male/ female) LOAEL = 1500 ppm (41.2 and 37.57 mg/ kg/ day, respectively) based on thinness in one male and hepatotoxicity as evidenced by changes in clinical chemistry parameters and microscopic lesions. 870.4200 Carcinogenicity rats See below 870.4300 No evidence of carcinogenicity HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Page 34 of 38 870.4200 Carcinogenicity mice 00079203 (1981), 41359301 (1989), 42509301 (1992) and 43202901 (1994) Doses: 0, 0, 200, 2500 or 10,000 ppm (equivalent to 28/ 34, 366/ 450 and 1635/ 1915 mg/ kg/ day, male/ female) Acceptable NOAEL = 200/ 2500 ppm (28/ 450 mg/ kg/ day, male/ female, respectively) LOAEL = 2500 ppm for males (equivalent to 366 mg/ kg/ day) based on gross liver nodules/ masses, hyperplastic nodules in the liver and centrilobular hepatocyte hypertrophy and 10,000 ppm for females (equivalent to 1915 mg/ kg/ day [limit dose]) based on decreased body weights, increased relative liver/ gall bladder weights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. Insufficient evidence for carcinogenicity. 870.4300 Combined chronic/ carcinogenicity/ rats 00108638 (1977) Doses: 0, 200, 1000, or 2500 ppm (equivalent to 0, 10.2/ 12.5, 53.4/ 67.5, or 138/ 179 mg/ kg/ day, male/ female) Acceptable NOAEL = 200 ppm for males and females (10.2/ 12.5 mg/ kg/ day, male/ female). LOAEL = 1000 ppm for males and females (equivalent to 53.3/ 67.5 mg/ kg/ day, male/ female) based on decreased body weight and food efficiency in males and females. In males at 2500 ppm the body weight decrement and food efficiency decrement occurred only for the first 6 months of the study. The carcinogenic potential of hexazinone is considered negative. Gene mutation 870.5100; Reverse mutation in Salmonella strains 40826201 (1977) 200, 400, 600, 800 and 1000 :g/ plate ­S9 and 400, 800, 1200, 1600 and 2000 :g/ mL + S9­ mix. Unacceptable No mutagenic potential was seen, but doses insufficent to cause cell toxicity. Gene mutation 870.5300; hamster CHO cells/ HPRT assay 00076956 (1980) Trial 1 were 2.0, 11.1, 13.1, 13.9 and 14.3 mM ­S9 and 2.0, 7.9, 8.9, 9.3 and 9.9 mM +S9. Trial 2 were 2.0, 5.9, 11.1, 13.1 and 13.9 mM ­S9 and 2.0, 7.9, 8.9, 9.3 and 9.9 mM + S9. Acceptable No evidence of mutagenic potential at cytotoxic doses. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Page 35 of 38 Cytogenics 870.5375; Chromosomal aberrations in hamster CHO cells 00130709 (1982) In Trial 1, 1.58, 3.94, 15.85 and 19.82 mM ­S9 and 0.32, 3.17, 7.93 and 15.85 mM + S9. In Trial 2, 1.58, 3.94, 7.93 and 15.85 ­S9 0.32, 3.17, 7.93 and 15.85 mM + S9 Acceptable Positive for structural chromosomal aberrations with and without S9. Other Effects 870.5385, In vivo Rat bone marrow cytogenics assay 00131355 (1982) Rat doses: 100, 300 or 1000 mg/ kg Unacceptable No evidence of mutagenic potential, but insufficient animals and cells were tested. Other Effects 870.5395 Mouse bone marrow micronucleus test 45124401 (2000) Mouse doses: 1000, 2000 and 3000 mg/ kg Acceptable No evidence of clastogenic or aneugenic effect in bone marrow at toxic doses.. Other Effects 870.5550, UDS in rat hepatocytes 00130708 (1983) Trial 1: 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 10.0 and 30.0 mM and Trial 2: 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 5.0, 10.0 and 30.0 mM. Acceptable No evidence of mutagenic potential at precipitating dose levels. 870.6200a Acute neurotoxicity screening battery Not required 870.6200b Subchronic neurotoxicity screening battery Not required 870.6300 Developmental neurotoxicity Not required ­ HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Page 36 of 38 870.7485 Metabolism and pharmacokinetics in the rat 00140162 & 00109237 (1980 &1982) Acceptable No parent was seen in urine or feces, which was rapidly absorbed and excreted. Two identified metabolites resulted from hydroxylation of the cyclohexyl ring and differed only by the metabolic conversion of the 6­ dimethyl amine to a secondary methyl amine. No sex­, or doserelated differences in the formation and excretion of these metabolites were found. 870.7600 Dermal penetration Not required Special studies None submitted 9.2 Summary of Toxicological Dose and Endpoints for HEXAZINONE for Use in Human Risk Assessment Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Dietary Risk Assessments Acute Dietary females 13­ 50 years of age NOAEL = 400 UF = 100 Acute RfD = 4.0 mg/ kg/ day 1x Developmental Toxicity ­ Rat LOAEL is 900 mg/ kg/ day based on decreased male and female fetal weight, kidneys with no papilla (malformation) and misaligned sternebrae (variation) Acute Dietary general population including infants and children An appropriate endpoint attributable to a single dose was not identified in the oral studies, including the rat and rabbit developmental studies. Chronic Dietary all populations NOAEL= 5.0 UF = 100 Chronic RfD = 0.05 mg/ kg/ day 1x Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Page 37 of 38 Incidental Oral Short­ Term (1 ­ 30 Days) Residential Only There are no residential uses at the present time and therefore, endpoints were not selected. Incidental Oral Intermediate­ Term (1 ­ 6 Months) Residential Only There are no residential uses at the present time and therefore, endpoints were not selected. Non­ Dietary Risk Assessments Dermal Short­ Term (1 ­ 30 days) No hazard was identified, therefore quantification of risk is not required. No systemic toxicity was seen at the limit dose following repeat dermal application, and there were no concerns for developmental or reproductive toxicity. Residential Occupational Dermal Intermediate­ Term 1 (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= N/ A N/ A Occupational MOE= 100 N/ A Dermal Long­ Term 1 (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= N/ A N/ A Occupational MOE= 100 N/ A Inhalation Short­ Term 2 (1 ­ 30 days) Oral NOAEL= 50 mg/ kg/ day Developmental Toxicity ­ Rabbit LOAEL = 125 mg/ kg/ day based on decreases in maternal food consumption and dose related body weight decrement and fetal weight decrement. Residential MOE= N/ A N/ A Occupational MOE= 100 N/ A HEXAZINONE/ 107201/ August/ 2002 TRED Toxicology Chapter Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Page 38 of 38 Inhalation Intermediate­ Term (1 ­ 6 Months) Oral NOAEL= 5.0 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE = N/ A N/ A Occupational MOE= 100 N/ A Inhalation Long­ Term (> 6 Months) Oral NOAEL= 5.0 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= N/ A N/ A Occupational MOE= 100 N/ A Cancer Classification: D ­ Not Classifiable as to human carcinogenicity 1 Since an oral NOAEL was selected 12.5% dermal absorption factor should be used for route to route exposures. 2 Absorption via the inhalation route is assumed to be equivalent to oral absorption. N/ A = Not Applicable; there are no residential uses.

epa

2024-06-07T20:31:42.941641

regulations

EPA-HQ-OPP-2002-0188-0023

Supporting & Related Material

­1­ TXR NO. 0051033 DATE: August 12, 2002 MEMORANDUM SUBJECT: HEXAZINONE ­ 3 rd Report of the Hazard Identification Assessment Review Committee. FROM: David G. Anderson Toxicologist. Reregistration Branch­ 2 Health Effects Division (7509C) THROUGH: Jess Rowland, Co­ Chair and Elizabeth Doyle, Co­ Chair Hazard Identification Assessment Review Committee Health Effects Division (7509C) TO: Carol Christensen, Risk Assessor Reregistration Branch­ 2 Health Effects Division (7509C) PC Code: 107201 On Dec 4, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for HEXAZINONE with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to HEXAZINONE was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. On April 02, 2002, HIARC assessed the potential for increased susceptibility of infants and children from exposure as required by the Food Quality Protection Act (FQPA) of 1996 under the 2002 OPP 10X guidance document. At this meeting, the HIARC applied a database uncertainty factor to account for the lack of a developmental toxicity study in rabbits. On July 30, 2002, HIARC reviewed the new rabbit developmental toxicity study submitted to the Agency on May 3, 2002. The conclusions drawn at the three meetings are presented in this report. ­2­ Committee Members in Attendance Members present were: Bill Burnam, Jonathan Chen, Pamela Hurley, John Liccione, Elizabeth Mendez, Jess Rowland, Brenda Tarplee. Member( s) in absentia: Ayaad Assaad, David Nixon, Beth Doyle, Sue Makris, Steve Knizer. Data evaluation prepared by: David G. Anderson, RRB2 Also in attendance were: Carol Christensen, Pauline Wagner Data Evaluation/ Report presentation David G. Anderson Toxicologist Report Concurrence Brenda Tarplee, Senior Scientist Science Information Management Branch ­3­ INTRODUCTION On December 4, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) reviewed the recommendations of the toxicology reviewer for HEXAZINONE with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to HEXAZINONE was also evaluated as required by the Food Quality Protection Act (FQPA) of 1996. On April 02, 2002, HIARC assessed the potential for increased susceptibility of infants and children from exposure as required by the Food Quality Protection Act (FQPA) of 1996 under the 2002 OPP 10X guidance document. At this meeting, the HIARC applied a database uncertainty factor to account for the lack of a developmental toxicity study in rabbits. On July 30, 2002, HIARC reviewed the new rabbit developmental toxicity study submitted to the Agency on May 3, 2002. The conclusions drawn at the three meetings are presented in this report. I FQPA HAZARD CONSIDERATIONS 1. Adequacy of the Toxicity Data base The HIARC considered that the toxicology database for hexazinone is complete, except for a needed confirmatory 28­ day inhalation study. 2. Evidence of Neurotoxicity The HIARC concluded that there is not a concern for neurotoxicity resulting from exposure to hexazinone. 3. Developmental Toxicity Study Conclusions 3.1 Developmental toxicity in rats (1987) Executive Summary: In a developmental toxicity study (MRID 40397501), hexazinone (99.26% a. i.; Lot# S30306A, Batch# 2/ 36) in 0.5% methylcellulose was administered orally via gavage to 25 Crl: CD ® BR female rats/ group at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day (GD) 7 through 16. The dosing volume was 10 mL/ kg (calculated by reviewers). All dams were sacrificed on GD 22 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in clinical signs, gross pathology, pregnancy rate, live fetuses, resorptions, pre­ or post­ implantation loss, corpora lutea, or implantations were noted at any dose level tested. No treatment­ related findings were noted in the 100, or 40 mg/ kg groups. ­4­ In the 900 mg/ kg dams, one treatment­ related death occurred; alopecia and an enlarged stomach containing fluid and food were noted at necropsy. Decreased (p< 0.05) body weight gains were noted during GDs 15­ 17 ( 37%) and 17­ 22 ( 17%). In addition, body weight gains were decreased (p< 0.05) for the overall (GDs 7­ 17) treatment interval ( 30%). Gravid uterine weights were not reported; however, adjusted (for gravid uterine weight) terminal body weights were slightly decreased ( 6%; p 0.05). A significant (p 0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 9­ 11, 15­ 17, 7­ 17, and 17­ 22. Decreased (p 0.05) food consumption was observed throughout treatment (GDs 7­ 17; 9 16­ 22%) and post­ treatment (GDs 17­ 22; 9 9%). A significant (p 0.05) trend by linear combination of dose ranks from analysis of variance (ANOVA) was noted for GDs 7­ 9, 9­ 11, 11­ 13, 13­ 15, 15­ 17, 7­ 17, and 17­ 22. Also a significantly decreased food consumption was seen at 400 mg/ kg/ day (GD9­ 11; 9 1%) and (GD 7­ 17; 9 8%). In addition, relative (to body) liver weights were increased (p 0.05) in the 400 (5.2%) and 900 (5.6%) mg/ kg dams compared to concurrent controls (4.9%). Decreased (p 0.05) terminal body weights were noted at 900 mg/ kg ( 6%). A significant (p 0.05) trend by linear combination of dose ranks from ANOVA was noted for relative liver weights and adjusted terminal body weights. In addition, a significant (p 0.05) trend by linear combination of dose ranks from ANOVA was noted for absolute liver weights. Despite this trend, the observed increases in absolute liver weights at 100, 400, and 900 mg/ kg ( 1­ 8%) were not statistically significant. Liver weight findings are considered equivocal. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. The maternal NOAEL is 100 mg/ kg/ day. In the 900 mg/ kg/ day group, male and female fetal weights were decreased ( 21%; p 0.05); a significant (p 0.05) trend by Jonckheere's test was noted for this parameter. At 400 mg/ kg/ day, the female fetal weights that were significantly decreased were not considered to be biologically significant. At necropsy, an increased (p 0.05) incidence of misaligned sternebra (1), a variation, was observed (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0066; litter incidence: 0.09). In addition, an increased (p 0.05) incidence of misaligned sternebrae (2+), a variation, was noted (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0033; litter incidence: 0.04). Furthermore, an increased incidence of kidneys with no papilla was observed (fetal incidence: 0.0347; litter incidence: 0.25) relative to concurrent controls (fetal incidence: 0.0062; litter incidence: 0.04). Although the incidence was not statistically significant, a dose­ related trend (p 0.05) was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day, based on decreased male and female fetal weight, increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The developmental toxicity NOAEL is 400 mg/ kg/ day. The developmental toxicity study in the rat is classified acceptable/ guideline (OPPTS 870.3700; ­5­ §83­ 3 a) and satisfies the guideline requirement for a developmental toxicity study in the rat. An unacceptable developmental feeding study in the rat shows (MRID# 00114486) a maternal body weight decrement at 482 mg/ kg/ day with a NOAEL of 94.5 mg/ kg/ day with a developmental NOAEL of 482mg/ kg/ day. This study tends to add support the acceptable rat developmental (by gavage) toxicity study. 3.2 Developmental Toxicity in the rabbit (2002) Executive Summary: In a developmental toxicity study (MRID 45677801) [DXP­ A3674] hexazinone (98.78 % a. i., batch/ lot# DXP­ A3694­ 329) was administered to 22 female [Hra:( NZW) SPF strain] rabbits/ group by gavage] at dose levels of 0, 20, 50, 125 or 175 mg/ kg bw/ day from days 7 through 28 of gestation. Maternal toxicity was demonstrated by statistically significant findings at 125 mg/ kg/ day of a body weight gain decrement of ­102 g between gd 7­ 9 and ­57 g between gd 9­ 11, food consumption decrement of 18%, abortions, death and clinical signs such as diarrhea, stained cageboard and tail. Only 1 dam and 1 litter survived to termination at 175 mg/ kg/ day. The maternal LOAEL is 125 mg/ kg bw/ day, based on body weight gain decrement, decreased food consumption, abortions, death and clinical signs including abnormal gait at 175 mg/ kg/ day. The maternal NOAEL is 50 mg/ kg bw/ day. No dose related external, visceral or skeletal findings were noted. Since only 1 dam with 1 litter survived to termination at the 175 mg/ kg/ day dose, evaluation of embryo/ fetal effects at this dose are meaningless. Random malformations were seen in control and the highest dose group with no dose relationship. Mean male and female fetal weight was reduced by 5% and female fetal weight was reduced by 10% at 125 mg/ kg/ day. Although this weight reduction was not list as being statistically significant, the author stated that this slight weight reduction at 125 mg/ kg/ day was a developmental effect level and this reviewer agrees. The developmental LOAEL is 125 mg/ kg bw/ day, based on mean male and female fetal weight decrement and female fetal weight decrement. The developmental NOAEL is 50 mg/ kg bw/ day. The developmental toxicity study in the rabbit is classified acceptable (guideline) and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rabbit. 3.3 Developmental Toxicity in the rabbit (1980) Executive Summary: In a developmental toxicity study (MRID 00028863), hexazinone (100% a. i.; Lot/ batch # E21216A) was administered orally via gavage in a dosing volume of 1 mL/ kg) to 17 female New Zealand White rabbits/ group at dose levels of 0, 20, 50, or 125 mg/ kg on GD 6 through 19. All does (except those that died or delivered prematurely) were sacrificed on GD 29, and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in mortality, clinical signs, body weights, gross pathology, fetal weights, sex ratios, pre­ implantation or post­ ­6­ implantation losses, or the number of corpora lutea, implantations, resorptions, live fetuses, or dead fetuses were observed. At 125 mg/ kg, food consumption was decreased (p 0.05), relative to concurrent controls, at the beginning of treatment from GD 7 through 11 ( 61­ 89%). Decreases in food consumption, that were not statistically significant, continued throughout treatment (GDs 12­ 19; 9 2­ 37%). Diminished food consumption resulted in decreased (not statistically significant) body weight gains in the does (­ 241.5 g) relative to concurrent controls (­ 7.2 g) during GDs 6­ 11. However, weight gain in these animals recovered quickly and was higher than control animals during subsequent treatment intervals (GDs 11­ 15 and 15­ 19). The maternal LOAEL is 125 mg/ kg/ day based on transient decreases in food consumption and body weight gains. The maternal NOAEL is 50 mg/ kg/ day. At 125 mg/ kg/ day, the following skeletal variations were noted (data presented as fetal incidence vs. 0 controls): (i) lagging ossification in extremities (0.0882); (ii) malaligned thoracic vertebrae (0.0294); and (iii) flexed wrist( s) (0.0294). In addition, non­ ossified thumb, an anomaly, was noted at an increased incidence (0.0294) relative to concurrent controls (0). In the absence of historical control data, these findings are considered treatment­ related. In addition, it could not be determined how many of these nominally increased incidences were from different litters, which would have increased concern for developmental toxicity. The developmental toxicity LOAEL is 125 mg/ kg/ day, based on possible skeletal abnormalities and total abnormalities. The developmental toxicity NOAEL is 50 mg/ kg/ day. The developmental toxicity study in the rabbit is classified unacceptable/ upgradable, pending submission of acceptable purity, concentration, stability and litter data and historical control data. A letter dated 9/ 26/ 01 from the registrant provided no additional information about this rabbit developmental toxicity study other than that the doses were not analyzed and that a repeat rabbit developmental toxicity was currently being conducted. 4. Reproductive Toxicity Study Conclusions (1991) 4.1 Executive Summary: In a two­ generation reproduction study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 30 male and 30 female Sprague­ Dawley rats in the diet at concentrations of 0, 200, 2000, or 5000 ppm (MRID 42066501). One litter was produced in the first generation and two litters were produced in the second generation. Test substance intake for the treated F0 groups was 11.8, 117, and 294 mg/ kg/ day, respectively, for males and 14.3, 143, and 383 mg/ kg/ day, respectively, for females. Test substance intake for the treated F1 groups was 15.3, 154, and 399 mg/ kg/ day, respectively, for males and 17.7, 180, and 484 mg/ kg/ day, respectively, for females. F0 and F1 parental animals were administered test or control diet for 73 or 105 days, respectively, prior to mating, throughout mating, gestation, and lactation, and until necropsy. Deaths of several F0 and F1 parental animals were considered incidental to treatment. No treatment­ related clinical signs of toxicity were observed in the adult animals of either generation. ­7­ Gross necropsy was unremarkable and no microscopic lesions were observed in selected tissues from the reproductive tracts of male and female parental animals. Body weights and body weight gains of the F0 males were not affected by treatment. Premating body weight gains by the mid­ and high­ dose F0 females were 76% and 62% (p # 0.05 for both), respectively, of the control level resulting in final premating body weights 93% and 87% (p # 0.05), respectively, of the controls. Body weights of the high­ dose F1 males and females were significantly reduced (p # 0.05) during the premating interval with overall weight gains 87% and 82%, respectively, of the control group amounts. Reductions in body weights and body weight gains during premating for the mid­ and high­ dose F0 and high­ dose F1 dams continued during gestation and lactation. Food consumption during premating was similar between the treated and control groups for males and females of both generations. However, during gestation significantly (p # 0.05) lower food consumption was noted for the high­ dose F1 dams during production of both litters and for the mid­ dose F1 dams during production of the second litter. There was a statistically significant increase in absolute P0 testes weight that appeared to be dose related, but a nominally decrease absolute F1 adult testes weight in the 5000 ppm dose groups. The F1 testes weight change did not appear to dose related. The testes weight changes in males would appear to be incidental. Therefore, the systemic toxicity LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced body weight and body weight gains by F1 males and F0 and F1 females. The systemic toxicity NOAEL is 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). No reproductive effects were seen in the study except for the weight effects on offspring. Live birth and viability indices and litter survival were similar between the treated and control groups. The lactation index for the F2b high­ dose litters was 85.8% (p # 0.05) compared to 97.5% for the control group. Pup body weights were decreased throughout lactation in the mid­ and high­ dose groups of all litters as compared with the control groups with statistical significance (p # 0.05) attained at most time points. The lower pup body weights were more pronounced in females than in males. F1 and F2a female pup weights were statistically significantly decreased at birth, day 7 and 14 of lactation at $ 2000 ppm. There were no obvious reproductive effects other than the pup weight decrement. Therefore, the offspring LOAEL is 2000 ppm (117­ 154 mg/ kg/ day for males and 143­ 180 mg/ kg/ day for females) based on reduced female pup body weights at birth and during lactation. The reproductive toxicity NOAEL was 200 ppm (11.8­ 15.3 mg/ kg/ day for males and 14.3­ 17.7 mg/ kg/ day for females). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a reproductive toxicity study [OPPTS 870.3800 (§ 83­ 4)] in rats. ­8­ 5. Additional Information from Literature Sources The published literature found on hexazinone were the papers on the same studies submitted to the Agency [ Kennedy, GL and Kaplan, AM (1984) Chronic Toxicity, Reproductive, and Teratogenic Studies of Hexazinone. Fundamental and applied Toxicology 4, 960­ 971]. 6. Pre­ and /or Postnatal Toxicity The HIARC concluded that there is not a concern for pre­ and postnatal toxicity resulting from exposure to hexazinone. A. Determination of Susceptibility No quantitative or qualitative evidence of increased susceptibility was seen following in utero or pre/ post natal exposure to rats or rabbits. In the rat developmental toxicity study, developmental effects were seen at a higher dose than the dose that caused maternal toxicity. In the rabbit study, fetal weight decrement was seen at the same dose that caused maternal weight decrement. In the two generation reproduction study, offspring toxicity was seen at the same dose that caused parental toxicity. B. Degree of Concern Analysis and Residual Uncertainties There is no evidence for increased susceptibility, therefore, no residual concerns . C. Hazard­ based Special FQPA Safety Factors The special FQPA Safety Factor can be reduced to 1x due to lack of evidence for increased susceptibility and no residual concerns. 7. Recommendation for a Developmental Neurotoxicity Study A. Evidence that suggests requiring a Developmental neurotoxicity study: None B. Evidence that do not support the need for a Developmental Neurotoxicity study No evidence of neurotoxicity or neuropathology was seen in the database. A 12­ 13% absolute female brain decrement was seen in the chronic dog study, but the brain weight decrement was associated with severe body weight decrement and may have been secondary to the malnutrition in these animals. Hexazinone differs structurally from atrazine such that it is unlikely to bind to the same receptor and not likely to result in similar effects. Based on the weight of evidence presented, the HIARC concluded that a developmental nuerotoxicity study is not required. ­9­ II. HAZARD IDENTIFICATION 1. Acute Reference Dose (RfD)( Population Subgroup: Females 13­ 50) Study Selected: Developmental toxicity Study in Rats § 870.3700 MRID No.: 40397501 Executive Summary: In a developmental toxicity study (MRID 40397501), hexazinone (99.26% a. i.; Lot# S30306A, Batch# 2/ 36) in 0.5% methylcellulose was administered orally via gavage to 25 Crl: CD ® BR female rats/ group at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day (GD) 7 through 16. The dosing volume was 10 mL/ kg (calculated by reviewers). All dams were sacrificed on GD 22 and their fetuses removed by cesarean and examined. When compared to concurrent controls, no treatment­ related changes in clinical signs, gross pathology, pregnancy rate, live fetuses, resorptions, pre­ or post­ implantation loss, corpora lutea, or implantations were noted at any dose level tested. No treatment­ related findings were noted in the 100, or 40 mg/ kg groups. In the 900 mg/ kg dams, one treatment­ related death occurred; alopecia and an enlarged stomach containing fluid and food were noted at necropsy. Decreased (p< 0.05) body weight gains were noted during GDs 15­ 17 ( 37%) and 17­ 22 ( 17%). In addition, body weight gains were decreased (p< 0.05) for the overall (GDs 7­ 17) treatment interval ( 30%). Gravid uterine weights were not reported; however, adjusted (for gravid uterine weight) terminal body weights were slightly decreased ( 6%; p 0.05). A significant (p 0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 9­ 11, 15­ 17, 7­ 17, and 17­ 22. Decreased (p 0.05) food consumption was observed throughout treatment (GDs 7­ 17; 9 16­ 22%) and post­ treatment (GDs 17­ 22; 9 9%). A significant (p 0.05) trend by linear combination of dose ranks from ANOVA was noted for GDs 7­ 9, 9­ 11, 11­ 13, 13­ 15, 15­ 17, 7­ 17, and 17­ 22. Also a significantly decreased food consumption was seen at 400 mg/ kg/ day (GD9­ 11; 9 1%) and (GD 7­ 17; 9 8%). In addition, relative (to body) liver weights were increased (p 0.05) in the 400 (5.2%) and 900 (5.6%) mg/ kg dams compared to concurrent controls (4.9%). Decreased (p 0.05) terminal body weights were noted at 900 mg/ kg ( 6%). A significant (p 0.05) trend by linear combination of dose ranks from ANOVA was noted for relative liver weights and adjusted terminal body weights. In addition, a significant (p 0.05) trend by linear combination of dose ranks from ANOVA was noted for absolute liver weights. Despite this trend, the observed increases in absolute liver weights at 100, 400, and 900 mg/ kg ( 1­ 8%) were not statistically significant. Liver weight findings are considered equivocal. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day on mortality and decreased body weight gains and food consumption. The maternal NOAEL is 100 mg/ kg/ day. ­10­ In the 900 mg/ kg/ day group, male and female fetal weights were decreased ( 21%; p 0.05); a significant (p 0.05) trend by Jonckheere's test was noted for this parameter. At 400 mg/ kg/ day, only female fetal weights were significantly decreased (2%) but were not considered to biologically significantly depressed. At 900 mg/ kg/ day, an increased (p 0.05) incidence of misaligned sternebrae (1), a variation, was observed (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0066; litter incidence: 0.09). In addition, an increased (p 0.05) incidence of misaligned sternebrae (2+), a variation, was noted (fetal incidence: 0.0217; litter incidence: 0.30) relative to concurrent controls (fetal incidence: 0.0033; litter incidence: 0.04). Furthermore, an increased incidence of kidneys with no papilla was observed (fetal incidence: 0.0347; litter incidence: 0.25) relative to concurrent controls (fetal incidence: 0.0062; litter incidence: 0.04). Although the incidence was not statistically significant, a dose­ related trend (p 0.05) was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day, based on decreased male and female fetal weight and increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The developmental toxicity NOAEL is 400 mg/ kg/ day. The developmental toxicity study in the rat is classified acceptable/ guideline (OPPTS 870.3700; §83­ 3 a) and satisfies the guideline requirement for a developmental toxicity study in the rat. Dose and Endpoint for Establishing RfD: Developmental NOAEL is 400 mg/ kg/ day. The LOAEL is 900 mg/ kg/ day based on increased kidneys with no papillae and misaligned sternebrae. Uncertainty Factor (UF): 100 (10X intraspecies variation; 10X interspecies extrapolation) Comments about Study/ Endpoint/ Uncertainty Factor: The malformations (kidneys with no papillae) are presumed to occur after a single and thus appropriate for this risk assessment. In the rabbit developmental study (MRID# 45677801) abortions occurred later in gestation (GD 18­ 27) and therefore was not considered to be appropriate for this exposure scenario. Also, the one death in the maternal animal at 125 mg/ kg/ day that occurred on gestation day 8 was discounted due to a lack of dose response and one death in control rabbits. At 175 mg/ kg/ day, maternal death occurred late in gestation. 2. Acute Reference Dose (RfD)( General Population) An appropriate endpoint attributable to a single dose was not identified in the oral studies, including the rat and rabbit developmental studies. Acute RfD (Females 13­ 50) = 400 mg/ kg (NOAEL) = 4.0 mg/ kg 100 (UF) ­11­ 3. Chronic Reference Dose (RfD) Study Selected: One­ Year Chronic Dog Study Guideline #: 870.4100 MRID No.: 42162301 Executive Summary: In a one­ year chronic toxicity study, hexazinone (98% a. i., Lot No. T02118994) was administered to groups of 5 male and 5 female beagle dogs in the diet at concentrations of 0, 200, 1500, or 6000 ppm (MRID 42162301). Time­ weighted average doses for the treated groups were 5.00, 41.24, and 161.48 mg/ kg/ day, respectively, for males and 4.97, 37.57, and 166.99 mg/ kg/ day, respectively, for females. All animals survived to scheduled necropsy. Treatment­ related clinical signs of toxicity included the observation of thinness in 1/ 5 mid­ dose males, 3/ 5 high­ dose males, and 1/ 5 high­ dose females. Body weights of the high­ dose groups were significantly (p # 0.05) less than those of the control throughout most of the study. Final body weights of the high­ dose males and females were 78% and 67%, respectively, of the control levels. Food consumption by the high­ dose groups was slightly (n. s.) less than that of the controls throughout the study with statistical significance (p # 0.05) attained for females at week 52. Overall food consumption (weeks 1­ 52) for high­ dose males and females was 85% (n. s.) and 74% (p # 0.05), respectively, of the control group levels. Body weights and food consumption for the low­ and mid­ dose groups were not affected by treatment. No treatment­ related ophthalmological lesions, changes in urinalysis parameters, or gross necropsy findings were noted. A moderate macrocytic anemia was observed in the high­ dose groups as evidenced by slight or significant (p # 0.05) decreases in RBC counts, hemoglobin, and hematocrit and increases in MCV and MCH in one or both sexes throughout the study. Cholesterol levels were significantly (p # 0.05) decreased in the high­ dose groups beginning at week 13 for males (52­ 64% of controls) and at week 26 for females (45­ 51% of controls). Albumin levels were significantly (p # 0.05) decreased in the mid­ dose males (93% of controls) at week 13 only, and in the high­ dose males (74­ 78% of controls) and females (75­ 82% of controls) throughout the study. Beginning on week 13 or 26, the high­ dose groups had aspartate aminotransferase levels 140­ 203% (p # 0.05) of the control values and alanine aminotransferase levels 206­ 276% (p # 0.05) of the control values. Alkaline phosphatase levels were significantly (p # 0.05) increased in the mid­ dose males (259­ 409% of controls) and females (163­ 194% of controls; n. s.) beginning at week 26 and in the high­ dose males (346­ 1363% of controls) and females (307­ 559% of controls) beginning at week 13. For the high­ dose animals, decreases in absolute testes weights in males and kidney, heart, and brain weights in females (­ 12%) and increases in relative liver weights in males and females were considered due to lower final body weights of these animals as compared with controls. Microscopic lesions in the liver of high­ dose animals included concentric membranous bodies in 4 males and 5 females, centrilobular single cell necrosis in 3 males and 3 females, hepatocellular pigment in 3 males and 3 females, and vacuolation in 3 males and 4 females. In addition ­12­ vacuolation was observed in one mid­ dose male and pigment and membranous bodies were each observed in one mid­ dose female. These lesions were not seen in control or low­ dose animals. Therefore, the LOAEL for hexazinone in male and female beagle dogs is 1500 ppm (41.24 and 37.57 mg/ kg/ day, respectively) based on thinness in one male and hepatotoxicity as evidenced by changes in clinical chemistry parameters and microscopic lesions. The NOAEL is 200 ppm (5.00 and 4.97 mg/ kg/ day, respectively). This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a chronic toxicity study [OPPTS 870.4100 (§ 83­ 1b)] in dogs. Dose and Endpoint for Establishing RfD: NOAEL of 5.0 mg/ kg/ day based body weight decrement, elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, and histopathologic lesions of the liver at 38 mg/ kg/ day (LOAEL). Uncertainty Factor( s): 100 (10X intraspecies variation; 10X interspecies extrapolation) Comments about Study/ Endpoint/ Uncertainty Factor( s): Dose and endpoint identified following long term exposure in the most sensitive species. 4. Incidental Oral Exposure: Short­ Term (1­ 30 days) and Intermediate­ Term (1 Month ­6 Months) Toxicity endpoints for incidental oral exposure were not selected since there are no residential exposure expected or anticipated based on the current use pattern. 5. Dermal Absorption No dermal absorption study is available. For dermal absorption, the NOAEL from the 21­ day dermal toxicity study at the limit dose of 1000 mg/ kg/ day was considered a lower bound for the LOAEL, which was compared with LOAEL of 125 mg/ kg/ day from the new developmental toxicity study in rabbits (MRID# 45677801). The ratio of these two numbers was used to estimate a dermal absorption factor of 12.5%. Dermal Absorption Factor: 12.5% Chronic RfD = 5.0 mg/ kg/ day (NOAEL) = 0.05 mg/ kg/ day 100 (UF) ­13­ 6. Short­ Term Dermal (1 Day ­ 1 Month) Exposure Study Selected: None MRID No.: None Executive Summary: None Dose and Endpoint for Risk Assessment: Not applicable Comments about Study/ Endpoint: Quantification of dermal risk is not required since no hazard was identified via the dermal route (no systemic toxicity was seen at the Limit Dose (1000 mg/ kg/ day) in the 21­ day dermal study in rabbits) and there are no concerns for pre/ post­ natal toxicity . 7. Intermediate­ Term Dermal (1­ 6 Months) Study Selected: Chronic Feeding Study in Dogs § 870.4100 MRID No.: 42162301 Executive Summary: [See Section II. 3. on the Chronic Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: NOAEL of 5.0 mg/ kg/ day is based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and the clinical observation of thinnest in one males at 38 mg/ kg/ day. Comments about Study/ Endpoint: The elevation in clinical chemistry parameters were seen at 3 and 6 months and thus appropriate for the exposure period. Since an oral NOAEL was selected, a 12.5% dermal absorption factor should be used for route to route extrapolation. 8. Long­ Term Dermal (longer than 6 Months) Exposure Study Selected: Chronic Feeding Study in Dogs § 870.4100 MRID No.: 42162301 Executive Summary: [See Section II. 3. on the Chronic Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: NOAEL of 5.0 mg/ kg/ day is based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and the clinical observation of thinnest in one males at 38 mg/ kg/ day. Comments about Study/ Endpoint: The elevation in clinical chemistry parameters were seen at 3 , ­14­ 6 and 12 months and thus appropriate for the exposure period. Since an oral NOAEL was selected, a 12.5% dermal absorption factor should be used for route to route extrapolation. 9. Short­ Term Inhalation Exposure (1 day to 1 Month) Study Selected: Developmental Toxicity in the Rabbit § 870.3700 MRID No.: 45677801 Executive Summary: In a developmental toxicity study (MRID 45677801) [DXP­ A3674] hexazinone (98.78 % a. i., batch/ lot# DXP­ A3694­ 329) was administered to 22 female [Hra:( NZW) SPF strain] rabbits/ group by gavage] at dose levels of 0, 20, 50, 125 or 175 mg/ kg bw/ day from days 7 through 28 of gestation. Maternal toxicity was demonstrated by statistically significant findings at 125 mg/ kg/ day of a body weight gain decrement of ­102 g between gd 7­ 9 and ­57 g between gd 9­ 11, food consumption decrement of 18%, abortions, death and clinical signs such as diarrhea, stained cageboard and tail. Only 1 dam and 1 litter survived to termination at 175 mg/ kg/ day. The maternal LOAEL is 125 mg/ kg bw/ day, based on body weight gain decrement, decreased food consumption, abortions, death and clinical signs including abnormal gait at 175 mg/ kg/ day. The maternal NOAEL is 50 mg/ kg bw/ day. No dose related external, visceral or skeletal findings were noted. Since only 1 dam with 1 litter survived to termination at the 175 mg/ kg/ day dose, evaluation of embryo/ fetal effects at this dose are meaningless. Random malformations were seen in control and the highest dose group with no dose relationship. Mean male and female fetal weight was reduced by 5% and female fetal weight was reduced by 10% at 125 mg/ kg/ day. Although this weight reduction was not listed as being statistically significant, the author stated that this slight weight reduction at 125 mg/ kg/ day was a developmental effect level and this reviewer agrees. The developmental LOAEL is 125 mg/ kg bw/ day, based on mean male and female fetal weight decrement and female fetal weight decrement. The developmental NOAEL is 50 mg/ kg bw/ day. The developmental toxicity study in the rabbit is classified acceptable (guideline) and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rabbit. Dose/ Endpoint for Risk Assessment: The maternal NOAEL of 50 mg/ kg/ day based on based on maternal body weight and food consumption decrement and fetal weight decrement at 125 mg/ kg/ day (LOAEL). Comments about Study/ Endpoint: In the absence of a inhalation study an oral NOAEL was selected. Absorption via the inhalation route is assumed to be equivalent to oral absorption. ­15­ 9. Intermediate­ Term inhalation (1 Month to 6 Months) Exposure. Study Selected: Chronic Feeding Study in Dogs § 870.4100 MRID No.: 42162301 Executive Summary: [See Section II 3. on the Chronic Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: NOAEL of 5.0 mg/ kg/ day based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and clinical observation of thinnest in one males at 38 mg/ kg/ day. Comments about Study/ Endpoint: The affects seen in clinical chemistry values at 3, 6 and 12 months are appropriate for these exposure periods. Absorption via the inhalation route is presumed to be equivalent to oral absorption. 10. Long­ Term Inhalation (longer than 6 Months) Exposure. Study Selected: Chronic Feeding Study in Dogs § 870.4100 MRID No.: 42162301 Executive Summary: [See Section II 3. on the Chronic Reference Dose (RfD).] Dose/ Endpoint for Risk Assessment: NOAEL of 5.0 mg/ kg/ day based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and clinical observation of thinnest in one males at 38 mg/ kg/ day. Comments about Study/ Endpoint: The affects seen in clinical chemistry values at 3, 6 and 12 months are appropriate for these exposure periods. Absorption via the inhalation route is presumed to be equivalent to oral absorption. 11. Margins of Exposure for Occupational/ Residential Risk Assessment A margin of exposure of 100 is adequate for occupational dermal and inhalation exposure. There is no non­ occupational (residential) exposures identified at this time. ­16­ 12. Recommendation for Aggregate Exposure Risk Assessments Aggregate exposure risk assessment is not required since there are no non­ occupational (residential) uses at the present time. III. CLASSIFICATION OF CARCINOGENIC POTENTIAL 1. Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No.: 00108638 Executive Summary: In this combined chronic/ oncogenicity study (MRID 00108638), hexazinone (94­ 96% a. i.; Lot/ Batch #: 6897­ 40 and 74.25) was administered in the diet to ChR­ CD rats (36/ sex/ group) for up to 25 months at nominal doses of 0, 0, 200, 1000, or 2500 ppm (equivalent to 0, 0, 10.2, 53.4, and 138.3 mg/ kg/ day in males and 0, 0, 12.5, 67.5, and 178.6 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, clinical signs, food consumption, hematology, clinical chemistry, organ weights, and gross or microscopic pathology. No adverse effects were observed in the 200 ppm animals. There were several signs of general toxicity, but a target organ could not be clearly identified at any dose. Terminal body weights were decreased 8% in1000 ppm and 20%, p 0.05, in the 2500 ppm females. A decrease in overall body weight gain (Days 0­ 728; calculated by the reviewers) was also observed in the 1000 (­ 10%) and 2500 ppm (­ 25%) females. Nominal decreases in body weight and body weight gain (­ 3 to ­5%) occurred in males at 1000 ppm during the study, which may have been biologically significant at the end of the study (­ 12% body weight and ­14% for body weight gain). Decreases (p­ values not calculated) in total food efficiency were observed in females at 1000 10 and 2500 ppm (­ 25%) and in males at 1000 ppm during the study with overall decrement in food efficiency in 1000 ppm males (­ 10%). In males at 2500 ppm, food efficiency was depressed for the first 6 months of the study (­ 25%), but from 6 months to the end of the study, it was increased 139%. The reviewer noted problems interpreting the body weights and food efficiency in males at the top dose level, which were not consistent with the mid­ dose level. For the first 6 months of the study in males, a body weight decrement due to probable toxicity was seen at 1000 and 2500 ppm. After 6 months food efficiency in males at the 1000 ppm remained less than controls (­ 56%) while food efficiency at 2500 ppm in males was higher than controls (+ 139%)( Table 4). By the end of the study, male body weight at 1000 ppm was ­12% and body weight gain ­14%, where as body weight and body weight gain in males at 2500 ppm was +3% for both weight and gain. The reason for this recovery in male body weight decrement at 2500 ppm is unknown, but it appears to be real. [Since absolute and relative liver weights were decreased in males at 2500 ppm, liver enzyme induction allowing the recovery seems unproven.] The body weight decrement at 1000 and 2500 ppm with recovery in body weight at 2500 ppm indicates the an adequate dose level to test for carcinogenicity in males was approached, but probably not attained. Other treatment groups were similar to the average of concurrent controls. ­17­ Dosing was considered adequate based on decreased body weights, body weight gains, and food efficiency in the 2500 and 1000 ppm females and food efficiency and body weights in the 2500 ppm males for the first 6 months. Body weight (­ 12%) and body weight gain (­ 14%) in males at 1000 ppm were decreased at the end of the study, in addition overall food efficiency (­ 14%) was decreased by the end of the study. Thus female body weight and body weight gain was decreased sufficiently to adequately test for carcinogenicity. Male body weight and body weight gain at1000 ppm appeared to be adequate to test for carcinogenicity by the end of the study, but the lack of dose response in male body weight and body weight gain at 2500 ppm (showing recovery after 6 months such that body weight and body weight gain were higher than control values) may indicate problems with the interpretation of the body weights and body weight gains at 1000 ppm. In the 2500 ppm males, creatinine was increased (NS) in the urine at months 18 and 24 and bilirubin was detected at month 18 and 24. The Sponsor reported that the urine was more alkaline in the 2500 ppm treatment groups (data not reported). Also at 2500 ppm, decreased (p 0.05) absolute and relative liver and kidney organ weights were observed in the males and increased (p 0.05) relative (to body) stomach and kidney organ weights were observed in the females. However, histopathological data did not corroborate these findings. The LOAEL is 1000 ppm for males and females (equivalent to 53.3 for males and 67.5 mg/ kg/ day for females) based on decreased body weight and food efficiency in males and females. In males at 2500 ppm the body weight decrement and food efficiency decrement occurred only for the first 6 months of the study. The NOAEL is 200 ppm for males and females (10.2 for males and 12.5 mg/ kg/ day for females). Neoplasm data were evaluated by two pathologists. An increase incidence of thyroid C­ cell adenomas was observed in the 2500 ppm males, but when analyzed by the Fisher's exact test (p> 0.10) or life­ table methods (p> 0.20) no significant differences were observed between controls and treated groups. Using life­ table analyses a significant (p< 0.05) dose­ response trend was observed in thyroid C­ cell tumors in only one of the two pathology reports. Female rats did not show any potential for C­ cell thyroid adenomas. The incidence, malignancy and latency of tumors were comparable among control and treated rats of both sexes. Under the conditions of this study, carcinogenic potential of hexazinone is considered negative. The submitted study is classified as acceptable for guideline 870.4300 combined chronic/ carcinogenicity study in rats. Discussion of Tumor Data: Neoplasm data were evaluated by two pathologists. An increase incidence of thyroid C­ cell adenomas was observed in the 2500 ppm males, but when analyzed by the Fisher's exact test (p> 0.10) or life­ table methods (p> 0.20) no significant differences were observed between controls and treated groups. Using life­ table analyses a significant (p< 0.05) dose­ response trend was observed in thyroid C­ cell tumors in only one of the two pathology reports. Female rats did not show any potential for C­ cell thyroid adenomas. The incidence, malignancy and latency of tumors were comparable among control and treated rats of both sexes. ­18­ The study in rats does not support a carcinogenic potential for hexazinone. Adequacy of the Dose Levels Tested: The dose levels in female rats was adequate to test for the carcinogenic potential hexazinone. There was an adequate body weight decrement and body weight gain decrement at the two top dose levels. The dose levels in male rats approached an adequate dose level to test for carcinogenic potential of hexazinone. There may have been an adequate body weight and body weight gain at the mid­ dose level at the end of the study to test for carcinogenic potential of hexazinone, however body weights of males at the top dose level behaved atypically. At the top dose level, males showed a adequate body weight decrement only for the first 6 months of the study and by the end of the study, body weights were higher than the average of the two controls. The reason for this reversible body weight decrement is unknown, but the top dose level in males was one­ half the top dose level of 5000 ppm in the 90­ day subchronic study in males where liver toxicity was seen. These body weight decrements in males and females are supported by a corresponding decrements in food efficiency. 2. Carcinogenicity Study in Mice MRID No. 41359301,42509301 and 4320290 § 870.4200 Executive Summary: In this mouse oncogenicity study (MRIDs 00079203, 41359301, 42509301 and 43202901), hexazinone ( 95% a. i.; Lot/ Batch #: H­ 11, 265 and 265­ 2) was administered in the diet to CD­ 1 mice (80/ sex/ group) for up to 104 weeks at nominal doses of 0, 200, 2500 or 10,000 ppm (equivalent to 28, 366 and 1635 mg/ kg/ day in males and 0, 34, 450 and 1915 mg/ kg/ day in females). No treatment­ related differences were observed in mortality, food consumption, food efficiency or hematology. Hepatotoxicity was evident at the terminal sacrifice. Macroscopic liver nodule/ mass (% treated vs % controls; n = 28­ 55) was observed in males at 2500 (39% vs 7%) and 10,000 ppm (33%). Increased incidences (% treated vs 0% controls; n = 38­ 55) in the following microscopic liver lesions were observed: hyperplastic nodule( s) (includes both foci of cellular alteration and adenoma) in males at 2500 (39% vs 20%) and 10,000 ppm (36%) and in females at 10,000 ppm (15% vs 3%); and necrosis (severity and type unspecified) in the 10,000 ppm males (36% vs 7%). Centrilobular hepatocyte hypertrophy was observed (% treated vs % controls) at the terminal sacrifice (n = 38­ 55) in males at 2500 (18% vs 0%) and 10,000 ppm (98%) and in females at 10,000 ppm (46% vs 0%) and in the dead and moribund males (n = 25­ 40) at 2500 (44% vs 0%) and 10,000 ppm (60%). Increased (p 0.05 or 0.01) liver/ gall bladder weights were observed at 10,000 ppm in males in both absolute and relative to body weights and in females in relative to body weight. Other signs of toxicity were evident. Distal tail tip sloughing and/ or discoloration was observed at 10,000 ppm in males at Weeks 13­ 104 and in females at Weeks 5 and 13­ 104. Macroscopically, tip of tail missing/ sloughed was observed at the terminal sacrifice in the 10,000 ppm males (31% vs 5%) and females (61% vs 11%) and in the dead and moribund 10,000 ppm females (46% vs 2%). The toxicological significance of these findings was unclear. Minor decreases (p 0.05 or 0.01) in body weights were observed in the 10,000 ppm treatment groups at ­19­ Weeks 13­ 104 in both sexes. Overall body weight gains (calculated by the reviewers) were decreased in the 10,000 ppm males ( 25%) and females ( 31%). The LOAEL is 2500 ppm for males (equivalent to 366 mg/ kg/ day) based on gross liver nodules/ masses, hyperplastic nodules in the liver and centrilobular hepatocyte hypertrophy and 10,000 ppm for females (equivalent to 1915 mg/ kg/ day [limit dose]) based on decreased body weights, increased relative liver/ gall bladder weights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. The NOAEL is 200 ppm (equivalent to 28 mg/ kg/ day) for males and 2500 ppm (equivalent to 450 mg/ kg/ day) for females. Liver samples were first evaluated using the term hyperplastic nodule which did not clearly distinguish neoplasia from non­ neoplasia. Reevaluation was conducted to make this distinction, and no significant differences were observed between the treatment groups and the concurrent controls. However positive trends (p< 0.05) were observed (% treated vs % controls) in focus/ foci of cellular alteration in males, hepatocellular neoplasm( s) (including adenoma, sarcoma, carcinoma, leukemia, and lymphoma) in females, and singular hepatocellular adenoma in females. Focus/ foci of cellular alteration were observed in males at 2500 (11.3% vs 5.0%) and 10,000 ppm (24.1%) and females at 10,000 ppm (12.5% vs 3.8%) beginning at Week 57. Singular hepatocellular adenoma was observed in the 10,000 ppm females (7.5% vs 2.5%) beginning at Week 77. Hepatocellular neoplasm( s) were observed in the 10,000 ppm females (8.8% vs 2.5%). A carcinoma in the 10,000 ppm treatment groups was first observed at Week 65. The incidence of carcinomas were within historical control ranges for each sex, while the incidence of adenomas were increased by 3.21% in the 10,000 ppm females. A dose­ dependent increase in adenomas was not observed in males. The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) concluded that hexazinone should be classified as a Group D (not classifiable as to human carcinogenicity)( 7/ 27/ 94). Under the conditions of this study, evidence of carcinogenic potential was equivocal: a positive trend test for neoplasia was observed in female mice, but no significant difference was determined by pair­ wise comparison. The submitted study is classified as acceptable for guideline 870­ 4200 carcinogenicity study in mice. Discussion of Tumor Data: A dose­ dependent increase in adenomas was not observed in males. Under the conditions of this study, evidence of carcinogenic potential was equivocal: a positive trend test for neoplasia was observed in female mice, but no significant difference was determined by pair­ wise comparison. Adequacy of the Dose Levels Tested: Adequate dose levels were used in male and female mice to test for the carcinogenic potential of hexazinone. Liver toxicity was seen at the top dose level in males and females. 3. Classification of Carcinogenic Potential HED's Carcinogenicity Peer Review Committee classified hexazinone as a Group D Chemical ­20­ (not classifiable as to human carcinogenicity) (7/ 27/ 94). This classification was based on the following weight of evidence considerations. In rats, females showed no evidence for carcinogenicity; males showed a significant trend only for thyroid adenomas. In mice, the evidence of carcinogenicity was equivocal: a positive trend test for liver tumors was observed in female mice, but no significant difference was seen by pair­ wise comparison (CPRC Report dated July 27, 1994). IV. MUTAGENICITY Adequacy of data base for Mutagenicity: The data base for mutagenicity is considered adequate based on pre­ 1991 mutagenicity guidelines. There is low concern for mutagenic potential of hexazinone. Hexazinone was found to be positive for mutagenicity in one chromosomal aberration assay (in vitro cytogenics) (MRID# 00130709), but negative in the remaining studies. It is concluded that the test material was clastogenic in both of the non­ activated trials and was also clastogenic in the one adequate S9­ activated trials. Under both test conditions, concentrations providing evidence of clastogenicity induced an acceptable level of cytotoxicity (> 50% relative cell survival). Thus, the findings can not be considered to be a secondary effect of cytotoxicity. Nevertheless, the outcome of the induced structural damage (i. e., primarily chromatid and chromosome breaks) is unclear since these types of structural aberrations would not likely be passed on to daughter cells. Because unambiguous positive results were achieved, it was concluded that the study provided adequate evidence that INA­ 3674­ 112 (hexazinone, technical) is clastogenic in an acceptable study. Gene Mutation 1. Guideline 870.5100, Reverse mutation in Salmonella EXECUTIVE SUMMARY: In a reverse gene mutation assay in bacteria (MRID 40826201), strains TA98, TA100, TA1535, TA1537 and TA1538 of S. typhimurium were exposed to Striazine 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino­ 1­ methyl­ (95% a. i.) in ethanol at concentrations of 200, 400, 600, 800 and 1000 : g/ plate without mammalian metabolic activation (S9­ mix) and at concentrations of 400, 800, 1200, 1600 and 2000 : g/ mL with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Crl: CD( SD) BR rat liver. The maximum concentrations of S­ triazine­ 2,4( 1H, 3H)­ dione, 3­ cyclohexyl­ 6­ dimethylamino1 methyl­ tested produced little or no cytotoxicity, were not limited by solubility and were not a limit dose for the assay. No statistically significant increases in the number of revertants per plate or positive linear dose­ response were seen. The solvent and positive controls induced acceptable responses in the corresponding strains. There was no evidence of induced mutant colonies over background. This study is classified as Unacceptable. It does not satisfy the requirement for FIFRA Test ­21­ Guideline [OPPTS 870.5100 (§ 84­ 2)] for in vitro mutagenicity [bacterial reverse gene mutation] data and should have used higher doses. 2. Guideline 870.5300, Gene mutation at HGPRT locus EXECUTIVE SUMMARY: In a mammalian cell gene mutation assay at the HGPRT locus (MRID No. 00076956), Chinese hamster CHO­ K1­ BH4 cells cultured in vitro were exposed to INA­ 3674­ 112, (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol in two trials. Concentrations used in Trial 1 were 2.0, 11.1, 13.1, 13.9 and 14.3 mM under nonactivated conditions and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM under activated conditions (S9­ mix). Concentrations used in Trial 2 were 2.0, 5.9, 11.1, 13.1 and 13.9 mM without S9­ mix and concentrations of 2.0, 7.9, 8.9, 9.3 and 9.9 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced male Charles River CD® rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. In Trial 1, the cultures treated at 14.3 mM were not plated for mutation determination due to cytotoxicity and in both Trials 1 and 2, those cultures treated at 13.9 mM were excluded from analysis because no mutants were seen. No statistically significant increases in mutant frequency over solvent control values were seen with or without S9­ mix in either Trial 1 or 2. The expected marked increase in the mutation were seen with the positive controls. There was, however, no indication that INA­ 3674­ 112 induced a mutagenic effect either in the presence or the absence of S9 activation. This study is classified as acceptable. It satisfies the requirement for FIFRA Test Guideline OPPTS [870.5300 (§ 84­ 2)] for in vitro mutagenicity (mammalian forward gene mutation) data. Chromosomal Aberrations 3. Guideline: 870.5375: In vitro mammalian cytogenics (chromosomal aberrations) in Chinese hamster CHO cells. EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (MRID No. 00130709), Chinese hamster ovary CHO­ K1 ­BH4 cell cultures were exposed to INA­ 3674­ 112 (Hexazinone, 95% a. i.) in ethanol in two separate trials. Exposure was for two hours with activation and for 10 hours without activation. Cells were harvested 10 hours after the start of treatment. In Trial 1, cells were treated at concentrations of 1.58, 3.94, 15.85 and 19.82 mM without metabolic activation (S9­ mix) and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. In Trial 2, cells were treated at concentrations of 1.58, 3.94, 7.93 and 15.85 without S9­ mix and at concentrations of 0.32, 3.17, 7.93 and 15.85 mM with S9­ mix. The S9­ fraction was obtained from Aroclor 1254 induced CD rat livers. INA­ 3674­ 112 was tested up to cytotoxic concentrations. Based on the results of a preliminary cytotoxicity test, upper concentrations of 23.78 mM without S9­ mix and 47.56 mM with S9­ mix were selected for the first cytogenetic assay but these concentrations proved excessively cytotoxic and were not scored for chromosomal aberrations. Without S9 activation, statistically significant increases (p< 0.01) in structural aberrations per cell (excluding gaps), lesions per cell and percent abnormal cells were seen at 15.85 mM (Trials 1 and 2) and 19.82 mM (tested in Trial 1 only). Relative percent survival (RPS) at this level was . 50%. The percent abnormal cells averaged over all cultures from both trials was 28.0% and 21.5% at 19.82 and 15.85 mM, respectively, compared to the solvent control values of 2.0% (0.5% ethanol in Trial 2) and 7.0% (0.75% ethanol in Trial 1). The percent abnormal cells in positive control cultures was 18% in both Trial ­22­ 1 (4.83 mM EMS) and Trial 2 (6.44 mM EMS). In the presence of S9­ mix, no statistically significant increases in chromosomal aberration induction were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix. Statistically significant increases were seen at 15.85 mM in Trial 2; RPS at 15.85 mM was 75%. There was a statistically significant dose­ related trend for all three parameters. The statistically significant (p <0.01) increases at 15.85 mM remained when the data from Trial 1 and 2 were combined (average of 20% abnormal cells compared to 10% for the solvent control). The predominant aberrations with or without S9­ mix were chromatid and isochromatid breaks. Solvent and positive controls (except the positive control in Trial 1 with S9­ mix) induced the appropriate responses. INA3674 112 was positive for the induction of structural chromosomal aberrations in both the presence and absence of S9­ mix. This study is classified as Acceptable/ guideline and satisfies the requirement for FIFRA Test 4. Guideline 870.5385: In vivo cytogenics assay in rat bone marrow cells EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (MRID 00131355), in bone marrow cells of Sprague­ Dawley CD rats, three rats/ dose/ sex/ harvest time were exposed to H# 14,555 in corn oil ( assumed 100% a. i.) at doses of 100, 300 and 1000 mg/ kg by oral gavage. Bone marrow cells were harvested at 6, 12, 24 and 48 hours post­ treatment. The highest dose tested (1000 mg/ kg) was lethal. A major limitation of this study was the number of animals treated and the number of cells analyzed per animal. At most, three rats/ sex/ dose/ harvest time were treated with, at most, 50 cells per rat analyzed. Few or no analyzable cell were available from many rats. Positive control values were significantly (p= 0.03) increased. There was no evidence that H# 14, 14,555 induced an increase in the incidence of chromosomal aberrations in the bone marrow cells of treated animals. This study is classified as Unacceptable. The number of cells analyzed and the number of rats treated was insufficient. The study does not satisfy the requirement for FIFRA Test Guideline [OPPTS 870.5385 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. 5. Guideline 870.5395: Micronucleus assay in mouse bone marrow EXECUTIVE SUMMARY: In a Crl: CD­ 1 (ICR) BR mouse bone marrow micronucleus assay (MRID 45124401), 5 mice/ sex/ dose/ harvest time were treated orally with Hexazinone 25L (Lot No. 9912033, 25% Hexazinone a. i. (24.5% by analysis) and 75% inert ingredients) at doses of 1000, 2000 and 3000 mg/ kg. Bone marrow cells were harvested at 24 and 48 hours posttreatment and examined for micronucleated polychromatic erythrocytes (MPCEs). The vehicle was Milli­ Q ® water. Signs of toxicity noted at 3000 mg/ kg included: death, convulsions, half­ shut eyes, head­ tilt, irregular respiration, lethargy, low carriage, pallor, prostration, uncontrollable spinning, shovelnosing straining up on toes and tremors. Micronuclei were scored in bone marrow from mice treated at 3000 mg/ kg and from the solvent and positive controls. Mice from the two lower dose ­23­ groups were not evaluated for micronuclei induction. No statistically significant increases in the frequency of MPCEs or in the PCE/ NCE ratio over the solvent control values were seen in either sex at either the 24 or 48 hour harvest time. The solvent and positive control values were appropriate and within the testing laboratory's historical control ranges. There was no evidence that Hexazinone 25L induced a clastogenic or aneugenic effect in bone marrow at any harvest time. This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline [OPPTS 870.5395 (§ 84­ 2)] for in vivo cytogenetic mutagenicity data. Other genetic Studies 6. Guideline 8760.5550: Unscheduled DNA synthesis assay in rat hepatocytes EXECUTIVE SUMMARY: In an unscheduled DNA synthesis assay (MRID 00130708), primary rat hepatocyte cultures were exposed to INA­ 3674­ 112 (Lot No. 7612­ 5E6E, 95% a. i.) in ethanol for 18 hours at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 10.0 and 30.0 mM in Trial 1 and at concentrations of 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 5.0, 10.0 and 30.0 mM in Trial 2. INA­ 3674­ 112 was tested up to the highest achievable concentration in the solvent. Two slides per dose, 25 cells per slide were evaluated for UDS induction in Trial 1. One slide per dose, 25 cells per slide were evaluated in Trial 2. The author did not report that the slides were coded prior to analysis. The average net nuclear grain counts of test material treated cells in Trial 1 were all less than zero with the exception of one slide at 1 x 10 ­5 mM (0.1 ± 9.6) and one slide at 1.0 mM (1.6 ± 5.2). The average net nuclear grain count was below zero for all test material concentrations in Trial 2 with the exception of 0.1 mM where the average net nuclear grain count was 0.0 ± 2.9. The criterion for a positive response was an average net nuclear grain count of at least five in two experiments at any tested concentration. The results were thus negative. The number of cells in repair was not reported. The solvent and positive (DMBA) controls induced the appropriate responses. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. This study is classified as Acceptable/ Guideline. It satisfies the requirement for FIFRA Test Guideline; OPPTS 870.5550 [§ 84­ 2] for other genotoxic mutagenicity data. Compliance statements were not provided. V. HAZARD CHARACTERIZATION Hexazinone is a herbicide used to control a broad spectrum of weeds including woody plants in alfalfa, rangeland, pastures, woodlands, pineapple, sugarcane and blue berries. Non­ crop areas include ornamental plants and forests. Hexazinone is used as a pre­ emergent, post emergence herbicide as well as by direct spray and soil applications. There are no non­ occupational (residential) uses. Hexazinone has low acute toxicity by the oral (Category III), dermal (Category IV ) and inhalation routes (Category III). Primary eye irritation is severe, causing corneal opacity and moderate irritation in unwashed eyes (Category I). It causes mild skin irritation and is classified Category IV for skin irritation. It is not a skin sensitizer in the Guinea pig. ­24­ Body weight decrement and liver toxicity were the most frequent effects shown in studies with hexazinone. Liver toxicity was seen in the chronic dog and mouse studies. Body weight decrement was seen in the chronic rat studies and the studies on reproduction. In a reproduction study, pup weight decrement occurred at the same dose as parental body weight decrement. No reproductive effects were seen in the study other than pup weight decrement. The rat prenatal study showed fetal weight decrement and possibly renal malformations but no increased susceptibility. The new rabbit study showed fetal weight decrement at the same dose causing maternal weight decrement. Thus, no offspring susceptibility is seen in rat or rabbit prenatal studies or the rat reproduction study. The 21­ day dermal study in the rabbit showed no systemic toxicity and mild dermal irritation at the limit dose. The chronic study in dogs showed severe body weight decrement, changes in liver related clinical chemistry values, and microscopic lesions. Body weight decrement was seen in a chronic carcinogenicity studies in rats and mice. Liver toxicity was seen in mice. The mouse carcinogenicity study showed an increased trend for liver carcinomas, but no pair wise significant increases. The rat study showed no carcinogenic potential. Based on these studies in rats and mice, hexazinone was classified in a group D, not classifiable as a carcinogen. Mutagenicity is of low concern. A reverse mutation assay was unacceptable, but the potential concern is mitigated by an negative in vivo mutation assay and the remaining negative studies on potential genetic damage. Rat metabolism studies showed that hexazinone was rapidly absorbed and excreted and essentially no difference in the metabolism of males and females at high or low dose levels. Almost no parent hexazinone was recovered in urine or feces. Two major metabolites were recovered from feces and urine, in addition to lesser amounts of a third metabolite and small amounts conjugated products from urine. ­25­ VI. DATA REQUIREMENTS The HIARC requested a 28­ day inhalation study with hexazinone as confirmation. There was concern for potential inhalation exposure based on the use pattern. A 1976 21­ day inhalations study in rats (MRID# 00063972) was considered unacceptable as documented. VII. ACUTE TOXICITY Acute Toxicity of Hexazinone Guideline No. Study Type MRIDs # Results Toxicity Category 81­ 1 Acute Oral/ Rat 41235004 (1989) LD50 = 1200 mg/ kg III 81­ 2 Acute Dermal/ Rabbit 00104974 LD50 >5278 mg/ kg IV 81­ 3 Acute Inhalation 41756701 (1990) LC50 > 3.94 mg/ L( 4 hour) 1 III 81­ 4 Primary Eye Irritation 00106003 (1982) Irreversible corneal opacity, Severe I 81­ 5 Primary Skin Irritation 00106004 (1982) Mild IV 81­ 6 Dermal Sensitization 41235005 (1989) NA Not a skin sensitizer 81­ 8 Acute Neurotoxicity Not conducted 1 These effects are consistent with an unreviewed and unacceptable three week inhalation study with dust [( MRID# 00063972 (1976); summary only submitted] reporting no significant toxic effects at 2.5 mg/ L, the only dose tested. ­26­ VII. Summary of Toxicological Dose and Endpoints for HEXAZINONE Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Dietary Risk Assessments Acute Dietary females 13­ 50 years of age NOAEL = 400 UF = 100 Acute RfD = 4.0 mg/ kg/ day 1x Developmental Toxicity ­ Rat LOAEL is 900 mg/ kg/ day based on decreased male and female fetal weight, kidneys with no papilla (malformation) and misaligned sternebrae (variation) Acute Dietary general population including infants and children An appropriate endpoint attributable to a single dose was not identified in the oral studies for general population, including the rat and rabbit developmental studies. Chronic Dietary all populations NOAEL= 5.0 UF = 100 Chronic RfD = 0.05 mg/ kg/ day 1x Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Incidental Oral Short­ Term (1 ­ 30 Days) Residential Only There are no residential uses at the present time and therefore, endpoints were not selected. Incidental Oral Intermediate­ Term (1 ­ 6 Months) Residential Only There are no residential uses at the present time and therefore, endpoints were not selected. Non­ Dietary Risk Assessments Dermal Short­ Term (1 ­ 30 days) No hazard was identified, therefore quantification of risk is not required. No systemic toxicity was seen at the limit dose following repeat dermal application, and there were no concerns for pre and/ or post natal toxicity. Residential Not Applicable Occupational Not Applicable Dermal Intermediate­ Term 1 (1 ­ 6 Months) Oral NOAEL= 5.0 Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= Not Applicable Not Applicable Occupational MOE= 100 Not Applicable Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment ­27­ Dermal Long­ Term 1 (1 ­ 6 Months) Oral NOAEL= 5.0 Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= Not Applicable Occupational MOE= 100 Not Applicable Inhalation Short­ Term 2 (1 ­ 30 days) Oral NOAEL= 100 Developmental Toxicity ­ Rabbit LOAEL = 50 mg/ kg/ day based on decreases in maternal food consumption and dose related body weight decrement and fetal weight decrement. Residential MOE= Not Applicable Not Applicable Occupational MOE= 100 Not Applicable Inhalation Intermediate­ Term (1 ­ 6 Months) Oral NOAEL= 5.0 Chronic one­ year feeding ­ Dog LOAEL = 41.24 mg/ kg/ day, male; 37.57 mg/ kg/ day, female, based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE =Not Applicable Not Applicable Occupational MOE= 100 Not Applicable Inhalation Long­ Term (> 6 Months) Oral NOAEL= 5.0 Chronic one­ year feeding ­ Dog LOAEL = 41.24 mg/ kg/ day, male ;37.57 mg/ kg/ day, female, based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Residential MOE= Not Applicable Not Applicable Occupational MOE= 100 Not Applicable Cancer Classification: D ­ Not Classifiable as to human carcinogenicity 1 Since an oral NOAEL was selected 12.5% dermal absorption factor should be used for route to route exposures. 2 Absorption via the inhalation route is assumed to be equivalent to oral absorption.

epa

2024-06-07T20:31:42.954794

regulations

EPA-HQ-OPP-2002-0188-0024

Supporting & Related Material

TXR NO. 0051049 August 08, 2002 MEMORANDUM SUBJECT: HEXAZINONE ­ 2 nd Report of the FQPA Safety Factor Committee. NOTE: THIS REPORT REPLACES THE PREVIOUS REPORT OF THE FQPA SAFETY FACTOR COMMITTEE DATED MAY 15, 2002 (HED DOC. NO. 0050750). FROM: Brenda Tarplee, Executive Secretary FQPA Safety Factor Committee Health Effects Division (7509C) THROUGH: Ed Zager, Chairman FQPA Safety Factor Committee Health Effects Division (7509C) TO: Carol Christensen, Risk Assessor Reregistration Branch 2 Health Effects Division (7509C) PC Code: 107201 The Health Effects Division (HED) FQPA Safety Factor Committee (SFC) met on August 5, 2002 to reevaluate the hazard and exposure data for Hexazinone with regard to making a decision on the additional safety factor for the protection of infants and children. The SFC concluded that, based on reliable data, no additional safety factor is necessary to protect the safety of infants and children in assessing Hexazinone exposures and risks. This report replaces the previous report of the FQPA Safety Factor Committee dated May 15, 2002 (HED Doc. No. 107201). 2 I. HAZARD ASSESSMENT On July 30, 2002, the Hazard Identification Assessment Review Committee (HIARC) reevaluated the toxicity endpoints selected for Hexazinone risk assessment as well as the FQPA assessment in light of newly reviewed data: rabbit developmental toxicity study. The following summarizes the conclusions of the committee at this meeting. 1. Adequacy of the Toxicology Database On July 30, 2002, the HIARC concluded that the toxicology data base for Hexazinone contains acceptable guideline prenatal developmental toxicity studies in the rat and the rabbit as well as an acceptable guideline 2­ generation reproduction study conducted in rats. In addition, the HIARC concluded that a developmental neurotoxicity study with Hexazinone is not required. 2. Determination of Susceptibility The data provided no indication of increased susceptibility of rats or rabbits to in utero and/ or postnatal exposure to Hexazinone. The recently submitted rabbit developmental study showed fetal weight decrement at the same dose as maternal weight decrement. 3. Degree of Concern and Residual Uncertainties The HIARC concluded that there are no residual uncertainties for pre­ and/ or post­ natal toxicity in any of the available studies with Hexazinone. II. EXPOSURE ASSESSMENT No changes were made in the exposure assessment since the last review for Hexazinone. 1. Dietary (Food) Exposure Considerations (Correspondence: C. Christensen to B. Tarplee dated April 3, 2002 and May 1, 2002; dietary food responses provided by S. Kinard and J. Punzi) Hexazinone is a contact and residual herbicide used to control many annual, biennial and perennial weeds and woody plants. Tolerances are currently established for combined residues of Hexazinone and its metabolites in or on alfalfa, pasture and range grasses, blueberries, pineapple, sugarcane, molasses, milk and meat (40 CFR§ 180.396). On January 29, 2002 and March 12, 2002, the HED Metabolism Assessment Review Committee (MARC) met to determine which metabolites should be included in the tolerance expression and risk assessment for Hexazinone. The MARC concluded that: parent plus metabolites A, B, C, D, and E (calculated as Hexazinone) are the residues of concern to be included in tolerance expression and risk assessment for plants and rotational crops. Additionally, the residues of concern to be included in the tolerance expression for ruminants are Hexazinone plus metabolites B, C, C­ 2, and F in milk, and 3 Hexazinone plus metabolites B and F in tissue. For purposes of risk assessment, the residues of concern in/ on ruminants are Hexazinone plus metabolites B, C, C­ 1, C­ 2, and F (April 3, 2002; Draft memo provided to FQPA SFC). The HED Dietary Exposure Evaluation Model (DEEM) is used to assess the risk from dietary exposure to Hexazinone residues in food. These are currently Tier 1 analyses based on tolerance level residues and assuming that 100% of crops are treated with Hexazinone. Since there are data gaps for the magnitude of the residues of Hexazinone and metabolites A, B, C, D, and E in/ on pasture and range grass (forage and hay), tolerances established for these feed items and for secondary residues in/ on milk and meat, cannot be reassessed. Therefore, HED is recommending that the use on pasture and range grasses be discontinued and that tolerances resulting from these uses be revoked. The FQPA SFC based its safety factor recommendation on the assumption that the use of Hexazinone on pasture and range grasses is withdrawn and all established tolerances associated with this use are revoked. 2. Dietary (Drinking Water) Exposure Considerations (Correspondence: C. Christensen to B. Tarplee dated April 3, 2002; dietary water responses provided by J. Melendez and L. Liu) The environmental fate database is adequate and indicate that Hexazinone is persistent and mobile in soil and aquatic environments. The mobility of Hexazinone was demonstrated in batch equilibrium data and confirmed in field and forestry dissipation data. The batch equilibrium data also suggest that its degradates are very mobile. Therefore, Hexazinone and its degradates may be of concern for surface water and groundwater contamination. On January 29, 2002 and March 12, 2002, the HED Metabolism Assessment Review Committee (MARC) concluded that Hexazinone, G3170, and all metabolites with conjoined cyclohexyl and triazine rings should be included in the drinking water risk assessment for Hexazinone. The following degradates were detected in the laboratory fate studies and/ or monitored in the field dissipation and the groundwater study: A, A­ 1, C, D, 1, 2, and G3170. The registrant submitted a small­ scale prospective groundwater monitoring study for Hexazinone. The study was conducted in a field of alfalfa underlain with sandy soil in Merced County, California. The site is located within the recharge area for a shallow unconfined aquifer. The organic matter content of the soil was # 0.7%, the pH was 7.5­ 8.9 in the upper 1.5 feet, and there were no continuous impeding layers. Results indicated that Hexazinone and its degradates are very mobile and persistent. The maximum total residue detected in the groundwater study is used in the risk assessment and is supported by modeling output. 4 The Board of Pesticides Control in the Department of Agriculture, Food and Rural Resources in the State of Maine conducted a statewide assessment to determine the impact of highly leachable pesticides (including Hexazinone, a herbicide used in the production of blueberries) on surface water and ground waters in Maine. Although the total amounts of Hexazinone used on blueberries in Maine is very low (only approximately 1% of the total sale in the U. S.), the chemical was detected in groundwater and surface water at very high frequency. Degradate B was also detected in surface water and groundwater; however, no detailed information was provided. Tier I modeling was used to estimate the maximum concentrations of Hexazinone likely to be found in surface (FIRST) and ground (SCIGROW) waters. The models used take into consideration the percent area crop and the index reservoir. Because of the high mobility of Hexazinone, and its high solubility, it appears that the chemical may be preferentially dissolved in the ponds, rivers and reservoirs (as opposed to adsorbed to sediments). It is noted that the SCIGROW result obtained is of the same order of magnitude than the results obtained in the prospective groundwater study. 3. Residential Exposure Considerations (Correspondence: C. Christensen to B. Tarplee dated April 3, 2002) There are currently no registered residential uses of Hexazinone. III. SAFETY FACTOR RECOMMENDATION AND RATIONALE 1. FQPA Safety Factor Recommendations The FQPA SFC recommends that OPP depart from the default 10X additional safety factor and instead use a different additional safety factor of 1X. This recommendation is based on reliable data supporting the findings set forth below. A. Traditional Additional Safety Factor (Addressing Data Deficiencies) On July 30, 2002, the HIARC found no data deficiencies and hence concluded that no additional traditional safety factors were needed with regard to the completeness of the Hexazinone toxicity database (See Section I. 1.). B. Special FQPA Safety Factors The FQPA SFC recommended, that no Special FQPA Safety Factor is necessary to protect the safety of infants and children in assessing Hexazinone exposure and risks. 2. Rationale and Findings Regarding Recommendation on Special FQPA Safety Factor The Committee concluded that no Special FQPA safety factor was needed because: 5 The toxicology database for Hexazinone contains acceptable guideline developmental and reproduction studies and these studies demonstrate that there is no concern for quantitative or qualitative increased susceptibility of the young. The HIARC concluded that a developmental neurotoxicity study with Hexazinone is not required. There are no residual uncertainties identified in the exposure databases. The dietary food exposure assessment is Tier 1, screening level, which is based on tolerance level residues and assumes 100% of all crops are treated with Hexazinone. The dietary drinking water assessment uses monitoring data (ground water) and modeling results (surface water) based on chemical­ specific data and include extrapolated estimates for all degradates of concern. These assessments will not underestimate the exposure and risks posed by Hexazinone. NOTE: This safety factor recommendation is based on the assumption that the use of Hexazinone on pasture and range grasses is withdrawn (due to the lack of field trial residue data for forage and hay) and that all established tolerances associated with this use are revoked. 3. Application of the FQPA Safety Factors (Population Subgroups / Risk Assessment Scenarios) The FQPA SFC recommends that no Special FQPA Safety Factor is necessary to protect the safety of infants and children in assessing Hexazinone exposure and risks. This recommendation is applicable to all population subgroups for all exposure routes and durations. No other FQPA safety factor would be appropriate for Hexazinone. 6 4. Summary of FQPA Safety Factors Summary of FQPA Safety Factors for Hexazinone LOAEL to NOAEL (UFL) Subchronic to Chronic (UFS) Incomplete Database (UFDB) Special FQPA Safety Factor (Hazard and Exposure) Magnitude of Factor 1X 1X 1X 1X Rationale for the Factor No LOAEL to NOAEL extrapolations performed No subchronic to Chronic extrapolations performed Database is sufficiently complete to assess risks to infants and children. No residual concerns regarding pre or post­ natal toxicity or completeness of the toxicity or exposure databases Endpoints to which the Factor is Applied Not Applicable Not Applicable Not Applicable Not Applicable

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regulations

EPA-HQ-OPP-2002-0188-0025

Supporting & Related Material

[Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 1 of 9 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: 05/ 14/ 2002 revised 07/ 30/ 2002 SUBJECT: Hexazinone Acute and Chronic Dietary Exposure Assessments for the TRED. PC Code: 107201 DP Barcode: D279898 REVIEWER: John S. Punzi, Ph. D., Chemist Reregistration Branch II Health Effects Division (7509C) THROUGH: Richard Griffin, DESAC Reviewer Branch/ Health Effects Division (7509C) Alan Nielsen, Branch Senior Scientist Branch/ Health Effects Division (7509C) TO: Dirk Helder, Chemical Review Manager Reregistration Branch II Special Review and Reregistration Division (7509C) and Carol Christensen, Risk Assessor Reregistration Branch II Health Effects Division (7509C) Executive Summary The purpose of this memorandum is to report the revised results of a Tier 1 dietary exposure analysis for hexazinone. In this analysis the acute and chronic dietary exposure and risk estimates resulting from food intake were determined for the U. S. population and various population subgroups. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 2 of 9 Acute and chronic dietary exposure assessments were performed in order to determine the exposure and risk estimates which result from the use of hexazinone on the crops included in the reregistration eligibility decision. The document has been revised to reflect a 07/ 30/ 02 HIARC revist. Hexazinone residues of concern for plants are parent plus metabolites A, B, C, D, E (see D279897, S. Kinard, 02/ 05/ 2002, for structures and metabolite discussion). The tolerance values for hexazinone in/ on blueberry, pineapple, and sugarcane are based on the enforcement analytical method's limit of quantitation (LOQ) and all non detectable residues were found in residue studies (see D279899, J. Punzi, 05/ 15/ 2002). This analysis used a single residue estimate based on the reassessed tolerance for blueberry, pineapple, and sugarcane. Default processing factors and 100% crop treated were used for residue input into DEEM. Hexazinone residues of concern in ruminant milk are hexazinone plus metabolites B, C, C­ 2, and F. Hexazinone residues of concern in ruminant tissue are hexazinone plus metabolites B and F. For purposes of risk assessment however, the residues of concern in livestock milk and tissue are hexazinone plus metabolites B, C, C­ 1, C­ 2, and F. The livestock feeding study indicates significant residues in milk at all feeding levels and quantifiable residues in kidney. When the residue levels are corrected for exaggerated rates the values are less than the sum of the LOQ's for the residues of concern. Based on the analytical method's LOQ the residue estimate for meats and milk are 0.24 ppm. Default processing factors and 100% crop treated were used for residue input into DEEM. The chronic dietary risk estimates are provided for the U. S. population (total) and various population subgroups. This assessment concludes that the exposure is below HED's level of concern for all population subgroups examined. Exposures, as a percentage of the RfD, ranged from approximately 3% for females aged 13 through 50 years to 15% for children aged 1 through 6 years. The acute dietary risk estimates are provided for the population subgroup consisting of females aged 13 through 50 years only. This assessment concludes that the exposure is below HED's level of concern for this subgroup. Exposures as a percentage of the RfD are calculated to be less than 1% at the 95 th percentile. I. Introduction Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic assessments, the risk is expressed as a percentage of a maximum acceptable dose. This dose is the highest daily dose which HED has deemed will pose no unreasonable adverse health effects and is called the population adjusted dose (PAD). The PAD is equivalent to the Reference Dose (RfD) divided by the FQPA Safety Factor. Dietary risk is expressed as a percentage of the PAD. HED's level of concern is exceeded when the dietary risk exceeds 100% of the PAD. References which discuss the acute and chronic risk assessments in more detail are available on the EPA/ pesticides web site: "Available Information on Assessing Exposure from [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 3 of 9 Pesticides, A User's Guide", 6/ 21/ 2000, web link: http:// www. epa. gov/ fedrgstr/ EPA­ PEST/ 2000/ July/ Day­ 12/ 6061. pdf ; or see SOP 99.6 (8/ 20/ 99). II. Residue Information Hexazinone tolerances are established under 40 CFR §180.396 (a) and (b). The tolerance for plant and animal commodities, is currently expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). Tolerances are currently established for; alfalfa; alfalfa hay; blueberries; cattle, goat, hog, and horse fat, meat, and meat by products; range grasses, pasture grasses, milk, pineapple and sugarcane. Current tolerances range from 0.1 ppm in/ on meats and milk to 10 ppm on grasses. Reassessed tolerances range from 0.1 ppm to 4 ppm. Tolerances are not currently needed for livestock fat, hog meat, and hog meat by products. HED is recommending that in order to reassess the established hexazinone tolerances for milk and the fat, meat, and meat byproducts of livestock and to compute a maximum theoretical dietary burden (MTDB) of hexazinone to livestock, uses on pasture and rangeland grasses must be revoked. A MTDB could not be calculated including grass and grass hay since additional residue data are required for use patterns in which significant residues are expected in/ on the RACs. HED recognizes that the estimated 100,000 acres of pasture and rangeland treated with hexazinone is relatively low. Since grass and grass hay are considered major dietary components of ruminants (up to 60% of the diet per current OPPTS GLN) a MTDB for livestock could not be developed when grasses are included in the registered uses. HED has determined that a MTDB could be constructed from other potential feed items for livestock and subsequently tolerances for meats and milk can be reassessed. Hexazinone residues of concern for plants are parent plus metabolites A, B, C, D, E (see D279897, S. Kinard 02/ 05/ 2002, for structures and metabolite discussion). The tolerance values for hexazinone in/ on blueberry, pineapple, and sugarcane are based on the analytical method's limit of quantitation (LOQ) and all non detectable residues were found in residue studies (see D279899, J. Punzi, 05/ 05/ 2002). This analysis used a single residue estimate based on the reassessed tolerance for blueberry, pineapple, and sugarcane. Default processing factors and 100% crop treated were used for residue input into DEEM. Hexazinone residues of concern in ruminant milk are hexazinone plus metabolites B, C, C­ 2, and F. Hexazinone residues of concern in ruminant tissue are hexazinone plus metabolites B and F. For purposes of risk assessment however, the residues of concern in livestock milk and tissue are hexazinone plus metabolites B, C, C­ 1, C­ 2, and F. The livestock feeding study indicates significant residues in milk at all feeding levels and quantifiable residues in kidney. When the residue levels are corrected for exaggerated rates the values are less than the sum of the LOQ's for the residues of concern. Based on the analytical method's LOQ the reside estimate for meats and milk are 0.24 ppm. Default processing factors and 100% crop treated were used for residue input into DEEM. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 4 of 9 Residue Data used for Acute and Chronic Assessments: This TIER 1 analysis used a single residue estimate based on the reassessed tolerance for blueberry, pineapple, and sugarcane. Default processing factors and 100% crop treated were used for residue input into DEEM. For purposes of risk assessment however, the residues of concern in livestock milk and tissue are hexazinone plus metabolites B, C, C­ 1, C­ 2, and F. The same data are being used in both acute and chronic analysis. III. DEEM™ Program and Consumption Information Hexazinone acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model (DEEM™) software, Version [7.76], which incorporates consumption data from USDA's Continuing Surveys of Food Intake by Individuals (CSFII), 1989­ 1992. The 1989­ 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive days, and therefore represent more than 30,000 unique "person days" of data. Foods "as consumed" (e. g., apple pie) are linked to raw agricultural commodities and their food forms (e. g., apples­ cooked/ canned or wheat­ flour) by recipe translation files internal to the DEEM software. Consumption data are averaged for the entire U. S. population and within population subgroups for chronic exposure assessment, but are retained as individual consumption events for acute exposure assessment. For chronic exposure and risk assessment, an estimate of the residue level in each food or foodform (e. g., orange or orange­ juice) on the commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms on the commodity residue list to arrive at the total average estimated exposure. Exposure is expressed in mg/ kg body weight/ day and as a percent of the cPAD. This procedure is performed for each population subgroup. For acute exposure assessments, individual one­ day food consumption data are used on an individual­ by­ individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic (Tier 1 or Tier 2) exposure assessment, or "matched" in multiple random pairings with residue values and then summed in a probabilistic (Tier 3/ 4) assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user (i. e., those who reported eating relevant commodities/ food forms) and a per­ capita (i. e., those who reported eating the relevant commodities as well as those who did not) basis. In accordance with HED policy, per capita exposure and risk are reported for all tiers of analysis. However, for tiers 1 and 2, significant differences in user vs. per capita exposure and risk are identified and noted in the risk assessment. HED notes that there is a degree of uncertainty in extrapolating exposures for certain population subgroups which may not be sufficiently represented in the consumption surveys, (e. g., nursing and non­ nursing infants or Hispanic females). Therefore, risks estimated for these [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 5 of 9 subpopulations were included in representative populations having sufficient numbers of survey respondents (e. g., all infants, or females 13­ 50 years). IV. Toxicological Information The toxicological endpoint summary table below reflects the HIARC document (01/ 16/ 2002, TXR# 0050371), the FQPA SF committee report (05/ 15/ 2002, TXR# 0050750) and an additional HIARC meeting on 07/ 30/ 02. Table 1. Summary of Toxicological Doses and Endpoints for [CHEMICAL] for Use in Dietary Exposure Assessment Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF* and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary [Female 13­ 50] NOAEL = [400] mg/ kg/ day UF = [100] Acute RfD = [4.0] mg/ kg/ day FQPA SF = [1] aPAD =[ 4.0] mg/ kg/ day [Developmental Toxicity­ Rat] LOAEL = [ 900] mg/ kg/ day based on [decreased fetal weight, malformation of kidneys] Chronic Dietary all populations NOAEL= [5] mg/ kg/ day UF = [100] Chronic RfD = [0.05] mg/ kg/ day FQPA SF = [1] cPAD = [0.05] mg/ kg/ day [Chronic One Year Feeding­ Dog] LOAEL = [ ~40] mg/ kg/ day based on [hepatotoxicity] V. Results/ Discussion As stated above, for acute and chronic assessments, HED's level of concern is exceeded when the dietary risk exceeds 100% of the PAD. The DEEM analyses can estimate the dietary exposure of the U. S. population and 26 population subgroups. The results reported in Table 2 are for the appropriate subpopulation, females aged 13 to 50 years. The results reported in Table 3 are for the U. S. Population (total), all infants (< 1 year old), children 1­ 6, children 7­ 12, females 13­ 50, males 13­ 19, males 20+, and seniors 55+. The results for the other population subgroups are included in the appendices. They are not included in the tables because the numbers of respondents in the other subgroups were not sufficient; and therefore, the exposure estimates for these subgroups contained higher levels of uncertainty. However, the respondents in these subgroups were also part of larger subgroups which are listed in the Tables. For example, nursing and non­ nursing infants are included in all infants. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 6 of 9 Results of Acute Dietary Exposure Analysis Results are reported at the 95th percentile of exposure because the assessment incorporated 100% CT. The acute dietary risk estimates are provided for the population subgroup consisting of females aged 13 through 50 years only. This assessment concludes that the exposure is below HED's level of concern for this subgroup. Exposures as a percentage of the RfD are calculated to be less than 1% at the 95 th percentile. Table 2. Results of Acute Dietary Exposure Analysis at the 95 th Percentile of Exposure Population Subgroup aPAD (mg/ kg/ day) Exposure (mg/ kg/ day) % aPAD Females 13­ 50 years old 4. 0 0.003611 <1 Results of Chronic Dietary Exposure Analysis Table 3. Results of Chronic Dietary Exposure Analysis Population Subgroup cPAD (mg/ kg/ day) Exposure (mg/ kg/ day) % cPAD U. S. Population (total) 0. 05 0. 002167 4 All Infants (< 1 year) 0. 05 0. 003752 7 Children 1­ 6 years 0. 05 0. 007449 15 Children 7­ 12 years 0. 05 0. 003964 8 Females 13­ 50 0.05 0.001308 3 Males 13­ 19 0.05 0.002334 5 Males 20+ years 0. 05 0. 001208 2 Seniors 55+ 0.05 0.001159 2 The chronic dietary risk estimates are provided for the U. S. population (total) and various population subgroups. This assessment concludes that the exposure is below HED's level of concern for all population subgroups examined. Exposures, as a percentage of the RfD, ranged from approximately 3% for females aged 13 through 50 years to 15% for children aged 1 through 6 years. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 7 of 9 VII. Conclusions The Tier 1 acute and chronic dietary risk assessments were conducted for all supported hexazinone food uses. Dietary risk estimates are provided for the U. S. population (total) and various population subgroups. This assessment concludes that for all supported registered commodities, the acute risk estimates are below the Agency's level of concern at the 95 th exposure percentile for the population subgroup consisting of females aged 13 to 50 years. The acute dietary exposure estimate for this group is <1% of the aPAD. This assessment also concludes that for all commodities, the chronic risk estimates are below the Agency's level of concern for the U. S. population (total) (4% of the cPAD) and all population subgroups. The most highly exposed population subgroup is children aged 1 to 6 years. The chronic dietary exposure estimate for the highest exposed population subgroup is 15% of the cPAD. [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 8 of 9 Appendix U. S. Environmental Protection Agency Ver. 7.76 DEEM Chronic analysis for HEXAZINONE (1989­ 92 data) Residue file name: C:\ WINDOWS\ Desktop\ hexazinone\ 107201accr. RS7 Adjustment factor #2 NOT used. Analysis Date 07­ 31­ 2002/ 14: 53: 38 Residue file dated: 07­ 31­ 2002/ 14: 52: 49/ 8 Reference dose (RfD, Chronic) = .05 mg/ kg bw/ day =============================================================================== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Percent of Subgroup body wt/ day Rfd ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­­­ U. S. Population (total) 0.002167 4.3% U. S. Population (spring season) 0.002199 4.4% U. S. Population (summer season) 0.002113 4.2% U. S. Population (autumn season) 0.002263 4.5% U. S. Population (winter season) 0.002095 4.2% Northeast region 0.002137 4.3% Midwest region 0.002400 4.8% Southern region 0.001990 4.0% Western region 0.002215 4.4% Hispanics 0.002339 4.7% Non­ hispanic whites 0.002172 4.3% Non­ hispanic blacks 0.001975 4.0% Non­ hisp/ non­ white/ non­ black 0.002334 4.7% All infants (< 1 year) 0.003752 7.5% Nursing infants 0.001188 2.4% Non­ nursing infants 0.004830 9.7% Children 1­ 6 yrs 0.007449 14.9% Children 7­ 12 yrs 0.003964 7.9% Females 13­ 19 (not preg or nursing) 0.001829 3.7% Females 20+ (not preg or nursing) 0.001143 2.3% Females 13­ 50 yrs 0.001308 2.6% Females 13+ (preg/ not nursing) 0.001968 3.9% Females 13+ (nursing) 0.002252 4.5% Males 13­ 19 yrs 0.002335 4.7% Males 20+ yrs 0.001208 2.4% Seniors 55+ 0.001160 2.3% Pacific Region 0.002206 4.4% ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ [Hexazinone] Dietary Exposure Assessment DP Barcode: [D279898] PC Code: [107201] Page: 9 of 9 Attachment (electronic file id 107201accr. rs7). cc: JSPunzi (RRB2), Hexazinone Reg. Std. File, Hexazinone SF, RF, LAN. 7509C: RRB2: John S. Punzi: CM2: Rm 712M: 703­ 305­ 7727: 05/ 15/ 2002. (Revised 07/ 31/ 02).

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regulations

EPA-HQ-OPP-2002-0188-0026

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: August 22, 2002 SUBJECT: Response to DuPont's Comments Concerning the HED Chapter for the Hexazinone Tolerance Reassessment Eligibility Decision. PC Code 107201. Case 0026. DP Barcode D284193. FROM: Carol Christensen, MPH Reregistration Branch II Health Effects Division (7509C) THRU: Al Nielsen, Branch Senior Scientist Reregistration Branch II Health Effects Division (7509C) TO: Dirk Helder, Chemical Review Manager Special Review and Reregistration Division (7508C) This document acknowledges the comments received from the registrant, DuPont, citing errors in the HED Chapter for the Hexazinone Tolerance Reassessment Eligibility Decision (TRED) and related materials. The Agency has provided its response to these comments herein. The comments are also directly reflected in the Revised HED Chapter for the Hexazinone TRED (D275621, August 22, 2002) and accompanying disciplinary chapters and memoranda, where appropriate. The comments consisted primarily of editorial suggestions, an objection to the 28­ day inhalation study requirement, and a statement that because the Agency has received a new developmental toxicity study in rabbits the 10X database uncertainty factor previously assigned for risk assessment be removed. Most of the editorial comments have been included. The comment objecting to the 28­ day inhalation study requirement is rejected. The new developmental toxicity study in rabbits is acceptable and is included in the risk assessment and the database uncertainty factor for lack of a developmental toxicity study in the rabbit is removed. Four minor comments regarding the residue chemistry and dietary exposure and risk assessment are also reflected in the documentation for the hexazinone TRED. ­2­ The following comments were received from DuPont on July 2 nd , 2002. The comments are repeated here by document type and section followed by the Agency's numbered responses. Toxicological Chapter for the TRED for Hexazinone Section 2.0 REQUIREMENTS C Guideline Numbers need to be filled in for Structural Chromosome Aberrations (870. 5375 and 870.5385) and Other Genotoxic Effects (870.5550) Agency Response 1: The guideline study 870.5385 is unacceptable and will not be listed in Table 1 (of the Toxicology chapter). The guideline study 870.5395 (an acceptable study) will listed instead. C Although not listed as a data gap, 870.5100 "Gene mutation ­ bacterial" is listed as a requirement that is not satisfied. DuPont has an Ames assay for the 75DF formulation that was conducted for another country. That assay was conducted in both Salmonella. and E. Coli at up to 5000 ug/ plate (= 3750 ug/ plate a. i.) and was negative for gene mutations in both. That study can be submitted, if needed, to satisfy this requirement. Agency Response 2: The new study in Salmonella and E. coli (MRID# 457101001) has been received and is in review, however no data gap for mutagenicity was determined because there is an acceptable in vivo mutation study and there is insufficient evidence of carcinogenicity in acceptable studies. Section 3.0 DATA GAPS C It is unclear as to why a 28­ day inhalation study is being requested. For which risk assessment is it needed? There are no residential uses of hexazinone. Most of the use patterns are outside the scope of WPS. The Agency comments on page 24 of the HIARC document, that it already has an unreviewed 21­ day inhalation study (MRID # 00063972, HLR 447­ 76). In that study, groups of ten male rats were exposed 6 hours/ day, 5 day/ week for 3 weeks to 0 (control) or 2.5 mg/ L of 90% wettable powder formulation of hexazinone (~ 600 mg a. i./ kg/ day). Histopathology examination indicated that lung changes were similar between control and hexazinone exposed rats. Intermittent weight losses were noted throughout the test period but all rats showed a normal rate of weight gain during the recovery period. The Registrant acknowledges that this is an old study which was conducted prior to issuance of current guidelines. However, it indicates that repeated exposure to hexazinone dust poses negligible inhalation risks and that no further inhalation testing should be required. ­3­ Agency Response 3: The 21­ day inhalation study (MRID# 00063972) remains an unacceptable study (TXR No. 0051033); the study fails to meet the minimum standard for review. The 1976 study is unacceptable because it is a two page summary of a study, with no meaningful supporting data. In addition, there is considerable doubt about the particle size in the exposure chamber. A particle size expressed as an average instead of a mean mass areodynamic diameter is not meaningful. Other deficiencies exist, including: (1) failure to explain dust generator type; (2) failure to note the sampling area with respect to the exposed animal; (3) failure to supply concentrations of various mean mass areodynamic diameters of various particle sizes; (4) inconsistency in expression of particle sizes, i. e., average of 7.8 µm( 2.3­ 15 µm) and a note indicating that only 0.06% of the hexazinone was less than 10.9 µm; (5) no individual body weight data or individual pathology data was submitted; (6) only 5 of the 10 animals were subjected to gross and histological examination; (7) the study was not conducted under GLPs, which would at least confirm that the opinions expressed may have supporting data; and, (8) the particle size of 7.8 µm (even if incorrectly expressed as an average) is not sufficiently small to test the inhalation toxicity of hexazinone. The paucity of lung macrophages containing dust particles supports low exposure to the lung. If the registrant can show that there is no inhalation exposure to handlers, a data waiver will be considered. If the registrant wishes to resubmit the 21­ day inhalation study (MRID# 00063972) with the missing information and data, OPP will review it. Until this information is reviewed and accepted, the 21/ 28­ day inhalation study is required for confirmation. A new Rabbit Developmental Toxicity Study has recently been submitted. (DuPONT­ 7405, MRID 45677801). Agency Response 4: The recently submitted developmental toxicity study in rabbits (MRID 42677801) is acceptable and will be included in the risk assessment of hexazinone (TXR# 0050786). The acceptability of the study and its use in risk assessment are reflected throughout the HED chapters of the Hexazinone TRED. The database uncertainty factor (10x) is removed from the assessment of risk as a result of hexazinone exposure. Section 4.0 HAZARD ASSESSMENT Acute Toxicity, Page 5. References: The references for all the acute tox citations have been omitted from the reference list. Should they be included? ­4­ Agency Response 5: The references are included. Acute Dermal Rabbit, add date (1973). Agency Response 6: The date is added. Acute Inhalation: Is not correct as written since an LC50> 3.94 mg/ L (4 hour) would be a toxicity category IV. Either add a note similar to that used in the HIARC document (Section 8) that this was on a 25% formulation AND/ OR cite the 1973 study on the technical material 00104975 LC50> 7.5 mg/ L (1 hour) ~ LC50 1.9 mg/ L (4 hours) that was mentioned in the HIARC report Section 8.0. Either study (3.94 x 0.25 or 7.5/ 4) would result in a toxicity category III. Agency Response 7: Acute inhalation is correct as written and will not be changed. The acute inhalation study used to support the data requirements was changed from a study performed in 1973 to a study performed in 1990. The acute inhalation study performed in 1990 (MRID# 41756701) is a study of the technical grade of hexazinone and results in classification as an acute toxicity category III. This result is reflected in the HED Chapter of the risk assessment, the toxicology chapter and all HIARC documents (1/ 16/ 02, 4/ 29/ 02 and 8/ 12/ 02). Subchronic Toxicity, 870.3200, Subchronic Dermal, Page 7. Should read " 870.3200 21/ 28 Day Dermal Toxicity ­ Rabbit" since the guideline is for either rats or rabbits and the study was conducted in rabbits. Agency Response 8: The guideline toxicity study 870.3200 listed as a 21/ 28 day dermal toxicity study in the rat will be changed to 21/ 28 day dermal toxicity study in the rabbit since the study was conducted in this species. 90­ Day Inhalation, 870.3465, Page 8. As described above, the registrant does not agree that this is a data gap because the Agency has an unreviewed 21­ day repeated dose inhalation study. Agency Response 9: See Agency Response 3 (above). Prenatal Developmental, 870.3700b, Toxicity Study ­ Rabbit, Page 10. This should be updated to reflect that a new rabbit developmental study was submitted (5/ 19/ 02 MRID 45677801). Agency Response 10: See Agency Response 4 (above). 4.7 Mutagenicity: Overview. For clarification, we recommend inserting the following wording into the last sentence of the mutagenicity overview. "Because unambiguous positive results were achieved, it was concluded that the study ­5­ provided adequate evidence that INA­ 3674­ 112 (hexazinone technical) is clastogenic in vitro in an acceptable study. [However, negative results were obtained in two studies which assessed chromosome damage in vivo."] Agency Response 11: The in vivo studies for chromosomal damage are listed as negative. There is no reason to repeat the results in the last sentence of the 4.7 Mutagenicity Overview section of the Toxicology Chapter. Page 20, 870.5375 Mid paragraph "In the presence of S­ 9 mix, no statistically significant increases in chromosome aberrations were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix." Delete the latter part of the sentence; it is incorrect. Positive control values in both trials produced strong positive results (Trial 1 28­ 32% abnormal cells, Trial 2 36­ 40% abnormal cells). Agency Response 12: The statement will be deleted from the Toxicology chapter. Page 21, 870.5385 After, "Unacceptable…. The study does not satisfy the requirement for FIFRA Test Guidelines." Add, "However this Guideline is fulfilled by an acceptable mouse micronucleus study." Agency Response 13: Section 4.7.4 Guideline 870.5385: In vivo cytogenics assay in rat bone marrow cells will not be changed. The mouse micronucleus test is listed as acceptable in Section 4.7.5 and there is no reason to repeat the results in Section 4.7.4. Page 22, 870.5395 Change the last sentence from "It satisfy the requirements…." to "It satisfies the requirements…." Agency Response 14: The correction is accepted. Section 6.0 FQPA CONSIDERATIONS Page 25. The Agency assigned an additional 10x database uncertainty factor (UFdb) because a rabbit developmental study was unacceptable due to uncertainties in the LOEL. Immediately after the HIARC report issued, the Registrant submitted a new rabbit developmental study (DuPont­ 7405, MRID 45677801) to the Agency. The new rabbit developmental study was conducted using current guidelines and confirmed the results of the previous rabbit developmental study. The maternal and fetal rabbit NOAEL was 50 mg/ kg/ day. The maternal and fetal LOAEL was 125 mg/ kg/ day. Once the new rabbit study is reviewed, if it is selected as the basis of the ARfD, the registrant believes the extra 10x UFdb should be removed. ­6­ Agency Response 15: See Agency Response 4. Acute Toxicity Table. Header should read: "Acute Toxicity Data on HEXAZINONE" NOT "Acute Toxicity Data on FENBUTATIN­ OXIDE." Agency Response 16: The heading for the table "Acute Toxicity Data on FENBUTATIN­ OXIDE" will be changed to "Acute Toxicity Data on HEXAZINONE." Subchronic, Chronic, and Other Toxicity Tables. Registrant comments have been made above regarding removal of the 28­ day inhalation study requirement, the submission/ MRID of a new prenatal developmental study, and the availability of an unsubmitted gene mutation assay (with a 75DF formulation) in Salmonella and E. Coli. Agency Response 17: See Agency Responses 3, 4, and 2, respectively. Summary of Toxicological Endpoints. Registrant restates that additional 10x UFdb should be removed after new rabbit developmental toxicity study is reviewed and questions the need for establishment of long­ term occupational endpoints. Agency Response 18: See Agency Response 4. The Long­ Term endpoints were selected for completeness and for potential future need. ­7­ Hazard Identification and Review Committee (HIARC) Report Acute Dietary Reference Dose Females 13­ 50 pp. 3­ 5. For setting the acute reference dose (ARfD) for females of childbearing age, the Agency has selected a rat developmental study with NOAELs of 100 and 400 mg/ kg for maternal and fetal effects, respectively. The Agency assigned an additional 10x database uncertainty factor (UFdb ) because a rabbit developmental study was unacceptable due to uncertainties in the LOEL. A UFdb factor of 10x rather than 3x was used because, based on extrapolation to the rabbit pilot NOEL of 50 mg/ kg in the previous study, it was concluded the difference between rabbits and rats may be greater than 3x. The resulting ARfD was 0.4 mg/ kg (400 mg/ kg / 1000). Immediately after the HIARC report issued, the Registrant submitted a new rabbit developmental study (DuPont­ 7405, MRID 45677801) to the Agency. The new rabbit developmental study was conducted using current guidelines and confirmed the results of the previous rabbit developmental study. The maternal and fetal rabbit NOEL was 50 mg/ kg/ day. The maternal and fetal LOEL was 125 mg/ kg/ day based on weight effects, which were only slight in the fetus. A higher dose, 175 mg/ kg/ day produced severe maternal toxicity. Once the new rabbit study is reviewed, if it is selected as the basis of the ARfD, the registrant believes the extra 10x UFdb should be removed. If selected, this would result in an ARfD of 0.5 mg/ kg (50 mg/ kg / 100). This is essential the same (slight improvement) as the current ARfD, and thus there will be essentially no change in the acute dietary risk assessment. Agency Response 19: The rabbit developmental toxicity study has been reviewed and accepted by the Agency. The database uncertainty factor of 10X is removed from the acute dietary risk assessment. However, the Agency retains the use of the developmental toxicity study in the rat as the basis for the acute reference dose for females 13­ 50 years of age (acute reference dose is 4.0 mg/ kg/ day). Chronic Reference Dose, Last line page 6 – typographical error. "The LOAEL is… based on…[ findings listed] and clinical observations of thinnest in one male." Should read "thin appearance in one male." Agency Response 20: The statement is changed to read "thinness in one male" (p. 12 of HIARC report TXR No. 0051033 dated August 12, 2002). Occupational/ Residential Exposure. It is not clear to the Registrant why the occupational and residential exposure Sections 2.4.1 through 2.6 were included in a food Tolerance Reassessment. There are no residential uses of hexazinone, that could contribute to the aggregate exposure. It is the Registrant's understanding that occupational exposure assessment is beyond the scope of Tolerance Reassessment. ­8­ Occupational exposure was addressed under the 1994 Reregistration Eligibility Document. It was noted that a number of the major uses of hexazinone were outside the scope of the Worker Protection Standard (WPS). While agricultural uses and use on sod farms was within WPS; use on pastures, rangeland, plants grown for other than commercial purposes, ornamental plants in parks and golf course, and no­ agricultural uses such as vegetation along rights­ of­ way were outside of the scope of WPS. No worker exposure assessment was conducted. Therefore the Registrant considers the selection of Occupational/ Residential endpoints (e. g., dermal and inhalation exposure scenarios) to not be relevant to Tolerance Reassessment. Nonetheless, we offer the following comments to the endpoint selection, should these endpoints be considered relevant in the future. Agency Response 21: These comments will not be addressed as occupational and residential exposure as risk assessment was not performed for the HED Chapter of the Hexazinone TRED. These endpoints were selected for completeness of the toxicological database and for potential future need. Dermal Absorption. The review states that "No dermal absorption study is available." It would be clearer to say that "No dermal penetration study is available. For an estimate of dermal penetration, the NOAEL from the 21­ day rabbit dermal toxicity study…." Also, for clarification, add the MRID of the rabbit 21­ day study (MRID 41309005). The Agency extrapolated a dermal absorption factor by comparing the NOAEL in a 21­ day dermal study in rabbits to the LOAEL from a rabbit developmental rangefinding study. A 25% dermal absorption factor was derived. Rabbit Pilot Developmental LOAEL (oral) = 250 mg/ kg = 25% Rabbit 21­ Day Dermal NOAEL 1000 mg/ kg However, the new rabbit developmental study (DuPont­ 7405, MRID 45677801) indicates there is a greater difference between oral and dermal toxicity than indicated by the above calculation. Further, since no LOAEL was actually established on the Rabbit 21­ Day Dermal study, use of a dermal NOAEL in comparison to an oral LOAEL, overestimates the potential dermal penetration. Based on the new rabbit developmental study, dermal absorption is no greater than 12.5% Rabbit Developmental LOAEL (oral) = 125 mg/ kg =< 12.5% Rabbit 21­ Day Dermal NOAEL > 1000 mg/ kg ­9­ Agency Response 22: A dermal absorption factor of 12.5% is defined in the recent HIARC report. (TXR No. 0051033 dated August 12, 2002) Short­ Term (1 Day – 1 Month) Dermal Exposure and Intermediate Term (1­ 6 Months) and Long­ Term (> 6 Months) Dermal Exposures. Under 2.4.3, the Agency states the Dose and Endpoint for Risk Assessment for short­ term dermal Exposure is Not Applicable and that No Hazard and No Quantification are required (based on no effects in the 21­ day dermal study in rabbits). However, in the next section (2.4.4) the Agency proceeds to select longer­ term dermal endpoints based on the chronic dog study NOEL (5 mg/ kg/ day) and a 25% dermal absorption factor (i. e. equivalent to 20 mg/ kg/ day). For intermediate­ term scenarios, we believe selection of a subchronic endpoint would be more appropriate than selection of the chronic dog study with a 25% absorption factor. It is also consistent wit the Agency guidance document, Toxicology Endpoint Selection Process (February, 1997). Based on the labeled uses for hexazinone, we do not believe a long­ term dermal exposure scenario is relevant. It is difficult to identify a scenario where there would be daily, lifetime uninterupted dermal exposure to hexazinone. The registrant believes that the route specific rabbit dermal study is the most appropriate study to estimate subchronic human dermal exposure. The Agency has concluded that the repeated dose rabbit study (MRID 41309005) meets guidelines and is acceptable. It measured the proper endpoints to identify hexazinone toxicity (including body weights, clinical chemistry, liver histology). Considering lifespan differences, it is of appropriate duration for short term and intermediate endpoint selection. However, if the Agency deems that the duration of the subchronic rabbit dermal study is insufficient, acceptable subchronic oral studies of longer duration (90 days) are available. The NOAELs from the rat and dog 90­ day studies were 84 and 29 mg/ kg, respectively. Again the dog is the most sensitive species, but the subchronic NOAEL is more appropriate. As noted in the discussion above, the 25% absorption factor derived by comparing a LOAEL on a rabbit pilot developmental study to the NOAEL on the rabbit subchronic dermal study overestimated the Dermal Absorption Factor which, in reality, is likely to be less than 12.5%. Using the dog subchronic NOAEL (29 mg/ kg/ day) and applying a more appropriate dermal absorption factor <12.5% would result in an estimated dermal endpoint of > 232 mg/ kg/ day. This is much more comparable to the actual dermal NOAEL determined from the 21­ day rabbit study. ­10­ Also typographical error in 2.4.4 "thinnest in one males" should read "thin appearance in one male" Agency Response 23: The Agency's rationale for endpoint selection are included in the updated HIARC document (TXR No. 0051033 dated August 12, 2002) and the Agency will not comment further at this time. See Agency Response 22 concerning the dermal absorption factor. Intermediate (1­ 6 Months) and Long­ Term (> 6 Months) Inhalation Exposure Typographical error "thinnest in one males" should read "thin appearance in one male." Agency Response 24: This error is noted and will be changed in the Toxicology chapter. Section 4.0 Mutagenicity For clarification, we recommend inserting the following wording into the last sentence of the mutagenicity overview (additions are in bold). "Because unambiguous positive results were achieved, it was concluded that the study provided adequate evidence that INA­ 3674­ 112 (hexazinone technical) is clastogenic in vitro in an acceptable study. However, negative results were obtained in two studies which assessed chromosome damage in vivo." General Comment: for consistency with the rest of the document, INA­ 3674­ 112 should be changed to hexazinone or hexazinone technical. Agency Response 25: See Agency Response 11. Guideline 870.5300: Gene Mutation Assay in Mammalian Cells. Conclusion should be bolded as with others studies. "There was, however, no indication that INA­ 3674­ 112 induced mutagenic effect in either the presence or the absence of S9 activation." Agency Response 26: The comment is accepted as suggested by the registrant. (Section 4.2, p. 21 of the 3 rd Report of the HIARC, TXR No. 0051033 dated August 12, 2002.) Guideline 870.5395: Mouse Bone Marrow Micronucleus Assay. Change the last sentence from "It satisfy the requirements…." to "It satisfies the requirements…." Agency Response 27: See Agency Response 14. Guideline 870.5375: Structural Chromosome Aberration Assay; In vitro Cytogenetic Assay. Mid paragraph "In the presence of S­ 9 mix, no statistically ­11­ significant increases in chromosome aberrations were seen in Trial 1; however, very low positive control values indicated a problem with the S9­ mix." Delete the latter part of the sentence; it is incorrect. Positive control values in both trials produced strong positive results (Trial 1 28­ 32% abnormal cells, Trial 2 36­ 40% abnormal cells). Agency Response 28: See Agency Response 12. Guideline 870.5385: Structural Chromosome Aberration Assay; In vivo Cytogenetic Assay. Fourth sentence of second paragraph, "Few or no analyzable cell were available…" should be "Few or no analyzable cells were available…" Agency Response 29: Editorial comment will be made. Section 4.5, Guideline 870.5395: After, "Unacceptable…. The study does not satisfy the requirement for FIFRA Test Guidelines." add, "However, this Guideline is fulfilled by an acceptable mouse micronucleus study." Agency Response 30: See Agency Response 13. Section 5 FQPA Considerations Developmental Toxicity, Developmental Toxicity in the Rabbit. Last paragraph should be upgraded to indicate a Rabbit Developmental Toxicity (45677801) has just been submitted but not yet been reviewed. Agency Response 31: See Agency Response 4. The receipt and acceptance of the developmental toxicity study in the rabbit is reflected throughout the HED risk assessment documents, including the revised HIARC report (TXR No. 0051033 dated August 12, 2002.) Determination of the Need for Developmental Neurotoxicity Study, Evidence that suggest requiring a Developmental Neurotoxicity Study. Atrazine should not be considered as evidence suggesting requirement of a developmental neurotoxicity. Although atrazine and hexazinone contain a triazine ring, there are significant structural differences that contribute substantial differences in the biological response to these molecules by laboratory animals. EPA reached a similar conclusion in the Toxicology Disciplinary Chapter for the Tolerance Reassessment and Evaluation Decision Document, Section 1.0 – Hazard Characterization (May 16, 2002). The critical structural differences include substitutions of a cyclohexyl and a methyl group on the ring nitrogens and the presence of two ring oxo groups in hexazinone. As a result, hexazinone is less aromatic in character than the chloro­ s­ triazines. Collectively, these structural differences are considered to contribute differences in toxicological properties. Hexazinone has been classified ­12­ as a triazine­ dione by EPA, which further indicates this Agency acknowledges its differences from the chloro­ s­ triazine herbicide class. Hexazinone has been extensively tested for safety to mammals. A key difference between hexazinone and atrazine and other members of the chloro­ s­ triazine class is that chronic exposures to the latter produce a characteristic mammary tumor response in Sprague­ Dawley rats. The mode of action for this chloro­ s­ triazine induced tumor response has been associated with altered endocrine activity unique to this rat strain. In contrast hexazinone does not induce rat mammary tumors, which indicates the absence of the endocrine modulation responsible for this effect. Additional evidence supporting the absence of endocrine effects with hexazinone includes the absence of endocrine organ effects and effects on reproduction and development. The differences in chemical structures are considered to be critical to the observed differences in toxicological response between hexazinone and the chloro­ s­ triazines. Agency Response 32: As stated in the HED Chapter of the hexazinone risk assessment, there was no evidence of endocrine disruption in the hexazinone toxicological database. However, when appropriate screening and/ or testing protocols have been developed through the Endocrine Disruptor Screening Program (EDSP) hexazinone may be subject to additional screening and/ or testing to further characterize effects related to endocrine disruption. Section 7.0 Data Gaps "HIARC has requested a 28­ day inhalation study because of the concern for inhalation exposure based on the use pattern" It is unclear as to which use pattern is being considered. There are no residential uses of hexazinone. Most of the use patterns are outside the scope of WPS. Since no use patterns of concern are identified, it is impossible to determine duration of exposure. On the same page that it requests a 28­ day inhalation study, the Agency notes that it already has an unreviewed 21­ day inhalation study (MRID # 00063972, HLR 447­ 76). In that study, groups of ten male rats were exposed 6 hours/ day, 5 day/ week for 3 weeks to 0 (control) or 2.5 mg/ L of 90% wettable powder formulation of hexazinone. Using the guidance in (Whalan EPA, 1997) this represents an exposure of greater than 600 mg/ kg/ day (2.25 mg hexazinone a. i./ L x 11.38 L/ hr respiration x 6 hr/ day exposure/ 0.25 kg body weight ). Histopathology examination indicated that lung changes were similar between control and hexazinone exposed rats. Intermittent weight losses were noted throughout the test period but all rats showed a normal rate of weight gain during the recovery period . ­13­ The Registrant acknowledges that this is an old study which was conducted prior to issuance of current guidelines. However, it clearly indicates that repeated exposure to hexazinone dust poses negligible inhalation risk. It also suggests that no further inhalation testing is required since no lung toxicity was identified and since the exposure producing minimal to moderate toxicity was two orders of magnitude higher than the chronic NOAEL that has just been selected by the Agency to set an inhalation endpoint. Therefore the oral endpoint selected is overly protective. In the interest of conservation of animals we strongly urge that available information be considered before the Agency request another study and the repeated dose inhalation be removed as a data gap. Agency Response 33: See Agency Response 3 (above). For the rabbit developmental toxicity data gap we recommend changing the statement "is expected to be submitted" to "was not submitted in enough time for review prior to issuance of this document" Agency Response 34: This statement has been removed from the most recent HIARC report (August 12, 2002, TXR 0051033) and the receipt and acceptance of the developmental toxicity study in the rabbit is reflected appropriately in all supporting documentation to the HED risk assessment. ­14­ HED Chapter of the Hexazinone TRED Section 1.0 Executive Summary The most significant recommendation, in our view, contained in the draft documents pertains to the revocation of tolerances and associated use of hexazinone on grass. We acknowledge that guidelines and interpretations regarding the practicality of grower control over cattle grazing intervals have changed since data supporting this use pattern were last submitted. However, as indicated in your review, this is a rather minor use and our information indicates that the current label restrictions regarding cutting and grazing are being complied with. Therefore, the tolerances supporting the use are sufficient. Given the above, we request that the existing tolerances and use pattern be maintained while we conduct new residue work to support EPA's interpretation regarding a zero day grazing interval. Agency Response 35: The Agency cannot reassess the tolerances for pasture and rangeland grasses without these data. These data remain outstanding for hexazinone and must be fulfilled before tolerance reassessment can be completed. Therefore, no changes are made to the Executive Summary concerning this issue. We understand that our recently submitted Rabbit Developmental Toxicity Study (DuPont­ 7405, MRID 45677801) was not reviewed in time to be included in the Draft TRED. In view of the pivotal importance of this study to the overall conclusions of the final TRED (specifically, the current proposal to declare a significant gap in the toxicology data base, the selection of appropriate end points for regulatory purposes and the imposition of an additional 10X safety factor due to an incomplete data base), we respectfully request that this study be reviewed as quickly as possible to be included in the final TRED. Agency Response 36: See Agency Response 4 (above). We also note in the toxicology review that "Gene mutation – bacterial" is listed as an unsatisfied requirement. We have recently submitted (June 28, 2002, no MRID yet assigned) a new Ames assay with the 75 DF formulation which we believe will satisfy this requirement. Agency Response 37: See Agency Response 2 (above). Finally, we do not believe a 28­ day inhalation study should be required until the existing and submitted 21­ day inhalation study (MRID 00063972) has been reviewed. ­15­ Agency Response 38: See Agency Response 3 (above). Section 3.0 Hazard Characterization Hazard Profile. Table 1: Acute Toxicity: For Inhalation LC50> 3.94 mg/ L (4 hour), add (25% formulation). Agency Response 39: See Agency Response 7 (above). Table 2: Toxicity Profile. 870.3465, "A 28­ day inhalation study is required." As noted in the HIARC document, an unreviewed 21­ day inhalation study is available (MRID 00063972) which indicates that repeated exposure to hexazinone dust poses negligible inhalation risks and that no further inhalation testing should be required. The Registrant requests that existing data be reviewed before additional testing is required. Agency Response 40: See Agency Response 3 (above). No change is made in response to this comment. 870.3700b Prenatal Developmental Toxicity. Unacceptable/ Upgradeable. The registrant has submitted a new rabbit developmental study (DuPONT­ 7405, MRID 45677801) which addressed the deficiencies and supports the conclusions of the original study Agency Response 41: See Agency Response 4 (above). This study is acceptable and appropriately listed in the Toxicological Profile Table 2 in the HED Chapter of the Hexazinone Risk Assessment. 870.5100 Reverse mutation in Samonella Strains. Unacceptable: DuPont has conduct a Ames assay for the 75DF formulation in both Salmonella and E. Coli at up to 5000 ug/ plate (= 3750 ug/ plate a. i.) that can be submitted, if needed, to satisfy this requirement. The results were negative for gene mutations in both species. Agency Response 42: See Agency Response 2 (above). 870.5385 In vivo Rat Bone Marrow Cytogenetics Assay. Unacceptable. Add, "However this Guideline is fulfilled by an acceptable mouse micronucleus study." Agency Response 43: See Agency Response 13 (above). FQPA Considerations and Dose Response Assessment: Acute Reference Dose Females 13­ 50. The Agency assigned an additional 10x database uncertainty factor because a rabbit developmental study was unacceptable due to uncertainties in the LOEL. A new rabbit developmental study (DuPont­ 7405, MRID ­16­ 45677801) to the Agency which addresses the deficiencies and supports the previous study. Once the new rabbit study is reviewed, the registrant believes the extra 10x uncertainty factor should be removed. Agency Response 44: See Agency Response 4 (above). Acute Aggregate Risk Assessment. The headings for the last three columns for Table 11 (page 42) should specify µg/ l rather than g/ l. Agency Response 45: The headings are written as µg/ l in Table 11. ­17­ Report of the FQPA Safety Factor Committee 3. Degree of Concern and Residual Uncertainties. For setting the acute reference dose (ARfD) for females of childbearing age, the Agency assigned an additional 10x database uncertainty factor (UFdb ) because a rabbit developmental study was unacceptable due to uncertainties in the LOEL. A UFdb factor of 10x rather than 3x was used because, based on extrapolation to the rabbit pilot NOEL of 50 mg/ kg in the previous study, it was concluded the difference between rabbits and rats may be greater than 3x. Immediately after the HIARC report issued, the Registrant submitted a new rabbit developmental study (DuPont­ 7405, MRID 45677801) to the Agency. The new rabbit developmental study was conducted using current guidelines and confirmed the results of the previous rabbit developmental study. The maternal and fetal rabbit NOAEL was 50 mg/ kg/ day. The maternal and fetal LOAEL was 125 mg/ kg/ day based on weight effects, which were only slight in the fetus. A higher dose, 175 mg/ kg/ day produced severe maternal toxicity. Once the new rabbit study is reviewed, if it is selected as the basis of the ARfD, the registrant believes the extra 10x UFdb should be removed. Agency Response 46: See Agency Response 4 (above). The receipt and acceptance of the developmental toxicity study in the rabbit is also reflected in report Hexazinone 2 nd Report of the FQPA Safety Factor Committee (TXR No. 0051049 dated August 8, 2002.) ­18­ Dietary Risk Assessment An acute endpoint is only given for females 13­ 50. We assume this group is considered by EPA to be the most sensitive sub­ population. Agency Response 47: The toxic endpoint with which acute dietary exposure is assessed is a decrease in male and female fetal body weight and increased incidence of malformations and variations of the fetus. Because the toxic endpoint for acute dietary exposure concerns in utero exposure, the risk assessment is performed for females of childbearing age (females 13­ 50) since only members of this group are at risk of being pregnant at the time of exposure. In several places we note the risk assessment is based on the reassessed tolerances for blueberry, pineapple, and sugarcane. For blueberries and pineapple 0.3 ppm is utilized, presumably one­ half of the new proposed tolerance of 0.6 ppm. However, for sugarcane 0.6 ppm (tolerance) is utilized. This appears to be an inconsistency. Stated differently, it is not clear to us why 0.3 ppm was selected for blueberry and pineapple while 0.6 ppm was selected for sugarcane. Agency Response 48: This was an error and has been corrected in the documents prepared for Phase III of the public participation process. Residue estimates for blueberry and pineapple are 0.6 ppm. (See Revised Acute and Chronic Dietary Exposure Assessment for the Hexazinone TRED, July 30, 2002.) Clarity is needed around the definition of LOQ. There are both enforcement methods (sum of LOQs is 0.55 ppm) and data collection methods (sum of LOQs is 0.3 ppm). We recommend that the enforcement LOQs be used consistently throughout the document. Agency Response 49: The LOQ's for the enforcement method is used for dietary exposure estimates. We note that a more up to date consumption database exists, CSFII 94­ 96/ 98. Why was the older database, CSFII 89­ 92, used? Agency Response 50: At this time, it is Agency policy to use the CSFII 1988­ 1992 food consumption database to perform dietary exposure and risk assessment.

epa

2024-06-07T20:31:42.974160

regulations

EPA-HQ-OPP-2002-0188-0027

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: August 22, 2002 SUBJECT: REVISED: HED Chapter for the Hexazinone Tolerance Reassessment Eligibility Decision PC Code 107201. Case 0266. DP Barcode D275621. FROM: Carol Christensen, MPH Reregistration Branch II Health Effects Division (7509C) THRU: Al Nielsen, Branch Senior Scientist Reregistration Branch II Health Effects Division (7509C) TO: Dirk Helder Chemical Review Manager Special Review and Reregistration Division (7508C) The following human health risk assessment has been prepared by the Health Effects Division (HED) for the Phase III Public Comment Period of the tolerance reassessment process for hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H)­ dione]. The HED chapter reflects the Agency's current guidelines concerning the retention of the Food Quality Protection Act (FQPA) safety factor and risk assessment. The chapter is based upon the product chemistry review by Ken Dockter, the toxicology review by David Anderson, the residue chemistry and dietary exposure and risk analysis by John Punzi, the drinking water exposure assessment by Larry Liu of the Environmental Fate and Effects Division (EFED), and the incident review by Jerry Blondell and Monica Spann. Table of Contents 1.0 Executive Summary ......................................................... 3 2.0 Physical and Chemical Properties .............................................. 5 3.0 Hazard Characterization ...................................................... 7 3.1 Hazard Profile ....................................................... 7 3.2 FQPA Considerations ................................................ 16 3.3 Dose Response Assessment ............................................ 16 3.3.1 Acute Reference Dose (RfD) ­ Females 13­ 50 ...................... 17 3.3.2 Chronic Reference Dose (RfD) .................................. 18 3.4 Endocrine Disruption ................................................. 19 4.0 Exposure Assessment and Characterization ..................................... 20 4.1 Summary of Registered Use Patterns .................................... 20 4.2 Dietary (Food) Exposure/ Risk Pathway .................................. 21 4.2.1 Residue Profile ............................................. 21 4.2.2 Acute Dietary Exposure (Females 13­ 50) .......................... 28 4.2.3 Chronic Dietary .............................................. 29 4.3 Water Exposure/ Risk Pathway ......................................... 31 4.3.1 Environmental Fate ........................................... 33 4.3.2 Drinking Water Exposure Estimates .............................. 34 4.4 Residential Exposure/ Risk Pathway ..................................... 38 4.4.1 Other Non­ Occupational Exposures .............................. 38 5.0 Aggregate Risk Assessment and Characterization ................................ 39 5.1 Acute Aggregate Risk Assessment ...................................... 40 5.2 Chronic Aggregate Risk Assessment ..................................... 41 6.0 Cumulative Risk ........................................................... 42 7.0 Incident Data ............................................................. 43 8.0 Data Needs ............................................................... 44 References .................................................................. 45 3 1.0 Executive Summary Hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H) dione is a triazine­ dione herbicide registered for use on alfalfa, blueberries, pasture and range grasses, pineapple, and sugarcane. It is also registered for use on ornamental plants, forest trees, and noncrop areas. There are no residential uses of the chemical. Hexazinone is used to control a variety of weed species and works through inhibition of photosynthesis. Hexazinone may be applied for pre­ or post­ emergence weed control by layby, directed spray, broadcast spray, or basal soil treatments and can be applied using either ground or aerial equipment. It is formulated as a dry flowable (DF), emulsifiable concentrate (EC), granular (G), and soluble concentrate (SC) and these formulations are registered for food/ feed uses. The range of percentage of active ingredient in product formulations is 10­ 90%. The application rates range from 1­ 4 lbs. active ingredient per acre and the number of applications typically limited to one per year or per crop cycle. Hexazinone is mainly an early season use, pre­ harvest intervals (PHIs) of 180­ 234 days, but there are PHIs of 30 days for some uses. There are approximately 400,000 pounds of active ingredient used per year. Hexazinone has low acute toxicity by the oral (Category III), dermal (Category IV) and inhalation routes (Category III). It has low acute dermal toxicity (Category IV) and causes mild skin irritation (Category IV). Hexazinone is not a skin sensitizer. However, the chemical causes severe primary eye irritation (Category I). In chronic studies of hexazinone's toxicity, body weight decrement and liver toxicity, including changes in liver related clinical chemistry values, and microscopic lesions are noted. Hexazinone is classified as a group D for carcinogenic potential, not classifiable as to human carcinogenicity. Hexazinone is not known to be an endocrine disruptor nor is there evidence of neurotoxicity in the toxicological database. The hexazinone rat metabolism study indicated that the chemical is rapidly absorbed and excreted and there is essentially no difference in the metabolism between males and females at high or low doses. A small amount of hexazinone parent and two major metabolites, metabolites A (3­( 4­ hydroxycyclohexyl)­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione) and C (3­( 4­ hydroxycyclohexyl)­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione) were recovered. (Chemical structures begin on p. 24.) There is no evidence of qualitative or quantitative susceptibility in prenatal developmental studies in the rat or rabbit or in post­ natal reproduction studies in the rat. A recently submitted rabbit developmental study showed fetal weight decrement at the same dose as maternal weight decrement. A developmental neurotoxicity study for hexazinone is not required. There are no residual uncertainties for pre­ and/ or post­ natal toxicity in any of the available studies with hexazinone. Therefore, the FQPA Safety Factor Committee recommended that OPP depart from the default 10X additional safety factor and instead use a different additional safety factor of 1X when assessing the risk of hexazinone to human health. There is no "special" FQPA safety factor necessary to protect the safety of infants and children (no enhanced susceptibility of fetuses/ offspring). 4 Hexazinone exhibits systemic and liver toxicity in studies of chronic exposure. Toxicological endpoints were established for acute and chronic dietary exposure scenarios as well as dermal (intermediate­ and long­ term) and inhalation (short­, intermediate­, and long­ term) exposure scenarios. Incidental oral endpoints were not selected because there are no residential uses for hexazinone and a short­ term dermal endpoint was not selected because no hazard was identified. No adverse effects attributed to a single exposure were identified for the general population. For the purposes of this tolerance reassessment eligibility decision (TRED), only the acute and chronic dietary exposure scenarios will be addressed. Occupational exposure and risk were considered in the previous reregistration eligibility decision (RED, 1994). An acute dietary endpoint was identified for females 13­ 50 years of age. The endpoints of decreased male and female fetal weight, increased incidence of kidneys with no papilla and an increased incidence of misaligned sternebrae in the fetuses were identified from a developmental toxicity study in rats. Because the toxic endpoint for acute dietary exposure concerns in utero exposure, the risk assessment is performed for females of childbearing age (females 13­ 50), since only members of this group are at risk for being pregnant at the time of exposure. The dose selected for establishing the acute reference dose (RfD) is the developmental No Observed Adverse Effect Level (NOAEL) of 400 mg/ kg/ day. The chronic dietary endpoint was identified in an oral toxicity study in the dog and is based upon severe body weight decrement, clinical chemistry changes in the liver and microscopic lesions in the liver [NOAEL= 5.0 mg/ kg­ bw/ day]. Tolerances for residues of hexazinone in/ on plant, livestock, and processed commodities are currently expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). The tolerance expression should be modified to include the specific metabolites (A, B, C, C­ 2, D, E, and F) by the appropriate chemical name (See Table 4, p. 23). Reassessed tolerances range from 0.1 ppm to 4.0 ppm. Tolerances are reassessed for alfalfa (hay and forage), blueberry, pineapple, and sugarcane as well as for secondary residues in cattle, goat, horse, sheep, and milk. HED is recommending that tolerances be revoked for livestock fat, hog meat and meat by­ products based on the results of the metabolism and feeding studies. HED is also recommending that tolerances for pasture/ rangeland grasses be revoked due to a lack of adequate field trial data. Tolerance reassessment for secondary residues in meat and milk when grass is a significant feed item could not be completed. However, HED has determined that a potential diet can be constructed for other registered feed items, and subsequently tolerances for meats and milk can be reassessed. It is important to note that the tolerance reassessment and risk assessment performed in this document assumes the tolerances for pasture/ rangeland grasses are revoked and the uses withdrawn from the label. In addition, a tolerance is proposed for alfalfa seed in this TRED. Estimated acute dietary (food only) risk for females age 13­ 50 associated with the use of hexazinone does not exceed the Agency's level of concern. The acute dietary risk for females 13­ 50 years of age is approximately 1% of the acute population adjusted dose (aPAD). The chronic dietary (food only) risk estimate does not exceed the Agency's level of concern for any population subgroups examined including the most highly exposed sub­ group, children 1­ 6 years 5 N N N N O O of age. The chronic dietary risk for this subgroup is approximately 15% of the chronic PAD and approximately 4% for the general U. S. population. Since the acute and chronic dietary exposure assessments utilized tolerance level residue values and assumed 100% of the crops are treated, risk estimates are considered upper­ end. Aggregate acute and chronic exposure and risk estimates include the contribution of risk from all dietary (food+ water) sources. Short­ and intermediate­ term aggregate exposure and risk assessments were not performed since there are no residential uses for hexazinone. Drinking water estimated environmental concentrations (EECs) were derived from both model and monitoring results. The chemical is persistent and mobile in the environment. Hexazinone parent, drinking water degradate G3170, and all metabolites with conjoined cyclohexyl and triazine rings were included in the drinking water exposure and risk assessment. (Chemical structures on p. 23 and 31.) The FIRST model was used to estimate concentrations of hexazinone and its metabolites in surface water using model parameters for alfalfa. The results of a prospective water monitoring study were used to estimate concentration of the chemical in groundwater. Neither acute nor chronic aggregate risk exceed the Agency's level of concern. Therefore, the Agency can conclude with reasonable certainty that residues of hexazinone plus its metabolites of concern would not likely result in an aggregate risk to infants and children. The Agency based this determination on a comparison of estimated concentration of hexazinone and its metabolites to calculated drinking water levels of comparison or "DWLOCs." The database for hexazinone is considered adequate for risk assessment, however, data deficiencies have been identified. The Agency requires a 28­ day inhalation study. Residue chemistry data requirements include outstanding label amendments (new labels should reflect cancelled use on pasture/ rangeland grasses) and a field rotational crop study for corn and wheat. 2.0 Physical and Chemical Properties Hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H dione] is a contact and residual herbicide used to control a broad spectrum of weeds including woody plants found in alfalfa, rangeland, pastures, woodlands, pineapple, sugarcane and blueberries. Non­ crop areas include ornamental plants and forests. Hexazinone interferes with electron transport in chloroplast membranes which allows oxidation of plant lipids and proteins. Upon exposure to the chemical, damaged cell membranes leak, causing the cells to dry and disintegrate. Hexazinone is registered for pre­ emergent, post­ emergence, directed spray and soil applications. Chemical end­ use products are formulated as a granular, water dispersible granules, emulsifiable concentrates, ready­ to­ use liquids, and soluble concentrates/ solids. Products are applied by aerial, broadcast, and directed spray. There are no reported impurities of toxicological concern in hexazinone. There is a single hexazinone technical [T] product registered under PC Code 107201, the Dupont 98.7 % T; EPA Reg. No. 352­ 399. (K. Dockter, Product Chemistry Chapter for the Tolerance 6 Reassessment Eligibility Decision, April 23, 2002.) Identity: 3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H) dione Class: Triazine Empirical formula: C12 H20 N4 O2 Molecular weight: 252.3 CAS Registry No.: 51235­ 04­ 2 Color: White Physical state: crystalline solid Odor: mildly pungent MP: 113.5 C Bulk density: 0.61 g/ mL Water solubility: 2.98 g/ 100g@ 25 C vapor pressure: 1.9 x 10 ­7 mm Hg@ 25 C log Pow : 2.76 Stability: stable in slightly acidic or alkaline media at elevated temperatures, slowly degrades under artificial sunlight. Approximately 1% decomposition when stored 2 years under ambient conditions. There is the potential for exposure to the chemical via all routes, oral, dermal and inhalation. Hexazinone has low vapor pressure but high water solubility, indicating a strong potential to enter and remain in water systems. There is low potential for bioaccumulation based on this chemical's properties. This tolerance reassessment eligibility decision document will assess the exposure and risks via the oral route (food and water pathways) only. There are no residential uses for hexazinone. Occupational exposures and risk were considered at the time of the Reregistration Eligibility Document (RED, 1994) and risk mitigation recommendations were made at that time. The purpose of this document is to reassess the hexazinone tolerances in accordance with FQPA. 7 3.0 Hazard Characterization 3.1 Hazard Profile The acute toxicity of hexazinone is presented in Table 1. All studies were performed using hexazinone technical as the test substance. Table 1: Acute Toxicity of Hexazinone Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity 41235004 LD50 = 1200 mg/ kg III 870.1200 Acute dermal toxicity 00104974 LD50 > 5278 mg/ kg IV 870.1300 Acute inhalation toxicity 41756701 (1990) LC50 > 3.94 mg/ L( 4 hour) III 870.2400 Acute eye irritation 00106003 Irreversible corneal opacity I 870.2500 Acute dermal irritation 00106004 Mild IV 870.2600 Skin sensitization 41235005 Not a dermal sensitizer in the Buehler test in Guinea pigs NA The toxicity profile for hexazinone is shown in Table 2. 8 Table 2: Toxicity Profile Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90­ Day oral toxicity rats 0010977 (1973) Dose: 0, 200, 1000 or 5000 ppm (equivalent to 0, 16.0/ 16.4, 81.0/ 87.3, 440/ 451 mg/ kg/ day, male/ female) Acceptable NOAEL = 1000 ppm (81.0/ 87.3 mg/ kg/ day male/ female) LOAEL = 5000 ppm (440/ 451 mg/ kg/ day male/ female) based on decreased body weight and food efficiency. 870.3150 90­ Day oral toxicity in non­ rodents 00114484 (1973) Doses of 0, 200, 1000, or 5000 ppm (equivalent to 0/ 0, 5.1/ 7.0, 25.9/ 31.6, 122.5/ 137.3 mg/ kg/ day, males/ females) Acceptable NOAEL = 1000 ppm (equivalent to 25.9/ 31.6 mg/ kg/ day for males/ females). LOAEL = 5000 ppm (equivalent to 122.5/ 137.3 mg/ kg/ day in males/ females) based on decreased body weight gains, increased relative liver weights, and increased alkaline phosphatase levels in both sexes and transiently decreased food consumption in the females. 870.3200 21/ 28­ Day dermal toxicity in rabbits 41309005 (1989) Doses: 0, 50, 400, or 1000 mg/ kg/ day Acceptable NOAEL = 1000 mg/ kg/ day. LOAEL = was not identified for systemic and dermal toxicity. 870.3250 90­ Day dermal toxicity Not required 870.3465 90­ Day inhalation toxicity The 90­ day inhalation study is not required, however a 28­ Day inhalation study is required ­ Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 9 870.3700a Prenatal developmental in rats 40397501 (1980) Doses: 0, 40, 100, 400, or 900 mg/ kg Acceptable Maternal NOAEL = 100 mg/ kg/ day LOAEL = 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals between and at 900 mg/ kg/ day mortality and decreased body weight gains and food consumption. Developmental NOAEL = 400 mg/ kg/ day LOAEL = 900 mg/ kg/ day and at 900 mg/ kg/ day an increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). 870.3700a Prenatal developmental in rats 00114486 (1974) Doses: 0, 18.9, 94.5, and 482.0 mg/ kg/ day Unacceptable/ Upgradable Maternal: NOAEL is 1000 ppm (equivalent to 94.5 mg/ kg/ day). LOAEL = 5000 ppm (equivalent to 482.0 mg/ kg/ day) based on decreased body weights, body weight gains, and food efficiency. Developmental: NOAEL = 5000 ppm (equivalent to 482.0 mg/ kg/ day). LOAEL was not observed. 870.3700b Prenatal developmental in rabbits 45677801 (2002) Doses: 0, 50, 125, 175 mg/ kg/ day Acceptable Maternal: NOAEL= 50 mg/ kg/ day. LOAEL= 125 mg/ kg/ day based on body weight gain decrement, decreased food consumption, abortions, death and clinical signs including abnormal gait at 175 mg/ kg/ day. Developmental: NOAEL = 50 mg/ kg/ day. LOAEL= 125 mg/ kg/ day based on mean male and female fetal weight decrement and female fetal weight decrement. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 10 870.3700b Prenatal developmental in rabbits 00028863 (1980) Doses: 0, 20, 50, or 125 mg/ kg/ day Unacceptable/ Upgradable Maternal NOAEL = 50 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on transient decreases in food consumption and body weight gains. Developmental NOAEL = 50 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on possible skeletal abnormalities and total abnormalies. 870.3800 Reproduction and fertility effects in rats 42066501 (1991) Acceptable 0, 200, 2000 or 5000 ppm M: 0, 11.8, 117 or 294 mg/ kg/ day F: 0, 14.3, 143 or 383 mg/ kg/ day Parental/ Systemic NOAEL = 14.3 mg/ kg/ day LOAEL = 143 mg/ kg/ day based on male body weight decrement. Reproductive NOAEL = 383 mg/ kg/ day LOAEL = None based on no effects on or organs of reproduction. Offspring NOAEL = 14.3 mg/ kg/ day LOAEL = 143 mg/ kg/ day based on reduced female pup weight at birth and during lactation. 870.4100a Chronic toxicity in rats See 870.4300 870.4100b Chronic toxicity dogs 42162301 (1991) Doses: 0, 200, 1500, or 6000 ppm (equivalent to 5.00/ 4.97, 41.24/ 37.6 and 161/ 167 mg/ kg/ day, male/ female. Acceptable NOAEL = 200 ppm (5.0/ 4.97 mg/ kg/ day, male/ female) LOAEL = 1500 ppm (41.24 and 37.6 mg/ kg/ day, respectively) based on thinness in one male and hepatotoxicity as evidenced by changes in clinical chemistry parameters and microscopic lesions. 870.4200 Carcinogenicity rats See below 870.4300 No evidence of carcinogenicity Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 11 870.4200 Carcinogenicity mice 00079203 (1981), 41359301 (1984), 42509301 (1992) and 43202901 (1994) Doses: 0, 0, 200, 2500 or 10,000 ppm (equivalent to 28/ 34, 366/ 450 and 1635/ 1915 mg/ kg/ day, male/ female) Acceptable NOAEL = 200 ppm (28/ 450 mg/ kg/ day, male/ female, respectively) LOAEL = 2500 ppm for males (equivalent to 366 mg/ kg/ day) based on gross liver nodules/ masses, hyperplastic nodules in the liver and centrilobular hepatocyte hypertrophy and 10,000 ppm for females (equivalent to 1915 mg/ kg/ day [limit dose]) based on decreased body weights, increased relative liver/ gall bladder weights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. Insufficient evidence for carcinogenicity in mice. 870.4300 Combined chronic/ carcinogenicity/ rats 00108638 (1977) Doses: 0, 200, 1000, or 2500 ppm (equivalent to 0, 10.2/ 12.5, 53.4/ 67.5, or 138/ 179 mg/ kg/ day, male/ female) Acceptable NOAEL = 200 ppm for males and females (10.2/ 12.5 mg/ kg/ day, male/ female). LOAEL = 1000 ppm for males and females (equivalent to 53.3/ 67.5 mg/ kg/ day, male/ female) based on decreased body weight and food efficiency in males and females. In males at 2500 ppm the body weight decrement and food efficiency decrement occurred only for the first 6 months of the study. The carcinogenic potential of hexazinone is considered negative in rats. Gene mutation 870.5100; Reverse mutation in Salmonella strains 40826201 (1977) 200, 400, 600, 800 and 1000 : g/ plate ­S9 and 400, 800, 1200, 1600 and 2000 : g/ mL + S9­ mix. Unacceptable No mutagenic potential was seen, but doses insufficient to cause cell toxicity. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 12 Gene mutation 870.5300; hamster CHO cells/ HPRT assay 00076956 (1980) Trial 1 were 2.0, 11.1, 13.1, 13.9 and 14.3 mM ­S9 and 2.0, 7.9, 8.9, 9.3 and 9.9 mM +S9. Trial 2 were 2.0, 5.9, 11.1, 13.1 and 13.9 mM ­S9 and 2.0, 7.9, 8.9, 9.3 and 9.9 mM + S9. Acceptable No evidence of mutagenic potential at cytotoxic doses. Cytogenics 870.5375; Chromosomal aberrations in hamster CHO cells 00130709 (1982) In Trial 1, 1.58, 3.94, 15.85 and 19.82 mM ­S9 and 0.32, 3.17, 7.93 and 15.85 mM + S9. In Trial 2, 1.58, 3.94, 7.93 and 15.85 S9 0.32, 3.17, 7.93 and 15.85 mM + S9 Acceptable Positive for structural chromosomal aberrations with and without S9. Other Effects 870.5385, In vivo Rat bone marrow cytogenics assay 00131355 (1982) Rat doses: 1000, 2000 or 3000 mg/ kg Unacceptable No evidence of mutagenic potential, but insufficient animals and cells were tested. Other Effects 870.5395 Mouse bone marrow micronucleus test 45124401 (2000) Mouse doses: 1000, 2000 and 3000 mg/ kg Acceptable No evidence of clastogenic or aneugenic effect in bone marrow at toxic doses. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 13 Other Effects 870.5550, UDS in rat hepatocytes 00130708 (1983) Trial 1: 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 10.0 and 30.0 mM and Trial 2: 1 x 10 ­5 , 1 x 10 ­4 , 1 x 10 ­3 , 1 x 10 ­2 , 0.1, 1.0, 5.0, 10.0 and 30.0 mM. Acceptable No evidence of mutagenic potential at precipitating dose levels. 870.6200a Acute neurotoxicity screening battery Not required 870.6200b Subchronic neurotoxicity screening battery Not required. 870.6300 Developmental neurotoxicity Not required. 870.7485 Metabolism and pharmacokinetics 00140162 & 00109237 (1980 &1982) Acceptable No parent was seen in urine or feces, which was rapidly absorbed and excreted. Two identified metabolites resulted from hydroxylation of the cyclohexyl ring and differed only by the metabolic conversion of the 6­ dimethyl amine to a secondary methyl amine. No sex­, or dose­ related differences in the formation and excretion of these metabolites were found. 870.7600 Dermal penetration Not required Special studies None submitted The toxicological database for hexazinone is considered complete for hazard characterization. The toxicity profile of hexazinone can be characterized for potential reproductive, developmental and neurological effects. Primary effects of hexazinone toxicity include body weight decrement and liver toxicity. There is no evidence of developmental or 14 reproductive susceptibility in the studies for the chemical. Hexazinone is considered a Group D carcinogen, not classifiable as to carcinogenicity. There is an adequate metabolism study in the rat. However, the Agency requires a 28­ day inhalation study for hexazinone because of concern for potential inhalation exposure based on the use pattern. (D. Anderson, Toxicology Disciplinary Chapter, May 30, 2002.) Hexazinone has low acute toxicity by the oral (Category III), dermal (Category IV ) and inhalation routes (Category III). However, primary eye irritation is severe, causing corneal opacity and moderate irritation in unwashed eyes (Category I). It causes mild skin irritation (Category IV) and is not a skin sensitizer in the Guinea pig. The 21­ day dermal study in the rabbit showed no systemic toxicity and mild dermal irritation at the limit dose. Body weight decrement, decreased food consumption, and kidney and liver effects were seen in acute and chronic studies with hexazinone. The chronic dog and mouse studies resulted in liver toxicity. Both chronic rat studies and the rat reproduction study show body weight decrement. The chronic study in dogs showed severe body weight decrement in addition to changes in liver related clinical chemistry values and microscopic lesions in the liver. In a rat reproduction study, pup weight decrement occurred at the same dose as parental body weight decrement. No other reproductive effects were seen in the study. The rat prenatal developmental toxicity study showed fetal weight decrement and renal malformations, but no increased susceptibility. The rabbit prenatal developmental toxicity study developmental effects were seen at the same dose showing maternal toxicity; no susceptibility was identified in this study. Body weight decrement was seen in both the chronic carcinogenicity study in rats and mice. The mouse carcinogenicity study showed an increased trend for liver carcinomas, but no pair wise significant increases were identified. The rat study showed no carcinogenic potential. Because there is no evidence of carcinogenicity in rats and insufficient evidence of carcinogenicity in the mouse, the RfD/ Peer Review Committee classified hexazinone as a group D chemical, not classifiable as to human carcinogenicity. Rat metabolism studies showed that hexazinone was rapidly absorbed and excreted with essentially no difference in the metabolism of males and females at high or low dose levels. Almost no parent hexazinone was recovered in urine or feces. Metabolites A (66%) [3­( 4­ hydroxycyclohexyl)­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione] and C (28%) [3­( 4­ hydroxycyclohexyl)­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione] were recovered from feces and urine, in addition to lesser amounts of metabolite B (9%) [( 3­ (cyclohexyl)­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H)­ dione] and small amounts of conjugated products in urine (< 5%). These metabolites are also present in plant and animal commodities as well as in environmental studies. For the purposes of risk assessment, the toxicity of the metabolites and/ or degradates were assumed to be equal to the parent hexazinone due to similarity in structure. However, hexazinone is not likely to be toxicologically related to 15 other triazine pesticides. The Hazard Identification and Review Committee (HIARC) requested a 28­ day inhalation toxicity study with hexazinone because of the concern for potential inhalation exposure based on the use pattern. 3.2 FQPA Considerations The toxicology database for hexazinone contains acceptable developmental and reproduction studies in the rat and in the rabbit; there is no quantitative or qualitative evidence of increased susceptibility in the fetuses or offspring in these studies. The HIARC concluded that a developmental neurotoxicity study with hexazinone is not required because there is no evidence of neurotoxicity in the database. There are no residual uncertainties identified in the exposure databases. The dietary food exposure assessment is Tier 1, screening level, which is based on tolerance level residues and assumed 100% of all crops are treated with hexazinone. The dietary drinking water assessment uses monitoring data (groundwater) and modeling results (surface water) based on chemicalspecific data and includes extrapolated estimates for all degradates of concern. These assessments will not underestimate the exposure and risks posed by hexazinone. The safety factor recommendation is based on the assumption that the use of hexazinone on pasture and rangeland grasses is withdrawn (due to lack of field trial residue data for forage and hay) and that all established tolerances associated with this use are revoked. The FQPA SFC recommends OPP depart from the default 10X additional safety factor and instead use a different additional safety factor of 1X to assessing exposure and risk associated with the use of hexazinone; no additional traditional safety factors are needed with regard to the completeness of the hexazinone toxicity database and no Special FQPA Safety Factor is necessary to protect the safety of infants and children. (B. Tarplee, Hexazinone ­ 2 nd Report of the FQPA Safety Factor Committee, August 8, 2002.) 3.3 Dose Response Assessment Toxicological endpoints were established for exposure scenarios of interest to this risk assessment. For this tolerance reassessment eligibility decision for hexazinone, only the acute and chronic dietary exposure scenarios will be assessed. Acute dietary exposure to the general population is not included in this assessment since there was no appropriate endpoint attributable to a single­ dose identified in the database. Three toxicological studies determined endpoint doses for the relevant exposure scenarios: a developmental toxicity study in the rat and in the rabbit and a chronic feeding study in the dog. The HIARC also selected endpoints for the dermal and inhalation routes of exposure. However, as there are no exposure scenarios pertaining to these routes of exposure assessed in this action, these endpoints are not listed in Table 3. A discussion 16 of the dose­ response relationships for acute and chronic dietary endpoints follows presentation of Table 3. (Hexazinone­ 3 rd Report of the Hazard Identification Assessment Review Committee (HIARC), TXR 0051033, August 12, 2002.) 17 Table 3: Hazard Endpoint Selection Exposure Scenario Dose (mg/ kg/ day) UF /MOE Hazard and Exposure Based Special FQPA Safety Factor Study and Endpoint for Risk Assessment Dietary Risk Assessments Acute Dietary females 13­ 50 years of age NOAEL = 400 UF = 100 Acute RfD = 4.0 mg/ kg/ day 1x aPAD= 4.0 mg/ kg/ day Developmental Toxicity ­ Rat Decreased male and female fetal weight, kidneys with no papilla (malformation) and misaligned sternebrae (variation) Acute Dietary general population including infants and children An appropriate endpoint attributable to a single dose was not identified in the oral studies. Chronic Dietary all populations NOAEL= 5.0 UF = 100 Chronic RfD = 0.05 mg/ kg/ day 1x cPAD= 0.05 mg/ kg/ day Chronic one­ year feeding ­ Dog LOAEL = 41.24 male; 37.57 female mg/ kg/ day based on severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase. Cancer Group D ­ Not Classifiable as to human carcinogenicity 3.3.1 Acute Reference Dose (RfD) ­ Females 13­ 50 The study selected to define the dose­ response relationship for risk assessment of acute dietary exposure to females 13­ 50 is a developmental toxicity study in the rat (MRID 40397501). In this study, hexazinone was administered orally to female rats at dose levels of 0, 40, 100, 400, or 900 mg/ kg on gestation day 7 through 16. There were no treatment­ related changes in clinical signs, gross pathology, pregnancy rate, live fetuses, resorption, pre­ or post­ implantation loss, corpora lutea, or implantations noted at any dose level tested in the dams. At the highest dose tested, one treatment related death, alopecia and enlarged stomach, decreased body weight gain and decreased food consumption occurred. The maternal LOAEL is 400 mg/ kg/ day based on decreased food consumption during dosing and nominal decreases in body weight gain from day 7 to day 17 and at all measured intervals in the dosing regimen. The maternal NOAEL is 100 18 mg/ kg/ day. In the fetuses at the highest dose tested male and female fetal weights were decreased and there was an increased incidence of misaligned sternebrae. Furthermore, an increased incidence of kidneys with no papilla was observed. Although the incidence was not statistically significant, a dose­ related trend was observed. The developmental toxicity LOAEL is 900 mg/ kg/ day, based on decreased male and female fetal weight and increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation). The malformations are presumed to occur after a single dose and thus appropriate for acute risk assessment. The dose selected for establishing the acute reference dose (aRfD) for females 13­ 50 is the developmental NOAEL of 400 mg/ kg/ day. Because the toxic endpoint for acute dietary exposure concern in utero exposure, the risk assessment is performed for females of childbearing age (females 13­ 50), since only members of this group are at risk of being pregnant at the time of exposure. Traditional uncertainty factors (UFs) of 10X (10X intraspecies variation; 10X interspecies extrapolation) are applied to the RfD. There are no additional traditional or "special" uncertainty factors applied to the RfD (1X) because there is no susceptibility identified in the hazard database. 3.3.2 Chronic Reference Dose (RfD) The study selected to define the dose­ response relationship for risk assessment is a oneyear chronic dog study (MRID 42162301). Hexazinone was administered to beagle dogs in the diet. Time­ weighted average doses for the treated groups were 5.00, 41.24, and 161.48 mg/ kg/ day, respectively, for males and 4.97, 37.57, and 166.99 mg/ kg/ day, respectively, for females. All animals survived to scheduled necropsy. Treatment­ related clinical signs of toxicity included the observation of thinness, decreased body weight, and decreased food consumption. Clinical chemistry changes such as moderate macrocytic anemia, decreases in RBC counts, hemoglobin, and hematocrit and increases in MCV and MCH in one or both sexes throughout the study. For the high­ dose animals, decreases in absolute testes weights in males and kidney, heart, and brain weights in females (­ 12%) and increases in relative liver weights in males and females were considered due to lower final body weights of these animals as compared with controls. Liver effects were seen in the high dose animal group. This group had aspartate aminotransferase levels 140­ 203% (p # 0.05) of the control values and alanine aminotransferase levels 206­ 276% (p # 0.05) of the control values. Alkaline phosphatase levels were also significantly (p # 0.05) increased in the mid­ dose males (259­ 409% of controls) and females (163­ 194% of controls) beginning at week 26 and in the high­ dose males (346­ 1363% of Acute RfD (Females 13­ 50) = 400 mg/ kg/ day = 4.0 mg/ kg/ day 100 (UF) 19 controls) and females (307­ 559% of controls) beginning at week 13. Microscopic lesions in the liver of high­ dose animals included concentric membranous bodies in 4 males and 5 females, centrilobular single cell necrosis in 3 males and 3 females, hepatocellular pigment in 3 males and 3 females, and vacuolation in 3 males and 4 females. In addition vacuolation was observed in one mid­ dose male and pigment and membranous bodies were each observed in one mid­ dose female. These lesions were not seen in control or low­ dose animals. The study selected for the chronic dietary endpoint is of the appropriate duration for assessing long­ term exposure. The RfD/ peer Review Committee chose the same dose and endpoint in 1994, which formed the basis of the Chronic RfD for the 1994 RED. The dose selected for establishing the chronic dietary endpoint is the NOAEL of 5.0 mg/ kg/ day. The LOAEL is 38 mg/ kg/ day based on elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), other changes in clinical chemistry values, liver microscopic findings and body weight decrement and clinical observation of thinness in one male (4 of 10 males and females at the next higher dose). An uncertainty factor of 100 (10x interspecies and 10x intra­ species) is applied to the endpoint. 3.4 Endocrine Disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific bases for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). In the available toxicity studies on hexazinone, there was no evidence of endocrine disruptor effects. When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, hexazinone may be subject to additional screening and/ or testing to further characterize effects related to endocrine disruption. Chronic RfD = 5.0 mg/ kg/ day (NOAEL) = 0.05 mg/ kg/ day 100 (UF) 20 4.0 Exposure Assessment and Characterization 4.1 Summary of Registered Use Patterns Hexazinone [3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H) dione is a triazine­ dione herbicide registered for use on alfalfa, blueberries, pasture and range grasses, pineapple, and sugarcane. It is also registered for use on ornamental plants, forest trees, and non­ crop areas. Hexazinone is used to control a variety of weed species including geratum, alder, and alexander grass and works through inhibition of photosynthesis. Hexazinone is a proprietary chemical of E. I. du Pont de Nemours and Company, Inc. which is the sole producer and primary registrant of this broad spectrum herbicide. Hexazinone formulations, sold under the trade name Velpar®, may be applied pre­ or post­ emergence by layby, broadcast, directed spray, or basal soil treatments using ground or aerial equipment. (J. Punzi, Hexazinone Tolerance Reassessment Eligibility Decision Residue Chemistry Chapter, DP Barcode D279899, May 20, 2002.) Hexazinone is formulated as a dry flowable (DF), emulsifiable concentrate (EC), soluble concentrate (SC) and as a granular (G) and these end­ use products are registered to DuPont for food/ feed uses. The range of percentage of active ingredient in the product formulations is 10­ 90%. The application rates range from 1­ 4 lbs. active ingredient per acre. The number of applications per year (or season) are typically limited to one per year. Hexazinone is mainly an early season use, PHIs range from 180­ 234 days, but PHIs are 30­ 60 days for alfalfa and blueberry, respectively. A profile of hexazinone usage has been developed by the OPP Biological and Economic Analysis Division (BEAD). The use profile is based on data from US EPA, USDA and the National Center for Food and Agricultural Policy. From 1991 through 2000, the total annual domestic usage of hexazinone averaged approximately 400,000 pounds of active ingredient for over 700,000 acres treated. Hexazinone's largest markets in terms of total pounds active ingredient includes alfalfa, woodland, and pasture and rangeland. Alfalfa is the crop with the highest percent of crop treated. Crops with less than 1 percent treated include blueberries, other hay, and sugarcane. (F. Hernandez, Quantitative Usage Analysis for Hexazinone, September 10, 2001.) There are no registered uses for this chemical at residential sites. Occupational exposures are not considered in this tolerance reassessment action. The populations of concern for this assessment are those who may be exposed through consuming crops treated with hexazinone or consuming water containing hexazinone residues. 4.2 Dietary (Food) Exposure/ Risk Pathway Tolerance reassessment and dietary risk assessment for hexazinone is based on the residue data summarized in this section. Tolerances for residues of hexazinone in/ on plant, 21 animal, and processed commodities are currently expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). Permanent tolerances are established for plant and animal commodities under 40 CFR §180.396( a). Hexazinone tolerances with regional (Florida sugarcane) registrations are established under 40 CFR §180.396( c). Tolerances exist for blueberry, pineapple, sugarcane, alfalfa and grasses as well and meats and milk. Current tolerances range from 0.02 to 0.5 ppm on raw agricultural commodities, 8.0­ 10.0 ppm on agricultural feed items, and are 0.1 ppm for secondary residues in meats and milk. HED is requesting the registrant to propose a tolerance for hexazinone residues of concern in/ on alfalfa seed of 2.0 ppm based upon a residue field trial study at 1.5x the maximum registered rate on alfalfa grown for seed. Reassessed tolerances range from 0.1 to 4.0 ppm. (J. Punzi, Hexazinone Tolerance Reassessment Eligibility Decision Residue Chemistry Chapter, DP Barcode D279899, May 20, 2002.) 4.2.1 Residue Profile The HED Metabolism Assessment Review Committee (MARC) has reviewed the hexazinone toxicology and metabolism data (meeting dates 1/ 29/ 02 and 3/ 12/ 02) and recommends that the tolerance expression for plant material should include hexazinone (parent) and metabolites A, B, C, D, and E. The tolerance expression for milk should include hexazinone (parent) and metabolites B, C, C­ 2, and F, and the tolerance expression for ruminant tissue should include hexazinone (parent) and metabolites B and F. The tolerance expression should be modified to include the specific metabolites (A, B, C, C­ 2, D, E and F) by the appropriate chemical name (See Table 4). The Agency has determined that tolerances for hexazinone residues in eggs and poultry tissue are not required based on the results of the respective poultry metabolism and feeding studies (CFR §180.6( a)( 3)). (S. Kinard, The Outcome of the HED Metabolism Review Committee for Water, April 25, 2002.) Adequate residue data have been submitted to reassess the tolerances for alfalfa (seed, forage, hay), blueberries, pineapple, sugarcane, and associated livestock commodities (meat, milk). Residue data are not adequate to reassess tolerances for pasture and rangeland grass (forage and hay) and a recommendation has been made to revoke those tolerances and to withdraw this use from the product labels. Data depicting magnitude of the residues of hexazinone and metabolites A, B, C, D, and E in/ on grass forage and hay harvested the day following a single broadcast application of representative formulations at 1.125 lb ai/ A are listed as data requirements in the Residue Chemistry chapter. However, these data are not listed as required in this action because the tolerance reassessment and risk assessment will assume that the tolerances are revoked and the uses withdrawn from the label due to the lack of field trial data. The MARC also recommended that for the purposes of risk assessment estimates of dietary exposure and risk should be based on residue estimates of hexazinone (parent) and metabolites B, C, C­ 1, C­ 2, and F for ruminant commodities and metabolites A, B, C, D, and E for plant commodities. The metabolites and parent hexazinone are assumed to have equal 22 toxicity based upon similarity in chemical structure. Metabolism in Plants and Animals The qualitative nature of hexazinone residue in plants and animals is adequately understood based on submitted metabolism studies in alfalfa, pineapple, sugarcane, ruminants, and poultry. Plants: Plant metabolism studies indicate that root uptake is the principal mechanism for the absorption of hexazinone by plants from soils. Hexazinone is translocated through the xylem to the foliage where it blocks the photosynthetic process. Hexazinone is metabolized by hydroxylation to metabolite A which is then metabolized to metabolite C by demethylation, and to metabolite E after oxidation. In an alfalfa metabolism study, alfalfa was sprayed with [ 14 C] hexazinone dissolved in water at an application rate equivalent to 1.0 lb ai/ 100 gal/ A. Alfalfa samples were collected at two, three, and six months after treatment. Total radioactive residues (TRR), calculated as hexazinone, declined at each sampling interval, and were 0.6, 0.5, and 0.1 ppm (95, 84, and 80% respectively). Analysis of the two­ month alfalfa cutting identified hexazinone (2.7% TRR), free metabolite A (7.1% TRR), free metabolite B (0.7% TRR), and conjugated metabolites A, B, and C (4.5% TRR). The remaining radioactive residues were found in water­ soluble, polar materials comprised of amino acids, sugars, polybasic acids, and smaller amounts of natural products. In a pineapple metabolism study, 94­ 99% of TRR was extractable with the following components identified in the pulp: hexazinone (0.8­ 1.8% TRR), metabolite A (23­ 28% TRR), metabolite C (13­ 15% TRR), metabolite D (16­ 21% TRR), and metabolite F (1­ 2% TRR). The following components were identified in sugarcane: metabolite E (30% TRR), metabolite C (23% TRR), metabolite A (14% TRR), metabolite B (1% TRR), metabolite D (3% TRR), and hexazinone (< 1% TRR). Animals: A lactating goat was dosed orally with [ 14 C] hexazinone radiolabeled in the triazine ring at a dose rate of 136.4 mg/ day, equivalent to 2.2 mg/ kg/ body weight for five consecutive days. TRRs, expressed as hexazinone equivalents, were 6.74 ppm in milk, 3.03 ppm in liver, 2.54 ppm in kidney, 0.27 ppm in muscle, and 0.03 ppm in fat. Residues were adequately extracted, characterized, and identified, and on this basis the MARC concluded that the hexazinone tolerance expression for milk should include hexazinone plus metabolites B, C, C­ 2. The MARC also concluded that the hexazinone tolerance expression for ruminant tissue should include hexazinone plus metabolites B and F and that residues of hexazinone and metabolites B, C, C­ 1, C­ 2, and F should be taken into account for risk assessment. In a poultry metabolism study five laying hens were dosed orally at 6.9 mg/ day with carbonyl­ labeled [ 14 C] hexazinone for six consecutive days. The daily dose rate was equivalent to 57 ppm in the feed, which is 38x the maximum theoretical dietary burden. No single metabolite in edible poultry tissue was greater than 0.04 ppm, and unidentified metabolites represented less than 0.05 ppm in all edible tissues. For these reasons, poultry tolerances are not necessary. 23 N N N O O CH 3 N CH 3 CH 3 N N N O O CH 3 N CH 3 CH 3 HO N N N O O CH 3 N H CH 3 Table 4: Chemical Structures of Hexazinone and its Regulated Metabolites (Metabolites A through F) Common Name/ Code Chemical name Structure Hexazinone 3­ cyclohexyl­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H dione Metabolite A 3­( 4­ hydroxycyclohexyl)­ 6­ (dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H)­ dione Metabolite A­ 1 is hydroxylated at the 2­ position of the cyclohexyl ring; Metabolite A­ 2 is hydroxylated at the 3­ position of the cyclohexyl ring. Metabolite B 3­ cyclohexyl­ 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H dione Common Name/ Code Chemical name Structure 24 N N N O O CH 3 N H CH 3 HO N N NH O O CH 3 O N N NH O O CH 3 O HO N N N O O CH 3 NH 2 Metabolite C 3­( 4­ hydroxycyclohexyl)­ 6­ methylamino 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H dione Metabolite C­ 1 is hydroxylated at the 2­ position of the cyclohexyl ring; Metabolite C­ 2 is hydroxylated at the 3­ position of the cyclohexyl ring. Metabolite D 3­ cyclohexyl­ 1­ methyl­ 1,3,5­ triazine 2,4,6­( 1H, 3H, 5H)­ trione Metabolite E 3­( 4­ hydroxycyclohexyl)­ 1­ methyl 1,3,5­ triazine­ 2,4,6­( 1H, 3H, 5H)­ trione Metabolite F 3­ cyclohexyl­ 6­ amino­ 1­ methyl 1,3,5­ triazine­ 2,4­( 1H, 3H)­ dione 25 Residue Analytical Methods Plant Matrices: Adequate methods are available for purposes of enforcement of tolerances and data collection for residues of hexazinone and metabolites A, B, C, D, and E in/ on plant commodities. For tolerance enforcement, the Pesticide Analytical Manual (PAM) Volume II lists Method I as available for the determination of hexazinone residues of concern in/ on plant commodities. The combined limit of quantitation (LOQ) for hexazinone residues (parent and metabolites) by Method I in PAM Volume II, is 0.55 ppm. For data collection, the registrant utilized Methods 92013­ V2 and 92013­ V3 during analyses of samples collected from a recent field residue study submission on alfalfa. Methods 92013­ V2 and 92013­ V3 have been deemed adequate for data collection based on acceptable method validation and concurrent recovery data. Animal Tissue / Milk: The registrant has proposed a liquid chromotography/ mass spectroscopy (LC/ MS) method (AMR 3783­ 96) as an enforcement method for livestock commodities. The proposed method would determine residues of parent hexazinone, metabolite B, metabolite C and its isomer (C­ 2), and metabolite F in milk. In livestock tissues, Method AMR 3783­ 96 would determine residues of parent hexazinone, metabolite B, and metabolite F. The reported limits of quantitation (LOQ) s were 0.02 ppm for hexazinone and metabolite B and 0.05 ppm for metabolites C, C­ 2, and F. This method has been subjected to a successful independent laboratory validation (ILV) and a radiovalidation study and, if method validation by the Agency is successful, the method will be proposed for inclusion in PAM Volume II (no additional data concerning this guideline topic will be required for reregistration). Multi­ Residue Methods The reregistration requirements for multiresidue methods data are fulfilled. However, the 10/ 99 FDA PESTDATA database (PAM Volume I, Appendix I) indicates that hexazinone (and metabolites A, B, C, D, and E) are only partially recovered (50­ 80%) using Multiresidue Method Sections 302 (Luke Method; Protocol D) and are not recovered using Sections 303 (Mills, Onley, Gaither; Protocol E ­ nonfatty foods) and 304 (Mills; Protocol E ­ fatty foods). Field Trial Data Reassessed tolerances and the dietary risk assessment are based on field trail data conducted on blueberries, alfalfa, pineapple, and sugarcane. Pending label revisions for certain crops, the reregistration requirements for data depicting "magnitude of the residue" in/ on the following raw agricultural commodities (RACs) are satisfied: alfalfa forage, alfalfa hay, alfalfa seed, blueberries, pineapple, and sugarcane. An adequate number of field trials have been conducted for these RACs, and the trials were conducted using registered hexazinone formulation( s) at the maximum registered rate. However, the reregistration requirements for data depicting magnitude of the residue in/ on grass forage and grass hay are not satisfied. The lack of 26 these data prevent calculation of a maximum theoretical dietary burden (MTDB) for livestock which includes these feed items. The Health Effects Division (HED) is recommending that in order to reassess the established hexazinone tolerances for milk and the fat, meat, and meat byproducts of livestock and to compute a maximum theoretical dietary burden (MTDB) of hexazinone to livestock, uses on pasture and rangeland grasses must be revoked and the uses withdrawn. A MTDB could not be calculated including grass and grass hay since additional residue data are required for use patterns in which significant residues are expected in/ on the RACs. HED recognizes that the estimated 100,000 acres of pasture and rangeland treated with hexazinone is relatively low. However, since grass and grass hay are considered major components of ruminant diets (up to 60% of the diet per current OPPTS GLN) a MTDB for livestock could not be developed when grasses are included in the registered uses. Therefore, it is important to note that the tolerance reassessment and risk assessment presented in this document does not include the use of hexazinone on pasture/ rangeland grasses; it assumes that these tolerances are revoked and the uses withdrawn from the label. However, HED has determined that a MTDB could be constructed from other potential feed items for livestock and subsequently tolerances for meats and milk can be reassessed. Reassessed tolerances range from 0.1 ppm to 4.0 ppm. Tolerances are not currently needed for livestock fat, hog meat, and hogmeat by­ products due to the results of metabolism and feeding studies. Blueberries: Data indicate that the combined residues of hexazinone and its regulated metabolites, as measured by the data­ collection method were less than the detection level (< 0.05 ppm for each compound/ metabolite) in/ on: (1) 12 samples of lowbush blueberries harvested 433­ 446 days following a single application of the 2 lb/ gal EC or 90% SC formulation at 3 or 6 lb ai/ A (1.5 or 3.0x the maximum registered rate) using ground or aerial equipment; and (2) 12 samples of highbush blueberries harvested 68­ 97 days following a single application of the 2 lb/ gal EC or 90% SC formulation at 2 or 4 lb ai/ A (0.8 or 1.3x the maximum registered rate). Based on the combined LOQs (0.55 ppm) of the enforcement method, HED is now recommending that the RAC tolerance be reassessed from 0.2 ppm to 0.6 ppm. Pineapple: Data indicate that the combined residues of hexazinone and its regulated metabolites, as measured by the data­ collection method, were less than the detection level (< 0.05 ppm for each compound/ metabolite) in/ on pineapple fruits harvested at a minimum PHI of 181 days following five ground applications of a representative hexazinone formulation at 0.45­ 0.9 lb ai/ A for a total rate of 3.6 lb ai/ A. Based on the combined LOQs (0.55 ppm) of the enforcement method, HED is now recommending that the RAC tolerance be reassessed from 0.5 ppm to 0.6 ppm. Sugarcane: Data indicate that the combined residues of hexazinone and its regulated metabolites, as measured by the data­ collection method, were less than the detection level (< 0.05 ppm for each compound/ metabolite) in/ on samples of sugarcane treated with the 90% SC formulation of hexazinone. In Hawaii, sugarcane was harvested 179­ 181 days following a total 27 of four applications (one pre­ emergence application at 1.35 or 1.47 lb ai/ A, a post­ emergence application at 0.45 lb ai/ A per application, followed by two post­ emergence applications at 1.8 lb ai/ A per application) for a total rate of 5.4­ 5.5 lb ai/ A per season (1.5x the maximum seasonal rate in HI). Similar results were found in field trials in Texas and Puerto Rico. Based on the combined LOQs (0.55 ppm) of the enforcement method, HED is now recommending that the RAC tolerance be reassessed from 0.2 ppm to 0.6 ppm. Alfalfa: Data indicate that the combined residues of hexazinone and its regulated metabolites did not exceed the established tolerances of 2.0 ppm in/ on alfalfa forage and 8.0 ppm in/ on alfalfa hay harvested 29­ 31 days following a single broadcast dormant or non­ dormant application of the 2 lb/ gal EC or 90% SC formulation at 1.5 lb ai/ A (~ 1x). The maximum combined residues in/ on treated samples were <1.87 ppm and <3.33 ppm for alfalfa forage and hay, respectively. Based on these data, the established tolerance for alfalfa forage is reassessed at its existing level of 2.0 ppm; however, the tolerance for alfalfa hay should be lowered from 8.0 ppm to 4.0 ppm. Data indicate that the combined residues of hexazinone and its regulated metabolites ranged from <1.30 ppm (sum of the LOQs) to <1.46 ppm in/ on alfalfa seed following a single broadcast dormant application of the 2 lb/ gal EC or 90% SC formulation at 0.75 lb ai/ A (1.5x the maximum registered rate on alfalfa grown for seed). Processing Data Pineapple: Residues of hexazinone and its regulated metabolites did not concentrate in pineapple juice. Metabolite B concentrated (3x) in process residue, based on quantified residues of 0.06 ppm in pineapple process residue and 0.02 ppm in/ on pineapple RAC after treatment with hexazinone at a 1x rate. Sugarcane: Residues declined in raw sugar (reduction factor of 0.2x) and processed sugar (reduction factor of 0.2x). The maximum average combined residue of hexazinone and its regulated metabolites was 1.92 ppm for "A molasses." Secondary Residue / Livestock Commodities Poultry: Based on the results of a poultry metabolism study, the Agency has determined that tolerances (and dietary risk assessment) for hexazinone residues in eggs and poultry tissues are not required under the provision of Category 3, 40 CFR §180.6( a)( 3) In the poultry study, liver tissue contained the highest TRR (0.19 ppm). Considering that the feeding level was 38x of the maximum theoretical dietary burden, the maximum residue in poultry tissue would be 0.005 ppm, an order of magnitude below the limit of detection for hexazinone metabolites. Ruminants: The results of a ruminant (goat) metabolism study suggested a very significant transfer of hexazinone residues of concern to meat and milk. Hexazinone residues of concern may transfer to milk and edible tissues of livestock animals as a result of ingestion of treated feed items such as: alfalfa forage, hay, meal, and silage; pineapple process residue; and 28 sugarcane molasses. Tolerances and risk assessment for hexazinone and metabolites in milk, meat and meat byproducts are based on an estimate of exposure or "dietary burden" to livestock from the above feed items and an estimate of the level of residue "transfer" to milk and meat that may occur. The rate of transfer of hexazinone and metabolites is based on the results of a feeding study in dairy cattle. Based on residue estimates for alfalfa forage, alfalfa hay, and sugarcane molasses (and excluding the current registration for grass and grass hay) a maximum dietary burden of 4.64 ppm estimated for ruminants forms the basis for tolerances in milk (0.2 ppm), meat (0.1 ppm) and meat byproducts (0.1 ppm). Residues in ruminant fat and hog commodities are not expected and a revocation of tolerance is recommended under the provision of Category 3, 40 CFR §180.6( a)( 3). 4.2.2 Acute Dietary Exposure (Females 13­ 50) Acute dietary (food) risk estimates associated with the use of hexazinone and its metabolites do not exceed the Agency's level of concern (> 100% of the aPAD) for females 13­ 50 years of age. The acute dietary risk estimate for females 13­ 50 years of age is approximately 1% of the acute Population Adjusted Dose (aPAD). The acute dietary exposure assessment for hexazinone is a tier I analysis. This is the most conservative type of analysis assuming that residues on foods as consumed are equal to the tolerance levels and that 100% of each crop is treated. The tolerance values for hexazinone in/ on blueberry, pineapple, and sugarcane are based on the analytical method's limit of quantitation (LOQ) and all studies resulted in non­ detectable residues. The same residue data, therefore, are used in both the acute and chronic analysis. (J. Punzi, Revised Acute and Chronic Dietary Exposure Assessments for the TRED, July 30, 2002.) The hexazinone acute dietary exposure assessment was conduced using the Dietary Exposure Evaluation Model (DEEM TM ) software Version 7.76, which incorporates consumption data from USDA's Continuing Survey of Food Intake by Individuals (CSFII), 1989­ 92. The 1989­ 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive days, and therefore represent more than 30,000 unique person days of data. Foods as consumed (e. g., apple pie) are linked to raw agricultural commodities and their food forms (e. g., apples­ cooked/ canned or wheat­ flour) by recipe translation files internal to the DEEM software. Consumption data are retained as individual consumption events for acute exposure assessment. For acute exposure assessments, individual one­ day food consumption data are used on an individual­ by­ individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic (Tier 1 or 2) exposure assessment, or matched in multiple random pairings with residue values and then summed in a probabilistic (Tier 3/ 4) assessment. The resulting distribution of exposure is expressed as a percentage of the aPAD in both a user (i. e., those who reported eating relevant commodities/ food forms) and a per­ capita (i. e., those who reported eating the relevant commodities as well as those who did not) basis. In accordance with HED 29 policy, per capita exposure and risk are reported for all tiers of analysis. The acute population adjusted dose (aPAD) is calculated as the acute RfD divided by the chemical­ specific FQPA safety factor (1x). The calculated acute exposure (residue x consumption) was compared to an aPAD of 4.0 mg/ kg/ day. The results are displayed in Table 5. Table 5: Summary of Acute Dietary Exposure and Risk for Hexazinone Population of Concern Dietary Exposure (mg/ kg­ bw/ day) % aPAD Females 13­ 50 years of age 0.003611 <1.0 4.2.3 Chronic Dietary Exposure Chronic dietary (food) risk estimates associated with the use of hexazinone do not exceed the Agency's level of concern (> 100% cPAD) for any population subgroup, including the most highly exposed subgroup children 1­ 6. The chronic dietary risk for children ages 1­ 6 is approximately 15% of the chronic population adjusted dose (cPAD) and approximately 4% for the general population. (J. Punzi, Acute and Chronic Dietary Exposure Assessment for the TRED, July 30, 2002.) A tier I analysis was done for the chronic dietary risk assessment. This is the most conservative type of analysis assuming that residues on foods as consumed are equal to the tolerance levels and that 100% of the each crop is treated. Hexazinone chronic dietary exposure assessment were conducted using the Dietary Exposure Evaluation Model (DEEM TM ), software Version 7.76 which incorporates consumption data from USDA's Continuing Survey of Food Intake by Individuals (CSFII), 1989­ 1992. Consumption data are averaged for the entire U. S. population and within population subgroups for chronic dietary exposure assessment. For chronic exposure and risk assessment, an estimate of the residue level in each food or food­ form (e. g., orange or orange­ juice) on the commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms to arrive at the total estimated exposure. Chronic population adjusted dose (cPAD) is the chronic RfD divided by the FQPA safety factor. The calculated chronic exposure (residue x consumption) was compared to a cPAD of 0.05 mg/ kg/ day, which reflects a special FQPA factor of 1x for hazard and exposure. The procedure is performed for each population subgroup. Results of this chronic dietary exposure and risk assessment are shown in Table 6. 30 Table 6: Summary of Chronic Dietary Exposure and Risk Values for Hexazinone Population Subgroup Dietary Exposure (Mg/ kg/ day % cPAD U. S. Population 0.002167 4 All Infants (< 1 year) 0.003752 7 Children 1­ 6 years 0.007449 15 Children 7­ 12 years 0.003964 8 Females 13­ 50 years 0.001308 3 Males 13­ 19 years 0.002334 5 Males 20+ years 0.001208 2 Seniors 55+ years 0.001159 2 HED notes that there is a degree of uncertainty in extrapolating exposures for certain population subgroups which may not be sufficiently represented in the consumption surveys, (e. g., nursing and non­ nursing infants or Hispanic females). Therefore, risk estimates provided include only representative sub­ populations that have sufficient numbers of survey respondents (e. g., all infants, or females 13­ 50 years of age). 31 4.3 Water Exposure/ Risk Pathway Environmental fate data suggest that the parent and degradates are likely to be persistent and mobile in the environment. Leaching and runoff are expected to be primary dissipation routes. Metabolites A, B, D, 1 (JS472), and 2 (JT677) are major metabolites found in soil/ aquatic studies. Metabolites A­ 1, C and G3170 are detected in ground water analysis. Due to lack of toxicity data for these metabolites, MARC assumes they have similar toxicity as the parent because of the structure similarities (except G3170). Metabolite G3170 was detected at the highest level in the California prospective groundwater study (PGW) and there are no toxicity information available to indicated that it is of less toxicological concern than the parent. Therefore, MARC concludes that parent, G3170, and all degradates with conjoined cyclohexyl and triazine rings (specifically, A, A­ 1, B, C, D, 1 (JS472), and 2 (JT677)) are residues of concern for risk assessment in water. (S. Kinard, The Outcome of the HED Metabolism Assessment Review Committee for Water, April 25, 2002.) Drinking water degradates A, A­ 1, B, C and D are shown in Table 4; degradates G3170, 1, and 2 are shown in Table 7 below. 32 N N N O O H C H 3 N (CH 3 ) 2 N N N O O CH 3 N( CH 3 ) 2 O N N N O N CH 3 O CH 3 CH 3 O Table 7: Drinking Water Degradates Common Name Chemical Name Structure Metabolites G3170 6­( methylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­ (1H, 3H) dione Metabolite 1, JS472 3­( 4­ ketocyclohexyl)­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4­( 1H, 3H)­ dione Metabolite 2, JT677 3­( 2­ ketocyclohexyl)­ 6­( dimethylamino)­ 1­ methyl­ 1,3,5­ triazine­ 2,4( 1H, 3H) dione The environmental fate data suggest that the parent and degradates are likely to be persistent and mobile in the environment. Leaching and runoff are expected to be primary dissipation routes. Estimated Environmental Concentrations (EECs) in surface waters were estimated using the Tier I model FIRST. The EECs in groundwater were estimated using an available small­ scale prospective groundwater monitoring study. In addition, there are monitoring data available from the state of Maine, but these data are used for comparison purposes only. The surface water concentrations, for hexazinone residues were as follows: acute (peak) 33 value, 130 ppb, and the chronic annual average value, 47 ppb, based on the application of hexazinone on alfalfa, which is the major food/ feed use for the chemical. These values represent upper­ bound estimates of the concentrations that might be found in surface water due to the use of hexazinone on a representative crop. The groundwater screening concentration for hexazinone residues is 41.8 ppb. It is noted that the groundwater screening concentration for hexazinone residues, based on the groundwater prospective monitoring study is of the same order of magnitude of the groundwater concentration estimated from the Tier I model SCIGROW (i. e., 20.2 ppb). (Tier I Estimated Environmental Concentrations of Hexazinone for Use in the Human Health Risk Assessment, D215026, May 2, 2002.) 4.3.1 Environmental Fate Based on the available information, hexazinone appears to be persistent and mobile in soil and aquatic environments. Hexazinone is stable to hydrolysis (pH levels 5,7, and 9) and stable to aqueous photolysis (pH 7). Studies of the chemical's half­ life in aerobic and anaerobic soil and aquatic environments show that hexazinone half­ life in the environment range from 60­ 230 days. Data on hexazinone metabolites of concern indicate that they are highly mobile in the environment. Based on the environmental fate properties of hexazinone and its degradates, it can be concluded they may be of concern for surface water and groundwater contamination. Hexazinone is not to be applied under the following conditions to limit the migration of hexazinone to drinking water: (1) when rainfall is expected immediately after application; (2) to the field where the water table is shallow or the water body is nearby; and (3) to soils containing low organic matter and/ or high sand content. Hexazinone possesses high solubility in water and a low adsorption coefficient in soil. Therefore, this chemical is expected to be very mobile in the environment, especially in soils with low organic matter and/ or high sand content. Results from aquatic metabolism studies suggest that the parent compound is expected to be relatively persistent when it reaches surface water. Although some degradation could occur in the surface water, the chemical structures and the fate properties of the resulting degradates are similar to the parent. According to the aerobic soil metabolism, 19% and 11% of the applied were found as Degradates A­ 1 and 1, respectively, after one year of incubation. Hexazinone can be applied aerially and, therefore, there is a potential for runoff from spray drift. Hexazinone is expected to be less persistent in the upper layer of the water body than the deep layer. The bioconcentration potential is very low for this chemical. There is no Safe Drinking Water Act Maximum Contaminate Level (MCL) for the chemical. There are many degradates included in the hexazinone drinking water exposure assessment. They include degradates G3170, A, A­ 1, B, C, D, 1( JS472), 2( JT677). It is noted that although Degradate C was not found in any of the laboratory fate studies, the field dissipation and the small­ scale prospective groundwater monitoring study observed this degradate. In addition, degradates D and 2 were the major degradates found in the anaerobic 34 aquatic metabolism study; however, the field dissipation and the small­ scale prospective groundwater monitoring studies did not monitor these two degradates. Therefore, the fate of degradates D and 2 could not be assessed in the natural environment. The registrant believed that both field studies were mostly aerobic and the degradates were unlikely to be observed. The field dissipation studies did not monitor the fate of degradate G­ 3170, which was the degradate detected at the highest concentrations in the small­ scale prospective groundwater monitoring study. This degradate was not observed in the aerobic soil metabolism study. 4.3.2 Drinking Water Exposure Estimates The Agency currently lacks sufficient water­ related exposure data from monitoring to complete a quantitative drinking water exposure analysis and risk assessment for hexazinone and its degradates. The Agency is presently relying on a computer model, FIRST, to estimate the environmental concentrations (EECs) in surface water. This model takes into account the use patterns and the environmental profile of the pesticide, but does not include consideration of the impact that processing raw water for distribution as drinking water could have on the removal or metabolism of pesticides from the source water. The registrant submitted a small­ scale prospective groundwater monitoring study and the results indicate that hexazinone and its metabolites are very mobile and persistent in the environment. The results of this monitoring study are used to estimate concentrations of hexazinone and its degradates in groundwater. The State of Maine Board of Pesticides Control in the Department of Agriculture, Food and Rural Resources performed a statewide assessment to determine the impact of highly leachable pesticides including hexazinone. This study is considered informative but not used to derive estimated environmental concentrations for drinking water exposure and risk assessment. The estimated environmental concentrations of hexazinone and degradates in groundwater are based upon the prospective groundwater monitoring study. Surface Water The FIRST model is a new screening model designed to estimate the pesticide concentrations found in water for use in drinking water assessments. The model provides highend values on the concentrations that might be found in a small drinking water reservoir due to the use of pesticide. Similar to GENEEC, the model previously used for Tier I screening level, FIRST is a single­ event model (one run­ off event), but can account for spray drift from multiple applications. FIRST uses a drinking water reservoir instead of a pond as the standard scenario. The FIRST scenario includes a 427 acres field immediately adjacent to a 13 acres reservoir, 9 feet deep, with continuous flow (two turnovers per year). The pond receives a spray drift event from each application, plus one runoff event. The runoff event moves a maximum of 8% of the applied pesticide into the pond. This amount can be reduced due to degradation on field and the effect of binding to soil. Spray drift is equal to 6.4% of the applied concentration from the 35 ground spray application and 16% for aerial applications. Model inputs used to develop the surface water estimated environmental concentrations using the FIRST model include estimating drinking water exposure based on application to alfalfa, the food/ feed item with the greatest percent of crop treated with hexazinone. In addition, the model assumes aerial application, an application rate of 1.5 lbs. a. i./ acre, application once per year, and no soil incorporation after application. FIRST also makes adjustments for the percent of the area cropped. While FIRST assumes that the entire watershed would not be treated, the use of a PCA is still a screen because it represents the highest percentage of crop cover of any large watershed in the US, and it assumes that the entire crop is being treated. Other conservative assumptions of FIRST include the use of a small drinking water reservoir surrounded by a runoff­ prone watershed, the use of the maximum use rate, assumption of no buffer zone, and a single large rainfall. Groundwater The registrant submitted a small­ scale prospective groundwater monitoring study for hexazinone (MRID45132801). In this study, hexazinone was broadcast applied once at 0.75 lb a. i./ A in January 1996 onto a field of alfalfa underlain with sandy soil in Merced County, California. Results indicated that hexazinone and its degradates are very mobile and persistent. As indicated earlier, the degradates D and 2 (which were the major degradates found in the anaerobic aquatic metabolism study), were not monitored in the small­ scale prospective groundwater monitoring studies. No information about the fate of degradates D and 2 under natural environment is currently available. Table 8 provides a summary with the maximum concentrations of the parent and its degradates, detected in the small­ scale prospective groundwater monitoring study. These concentrations (see column 2) were expressed in parent equivalents (see Column 3). The maximum total residues of hexazinone and its degradates detected in the groundwater study were 41.8 ppb (expressed as parent equivalents). 36 Table 8: Summary of Small­ Scale Prospective Groundwater Monitoring Study Chemical Maximum Concentration in Groundwater (ppb) Maximum Concentration in Groundwater (ppb, expressed as parent equivalent) Parent 9.2 9.2 A­ 1 (G3453) 3 2.8 B (A3928) 7.2 7.6 C (T3935) 1.2 1.1 1 (( JS472) 2.1 2.0 G3170 12.9 19.1 Total Residues (parent equivalent) Not applicable 41.8 The State of Maine also conducted a drinking water monitoring study, however these data are considered for informational purposes only and are presented here as a point of comparison. The Board of Pesticides Control in the Department of Agriculture, Food and Rural Resources in the State of Maine conducted a statewide assessment to determine the impact of highly leachable pesticides (including hexazinone, an herbicide used in the production of blueberries) on surface water and ground water in Maine. This assessment crossed a variety of agricultural and nonagricultural pesticide use sites. Surface water samples were collected in Narraguagus River and Pleasant River in Maine. Although the total amounts of hexazinone used on blueberry in Maine is very low (only approximately 1% of the total sale in the U. S.), the chemical was detected in groundwater and surface water at very high frequency (43­ 59% of ground water samples, and 31­ 90% of surface water samples). Although this monitoring study is inherently different than the ground water prospective monitoring study, it was observed that the maximum concentrations of parent hexazinone observed in groundwater in 1998 and 1999 (i. e. 2.15 and 1.97 ppb, respectively), were similar to the maximum concentration observed in the small scale ground water monitoring study (i. e., 9.2 ppb). Results are summarized in Table 9. 37 Table 9: Summary of Monitoring Information from the Board of Pesticides Control in the Department of Agriculture, Food and Rural Resources in the State of Maine Year No. of Samples Collected No. of Samples with Hexazinone Detected (% of Frequency) Range of Concentrations (ppb) Ground Water 1998 42 18 (43%) 0.14­ 2.15 1999 22 13 (59%) 0.22­ 1.97 Surface Water 1998 36 11 (31%) 0.22­ 0.94 1999 21 19 (90%) 0.13­ 3.80 2000 24 21 (88%) 0.13­ 2.65 2001 50 44 (88%) 0.08­ 2.45 Therefore, estimated environment concentrations in surface and groundwater were derived from both modeled data and a prospective groundwater monitoring study. Aggregate exposure and risks from consumption of hexazinone contaminated surface water as drinking water will utilize the FIRST peak untreated water concentration of 129.8 ppb for the acute scenario and the annual average untreated water concentration of 47.1 ppb for the chronic scenario. The FIRST model estimates include all drinking water degradates of concern in the risk assessment (calculated as hexazinone parent equivalents). Aggregate exposure and risk from consumption of hexazinone contaminated groundwater as drinking water will use the results of the prospective groundwater monitoring study, 41.8 ppb. Although this study did not monitor for the presence of degradates D and 2, it is still considered to be a conservative estimate of groundwater drinking water exposure since the total residues detected in this study are twice the residue level estimated through the SCI­ GROW model, which included all metabolites in the model estimate. The surface and groundwater drinking water estimated environmental concentrations are listed in Table 10. 38 Table 10: Estimated Environmental Concentrations in Surface and Groundwater for Hexazinone use on Alfalfa Model Hexazinone (Total Residues) Source FIRST 1.0 Peak Untreated Water Concentration 129.8 ppb Output FIRST 1.0 Annual Average Untreated Water Concentration 47.1 ppb Output Small­ Scale Prospective Groundwater Monitoring Study 41.8 ppb Monitoring Data SCI­ GROW Ground Water Concentration 20.2 ppb Output 4.4 Residential Exposure/ Risk Pathway There are currently no registered uses for hexazinone in the residential environment. However, the hexazinone label does include use of the chemical in rights­ of­ way areas and spray drift is always a potential source of exposure to residents nearby to this type of spraying operation. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from groundboom application methods. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off­ target drift and risks associated with the application of hexazinone by aerial as well as other application types where appropriate. 4.4.1 Other Non­ Occupational Exposures It is important to note that U. S. EPA, Region IX is working with the California Department of Pesticide Regulation, the US Forest Service and Native American tribes in California to determine the potential exposure to forestry herbicides, including hexazinone, that may be occurring to Native Americans through their use of forest plant materials. Native Americans use these plant materials in their diets, in the making of traditional basketry, for medicinal purposes, and in ceremonial activities. In response to the health concerns raised by the Native American communities, the California Department of Pesticide Regulation (DPR) and the USEPA (Region IX) launched a risk assessment effort in 1997. This effort includes five steps: 39 DPR measured plant residue and surface water levels following herbicide application; DPR agreed to assess the total exposures and risks involved using, where appropriate, the monitoring data collected; informing tribal physicians of state regulations requiring pesticide illness reporting; participation in mediated meetings with Native American communities to determine the key issues surrounding herbicide use; and, video production about inadvertent exposure to herbicides. The Office of Pesticide Programs is aware of this ongoing work and will communicate with USEPA Region IX, California DPR and other entities, as appropriate, to ensure that potential exposures and risks are assessed. 5.0 Aggregate Risk Assessment and Characterization The Food Quality Protection Act (FQPA) amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA) requires for establishing or reassessing a pesticide tolerance "that there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposure for which there is reliable information." The July 30, 3003 HIARC meeting resulted in endpoint selection for multiple exposure durations and routes, including the residential pathway. However, exposure is only expected to occur via the food and water pathways of exposure. If new uses are added to the label in the future which include possible exposure to persons in the residential environment, EPA will conduct this analysis. The toxicological endpoints appropriate for the dietary (oral) route of exposure are, therefore, the only hazard endpoints considered in this analysis. Acute and chronic aggregate risk is comprised of the combined exposures from food and water. Risk estimates are aggregated because it is assumed exposure may occur over the same time period to the same person. The HIARC selected an acute dietary endpoint for females 13­ 50 based upon decreased male and female fetal weight, kidneys with no papilla (malformation) and misaligned sternebrae (variation) at the LOAEL in the developmental rat study. However, no appropriate effect attributed to a single exposure was identified in the toxicology database for the general population. The chronic dietary aggregate assessment utilizes an endpoint based on a chronic oral study in the dog which demonstrated severe body weight decrement and clinical chemistry changes including elevated aspartate aminotransferase and alkaline phosphatase at the LOAEL. Drinking Water Levels of Comparisons (DWLOCs) are used to estimate aggregate risk from drinking water sources. DWLOCs are theoretical upper limits of a pesticide's allowable concentration in drinking water in light of total aggregate exposure to a pesticide in food and drinking water. A DWLOC will vary depending on the toxic endpoint, drinking water consumption, and body weight. The Agency uses DWLOCs internally in the risk assessment process as a surrogate measure of potential exposure associated with pesticide exposure through drinking water. In the absence of reliable monitoring data for pesticides which can be used directly and quantitatively in the risk assessment, it is used as a point of comparison against conservative model estimates of a pesticide's concentration in water. DWLOC values are not a 40 regulatory standard for drinking water. However, they do have an indirect regulatory impact through aggregate exposure and risk assessments. For this analysis, groundwater monitoring conclusions are used to compare with calculated DWLOC for groundwater and modeling results are used to compare with calculated DWLOCs in surface water. Aggregate risk estimates for food and water are summarized in Tables 11 and 12. The estimates of food exposure are considered to be conservative since tolerance level residue values and 100% of crop treatment is assumed. 5.1 Acute Aggregate Risk Assessment Since the calculated EECs are less than the DWLOC, the acute aggregate exposure from residues of hexazinone and its metabolites in food and drinking water do not exceed the Agency's level of concern. HED calculates DWLOCs by a two­ step process: exposure is subtracted from the aPAD to obtain the maximum exposure allowed in drinking water; DWLOCs are then calculated using that value and HED default body weight and drinking water consumption figures. In assessing human health risk, DWLOCs are compared to EECs. When EECs are less than DWLOCs, HED considers the aggregate risk [from food + water exposures] to be acceptable. Estimated environmental concentrations for hexazinone and its water degradates were compared to the acute DWLOCs since adequate monitoring data were not available to directly assess aggregate exposure to food and water. The Environmental Fate and Effects Division (EFED) provided Tier I FIRST estimates to determine acute dietary aggregate exposure and risk values. This model simulated hexazinone and its metabolites in drinking water concentrations (for the alfalfa use) of 130 µg/ L for the surface water peak untreated water concentration. The results of the Small­ Scale Prospective Groundwater Monitoring Study were used to estimate concentrations of hexazinone and its degradates in groundwater (42 µg/ L). Interestingly, the results of the monitoring study and the results of the SCI­ GROW model are roughly equivalent, 42 µg/ L as compared to 20.2 µg/ L. The DWLOC calculated for acute aggregate risk for females 13­ 50 years old is 120,000 µg/ L. These results are presented in Table 11. Therefore, HED concludes with reasonable certainty that residues of hexazinone and its metabolites in drinking water will not contribute significantly to the acute human health risk and that the acute aggregate exposure from residues of hexazinone and its metabolites in food and drinking water and will not exceed the Agency's level of concern for acute aggregate exposure for females 13­ 50. 41 Table 11. Acute DWLOC Calculation Population Subgroup Acute Scenario aPAD (mg/ kg/ day) Acute Food Exposure (mg/ kg/ day) 1 Max Acute Water Exposure (mg/ kg/ day) 2 Groundwater EEC ( : g/ l) 3 Surface Water EEC ( : g/ l) 4 Acute DWLOC ( : g/ l) 5 Females 13­ 50 4.0 0.003611 3.996 42 130 120,000 1 Acute food exposure is exposure estimate at the 95th percentile from the Tier I assessment performed. 2 Maximum acute water exposure (mg/ kg/ day) = [( acute PAD (mg/ kg/ day) ­ acute food exposure (mg/ kg/ day)] 3 Results of Small­ Scale Prospective Groundwater Monitoring Study are used for groundwater EEC. 4 The crop producing the highest level was modeled to produce the surface water EEC results, alfalfa. 5 Acute DWLOC( µg/ L) = [maximum acute water exposure (mg/ kg/ day) x body weight (kg)] [water consumption (L) x 10 ­3 mg/ µg] Assumptions: Body weights (60 kg adult female); water consumption 2 liters/ day adult. 5.2 Chronic Aggregate Risk Assessment Since the calculated DWLOCs are above the drinking water exposure estimates, chronic aggregate exposure from residues of hexazinone and its metabolites in food and drinking water sources do not exceed the Agency's level of concern for chronic aggregate exposure for any subpopulation EFED provided Tier I FIRST estimates to determine chronic dietary aggregate exposure and risk values. This model simulated drinking water concentrations of hexazinone and its degradates (for the alfalfa use) of 47 µg/ L for the surface water annual average untreated water concentration. The results of a Small­ Scale Prospective Groundwater monitoring study were used to estimate concentrations of hexazinone in groundwater (42 µg/ L). The DWLOC calculated for chronic aggregate risk for all populations range from 425­ 1700 : g/ L. These results are presented in Table 12. Because the EECs are less than the calculated DWLOC, HED concludes with reasonable certainty that residues of hexazinone and its metabolites in drinking water will not contribute significantly to the chronic human health risk and that the chronic aggregate exposure from residues of hexazinone and its metabolites in food and drinking water and will not exceed the Agency's level of concern for chronic aggregate exposure for any sub­ population. 42 Table 12: Chronic DWLOC Calculations Population Subgroup 1 Chronic Scenario cPAD mg/ kg/ day Chronic Food Exposure mg/ kg/ day Max Chronic Water Exposure mg/ kg/ day 2 Ground Water EEC (µg/ L) 3 Surface Water EEC (µg/ L) 3 Chronic DWLOC (µg/ L) 4 U. S. Population 0.05 0.002167 0.04783 42 47 1700 Females 13­ 50 0.05 0.001308 0.04869 42 47 1500 Infants (< 1 year) 0.05 0.003752 0.04625 42 47 460 Children 1­ 6 0.05 0.007449 0.04255 42 47 425 1 Children 1­ 6 are the most highly exposed sub­ group. 2 Maximum Chronic Water Exposure (mg/ kg/ day) = [Chronic PAD (mg/ kg/ day) ­ Chronic Dietary Exposure (mg/ kg/ day)] 3 The use of hexazinone on alfalfa was modeled to determine surface water EEC's and the results of groundwater monitoring study was used to determined groundwater EEC. 4 Chronic DWLOC( µg/ L) = [maximum chronic water exposure (mg/ kg/ day) x body weight (kg)] [water consumption (L) x 10 ­3 mg/ µg] Assumptions: Body weights (70 kg adult male; 60 kg adult female; 10 kg child); water consumption 2 liters/ day adult and 1 liter/ day infants and children. 6.0 Cumulative Risk The FQPA (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non­ occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low­ level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject 43 pesticide, even if the individual exposure levels to the other substances are also considered safe. HED did not perform a cumulative risk assessment as part of the TRED for hexazinone because HED has not yet initiated a comprehensive review to determine if there are any other chemical substances that have a mechanism of toxicity common with that of hexazinone. For purposes of this TRED, the Agency has assumed that hexazinone does not have a common mechanism of toxicity with other substances. On this basis, the registrant must submit, upon EPA's request and according to a schedule determined by the Agency, such information as the Agency directs to be submitted in order to evaluate issues related to whether hexazinone shares a common mechanism of toxicity with any other substance and, if so, whether any tolerances for hexazinone need to be modified or revoked. If HED identifies other substances that share a common mechanism of toxicity with hexazinone, HED will perform aggregate exposure assessments on each chemical, and will begin to conduct a cumulative risk assessment. HED has developed a framework for conducting cumulative risk assessments on substances that have a common mechanism of toxicity. This guidance was issued on January 16, 2002 (67 FR 2210­ 2214) and is available from the OPP Website at: http:// www. epa. gov/ pesticides/ trac/ science/ cumulative_ guidance. pdf. Before undertaking a cumulative risk assessment, HED will follow procedures for identifying chemicals that have a common mechanism of toxicity as set forth in the "Guidance for Identifying Pesticide Chemicals and Other Substances that Have a Common Mechanism of Toxicity" (64 FR 5795­ 5796, February 5, 1999). 7.0 Incident Data The Agency searched several databases for reports of poisoning incident data for hexazinone. These databases include the Office of Pesticide Programs (OPP) Incident Data System (IDS), the Poison Control Center data, California Department of Pesticide Regulation, and the National Pesticide Telecommunication Network (NPTN). Relatively few incidents have been reported. Cases listed in the IDS include individuals reporting burning and red welts on the legs, eye irritation and peeling on their hands and feet. Other databases included reports of eye effects and breathing difficulties after exposure. Because there are so few cases available, no recommendations can be made based on the few incident reports available. (J. Blondell, Review of Hexazinone Incident Reports, May 1, 2002.) 44 8.0 Data Needs Product Chemistry 1. The product chemistry data base is complete. Toxicology 2. The HIARC requested a 28­ day inhalation study on formulation with hexazinone because of the concern for potential inhalation exposure based on the use pattern. Residue Chemistry 3. Outstanding label amendments to reflect cancellation of use on pasture/ rangeland grasses. 4. Field rotational crop studies for corn and wheat. Environmental Fate 5. The environmental fate database is complete. 45 References Anderson, D. Hexazinone (PC Code 107201). Toxicology Disciplinary Chapter for the Tolerance Reassessment Eligibility Decision Document. August 12, 2002. TXR No. 0051040. DP Barcode D275620. Anderson, D. Hexazinone ­ 3rd Report of the Hazard Identification Assessment Review Committee. August 12, 2002. TXR No. 0051003. Blondell, J. and M. Spann. Review of Hexazinone Incident Reports. Chemical 107201. May 1, 2002. Dockter, K. Hexazinone. Product Chemistry Chapter for the Tolerance Reassessment Eligibility Decision (TRED) Document. April 23, 2002. DP Barcode D279324. Hernandez, F. Quantitative Usage Analysis for Hexazinone. September 10, 2001. Kinard, S. Hexazinone. The Outcome of the HED Metabolism Assessment Review Committee for Water. PC code 107201, April 25, 2002. DP Barcode D282111. Li, L. 2002. Data Analysis of Forestry Herbicides in Plants of Interest of California Tribes. Final Report. Retrieved from Http:// www. cdpr. ca. gov/ docs/ empm/ pubs/ forest/ reprts. htm. Liu, L. Tier I Estimated Environmental Concentrations of Hexazinone, for use in Human Health Risk Assessment Water Assessment. Environmental Fate and Effects Division. May 2, 2002. Punzi, J. Hexazinone. Acute and Chronic Dietary Exposure Assessments for the TRED. (PC Code 107201). July 30, 2002. DP Barcode D279898. Punzi, J. Hexazinone Tolerance Reassessment Eligibility Decision Residue Chemistry Considerations. May 20, 2002. (DP Barcode D279899). Segawa, R., C. Ando, A. Bradley, J. Walters, R. Sava, C. Gana, et al. (2001). Dissipation and Off­ site Movement of Forestry Herbicides in Plants of Importance to California Tribes. Final Report. Retrieved from Http:// www. cdpr. ca. gov/ docs/ empm/ pubs/ forest/ reprts. htm. Tarplee, B. Hexazinone ­ 2 nd Report of the FQPA Safety factor Committee. August 8, 2002. TXR. No. 0051049. Commodity Current Tolerance (ppm) a Range of residues (ppm) b Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition 46 Blueberries 0.2 <0.3 ppm (nondetectable; <0.05 ppm for each compound) 0.60 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Blueberry Cattle, fat 0. 1 Revoke c Cattle, mbyp 0.1 0. 10 Cattle, meat 0.1 0. 10 Goat, fat 0. 1 Revoke c Goat, mbyp 0.1 0. 10 Goats, meat 0.1 0. 10 Grasses, pasture 10 Revoke d Grass, forage Grass, hay Grasses, rangeland 10 Revoke d Hog, fat 0. 1 Revoke c Hog, mbyp 0.1 Revoke c Hog, meat 0.1 Revoke c Horses, fat 0. 1 Revoke c Horses, mbyp 0.1 0. 10 Horses, meat 0.1 0. 10 Milk 0.5 0. 20 Pineapple 0. 5 <0.35 (or <0.05 ppm for each compound) 0.60 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Sheep, fat 0. 1 Revoke c Sheep, mbyp 0.1 0. 10 Sheep, meat 0.1 0. 10 Tolerances needed under 40 CFR §180.396( a): Alfalfa, seed ­­ <1.30­< 1.46 2. 0 Table C (continued). Commodity Current Tolerance (ppm) a Range of residues (ppm) b Tolerance Reassessment (ppm) Comment/ Correct Commodity Definition 47 Tolerances listed under 40 CFR §180.396( c): Sugarcane 0. 2 <0.05 ppm (nondetectable) each for hexazinone and its metabolites 0.60 Tolerance should be increased based on the combined LOQ (0.55 ppm) of the enforcement method. Sugarcane molasses 5 (1.915 x 4x) ÷ 2x = 3.83 4.0 a Expressed in terms of the combined residues of hexazinone and its metabolites (calculated as hexazinone). b Refer to section on Magnitude of Residues in Crop Plant for detailed discussion of residues in crops. c Tolerances for fat are not required (Category 3, 40 CFR §180.6). d HED is recommending revocation of these tolerances and cancellation of uses, since grasses are a major feed item and required data are not available for reassessment.

epa

2024-06-07T20:31:42.983970

regulations

EPA-HQ-OPP-2002-0192-0001

Notice

Diquat Dibromide; Notice of Availability of Decision on Syngenta's Request to Modify Requirements and Closure of 1995 RED

58797 Federal Register / Vol. 67, No. 181 / Wednesday, September 18, 2002 / Notices Screening Program. Chlorpropham will be reevaluated at that time and additional studies may be required. Additionally, the Agency has evaluated the dietary risk associated with chlorpropham and has determined that provided the Special Local Need ( SLN) registration for Easter lily bulb use is amended to reduce the maximum rate of application from 3.99 pounds active ingredient/ acre to 2.0 pounds active ingredient/ acre, as agreed upon by stakeholders, there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to chlorpropham when considering dietary exposure and all other non­ occupational sources of pesticide exposure for which there is reliable information. Therefore, with this mitigation measure in place, 15 tolerances are now considered reassessed and 9 new tolerances will be established for residues of chlorpropham in/ on raw agricultural commodities under section 408( q) of the FFDCA. All registrants of pesticide products containing the active ingredient listed in this document have been sent the appropriate TRED document, and must respond to labeling requirements within 8 months of receipt. In addition, the Agency requests a response to the generic Data Call­ In ( DCI) letter from technical registrants within 90 days of receipt. The reregistration program is being conducted under Congressionallymandated time frames, and EPA recognizes both the need to make timely reregistration decisions and to involve the public. All comments received within 30 days of publication of this Federal Register notice will be considered by the Agency. If any comment significantly impacts this TRED, the Agency will amend its decision by publishing a Federal Register notice. B. What is the Agency's Authority for Taking this Action? The legal authority for this TRED falls under FIFRA, as amended in 1988 and 1996. Section 4( g)( 2)( A) of FIFRA directs that, after submission of all data concerning a pesticide active ingredient, `` the Administrator shall determine whether pesticides containing such active ingredient are eligible for reregistration,'' and either reregistering products or taking `` other appropriate regulatory action.'' List of Subjects Environmental protection, Pesticides, Tolerances. Dated: September 10, 2002. Lois A. Rossi, Director, Special Review and Reregistration Division, Office of Pesticide Programs. [ FR Doc. 02 23593 Filed 9 17 02; 8: 45 am] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0192; FRL 7197 9] Diquat Dibromide; Notice of Availability of Decision on Syngenta's Request to Modify Label Requirements and Closure of 1995 RED AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: This notice announces EPA's intention to modify certain occupational and residential risk mitigation measures that were imposed as a result of the 1995 Reregistration Eligibility Decision ( RED) for diquat dibromide. At the end of the comment period, the Agency will consider this action an immediate final decision and the 1995 RED closed, unless adverse comments are received. The Agency conducted this reassessment in response to new data submitted by the technical registrant, Syngenta Crop Protection, Inc. Syngenta has requested the Agency modify certain diquat dibromide label requirements including: Personal protective equipment ( PPE), closed loading system for aerial applications, reentry intervals, and allow residential broadcast spray uses. DATES: Comments, identified by docket identification ( ID) number OPP 2002 0192, must be received on or before October 18, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002 0192 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Tyler Lane, Special Review and Reregistration Division ( 7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 305 2737; email address: lane. tyler@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general, nevertheless, a wide range of stakeholders will be interested in obtaining information on the label adjustments for diquat dibromide, including environmental, human health, and agricultural advocates; the chemical industry; pesticide users; and members of the public interested in the use of pesticides on food. Since other entities also may be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. On the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up the entry for this document under the `` Federal Register Environmental Documents.'' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. Copies of the tolerance reassessment decision and supporting risk assessment documents for the reregistration of diquat dibromide may also be accessed at http:/ / www. epa. gov/ pesticides/ reregistration/ diquat_ dibromide. htm. 2. In person. The Agency has established an official record for this action under docket ID number OPP 2002 0192. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record is available for inspection in the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. VerDate Sep< 04> 2002 21: 00 Sep 17, 2002 Jkt 197001 PO 00000 Frm 00044 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 18SEN1. SGM 18SEN1 58798 Federal Register / Vol. 67, No. 181 / Wednesday, September 18, 2002 / Notices C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002 0192 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch ( PIRIB), Information Resources and Services Division ( 7502C), Office of Pesticide Programs ( OPP), Environmental Protection Agency, Rm. 119, Crystal Mall # 2, 1921 Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0/ 9.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP 2002 0192. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI That I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person identified under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Make sure to submit your comments by the deadline in this document. 7. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. Background A. What Action is the Agency Taking? In 1995, the Agency published its Reregistration Eligibility Decision ( RED) for diquat dibromide. Subsequent to the publication of the 1995 RED, the technical registrant submitted additional data to further refine diquat dibromide worker exposure and residential broadcast spray use scenarios. Changes to the PPE label requirements of the 1995 RED are based on the submission of additional data from a biomonitoring study of knapsack applications of the closely related chemical paraquat, and a reconsideration of the acute dermal toxicity endpoint. The Agency reevaluated the dermal toxicity endpoint and rendered a decision that the repeated dose dermal toxicity study used for the 1995 RED was not appropriate for use in the risk assessment because the skins of the rats used in the study were compromised. Instead, the Agency extrapolated a dermal toxicity endpoint from a shortterm oral study on rabbits. The Agency has also reevaluated dermal absorption assumptions. Previously, EPA assumed a standard absorption rate of 4.1%, based on a rat dermal absorption study. Syngenta cited a human dermal absorption study estimating a 0.3% dermal absorption rate for diquat dibromide ( Feldman RJ and Maibach HI, `` Percutaneous penetration of some pesticides and herbicides in man'' Tox. Appl. Pharm. 28 126 132, 1974). The Agency has relied on data provided by the Feldman­ Maibach study for previous risk assessments, and believes the study to be acceptable and the data valid for use in this risk assessment. The use of the dermal absorption factor of 0.3% further refines all aggregate margins of exposure ( MOEs) above the target MOE of 100, which would not be of concern to the Agency. The Agency has evaluated the request to modify the cited label requirements and summarized its assessment in the Occupational Risk Evaluation: `` Assessing Syngenta's Request to Modify Diquat Dibromide Label Requirements,'' dated February 14, 2002. In addition, the `` HED Risk Assessment for Tolerance Reassessment Eligibility Document ( TRED),'' March 6, 2002, and the `` Re­ characterization of Risk for the Diquat Dibromide Tolerance Reassessment Eligibility Decision ( TRED) Based on New Dermal Absorption Data,'' March 13, 2002, were used to aid in the assessment of aggregate risks from residential uses. Any labeling changes are presented in the `` Required Labeling Changes Summary Table,'' which summarizes the labeling requirements for this action. All supporting documents referenced in this document are available in the public docket and at http:// www. epa. gov/ pesticides/ reregistration/ diquat_ dibromide. htm. In summary, the Agency expects to change the label requirements of the 1995 RED for worker PPE and residential broadcast spray uses. The following table presents the 1995 RED decisions being reevaluated, the requests to change these requirements made by Syngenta, and the current Agency decisions to amend the 1995 RED: VerDate Sep< 04> 2002 21: 00 Sep 17, 2002 Jkt 197001 PO 00000 Frm 00045 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 18SEN1. SGM 18SEN1 58799 Federal Register / Vol. 67, No. 181 / Wednesday, September 18, 2002 / Notices July 1995 RED Syngenta Request Amendments to 1995 RED All workers required to wear a double layer of clothing ( coveralls over long sleeved shirt, long pants), chemical resistant gloves, chemical resistant footwear plus socks, chemical resistant headgear for overhead exposure, and a chemical resistant apron when cleaning equipment, mixing or loading) Reduced PPE requirements due potential for heat stress to field workers and applicators All workers must continue to wear protective footwear and coveralls over a single layer of clothes ( products with a dermal toxicity of III or IV may reduce PPE to protective footwear and coveralls over short pants and short sleeve shirts). Mixers, loaders and hand applicators must wear chemical resistant gloves, while applicators who are operating closed cab equipment are not required to wear chemical resistant gloves due to MOEs over 1,000. Respirators for mixing and loading No respirator requirements for mixing and loading due to potential for heat stress Respirator requirement for mixer/ loaders reduced to a face shield to prevent droplets from entering the eyes, mouth or nose areas Closed mixing system for aerial applications. Open mixing system for aerial applications Closed mixing/ loading requirements remain for aerial applications 7 Day restricted entry interval ( REI) for products used under the Worker Protection Standard ( WPS) unless there is no contact with treated surfaces ( such as mechanical harvesting) 4 Hour REI for potato desiccation and seed crops REI reduced to 24 hours for all WPS uses, based on default reentry analysis findings of MOEs between 150 and 1,500 and a toxicity category II for eye irritation 4 Day REI for non­ WPS uses other than aquatic and spot treatment at residential sites REI when spray is dry for non­ WPS uses REI reduced to `` when sprays are dry'' for non­ WPS uses, also based on default reentry analysis Prohibition of broadcast spray applications for homeowner and residential uses Broadcast spray applications for homeowner and residential uses Generic data requirements have been fulfilled for residential broadcast spray uses. Broadcast spray applications for homeowner and residential uses for enduse products will be decided on a case­ by­ case basis upon review of end­ use product toxicity, based on short­ term exposure and individual risk assessments. B. What is the Agency's Authority for Taking this Action? The legal authority for this decision falls under FIFRA, as amended in 1988 and 1996. Section 4( g)( 2)( A) of FIFRA directs that, after submission of all data concerning a pesticide active ingredient, `` the Administrator shall determine whether pesticides containing such active ingredient are eligible for reregistration,'' and either reregister products or take other `` appropriate regulatory action.'' List of Subjects Environmental protection, Chemicals, Aquatic herbicides. Dated: September 5, 2002. Lois Rossi, Director, Special Review and Reregistration Division, Office of Pesticide Programs. [ FR Doc. 02 23594 Filed 9 17 02; 8: 45 am] BILLING CODE 6560 50 S ENVIRONMENTAL PROTECTION AGENCY [ OPP 2002 0201; FRL 7194 5] Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. SUMMARY: This notice announces the initial filing of a pesticide petition proposing the establishment of regulations for residues of a certain pesticide chemical in or on various food commodities. DATES: Comments, identified by docket ID number OPP 2002 0201, must be received on or before October 18, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. C. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP 2002 0201 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By mail: Bipin Gandhi, Registration Division ( 7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: ( 703) 308 8380; e­ mail address: gandhi. bipin@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? You may be affected by this action if you are an agricultural producer, food manufacturer or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: Categories NAICS Codes Examples of potentially affected entities Industry 111 Crop production 112 Animal production 311 Food manufacturing 32532 Pesticide manufacturing This listing is not intended to be exhaustive, but rather provides a guide for readers regarding entities likely to be affected by this action. Other types of entities not listed in the table could also be affected. The North American Industrial Classification System ( NAICS) codes have been provided to VerDate Sep< 04> 2002 21: 00 Sep 17, 2002 Jkt 197001 PO 00000 Frm 00046 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 18SEN1. SGM 18SEN1

epa

2024-06-07T20:31:42.998821

regulations

EPA-HQ-OPP-2002-0194-0001

Notice

EPA Pesticide Program Dialogue Committee; Notice of Public Meeting.

< PRE> [ Federal Register: August 30, 2002 ( Volume 67, Number 169)] [ Notices] [ Page 55839­ 55840] From the Federal Register Online via GPO Access [ wais. access. gpo. gov] [ DOCID: fr30au02­ 100] ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ENVIRONMENTAL PROTECTION AGENCY [ OPP­ 2002­ 0194; FRL­ 7197­ 6] EPA Pesticide Program Dialogue Committee; Notice of Public Meeting AGENCY: Environmental Protection Agency ( EPA). ACTION: Notice. ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ SUMMARY: EPA's Office of Pesticide Programs will hold a public meeting of the Pesticide Program Dialogue Committee ( PPDC) on September 17 and 18, 2002. An agenda will be available by September 13, 2002, and posted on EPA's Web site at < A HREF=" http:// frwebgate. access. gpo. gov/ cgi­ bin/ leaving. cg i? from= leavingFR. html& log= linklog& to= http:// www. epa. gov/ pesticides/ ppdc/"> www. ep a. gov/ pesticides/ ppdc/</ A>. An agenda is being developed and will include the following topics: Alternative, i. e., non­ animal or reduced­ animal testing ( with special focus on acute toxicity testing), pesticide program resource allocations and expenditures, follow­ up reports from the May 2002, PPDC meeting, and other topics. DATES: The meeting will be held on Tuesday, September 17, 2002, from 9 a. m. to 5 p. m., and on Wednesday, September 18, 2002, from 9 a. m. to 3 p. m. ADDRESSES: The meeting will be held at the Old Town Holiday Inn Select, 480 King Street, Carlyle Conference Room fifth floor, Alexandria, VA. Telephone: ( 703) 549­ 6080. FOR FURTHER INFORMATION CONTACT: Margie Fehrenbach, Office of Pesticide Programs ( 7501C), Environmental Protection Agency, 1200 Pennsylvania Avenue, NW., Washington, DC 20460; telephone number: ( 703) 308­ 4775; fax [[ Page 55840]] number: ( 703) 308­ 4776; e­ mail address: < A HREF=" mailto: fehrenbach. margie@ epa. go v"> fehrenbach. margie@ epa. gov</ A>. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general. This action may, however be of interest to persons who are concerned about implementation of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA); the Federal Food, Drug, and Cosmetic Act ( FFDCA); and the amendments to both of these major pesticide laws by the Food Quality Protection Act ( FQPA) ( Public Law 104­ 170) of 1996. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at < A HREF=" http:// frwebgate. acc ess. gpo. gov/ cgi­ bin/ leaving. cgi? from= leavingFR. html& log= linklog& to= http:// www. ep a. gov/"> http:// www. epa. gov/</ A>. To access this document, on the Home Page select `` Laws and Regulations,'' `` Regulations and Proposed Rules,'' and then look up the entry for this document under the `` Federal Register­­ Environmental Documents.'' You can also go directly to the Federal Register listings at < A HREF=" http:// frwebgate. access. gpo. gov/ cgi­ bin/ leaving. cgi? from= leavingFR. h tml& log= linklog& to= http:// www. epa. gov/ fedrgstr/"> http:// www. epa. gov/ fedrgstr/</ A >. To access information about PPDC, go directly to the Home Page for EPA's Office of Pesticide Programs at < A HREF=" http:// frwebgate. access. gpo. gov/ cgi­ bin/ leaving. cgi? from= leavingFR. html & log= linklog& to= http:// www. epa. gov/ pesticides/ ppdc/"> http:// www. epa. gov/ pesticid es/ ppdc/</ A>. 2. In person. The Agency has established an official record for this action under docket ID number OPP­ 2002­ 0194. The official record consists of the documents specifically referenced in this action, any public comments received during an applicable comment period, and other information related to this action, including any information claimed as Confidential Business Information ( CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity Branch ( PIRIB), Rm. 119, Crystal Mall < greek­ i> 2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is ( 703) 305­ 5805. II. Background The PPDC is composed of 42 members appointed by EPA's Deputy Administrator. Committee members were selected from a balanced group of participants from the following sectors: 1. Pesticide user, grower, and commodity groups. 2. Industry and trade associations. 3. Environmental/ public interest and farmworker groups. 4. Federal, State and tribal governments. 5. Public health organizations. 5. Animal welfare and academia. PPDC was established to provide a public forum to discuss a wide variety of pesticide regulatory development and reform initiatives, evolving public policy, program implementation issues, science policy issues associated with evaluating, and reducing risks from use of pesticides. III. How Can I Participate in this Meeting? The PPDC meetings and workshops are open to the public under section 10( a)( 2) of the Federal Advisory Committee Act ( FACA), Public Law 92­ 463. Outside statements by observers are welcome. Oral statements will be limited to 3 to 5 minutes, and it is preferred that only one person per organization present the statement. Any person who wishes to file a written statement may do so before or after the meeting. These statements will become part of the permanent record and will be available for public inspection at the address in Unit I. B. 2. List of Subjects Environmental protection, Pesticides and pests. Dated: August 26, 2002. Marcia E. Mulkey, Director, Office of Pesticide Programs. [ FR Doc. < strong> 02</ strong>­< strong> 22219</ strong> < strong> Filed</ strong> 8­ 27­ < strong> 02</ strong>; 4: 06 pm] BILLING CODE 6560­ 50­ S </ PRE>

epa

2024-06-07T20:31:43.004161

regulations

EPA-HQ-OPP-2002-0196-0001

Notice

Diazinon; Receipt of Request for Amendments and Cancellations.

57589 Federal Register / Vol. 67, No. 176 / Wednesday, September 11, 2002 / Notices those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. C. How and To Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0197 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), OPP, Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP– 2002– 0197. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI That I Want To Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the registration activity. 7. Make sure to submit your comments by the deadline in this notice. 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. Registration Applications EPA received applications as follows to register pesticide products containing new active ingredients not included in any previously registered products pursuant to the provision of section 3( c)( 4) of FIFRA. Notice of receipt of these applications does not imply a decision by the Agency on the applications. Products Containing Active Ingredients Not Included in Any Previously Registered Products 1. File Symbol: 3125– LUR. Applicant: Bayer Corporation, 8400 Hawthorn Road, Kansas City MO, 64120– 0013.Product name: Olympus 70% Water Dispersible Granular Herbicide. Product type: Herbicide. Active ingredient: Propoxycarbazone­ sodium (methyl 2­[[[( 4,5­ dihydro­ 4­ methyl­ 5­ oxo­ 3­ propoxy­ 1H­ 1,2,4­ triazol­ 1­ yl) carbonyl] amino] sulfonyl] benzoate, sodium salt) at 70%. Proposed classification/ Use: None. For use on wheat to control certain grasses and broadleaf weeds. 2. File Symbol: 3125– LUE. Applicant: Bayer Corp. Product name: Olympus 70% Water Dispersible Granular Herbicide in Water­ Soluble Packets. Product type: Herbicide. Active ingredient: Propoxycarbazone­ sodium at 70%. Proposed classification/ Use: None. For use on wheat to control certain grasses and broadleaf weeds. 3.File Symbol: 3125– LUG. Applicant: Bayer Corp. Product name: Olympus Technical Herbicide. Product type: Herbicide. Active ingredient: Propoxycarbazone­ sodium at 95.3%. Proposed classification/ Use: None. For manufacturing use of end use products to be used to control certain grasses and broadleaf weeds on wheat. List of Subjects Environmental protection, Pesticides and pest. Dated: August 27, 2002. Debra Edwards, Acting Director, Registration Division, Office of Pesticide Programs. [FR Doc. 02– 22612 Filed 9– 10– 02; 8: 45 am] BILLING CODE 6560– 50– S ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0196; FRL– 7197– 8] Diazinon; Receipt of Requests for Amendments, and Cancellations AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: Several companies that manufacture diazinon [O, O­ diethyl O 2­ isopropyl­ 6­ methyl­ 4­ pyrimidinyl) phosphorothioate] pesticide products have asked EPA to cancel or amend the registrations for their end­ use products containing diazinon to delete all indoor uses, certain agricultural uses and certain outdoor non­ agricultural uses. Pursuant to section 6( f)( 1) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), EPA is announcing the Agency's receipt of these requests. These requests for voluntary termination of the above­ mentioned uses through registration cancellations or amendments were submitted to EPA in December 2001, and January, February, March, April, May, June, and July 2002. EPA intends to grant these requests by issuing a cancellation order at the close of the comment period for VerDate Sep< 04> 2002 18: 47 Sep 10, 2002 Jkt 197001 PO 00000 Frm 00022 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 11SEN1. SGM 11SEN1 57590 Federal Register / Vol. 67, No. 176 / Wednesday, September 11, 2002 / Notices this announcement unless the Agency receives substantive comments within the comment period that would merit its further review of these requests. Upon the issuance of the cancellation order, any distribution, sale, or use of diazinon products listed in this notice will only be permitted if such distribution, sale, or use is consistent with the terms of that order. DATES: Comments on the requested amendments to delete uses and the requested registration cancellations must be submitted to the address provided below and identified by docket ID number OPP– 2002– 0196. Comments must be received on or before October 11, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0196 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Laura Parsons, Special Review and Reregistration Division (7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 305– 5776; fax number: (703) 308– 7042; e­ mail address: parsons. laura@ epa. gov. SUPPLEMENTARY INFORMATION: This announcement consists of three parts. The first part contains general information. The second part addresses the registrants' requests for registration cancellations and amendments to delete uses. The third part proposes existing stocks provisions that will be set forth in the cancellation order that the Agency intends to issue at the close of the comment period for this announcement. I. General Information A. Does This Action Apply to Me? This action is directed to the public in general. You may be potentially affected by this action if you manufacture, sell, distribute, or use diazinon products. The Congressional Review Act, 5 U. S. C. 801 et seq., as added by the Small Business Regulatory Enforcement Fairness Act of 1996, does not apply because this action is not a rule, for purposes of 5 U. S. C. 804( 3). Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of This Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations, '' `` Regulations and Proposed Rules, '' and then look up the entry for this document under the Federal Register— Environmental Documents. You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. To access information about the risk assessment for diazinon, go to the Home Page for the Office of Pesticide Programs or go directly to http:// www. epa. gov/ pesticides/ op/ diazinon. htm. 2. In person. The Agency has established an official record for this action under docket ID number OPP– 2002– 0196. The official record consists of the documents specifically referenced in this action, any public comments received during an applicable comment period, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. C. How and To Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0196 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0/ 9.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP– 2002– 0196. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI That I Want To Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. VerDate Sep< 04> 2002 18: 47 Sep 10, 2002 Jkt 197001 PO 00000 Frm 00023 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 11SEN1. SGM 11SEN1 57591 Federal Register / Vol. 67, No. 176 / Wednesday, September 11, 2002 / Notices 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the notice or collection activity. 7. Make sure to submit your comments by the deadline in this notice. 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. Receipt of Requests to Cancel and Amend Registrations to Delete Uses A. Background Certain registrants requested in letters dated June, August, and September 2001, that their diazinon registrations be amended to delete all indoor uses, certain agricultural uses, and any other uses that the registrants do not wish to maintain. The requests also included deletions of outdoor non­ agricultural uses from the labeling of certain end­ use products so that such products would be labeled for agricultural uses only. Similarly, other diazinon end­ use registrants requested voluntary cancellation of their diazinon end­ use registrations with indoor use and/ or certain outdoor non­ agricultural uses, and any other uses that the registrants do not wish to maintain. Pursuant to section 6( f)( 1) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), EPA is announcing the Agency's receipt of these requests. These requested cancellations and amendments are consistent with the requests in December 2000 by the manufacturers of diazinon technical products, and EPA's approval of such requests, to terminate all indoor uses and certain agricultural uses from their diazinon product registrations because of EPA's concern with the potential exposure risk, especially to children. The indoor uses and agricultural uses subject to cancellation are identified in List 1 below: List 1— Uses to be Canceled 1. Indoor uses: Pet collars, or inside any structure or vehicle, vessel, or aircraft or any enclosed area, and/ or on any contents therein (except mushroom houses), including but not limited to food/ feed handling establishments, greenhouses, schools, residences, commercial buildings, museums, sports facilities, stores, warehouses and hospitals. 2. Agricultural uses: Alfalfa, bananas, Bermuda grass, dried beans, dried peas, celery, red chicory (radicchio), citrus, clover, coffee, cotton, cowpeas, cucumbers, dandelions, forestry, (ground squirrel/ rodent burrow, dust stations for public health use), kiwi, lespedeza, parsley, parsnips, pastures, peppers, potatoes (Irish and sweet), sheep, sorghum, squash (winter and summer), rangeland, Swiss chard, tobacco, and turnips (roots and tops). As mentioned above, the requests announced in this Federal Register notice also include registration cancellations and/ or amendments to terminate certain uses that the registrants do not wish to maintain. The specific requests are identified in Tables 1 and 2. EPA has begun the process of reviewing the requested amendments which cannot be finalized until the end of the public comment period and provided that no substantial comments need to be addressed. EPA also intends to grant the requested product and use cancellations by issuing a cancellation order at the close of the comment period for this announcement unless the Agency receives substantive comments within the comment period that would merit its further review of these requests. B. Requests for Voluntary Cancellation of End­ Use Products The registrants and end­ use product registrations containing diazinon for which cancellation was requested are identified in the following Table 1. TABLE 1.— END­ USE PRODUCT REGISTRATION CANCELLATION REQUESTS Company Registration No. Product Farnam Companies, Inc. 270– 282 Diazinon 2EC Prentiss Inc. 655– 457 Prentox Diazinon 4E Insecticide 655– 462 Prentox Diazinon 4S Insecticide 655– 519 Prentox Liquid Household Spray #1 Universal Cooperatives, Inc. 1386– 573 Diazinon Emulsifiable Lawn and Garden Insecticide 1386– 651 Security Brand 2% Diazinon Granules Lawn Insect Control Virbac AH, Inc. 2382– 168 Diazinon­ Pyriproxyfen Collar for Dogs and Puppies #1 2382– 171 Diazinon­ Pyriproxyfen Collar for Dogs and Puppies #3 2382– 172 Diazinon­ Pyriproxyfen Collar for Dogs and Puppies #2 ABC Compounding, Inc. 3862– 71 Drop Dead Insect Spray Cerexagri, Inc. 4581– 335 Knox Out 2 FM Amvac Chemical Corp. 5481– 224 Diazinon 4E 5481– 241 Alco Housing Authority Roach Concentrate U. S. Marketing Distributors 6409– 14 Professional Do it Yourself Exterminator's Kit Formula 400 Voluntary Purchasing Group Inc. 7401– 67 Ferti­ Lome Rose Spray Containing Diazinon and Daconil VerDate Sep< 04> 2002 18: 47 Sep 10, 2002 Jkt 197001 PO 00000 Frm 00024 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 11SEN1. SGM 11SEN1 57592 Federal Register / Vol. 67, No. 176 / Wednesday, September 11, 2002 / Notices TABLE 1.— END­ USE PRODUCT REGISTRATION CANCELLATION REQUESTS— Continued Company Registration No. Product Earth Care/ Division of United Industries Corp. 8660– 101 Vertagreen 5% Diazinon Insecticide 8660– 106 Vertagreen Diazion Pre­ Weed 8660– 115 Vertagreen Diazinon Pre­ Weed Plus The Andersons Lawn Fertilizer Division 9198– 189 Proturf Insecticide One Waterbury Companies, Inc. 9444– 89 CB Aqueous Residual Insecticide Athea Laboratories, Inc. 10088– 71 Roach and Ant Killer Verpas Products, Inc. 13926– 6 Diaciclon F– 5 Wagnol Inc. 33912– 1 Wagnol 40 Pest Control Spray Concentrate Contains Diazinon T­ Tex Corp. 39039– 5 Dryzon WP Livestock Premise and Sheep Insecticide Chem­ Tech Ltd. 47000– 63 Pressurized Household Insect Spray Concentrate Contains Diazinon and DDVP Marman USA, Inc. 48273– 25 Marman Diazinon AG 60 EC Control Solutions Inc 53883– 58 Martin's Diazinon 4E Indoor­ Outdoor Insecticide Arkopharma, Inc. 69607– 1 Double Duty Flea and Tick Collar for Dogs Under section 6( f)( 1)( A) of FIFRA, registrants may request, at any time, that EPA cancel any of their pesticide registrations. Section 6( f)( 1)( B) of FIFRA requires that EPA provide a 30– day period in which the public may comment before the Agency may act on the request for voluntary cancellation. In addition, section 6( f)( 1)( C) of FIFRA requires that EPA provide a 180– day comment period on a request for voluntary termination of any minor agricultural use before granting the request, unless: 1. The registrants request a waiver of the comment period. 2. The Administrator determines that continued use of the pesticide would pose an unreasonable adverse effect on the environment. In this case, all of the registrants have requested that EPA waive the 180– day comment period. In light of this request, EPA is granting the request to waive the 180– day comment period and is providing a 30– day public comment period before taking action on the requested cancellations. Because of risk concerns posed by certain uses of diazinon, EPA intends to grant the requested cancellations at the close of the comment period for this announcement unless the Agency receives any substantive comment within the comment period that would merit its further review of these requests. C. Requests for Voluntary Amendments To Delete Uses From the Registrations of End­ Use Products Pursuant to section 6( f)( 1)( A) of FIFRA, the following companies have submitted a request to amend the registrations of their pesticide end­ use products containing diazinon to delete certain uses from certain products. The following Table 2 identifies the registrants, the product registrations that they wish to amend, and the uses that they wish to delete through registration amendments. TABLE 2.— END­ USE PRODUCT REGISTRATION AMENDMENT REQUESTS Company Registration No. Product Name: Use Deletions Dragon Chemical Corp. 16– 119 Dragon 5% Diazinon Granules: Celery 16– 157 Diazinon 25% Diazinon Spray: Almonds 16– 166 Dragon Diazinon Water­ Based Concentrate: Almonds Southern Agricultural Insecticides, Inc. 829– 264 SA– 50 Brand 5% Diazinon Granules: Celery Universal Cooperative, Inc. 1386– 599 Diazinon 4 EC (AG): Beans, cucumbers, parsley, parsnips, peas, peppers, potatoes (Irish), squash (summer and winter), sweet potatoes Swiss chard, turnips, lawn pest control, nuisance pests in outside areas, grassland insects, and indoor ornamentals 1386– 648 5% Diazinon Insect Killer Granules: Celery Knox Fertilizer Co. Inc. 8378– 32 Shaw's 5% Diazinon Insect Granules: Celery VerDate Sep< 04> 2002 18: 47 Sep 10, 2002 Jkt 197001 PO 00000 Frm 00025 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 11SEN1. SGM 11SEN1 57593 Federal Register / Vol. 67, No. 176 / Wednesday, September 11, 2002 / Notices Under section 6( f)( 1)( A) of FIFRA, registrants may request, at any time, that their pesticide registrations be amended to delete one or more pesticide uses. The afore mentioned companies have requested to amend their registrations and have requested that EPA waive the 180– day comment period. In light of this request, EPA is granting the request to waive the 180– day comment period and is providing a 30– day public comment period before taking action on the requested amendments to delete uses. Because of risk concerns posed by certain uses of diazinon, EPA intends to grant the requested amendments to delete uses at the close of the comment period for this announcement, unless the Agency receives any substantive comment within the comment period that would merit its further review of these requests. III. Proposed Existing Stocks Provisions EPA received requests for voluntary cancellation of the diazinon registrations identified in Table 1 and requests for amendments to terminate certain uses of the diazinon registrations identified in Table 2. Pursuant to section 6( f) of FIFRA, EPA intends to grant these requests by issuing a cancellation order at the end of the 30– day comment period unless the Agency receives any substantive comment within the comment period that would merit its further review of these requests. In the event that EPA issues a cancellation order, EPA intends to include in that order the existing stocks provisions set forth in this section. For purposes of that cancellation order, the term `` existing stocks'' will be defined, pursuant to EPA's existing stocks policy at 56 FR 29362, of June 26, 1991, as those stocks of a registered pesticide product which are currently in the United States and which have been packaged, labeled, and released for shipment prior to the effective date of the cancellation or amendment. Any distribution, sale, or use of existing stocks after the effective date of the cancellation order that the Agency intends to issue that is not consistent with the terms of that order will be considered a violation of section 12( a)( 2)( K) and/ or 12( a)( 1)( A) of FIFRA. EPA intends that the cancellation order includes the following existing stocks provisions: 1. Distribution or sale of products bearing instructions for use on agricultural crops. The distribution or sale of existing stocks by the registrant of any product listed in Table 1 or 2 that bears instructions for use on the agricultural crops identified in List 1 will not be lawful under FIFRA 1– year after the effective date of the cancellation order. Persons other than the registrant may continue to sell or distribute the existing stocks of any product listed in Table 1 or 2 that bears instructions for any of the agricultural uses identified in List 1 after the effective date of the cancellation order. However, it is lawful to ship such stocks for export consistent with the requirements of section 17 of FIFRA, or to properly dispose of the existing stocks in accordance with all applicable law. 2. Distribution or sale of products bearing instructions for use on outdoor non­ agricultural sites. The distribution or sale of existing stocks by the registrant of any product listed in Table 1 or 2 that bears instructions for use on outdoor non­ agricultural sites will not be lawful under FIFRA 1– year after the effective date of the cancellation order. Persons other than the registrant may continue to sell or distribute the existing stocks of any product listed in Table 1 or 2 that bears instructions for use on outdoor non­ agricultural sites after the effective date of the cancellation order. However, it is lawful to ship such stocks for export consistent with the requirements of section 17 of FIFRA, or to properly dispose of the existing stocks in accordance with all applicable law. 3. Distribution or sale of products bearing instructions for use on indoor sites. The distribution or sale of existing stocks by the registrant of any product listed in Table 1 or 2 that bears instructions for use at or on any indoor sites (except mushroom houses), shall not be lawful under FIFRA as of the effective date of the cancellation order, except for shipping stocks for export consistent with the requirements of section 17 of FIFRA, or properly disposing of the existing stocks in accordance with all applicable law. 4. Retail and other distribution or sale of existing stock of products for indoor use. The distribution or sale of existing stocks by any person other than the registrants of products listed in Table 1 or 2 bearing instructions for any indoor uses except mushroom houses will not be lawful under FIFRA after December 31, 2002, except for shipping stocks for export consistent with the requirements of section 17 of FIFRA, or properly disposing of the existing stocks in accordance with all applicable law. 5. Use of existing stocks. EPA intends to permit the use of existing stocks of products listed in Table 1 or 2 until such stocks are exhausted, provided such use is in accordance with the existing labeling of that product. List of Subjects Environmental protection, Pesticides and pests. Dated: August 29, 2002. Susan Lewis, Acting Director, Special Review and Reregistration Division, Office of Pesticide Programs. [FR Doc. 02– 22989 Filed 9– 10– 02; 8: 45 am] BILLING CODE 6560– 50– S ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0236; FRL– 7198– 1] Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: This notice announces the initial filing of a pesticide petition proposing the establishment of regulations for residues of a certain pesticide chemical in or on various food commodities. DATES: Comments, identified by docket ID number OPP– 2002– 0236 must be received on or before October 11, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. C. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0236 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By mail: Jim Tompkins, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 305– 5704; and e­ mail address: tompkins. jim@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does This Action Apply to Me? You may be affected by this action if you are an agricultural producer, food manufacturer or pesticide manufacturer. Potentially affected categories and entities may include, but are not limited to: VerDate Sep< 04> 2002 18: 47 Sep 10, 2002 Jkt 197001 PO 00000 Frm 00026 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 11SEN1. SGM 11SEN1

epa

2024-06-07T20:31:43.008485

regulations

EPA-HQ-OPP-2002-0202-0001

Notice

Lindane Reregistration Eligibility Decision (RED) Notice of Availability for Comment

59500 Federal Register / Vol. 67, No. 184 / Monday, September 23, 2002 / Notices establish a Spinning Reserve market for PJM and PJM West and new compensation rules. PJM amended its August 29, 2002 filing to include conforming amendments to both the PJM Tariff and Operating Agreement consistent with the proposed Spinning Reserve market and new compensation rules. PJM requests an effective date of December 1, 2002 for the amendments filed on August 29, 2002 and September 11, 2002. Copies of this filing were served upon all parties listed on the official service list in Docket No. ER02– 2519– 000, all PJM members, and each state electric utility regulatory commission in the PJM control area and PJM West region. Comment Date: October 2, 2002. 7. PJM Interconnection, L. L. C. [Docket No. ER02– 2547– 000] Take notice that on September 10, 2002 PJM Interconnection, L. L. C. (PJM), submitted for filing an executed interim interconnection service agreement between PJM and Dominion Equipment, Inc. and an executed interconnection service agreement between PJM and Fairless Energy, LLC. PJM requests a waiver of the Commission's 60­ day notice requirement to permit the effective dates agreed to by the parties. Copies of this filing were served upon each of the parties to the agreements and the state regulatory commissions within the PJM region. Comment Date: October 1, 2002. 8. New York Independent System Operator, Inc. [Docket No. ER02– 2548– 000] Take notice that on September 11, 2002, the New York Independent System Operator, Inc. (NYISO) filed revisions to its Market Administration and Control Area Services Tariff (Services Tariff) to provide further clarity and improve the administration of the Installed Capacity market in the New York Control Area. The NYISO has served a copy of this filing to all parties that have executed Service Agreements under the NYISO's Open­ Access Transmission Tariff or Services Tariff, the New York State Public Service Commission and to the electric utility regulatory agencies in New Jersey and Pennsylvania. Comment Date: October 2, 2002. 9. Occidental Power Services, Inc. [Docket No. ER02– 2549– 000] Take notice that on September 12, 2002, Occidental Power Services, Inc. (OPSI) tendered for filing a proposed amendment to the Western Systems Power Pool (WSPP). The proposed amendment reflects the admission of OPSI to membership in the WSPP. OPSI requests that the Commission authorize the proposed amendment to become effective on September 12, 2002. Comment Date: October 3, 2002. 10. Tenaska­ Oxy Power Services, L. P. [Docket No. ER02– 2550– 000] Take notice that on September 12, 2002, Tenaska­ Oxy Power Services, L. P., 1701 E. Lamar Boulevard, Suite 100, Arlington, TX 76006 (TOPS) submitted for filing with the Federal Energy Regulatory Commission an application for blanket authorization and certain waivers under regulations of the Commission, and for an order accepting its Rate Schedule FERC No. 1 to be effective the earlier of November 11, 2002, or the date of a Commission order granting approval of its Rate Schedule. TOPS intends to engage in electric power and energy transactions as a marketer and a broker. In transactions where TOPS purchases power, including capacity and related services from electric utilities, qualifying facilities, and independent power producers, and resells such power to other purchasers, TOPS will be functioning as a marketer. In TOPS' marketing transactions, TOPS proposes to charge rates mutually agreed upon by the parties. In transactions where TOPS does not take title to electric power and/ or energy, TOPS will be limited to the role of a broker and will charge a fee for its services. TOPS is not in the business of producing electric power nor does it contemplate acquiring title to any electric power transmission facilities. Comment Date: October 3, 2002. Standard Paragraph E. Any person desiring to intervene or to protest this filing should file with the Federal Energy Regulatory Commission, 888 First Street, NE., Washington, DC 20426, in accordance with Rules 211 and 214 of the Commission's rules of practice and procedure (18 CFR 385.211 and 385.214). Protests will be considered by the Commission in determining the appropriate action to be taken, but will not serve to make protestants parties to the proceeding. Any person wishing to become a party must file a motion to intervene. All such motions or protests should be filed on or before the comment date, and, to the extent applicable, must be served on the applicant and on any other person designated on the official service list. This filing is available for review at the Commission or may be viewed on the Commission's web site at http:// www. ferc. gov using the `` RIMS'' link, select `` Docket #'' and follow the instructions (call 202– 208– 2222 for assistance). Protests and interventions may be filed electronically via the Internet in lieu of paper; See 18 CFR 385.2001( a)( 1)( iii) and the instructions on the Commission's web site under the `` e­ Filing'' link. Magalie R. Salas, Secretary. [FR Doc. 02– 24040 Filed 9– 20– 02; 8: 45 am] BILLING CODE 6717– 01– P ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0202; FRL– 7273– 8] Lindane Reregistration Eligibility Decision (RED); Notice of Availability for Comment AGENCY: Environmental Protection Agency (EPA) ACTION: Notices. SUMMARY: This notice announces the availability of the Reregistration Eligibility Decision (RED) document and technical support documents for the pesticide active ingredient, lindane. These documents have been developed using a public participation process designed by the EPA and the U. S. Department of Agriculture (USDA) to involve the public in the reassessment of pesticide tolerances under the Food Quality Protection Act (FQPA) and the reregistration of individual pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). This notice starts a 60– day public comment period for lindane, during which the public is invited to submit comments on the Agency's risk management decision. DATES: Comments, identified by docket ID number OPP– 2002– 0202, must be received on or before November 22, 2002 ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0202 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: Mark Howard, Special Review and Reregistration Division (7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 308– 8172; fax VerDate Sep< 04> 2002 19: 13 Sep 20, 2002 Jkt 197001 PO 00000 Frm 00009 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 23SEN1. SGM 23SEN1 59501 Federal Register / Vol. 67, No. 184 / Monday, September 23, 2002 / Notices number: (703) 308– 8005; e­ mail address: howard. markt@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general, nevertheless, a wide range of stakeholders will be interested in obtaining the revised risk assessments and submitting risk management comments on lindane including environmental, human health, and agricultural advocates; the chemical industry; pesticide users; and members of the public interested in the use of pesticides on food. As such, the Agency has not attempted to specifically describe all the entities potentially affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and most other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations, '' `` Regulations and Proposed Rules, '' and then look up the entry for this document under the `` Federal Register —Environmental Documents. '' You can also go directly to the FEDERAL REGISTER listings at http:// www. epa. gov/ fedrgstr/. You can obtain copies of the RED and related documents discussed in this notice from EPA's Office of Pesticide Programs' Home Page, http:// www. epa. gov/ pesticides/ using the following links: `` Reregistration Eligibility (REDs) '' under the heading `` Reregistration and Special Review'' and then `` Lindane. '' You can also go directly to the `` Lindane RED'' at http:/ /www. epa. gov/ pesticides/ reregistration/ status. htm. Available documents include the RED, supporting technical documents, and FEDERAL REGISTER notices. Information on pesticide reregistration and tolerance reassessment, including the purpose and status of Agency programs to complete REDs, Interim REDs, and tolerance reassessment decisions (TREDs), is available at http:// www. epa. gov/ pesticides/ tolerance. General information is available on the Office of Pesticide Programs' Home Page, http:// www. epa. gov/ pesticides/. 2. In person. The Agency has established an official record for this action under docket ID number OPP– 2002– 0202. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period, is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. C. How and to Whom Do I Submit Comments? You may submit comments on any part of the RED through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0202 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460. 2. In person or by courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Information Resources and Services Division (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA. The PIRIB is open from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. 3. Electronically. You may submit your comments electronically by e­ mail to: opp­ docket@ epa. gov, or you can submit a computer disk as described above. Do not submit any information electronically that you consider to be CBI. Avoid the use of special characters and any form of encryption. Electronic submissions will be accepted in WordPerfect 6.1/ 8.0/ 9.0 or ASCII file format. All comments in electronic form must be identified by docket ID number OPP– 2002– 0202. Electronic comments may also be filed online at many Federal Depository Libraries. D. How Should I Handle CBI that I Want to Submit to the Agency? Do not submit any information electronically that you consider to be CBI. You may claim information that you submit to EPA in response to this document as CBI by marking any part or all of that information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. In addition to one complete version of the comment that includes any information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public version of the official record. Information not marked confidential will be included in the public version of the official record without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed under FOR FURTHER INFORMATION CONTACT. E. What Should I Consider as I Prepare My Comments for EPA? You may find the following suggestions helpful for preparing your comments: 1. Explain your views as clearly as possible. 2. Describe any assumptions that you used. 3. Provide copies of any technical information and/ or data you used that support your views. 4. If you estimate potential burden or costs, explain how you arrived at the estimate that you provide. 5. Provide specific examples to illustrate your concerns. 6. Offer alternative ways to improve the notice or collection activity. 7. Make sure to submit your comments by the deadline in this notice. 8. To ensure proper receipt by EPA, be sure to identify the docket ID number assigned to this action in the subject line on the first page of your response. You may also provide the name, date, and Federal Register citation. II. Background A. What Action is the Agency Taking? The Agency has issued a RED for the pesticide active ingredient lindane. Under FIFRA, as amended in 1988 and 1996, EPA is conducting an accelerated reregistration program to re­ evaluate existing pesticides to make sure they VerDate Sep< 04> 2002 19: 13 Sep 20, 2002 Jkt 197001 PO 00000 Frm 00010 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 23SEN1. SGM 23SEN1 59502 Federal Register / Vol. 67, No. 184 / Monday, September 23, 2002 / Notices meet current scientific and regulatory standards. The data base to support the reregistration of lindane is substantially complete, and the Agency has identified risk mitigation measures that, if adopted by the registrant, will address the human health and ecological risks associated with the remaining uses of lindane. As part of the lindane RED, the Agency will revoke all existing lindane tolerances because all lindane products for which the tolerances were originally established have been cancelled. The Agency has also determined that the currently registered lindane seed treatment products would be eligible for reregistration if the registrants make the changes to the terms and conditions specified in the lindane RED and provide the required data, and if EPA is able to establish all required tolerances for residues of lindane in food. The RED document includes guidance and time frames for complying with any label changes for products containing lindane. The reregistration program is being conducted under Congressionally mandated time frames, and EPA recognizes both the need to make timely reregistration decisions and to involve the public. Therefore, EPA is issuing the lindane RED as a final document with a 60­ day public comment period. Although the 60­ day comment period does not affect the registrants's response due date, it is intended to provide an opportunity for public input and a mechanism for initiating any necessary amendments to the RED. All comments will be carefully considered by the Agency. If any comment significantly affects the lindane RED, EPA will amend the RED by publishing the amendment in the Federal Register. B. What is the Agency's Authority for Taking this Action? The legal authority for these RED falls under FIFRA, as amended in 1988 and 1996. Section 4( g)( 2)( A) of FIFRA directs that, after submission of all data concerning a pesticide active ingredient,`` the Administrator shall determine whether pesticides containing such active ingredient are eligible for reregistration. '' List of Subjects Environmental protection, Lindane, Pesticides and pests. Dated: September 13, 2002. Lois Ann Rossi, Director, Special Review and Reregistration Division, Office of Pesticide Programs. [FR Doc. 02– 24096 Filed 9– 20– 02; 8: 45 am] BILLING CODE 6560– 50– S ENVIRONMENTAL PROTECTION AGENCY [OPP– 2002– 0252; FRL– 7200– 9] Thiabendazole and Salts; Availability of Reregistration Eligibility Decision Documents for Comment AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: This notice announces availability and starts a 60– day public comment period on the Reregistration Eligibility Decision (RED) documents for the pesticide active ingredients thiabendazole and salts. The RED represents EPA's formal regulatory assessment of the health and environmental data base of the subject chemical and presents the Agency's determination regarding which pesticidal uses are eligible for reregistration. DATES: Comments, identified by docket ID number OPP– 2002– 0252, must be received on or before November 22, 2002. ADDRESSES: Comments may be submitted by mail, electronically, or in person. Please follow the detailed instructions for each method as provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0252 in the subject line on the first page of your response. FOR FURTHER INFORMATION CONTACT: By mail: Lorilyn Montford, Special Review and Reregistration Division (7508C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (703) 308– 8170; e­ mail address: montford. lorilyn@ epa. gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this Action Apply to Me? This action is directed to the public in general. This action may, however, be of interest to persons who are or may be required to conduct testing of chemical substances under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) or the Federal Food, Drug, and Cosmetic Act (FFDCA); environmental, human health, and agricultural advocates; pesticides users; and members of the public interested in the use of pesticides. Since other entities may also be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. If you have any questions regarding the applicability of this action to a particular entity, consult the person listed under FOR FURTHER INFORMATION CONTACT. B. How Can I Get Additional Information, Including Copies of this Document and Other Related Documents? 1. Electronically. You may obtain electronic copies of this document, and certain other related documents that might be available electronically, from the EPA Internet Home Page at http:// www. epa. gov/. To access this document, on the Home Page select `` Laws and Regulations, '' `` Regulations and Proposed Rules, '' and then look up the entry for this document under the `` Federal Register— Environmental Documents. '' You can also go directly to the Federal Register listings at http:// www. epa. gov/ fedrgstr/. To access RED documents and RED fact sheets electronically, go directly to the REDs table on the EPA Office of Pesticide Programs Home Page, at http:/ /www. epa. gov/ pesticides/ reregistration/ status. htm. 2. In person. The Agency has established an official record for this action under docket ID number OPP– 2002– 0252. The official record consists of the documents specifically referenced in this action, and other information related to this action, including any information claimed as Confidential Business Information (CBI). This official record includes the documents that are physically located in the docket, as well as the documents that are referenced in those documents. The public version of the official record does not include any information claimed as CBI. The public version of the official record, which includes printed, paper versions of any electronic comments submitted during an applicable comment period is available for inspection in the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, from 8: 30 a. m. to 4 p. m., Monday through Friday, excluding legal holidays. The PIRIB telephone number is (703) 305– 5805. C. How and to Whom Do I Submit Comments? You may submit comments through the mail, in person, or electronically. To ensure proper receipt by EPA, it is imperative that you identify docket ID number OPP– 2002– 0252 in the subject line on the first page of your response. 1. By mail. Submit your comments to: Public Information and Records Integrity Branch (PIRIB), Information VerDate Sep< 04> 2002 19: 13 Sep 20, 2002 Jkt 197001 PO 00000 Frm 00011 Fmt 4703 Sfmt 4703 E:\ FR\ FM\ 23SEN1. SGM 23SEN1

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2024-06-07T20:31:43.017574

regulations

EPA-HQ-OPP-2002-0202-0002

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES July 31, 2002 MEMORANDUM SUBJECT: Revised HED Risk Assessment for Lindane. DP Barcode D284581 Reregistration Case # 0315; PC code 009001 FROM: Becky Daiss, Environmental Health Scientist Reregistration Branch 4 Health Effects Division (7509C) THRU: Susan V. Hummel, Branch Senior Scientist Reregistration Branch 4 Health Effects Division (7509C) TO: Mark T Howard, Chemical Review Manager Reregistration Branch 3 Special Review & Reregistration Division (7508C) Attached is HED's revised risk assessment of the insecticide, lindane for purposes of issuing a Reregistration Eligibility Decision (RED) Document for this active ingredient. This document revises the June 13, 2002 version of the risk assessment to incorporate changes to the residue chemistry and occupational exposure sections based on updated information. It also includes technical corrections to the documentation for the worker exporsure assessment. This assessment incorporates information from the toxicology assessment conducted by Suhair Shallal, the residue chemistry and dietary exposure and risk assessments conducted by Thurston Morton, and the occupational and residential exposure assessment conducted by Dave Jaquith. The disciplinary science chapters and other supporting documents have also been revised in response to public comment where necessary and are included as appendices as follows: Revised Report of the Hazard Identification Assessment Review Committee. Suhair Shallal (6/ 18/ 01, 014595) Report of the FQPA Safety Factor Committee. Brenda Tarplee (8/ 2/ 00; 014272) Revised Product and Residue Chemistry Chapter. Thurston Morton (12/ 11/ 01, D279259) Toxicology Chapter. Suhair Shallal (9/ 28/ 00, D269338) Occupational and Residential Exposure Assessment. David Jaquith (6/ 4/ 02, D283397, 4/ 23/ 02, D282419, 4/ 24/ 02, D282418) Revised Dietary Exposure and Risk Estimates for Reregistration. Thurston Morton (12/ 13/ 01, D279260) Dietary Risk and Exposure Estimate for Lindane through Subsistence Diets for Indigenous People of Alaska. Thurston Morton (4/ 17/ 02, D282455) Environmental Fate and Effects Chapter. Nicholas Federoff (12/ 20/ 01, D254764; 5/ 20/ 02, D281832) 2 Table of Contents I. EXECUTIVESUMMARY .............................................. 1A UseandMajorFormulations .......................................... 1B RegulatoryHistory .................................................. 1C HazardIdentificationandDose­ ResponseAssessment ..................... 2D ExposureAssessment ................................................ 4E RiskAssessment/ Characterization ...................................... 6II PhysicalandChemicalProperties ......................................... 9III Hazard assessment .................................................... 9A ToxicologyAssessment............................................... 9B DoseResponseAssessment ........................................... 14i DeterminationofSusceptibility..................................... 14ii CancerClassification............................................ 15iii Toxicology Endpoint Selection .................................... 15iv EndocrineDisruptorEffects ...................................... 19v IncidentReports ................................................ 19IV ExposureandRiskAssessment ......................................... 20A DietaryExposure( FoodSources)...................................... 20i Background..................................................... 20ii SourcesofLindaneResiduesonFoods............................... 22iii Residue Chemistry Studies for Lindane ............................. 22B DietaryExposureEstimates .......................................... 27C DietaryRiskEstimates( FoodSources)................................. 29i AcuteDietaryExposureandRiskEstimates .......................... 29ii ChronicDietaryExposureandRiskEstimates ........................ 29iii Chronic Dietary Exposure and Risk Estimates for Indigenous People ..... 30iv CancerDietaryExposureandRiskEstimates ........................ 30D UncertaintiesinDietaryExposureAssessment ............................. 30E DrinkingWaterExposure ........................................... 31i MonitoringData ................................................ 32ii GroundWater ................................................. 32iii Surface Water ................................................. 33iv DrinkingWaterEstimatedEnvironmentalconcentrations .............. 33F DrinkingWaterRiskEstimates....................................... 34i DWLOCsforChronicExposure .................................... 34ii DWLOCforAcuteExposure...................................... 35iii Non­ Dietary Exposure ........................................... ­36­ 3 G. OccupationalExposureandRiskEstimates ............................. 36i CommercialSeedTreatment....................................... 37ii OnFarmSeedTreatment......................................... 38iiiOccupationalExposureandRisk ................................... 38V AggregateandCumulativeExposureandRiskCharacterization............... 40A AcuteAggregateRisk............................................... 41B Short­ andIntermediate­ TermAggregateRisk........................... 41C ChronicAggregateRisk ............................................. 41D CumulativeExposureandRisk ....................................... 42VI RiskCharacterization................................................. 43VII DataNeeds ........................................................ 46A ToxicologyDataRequirements ....................................... 46B Product andResidueChemistryDataRequirements ...................... ­47­ 1 I. EXECUTIVE SUMMARY A. Use and Major Formulations Lindane (gamma isomer of hexachlorocyclohexane, ­HCH) is a broad­ spectrum organochlorine insecticide/ acaricide which has been used on a wide range of soil­ dwelling and plant­ eating (phytophagous) insects. Worldwide, it is commonly used on a wide variety of crops, in warehouses, in public health to control insect­ borne diseases, and (with fungicides) as a seed treatment. Lindane is also presently used in lotions, creams, and shampoos for the control of lice and mites (scabies) in humans; these pharmaceutical uses are regulated by FDA. In the U. S., the only registered food/ feed use is seed treatment for field and vegetable crops. Lindane may be found in formulations with a host of fungicides and insecticides. Labels for products containing it must bear the Signal Word WARNING. Some formulations of lindane are classified as Restricted Use Pesticides (RUP), and as such may only be purchased and used by certified pesticide applicators. Lindane is no longer manufactured in the U. S. According to a REFS search, conducted on 5/ 29/ 01, there are approximately 34 federally registered end­ use products (EPs) containing lindane as the active ingredient and three Section 24 C registrations. Lindane end­ use products are formulated as dust (D), wettable powder (WP), emulsifiable concentrate (EC), flowable concentrate (FlC), and ready­ to­ use (RTU) solution. The reregistration of lindane is being supported by Centre International d'Etudes du Lindane (CIEL) and its member company holding U. S. registrations, Inquinosa, S. A. Currently, Inquinosa does not have any registered lindane end­ use products. In 1993, CIEL offered to voluntarily cancel all crop uses of lindane except seed treatment and certain non­ food uses. The Agency considers lindane seed treatment as a food use requiring tolerances based on existing data from radiolabeled studies indicating uptake of residues from the treated seeds into the aerial portion of the growing crop. B. Regulatory History Lindane is a List A reregistration pesticide. A Reregistration Standard for Lindane was issued 9/ 85. The Residue Chemistry Chapter to the Reregistration Standard was issued on 6/ 7/ 85, an addendum on 9/ 5/ 85, and an Update on 1/ 31/ 91. The Reregistration Standard along with its Science Chapters summarized the available data for each residue chemistry guideline and specified what additional data are required for reregistration purposes. Data Call­ In (DCI) Notices for lindane were issued by the Agency on 9/ 30/ 91, 3/ 3/ 95, 10/ 13/ 95, and 3/ 31/ 97. The information contained in this document outlines the current Residue Chemistry Science Assessments with respect to supporting seed treatment uses of lindane, as well as the reregistration of the pesticide. In 1983, EPA concluded a major Special Review effort of lindane based on carcinogenicity, fetotoxicity/ teratogenicity, reproductive effects, and acute effects on aquatic 2 organisms. This effort resulted in the cancellation of indoor uses of smoke fumigation devices and greatly limited the use of pet dips on dogs. In addition, there were uses that were allowed to continue only if certain imposed restrictions were implemented. The restrictions were based on the degree of associated hazards, and included changes in warning labels, the wearing of protective clothing, and restrictions to limit uses to certified pest control operators. In 1995, EPA announced (FR Vol. 60, No. 143, 38329­ 38331, 7/ 26/ 95) its decision not to initiate a Special Review of lindane based on worker health concerns arising from studies showing irreversible renal effects in the rat. The Agency has determined that these effects occur only in the kidneys of male rat and are not relevant for human risk assessment. Tolerances are currently established under 40 CFR §180.133 for residues of lindane per se in/ on various raw agricultural commodities at 0.01 ppm (pecans) to 3 ppm (cucumbers, lettuce, melons, mushrooms, pumpkins, squash, summer squash, and tomatoes). Lindane tolerances are also established at 4 ppm in the fat of meat from hogs and at 7 ppm in the fat of meat from cattle, goats, horses, and sheep. No tolerances have been established for processed food/ feed commodities. Adequate methods are available for the enforcement of tolerances for residues of lindane per se in/ on plant and animal commodities. The only food/ feed use of lindane which is being supported for reregistration is seed treatment on cereal grains (excluding rice and wild rice). Seed treatment uses on broccoli, Brussels sprouts, cabbage, cauliflower, lettuce, radishes, and spinach are no longer being supported for reregistration by Inquinosa. In addition, the established tolerances for the following commodities will be revoked because no registrants have committed to support the foreign or domestic uses for: apples, apricots, asparagus, avocados, celery, cherry, collards, cucumbers, eggplants, grapes, guavas, kale, kohlrabi, mangoes, melons, mushrooms, mustard greens, nectarines, okra, onions (dry bulb only), peaches, pears, pecans, peppers, pineapple, plums (fresh prunes), pumpkins, quinces, squash, strawberries, summer squash, swiss chard and tomatoes. C. Hazard Identification and Dose­ Response Assessment The toxicology database for lindane is complete with respect to the OPPTS Guideline requirements. In acute toxicity studies, lindane is a moderately toxic compound, EPA toxicity class II. It is neither an eye irritant nor dermal sensitizer. The toxicity endpoints used in this document to assess hazards include acute dietary and chronic dietary reference doses (RfDs), and short­, intermediate­ and long­ term dermal and inhalation no observable adverse affect levels (NOAELs). In light of the developing Agency policy on use of toxicology studies employing human subjects, HED selected doses and endpoints for risk assessment based solely on animal studies. The primary effect of lindane is on the nervous system; in acute, subchronic, and developmental neurotoxicity studies and chronic toxicity/ oncogenicity studies, lindane appears to 3 cause neurotoxic effects including tremors, convulsions and hypersensitivity to touch. This is further corroborated by the published literature in which human exposure has been seen to produce neurologic effects. Lindane also causes renal and hepatic toxicity via the oral, dermal and inhalation routes of exposure as seen in subchronic, 2­ generation reproduction and chronic toxicity studies in the rat, as well as in studies in the open literature (S. Shallal, D274510). In developmental toxicity studies, developmental effects were only seen at levels where maternal toxicity was also evident. In the rat developmental study, the developmental effects (extra rib and total skeletal variations) were seen at dose levels (20 mg/ kg/ day) greater than maternal toxicity (10 mg/ kg/ day). In the reproductive toxicity study, both systemic and developmental LOAELs are 13 mg/ kg; however a qualitative difference in maternal and offspring effects (reduced body weight of maternal animals and reduced viability and delayed maturation in pups) indicates an increased susceptibility to exposure. This is further corroborated by a developmental neurotoxicity study in which a qualitative and quantitative increase in susceptibility is seen. At the high dose (13.7 mg/ kg/ day) , animals in the F0 generation have a reduced body weight and body weight gain while at the mid­ dose (5.6 mg/ kg/ day), F1 animals have a reduced survival rate, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation as compared to controls. The OPP/ Cancer Assessment Review Committee (CARC) has completed the review of newly submitted carcinogenicity study in CD­ 1 mice along with other data. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC has classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on an increased incidence of benign lung tumors in female mice only. The Committee, therefore, recommended that the quantification of human cancer risk is not required. (S. Diwan, 11/ 29/ 01, TXR NO. 0050297) The International Programme on Chemical Safety (IPCS, 1991) states that lindane does not appear to have mutagenic potential. The available mutagenicity studies are negative; they include a dominant lethal mutation assay, sister chromatid exchange assay and mammalian cell culture gene mutation in V79 cells. However, these studies have been classified as unacceptable by EPA. The Food Quality Protection Act (FQPA) Safety Factor Committee evaluated the hazard and exposure data to determine if the 10x safety factor should be retained. The Committee recommended that the FQPA safety factor be reduced to 3X due to the following considerations: 1) the toxicology data base is complete; 2) the available data provide no indication of quantitative or qualitative increased susceptibility in rats from in utero exposure to lindane in the prenatal developmental study; 3) the offspring effects seen in the developmental neurotoxicity study were the same as those seen in the two­ generation reproduction study (no additional functional or morphological hazards to the nervous system were noted); 4) adequate actual data, surrogate data, and/ or modeling outputs are available to satisfactorily assess food exposure and to provide a screening level drinking water exposure assessment; 5) although the developmental 4 toxicity study in rabbits was classified unacceptable, the HIARC concluded that a new study is not required; and 6) there are currently no residential uses. A new developmental study is not required because: a) the developmental toxicity study in rabbits and rats using a subcutaneous route of administration shows no developmental effects at the maternally toxic dose; b) the skeletal effects observed in the developmental toxicity study in rats, with gavage as the route of administration, are within historical controls; c) more severe maternal effects are seen in the rabbit study with subcutaneous administration; d) the rat appears to be the more sensitive species for developmental effects; and e) a developmental neurotoxicity study has already been submitted. D. Exposure Assessment The HED Metabolism Assessment Review Committee (MARC) concluded that the total radioactive residues (TRRs) should be used for risk assessment purposes and calculation of dietary burdens, pending receipt of additional metabolism data (T. Morton, 8/ 30/ 00, D267069). The ChemSAC recommended comparing the results from the dietary analysis using the TRRs with the results from a dietary analysis based on feeding studies. Exposure to lindane was determined by using the ratio (ppm TRR/ ppm lindane parent). The results from the dietary analysis using the feeding study results and adjusting the lindane residues by the above ratio are summarized in this assessment. The Biological and Economic Analysis Division (OPP/ BEAD) verified the registrant's percent market share estimate for lindane (I. Yusuf email, 7/ 17/ 00). A canola processing study for lindane was recently reviewed (T. Morton, D269388, 5/ 10/ 01). Lindane was not detected in bleached/ deodorized canola oil (< 0.005 ppm). Therefore, ½ LOQ (0. 0025 ppm) was used as the residue estimate in DEEM and the DEEM™ adjustment factor was set to 1. DEEM™ default concentration factors (adjustment factor 1) were used for all other commodities. The Indigenous Peoples of the Arctic region of the U. S. (Alaska) rely heavily on subsistence diets as their food source. Therefore, it is considered appropriate for the Agency to perform a supplementary dietary risk and exposure assessment to assess the risk to the Indigenous People from worldwide use and manufacture of lindane. The dietary risk assessment for Indigenous People of Alaska for Lindane has been revised to incorporate new information pertaining to subsistence meat intake by children. (T. Morton, D282455, 4/ 17/ 02). Using the limited data available, we have extrapolated from this information and knowledge of the standard diet of the indigenous people of Alaska to arrive at a conservative estimate. The data used in this assessment is based on actual residues found in animal tissues in conjunction with typical subsistence diet consumption rates. Because factors such as bioaccumulation of lindane and the cumulative effects of combinations of chemicals which act through a common mode of action have not been incorporated into this assessment, it is therefore difficult to know the full range of residue to which indigenous populations may be exposed. Lindane does not occur naturally in the environment. Once released it can partition into all environmental media. Lindane has been detected in air, surface water, groundwater, sediment, soil, ice, snowpack, fish and other aquatic organisms, wildlife, and humans. Lindane has been 5 found in pristine environments; the pathway for contamination is varied and complex depending on atmospheric and oceanic circulation, gas/ particle partitioning, and solubility of the substance and the food chain. Monitoring data has shown that Lindane is detectable across the entire North American continent, from Washington D. C., Denver, Colorado, and the Niagra River water samples to air samples over the Adirondack Mountains in New York, Newport News, Virginia and Ontario, Canada, as well as, soil samples from around the Great Lakes and the Gulf of Mexico. The Environmental Fate and Effects Division (EFED) evaluated the potential for lindane to contaminate water. The presence of lindane in the environment, due to previous widespread agricultural use, is well documented in U. S. data bases. For example, In the U. S. EPA STORET data base, 720 detections in ground water were reported between the years 1968 and 1995, in nearly all regions of the country, with especially high numbers of detections in the South and West. For these 720 detections, the median and mean concentrations were 0.01 and 11 µg/ L, respectively. For surface waters, 8775 detections were reported with median and mean concentrations of 0.005 and 0. 18 µg/ L. STORET Detections were reported in nearly all regions of the conterminous U. S. In the USGS NAWQA study, lindane was detected in 2.58% of surface water samples (0. 67% at levels greater than 0.05 µ g/ L, maximum concentration reported was 0. 13 µ g/ L). For groundwater, USGS NAWQA reported a detection frequency of 0. 1 % (0. 07% at levels greater than 0.01 µ g/ L, maximum concentration reported was 0.032 µ g/ L). EFED models were used to calculate estimated environmental concentrations (EECs) in drinking water from surface water and groundwater contaminated with lindane as a result of seed treatment uses. Wheat and canola, which have the highest application rate in terms of lbs a. i per acre were used as the model crop scenarios. The Screening Concentration in Ground Water (SCI­ GROW) model was used to estimate concentrations of lindane in groundwater. The screening model, FQPA Index Reservoir Screening Tool (FIRST), was used to estimate surface water concentrations. Occupational exposure scenarios can be described as short term (1­ 7 days), intermediate term (7 days to several months), and long term or chronic (several months to a lifetime). All of the lindane exposure scenarios are appropriately described as short and intermediate term. HED has determined that there are potential exposures to mixers, loaders, applicators, or other handlers during usual use­ patterns associated with lindane. Based on the use patterns and potential exposures described above, 6 major exposure scenarios were identified to represent the extent of lindane uses: (1) on­ farm seed treatment with dry formulation­ open system, (2) on­ farm seed treatment with liquid formulation ­ closed system, (3) mixing/ loading and applying liquid with commercial seed­ treatment equipment, (4) bagging and otherwise handling treated seeds, (5) cleaning/ maintaining seed treatment equipment, and (6) loading/ planting treated seeds. Worker exposure data for lindane were required since one or more toxicological criteria had been triggered. Requirements for applicator exposure studies are addressed by Series 875 Group A (formerly Subdivision U of the Pesticide Assessment Guidelines). Three lindane specific 6 exposure studies have been used to estimate exposure, one addressing on­ farm treatment, one addressing commercial seed treatment, and one addressing planting of treated seed. E. Risk Assessment/ Characterization Dietary (food source)­ Anticipated residues were provided for all commodities and used when calculating the dietary risk associated with lindane for the RED (DP Barcode D279260, T. Morton, 12/ 13/ 01). Although the database for lindane is substantially complete, additional data are needed to eliminate the uncertainties associated with the exposure/ risk assessment. The anticipated residue values are the best estimates HED can provide using the residue data available at this time. These values have an inherent uncertainty associated with variations in analytical methods, geographical representation of field trials, seasonal variation of residue levels, use of TRR from metabolism studies, etc. The acute dietary exposure analysis was a tier 3 probabilistic assessment. In both acute and chronic risk assessments, exposure was compared to a population adjusted dose, (PAD), which is the reference dose (RfD) reflecting application of the FQPA 3X safety factor. HED considers dietary residue contributions greater than 100% of the PAD to be of concern. The dietary assessment was conducted using percent crop treated (% CT) and total radioactive residues (TRRs) from plant metabolism studies and from poultry and ruminant metabolism studies. A second dietary assessment was conducted which incorporated data generated from poultry and ruminant feeding studies which provided lindane only residue values. In this assessment, an average lindane only residue value was calculated from three dose levels and multiplied by the ratio of TRR: lindane derived from the corresponding poultry or ruminant metabolism studies. (Average lindane residue from feeding study X TRR from metabolism study/ lindane residue from metabolism study). The following assessments yielded higher percent aPAD and cPAD values which were used to calculate drinking water levels of comparison (DWLOCs). Acute Dietary (Food). The acute dietary analysis for lindane was conducted using the Dietary Exposure Evaluation Model (DEEM™) software. Results are reported as a percentage of the acute Population Adjusted Dose (aPAD) for the 99.9 th percentile of the population. Estimated acute dietary exposure is below HED's level of concern for all population subgroups at the 99.9 th percentile. The maximum dietary risk estimate is 17 % of the acute PAD (% aPAD) for the population subgroup all infants and 7 % of the aPAD for the U. S. Population when the feeding studies were adjusted using the metabolism studies. Chronic Dietary (Food). The chronic dietary analysis for lindane was conducted using the DEEM™ software. Results are reported as a percentage of the chronic Population Adjusted Dose (cPAD). Estimated chronic dietary risk is below HED's level of concern. The resulting risk estimates are 3 % of the chronic PAD (% cPAD) for the U. S. population and 11 % of the cPAD for children 1­ 6 years of age (the most highly exposed population subgroup. The remaining 7 population subgroups were <6 % of the cPAD when the feeding studies were adjusted using the metabolism studies. Acute Drinking Water. Acute DWLOCs were calculated based on the acute dietary exposure and default body weights and water consumption figures. The EECs for surface water and the EECs for groundwater were less than the acute DWLOCs for all sub­ populations indicating that acute aggregate exposure to lindane in food and water is less than HED's level of concern. Chronic Drinking Water. Chronic DWLOCs were calculated based on the chronic dietary (food) exposure and default body weights and water consumption figures. The EECs for surface water and groundwater were less than the chronic DWLOCs, indicating that chronic exposure to lindane in food and water is less than HED's level of concern. Special Populations. The Indigenous Peoples of the Arctic region of the U. S. (Alaska) rely heavily on subsistence diets as their food source. Therefore, HED performed a revised supplementary chronic dietary risk and exposure assessment to assess the risk to Indigenous People from worldwide use and manufacture of lindane (T. Morton, D282455, 4/ 17/ 02). Because the annual harvest rates were divided by 365 to obtain daily harvest rates, and the daily intake rates were used in the assessment, no acute dietary exposure analysis was conducted. The chronic dietary exposure analysis used subsistence food harvest amounts and total HCH residues in traditional foods, and adjusted the HCH exposure to obtain lindane exposure. To estimate subsistence food intake rates, EPA used data from the Alaska Department of Fish and Game Division of Subsistence data base. This data base provides subsistence food harvest amounts for nearly 180 Alaskan communities from 1990­ 2001. Since marine mammals represents the largest portion of the subsistence harvest, HED used the community with the highest representative seal harvest, the community with the highest walrus harvest, and the community with the highest whale harvest to estimate subsistence intake rates. Other subsistence food sources (e. g., land mammals, other marine mammals, fish, and birds) from the corresponding Alaskan community were also included in estimating subsistence intake. The combined subsistence food source exposures from Community 1 (the community with highest total intake of the three communities) amounts to 0.282065 mg/ day HCH. Adjusting total HCH to obtain lindane only exposure yields a lindane exposure for Community 1 of 0. 04231 mg/ day. (Total HCH is adjusted by factors of 0. 15 and 0.03 since lindane represents between 3 and 15% of total HCH residues). Based on revised exposure estimates and assuming a male adult body weight of 70 kg, the chronic dietary risk to adult male Indigenous People ranges from 0.000055 ­ 0. 0006 mg/ kg body weight/ day which is between 3 and 38 % of the cPAD. This is below HED's level of concern (cPAD = 0. 0016 mg/ kg bw/ day). The revised estimate of chronic dietary risk to adult female Indigenous People (body weight of 60 kg) ranges from 0.000064 0.0007 mg/ kg bw/ day or from 4 to 44 % of the cPAD, also below HED's level of concern. Assuming a child body weight of 10 kg and adjusting adult intake by a factor of 0.53 to account for adult versus child subsistence meat intake, the revised lindane dietary risk estimates for 8 children 1­ 6 years from subsistence food consumption range from 0.0002 ­ 0. 0022 mg/ kg bw/ day or from 13 to 138% of the cPAD. For children 7­ 12 years old, the lindane residue amount was divided by 29 kg (7­ 12 year body weight) to obtain the % cPAD from subsistence foods. The resulting range of lindane dietary risk estimates from subsistence food consumption for children 712 is 4 to 48% of the cPAD, which is below HED's level of concern. Residential Risk Estimates. No residential exposure scenarios have been identified for pesticide uses of lindane and therefore no risk estimates will be presented in this document for non­ occupational exposure to lindane. Occupational Risk Estimates. The Agency has refined occupational estimates using the toxicological endpoints chosen by OPP's Hazard Identification Assessment Committee (HIARC) and two recent worker exposure studies, one on commercial seed treatment and one on handling and planting of treated seeds, and The FQPA uncertainty factor of 3X is not applicable to occupational risk assessments. Resulting risk estimates are reported as Margins of Exposure (MOEs), and compared to the target MOE, which is 100 for all lindane occupational exposure scenarios. The Agency has determined that there are potential exposures to mixers, loaders, applicators, or other handlers during usual use­ patterns associated with lindane. The exposure scenario descriptions based on the use pattern of lindane are presented in Table 12. The daily exposures, as well as the resulting short and intermediate term MOEs are presented in Table 13. Short and intermediate (if applicable) term MOEs were calculated for dermal and inhalation exposure routes for a total of 6 worker exposure scenarios. The analysis indicates MOEs of concern (MOE< 100) for the following exposure scenarios/ pathways: dermal exposure from on farm seed treatment; inhalation exposure from commercial treatment (mixing/ loading/ application) of canola seed at both high and low­ end rates of 1. 5 and 0. 75 lb/ 100 lb seed; and inhalation exposure from commercial handling of canola seed treated at the high­ end application rate of 1. 5 lb/ 100 lb seed. All other exposure scenarios result in MOEs that are not of concern for either dermal or inhalation exposure pathways. Dermal MOEs for all scenarios range between 9 and 119000. Inhalation MOEs range from 30 to 16000. Aggregate Exposure and Risk. The Agency considered aggregate exposure and risk estimates for residents who might be exposed to lindane from multiple sources, such as residential use, food, and water. Since no residential exposure is expected, an aggregate risk estimate was not calculated. 9 Cl Cl Cl Cl Cl Cl II. Physical and Chemical Properties The chemical structure and physical properties of Lindane are given below. Empirical Formula: C6 H6 Cl6 Molecular Weight: 290.9 CAS Registry No.: 58­ 89­ 9 PC Code: 009001 Lindane is a white crystalline solid with a melting point of 112­ 113
C, specific gravity of 1.85, octanol/ water partition coefficient (Kow ) of 3135, and vapor pressure of 9.4 x 10 ­6 mm Hg at 20 C. Lindane is slightly soluble in water (10 ppm at 20 C) and in most organic solvents, including acetone and aromatic and chlorinated hydrocarbons. Lindane is only slightly soluble in mineral oils. Lindane is stable to light, heat, air, and strong acids, but decomposes in alkali solutions to trichlorobenzenes and HCl. Fate studies show that lindane is both moderately mobile (mean Koc = 1368) and highly persistent (soil half life of 2. 6 years). It is resistant to photolysis and hydrolysis (except at high pH), and degrades very slowly by microbial actions. Degradates are predominantly pentachlorocyclohexane, 1,2,4,­ trichlorobenzene, and 1, 2, 3­ trichlorobenzene. Also, lindane can possibly transform to the alpha and beta isomers of hexachlorocyclohexane by biological and phototransformation, although this issue remains to be conclusively resolved. Metabolites are not quantified since they comprise less than 10% of the total residue; they are also found in rat metabolism studies and have therefore been indirectly evaluated for their toxicologic effects. III. Hazard assessment A. Toxicology Assessment Based on available information to date, the Agency has determined that the adverse effects of primary concern for lindane are those related to neurotoxicity. Organochlorine pesticides, such as lindane, are known to cause delayed neurotoxic effects. Symptoms include a number of clinical signs and symptoms, including headaches, dizziness, nausea, vomiting, diarrhea and increased urination, blurred vision, labored breathing, muscle paralysis, slow heart rate, respiratory depression, convulsions, coma and even death. Numerous toxicological studies using laboratory animals are available addressing most of these toxicological endpoints for lindane. In acute, subchronic and developmental neurotoxicity studies, it was found to cause neurotoxic effects including tremors, convulsions, decreased motor activity, increased 10 forelimb grip strength, hypersensitivity to touch, hunched posture and decreased motor activity habituation. There also appears to be a greater susceptibility to exposure by offspring compared to parental animals in the developmental neurotoxicity study. Lindane has also been implicated as a possible endocrine disruptor in birds, mammals and possibly fish. Further studies to ascertain the validity of such evidence is necessary to make informed risk assessment decisions. Lindane is distributed to all organs at measurable concentrations within a few hours after oral administration. The highest concentrations are found in adipose tissue. The metabolism of lindane is initiated through one of several pathways: Dehydrogenation leading to
HCB, dehydrochlorination leading to formation of
pentachlorocyclohexene, dechlorination leading to formation of
tetrachlorohexene, or hydroxylation leading to formation of hexachlorocyclohexanol. Further metabolism leads to a large number of metabolites. Lindane is converted by enzymatic reactions, mainly in the liver. Lindane appears to affect the liver and kidney in male rats when administered through the oral, dermal or inhalation routes of exposure. Kidney lesions in males indicative of alpha 2µ globulin accumulation were observed in animals treated with  10 ppm, but are not considered relevant to human health risk assessment The liver effects include: incidence of periacinar hepatocytic hypertrophy which was significantly (p  0.01) increased in male and female rats dosed at 100 ppm (4. 81 and 6.00 mg/ kg/ day, respectively). In addition, increased liver and spleen weights, and decreased platelets were also noted. Lindane is not considered teratogenic when administered orally or subcutaneously. Developmental toxicity NOAELs were found to be at levels equal to or greater than maternal NOAELs, except in the developmental neurotoxicity study. The developmental neurotoxicity LOAEL was 5.6 mg/ kg/ day (NOAEL is 1.2 mg/ kg/ day) based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation compared to a maternal toxicity LOAEL of 13.7 mg/ kg/ day (NOAEL is 5.6 mg/ kg/ day) based on decreased body weight gains, decreased food consumption, and increased reactivity to handling. The data base for reproductive toxicity is considered complete. Both parental and offspring LOAELs are 13 mg/ kg; however there is a qualitative difference in the severity of effects. In the parental animals, toxicity was seen in the form of reduction in body weight gain during gestation while offspring toxicity was correlated with decreases in pup viability and pup body weight in the F1 and F2 generations as well as delayed maturation in the F2 generation. Evidence for quantitative increase in susceptibility could not be ascertained due to the wide spread in the doses tested. The OPP/ Cancer Assessment Review Committee (CARC) has completed the review of newly submitted carcinogenicity study in CD­ 1 mice along with other data. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC has classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on an increased incidence of benign lung tumors in female 11 mice only. The Committee, therefore, recommended that the quantification of human cancer risk is not required. In a mammalian cell gene mutation assay and an in vivo sister chromatid exchange assay, no mutagenic response was detected. These studies were classified as unacceptable by EPA. The open literature suggests, however, that technical grade HCH (hexachlorohexane; 6. 5%
HCH) may induce some mutagenic activity as evidenced in a dominant lethal mutation assay and sister chromatid exchanges. It has been noted, however, by the IPCS that lindane does not appear to have a mutagenic potential. The acute toxicity studies for lindane are summarized in Table 1, and the toxicology profile for lindane is summarized in Table 2. The toxicology database required to support the Reregistration of lindane is essentially complete. All required toxicology studies have been submitted and reviewed by Agency scientists. Table 1. Guideline Acute Toxicity Studies for Lindane STUDY TYPE MRID CATEGORY RESULT 81­ 1Acute oral­ rat 00049330 II LD50 88 mg/ kg ­ males 91 mg/ kg ­ females 81­ 2 Acute dermal­ rabbit 00109141 II LD50 1000 mg/ kg ­ males 900 mg/ kg ­ females 81­ 3 Acute inhalation­ rat Acc. 263946 III LC50 1.56 mg/ L both sexes 81­ 4 Eye irritation­ rabbit Acc. 263946 III PIS = 0.6 no corneal involvement irritation cleared after 24 hours 81­ 5 Dermal irritation­ rabbit Acc. 262946 IV PIS = 0 not an irritant 81­ 6 Dermal sensitization­ g. pig Acc. 262946 NA not a sensitizer Table 2. Guideline Toxicology Studies for Lindane Guideline No./ Study Type MRID No. ­year/ Classification Results 870.3250 90­ Day dermal toxicity in rabbit 41427601 ­1990 acceptable/ guideline NOAEL = 10 mg/ kg/ day LOAEL = 60 mg/ kg/ day based on lesion in the liver in males and females and adrenal gland weight increases in males 870.3465 90­ Day inhalation toxicity in rat 00255003 ­1983 acceptable/ guideline NOAEL = 0. 025 mg/ kg/ day LOAEL = 0. 13 mg/ kg/ day based on transient microscopic lesions in the kidney and increased kidney weights in the males. 40873501 ­1988 acceptable/ guideline NOAEL = 0. 08 mg/ kg/ day LOAEL = 0.25 mg/ kg/ day based on death of one male and one female Table 2. Guideline Toxicology Studies for Lindane Guideline No./ Study Type MRID No. ­year/ Classification Results 12 870.3700a Prenatal developmental in rat 00062656 ­1976 (Subcutaneous) unacceptable/ nonguideline Maternal NOAEL = 5 mg/ kg/ day LOAEL = 15 mg/ kg/ day based on reduced body weight Developmental NOAEL = >30 mg/ kg/ day LOAEL = not identified 42808001 ­1971 acceptable/ guideline Maternal NOAEL = 5 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on reduced body weight and food consumption Developmental NOAEL = 10 mg/ kg/ day LOAEL = 20 mg/ kg/ day based on skeletal variation. 870.3700b Prenatal developmental in rabbit 00062658 ­1976 (Subcutaneous) unacceptable/ nonguideline Maternal NOAEL = 5 mg/ kg/ day LOAEL = 15 mg/ kg/ day based on clinical signs, mortality, reduced body weight Developmental NOAEL 15 mg/ kg/ day LOAEL = not identified 42808002 ­1971 unacceptable/ nonguideline Maternal NOAEL 20 mg/ kg/ day LOAEL = not identified Developmental NOAEL 20 mg/ kg/ day LOAEL = not identified 870.3800 Reproduction and fertility effects in rat 42246101 ­1991 acceptable/ guideline NOAEL = 1. 7 mg/ kg/ day
; 0. 09mg/ kg/ day  LOAEL = 13 mg/ kg/ day
based on reduced body weight; 1.7 mg/ kg/ day  based on increased kidney weight and 2 globulin accumulation (not relevant for humans) NOAEL for reproductive toxicity =1. 7 mg/ kg/ day (20 ppm) LOAEL for reproductive toxicity = 13 mg/ kg/ day (150 ppm) based on reduced pup body weights and decreased viability in both generations and delayed maturation of the F2 pups 870.4300 Carcinogenicity mice special study ­1987 see below­ literature studies 870.4100a Chronic toxicity rodents 870.4200 Carcinogenicity rats 41094101 41853701 42891201 ­1993 acceptable/ guideline NOAEL =0. 6 mg/ kg/ day LOAEL = 4.8 mg/ kg/ day  ; 6 mg/ kg/ day
based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets no evidence of carcinogenicity 870.5300 Gene Mutation Mammalian Cell 00144500 ­1985 unacceptable/ uideline negative Table 2. Guideline Toxicology Studies for Lindane Guideline No./ Study Type MRID No. ­year/ Classification Results 13 870.5915 In Vivo Sister Chromatid Exchange 00024504 ­1984 unacceptable/ guideline negative 870.5450 dominant lethal assay 00062657 unacceptable/ guideline negative 870.6200a Acute neurotoxicity screening battery in rat 44769201 ­1999 acceptable/ guideline NOAEL = 6 mg/ kg/ day
; 20 mg/ kg/ day  LOAEL = 20 mg/ kg/ day (
) based on increased grip strength and decreased motor activity. 60 mg/ kg/ day (  ) based on tremors, convulsions, decreased motor activity and increased grip strength. 870.6200b Subchronic neurotoxicity screening battery in rat 44781101 ­1999 acceptable/ guideline NOAEL = 7. 9 mg/ kg/ day
; 7. 1 mg/ kg/ day  LOAEL = 30.2 mg/ kg/ day and 28.1 mg/ kg/ day based on hypersensitivity to touch and hunched posture. 870.6300 Developmental neurotoxicity in rat 45073501 ­1999 acceptable/ guideline Maternal NOAEL = 5. 6 mg/ kg/ day LOAEL = 13.7 mg/ kg/ day based on decreased body weight gains, decreased food consumption, and increased reactivity to handling. Offspring NOAEL = 1. 2 mg/ kg/ day LOAEL = 5.6 mg/ kg/ day based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. 870.7600 Dermal penetration 40056107­ 1987 rat 40056108­ 1987 rabbit acceptable/ guideline 18 % absorption at 10 hours literature studies Feldmann, RJ and HI Maibach, Percutaneous penetration of some pesticides and herbicides in man, Toxicology and Applied Pharmacology, 28: 126­ 132 (1974). Non­ guideline ~10% absorption in humans Table 2. Guideline Toxicology Studies for Lindane Guideline No./ Study Type MRID No. ­year/ Classification Results 14 Other: Tumorigenic responses to lindane in mice: potentiation by a dominant mutation. Special study dietary administration­ 1987 NOAEL = not identified LOAEL = 23 mg/ kg/ day (160 ppm) based on induction of tumors, increased liver weights, increased enzyme activity, and irreversible Clara cell hyperplasia in lung evidence of carcinogenicity­ induction of liver and lung tumors in the agouti, pseudoagouti and black mouse strains— only females; only 0 and 160 ppm Other Literature Studies In addition to the developmental and reproduction studies submitted to the Agency to fulfill the OPPTS Guidelines, HED's Hazard Identification Assessment Review Committee (HIARC) evaluated a segment of the extensive body of information published in the open literature dealing with lindane. These studies show that exposure to lindane, both transplacental and via mother's milk, is possible and that such exposure may result in adverse developmental effects on human offspring. According to Karmaus et al (1995), females exposed to lindane risk having offspring with reduced birthweight and length. Pompa et al (1994) has also been able to show that transfer of lindane and pentachlorobenzene from mother to newborn rabbits can occur. Rivera et al (1990) found that early postnatal exposure to lindane may induce behavioral changes in developing rats. Evidence of reproductive failure and fetotoxicity in mice has been compiled by Sircar et al. B. Dose Response Assessment i. Determination of Susceptibility There was evidence of qualitative increased susceptibility in the rat multi­ generation reproduction study: Both parental and offspring LOAELS are 13 mg/ kg; however there is a qualitative difference in the severity of effects. In the parental animals, toxicity was seen in the form of reduction in body weight gain during gestation while offspring toxicity was correlated with decreases in pup viability and pup body weight in the F1 and F2 generations as well as delayed maturation in the F2 generation. Evidence for quantitative increase in susceptibility could not be ascertained due to the wide spread in the doses tested. There is also quantitative increased susceptibility demonstrated in the rat developmental neurotoxicity study: Maternal toxicity observed at 120 ppm (13.7 mg/ kg/ day, LOAEL) is based on decreased body weight gains, decreased food consumption, and increased reactivity to handling (maternal NOAEL is 50 ppm; 5. 6 mg/ kg/ day). Offspring toxicity was observed at 50 ppm (5. 6 mg/ kg/ day, LOAEL) and is based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation (NOAEL is 10 ppm; 1. 2 mg/ kg/ day). 15 The offspring effects seen in the developmental neurotoxicity study were the same as those seen in the two­ generation reproduction study ­ no additional functional or morphological changes in the nervous system were noted. In the open literature, lindane is found in mother's milk and metabolites of lindane have been shown to cross the placental barrier. The Food Quality Protection Act (FQPA) Safety Factor Committee met on August 2, 2000 and evaluated the hazard and exposure data to determine if the 10x safety factor should be retained (Tarplee, DOC # 014272). The Committee recommended that the FQPA safety factor be reduced to 3x because: 1) the toxicology data base is complete; 2) the available data provide no indication of quantitative or qualitative increased susceptibility in rats from in utero exposure to lindane in the prenatal developmental study; 3) although the developmental toxicity study in rabbits was classified unacceptable, the HIARC concluded that a new study is not required; 4) the offspring effects seen in the developmental neurotoxicity study were the same as those seen in the two­ generation reproduction study; and 5) adequate actual data, surrogate data, and/ or modeling outputs are available to satisfactorily assess food exposure and to provide a screening level drinking water exposure assessment; and 6) there are currently no residential uses. ii. Cancer Classification On May 30, 2001, the HED Cancer Assessment Review Committee (CARC) met to evaluate the carcinogenic potential of lindane. At this meeting, the CARC could not make a determination of the carcinogenic potential of lindane because the NTP studies were of limited value and it was uncertain if the study on Agouti, Pseudoagouti and Black mice with limited data could be used for regulatory purposes. In addition, the CARC was informed that new histopathology data would be submitted. The Committee also requested additional information including results of a 90­ day subchronic range­ finding study in CD­ 1 mice, an earlier RfD Committee report and analyses of the older studies on lindane. The Committee met again on September 13, 2001 and reevaluated all the available information/ data including the old and the newly gathered information that was previously not available for review. Based on the most recent review of the data including the newly submitted carcinogenicity study in CD­ 1 mice and in accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC has classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on an increased incidence of benign lung tumors in female mice only. The Committee, therefore, recommended that the quantification of human cancer risk is not required. iii. Toxicology Endpoint Selection The Hazard Identification Committee (HIARC) met on June 13, 2000 to evaluate the existing toxicology database for lindane and identify toxicological endpoints and dose levels of concern appropriate for use in risk assessments for different exposure routes and durations, and assess/ reassess the reference dose (RfD). HIARC met again on May 22, 2001 to reconsider the 16 endpoint for occupational risk assessment for the inhalation route of exposure. Previously the endpoint was based on kidney lesions and increased kidney weights resulting from the accumulation of alpha 2 globulin. These effects have been deemed not relevant for human risk assessment. The conclusions and toxicology endpoints selected for dietary and non­ dietary risk assessments are presented in Table 3 below. The critical toxicology study for acute dietary risk assessment is the acute neurotoxicity study in rats. In an acute oral neurotoxicity study, groups of 10 rats/ sex/ dose were administered a single dose of lindane by gavage at concentrations of 0 (control), 6, 20, or 60 mg/ kg. Functional observational battery (FOB) and motor activity (MA) testing were performed prior to administration and within 3 hours (time of peak effect) of dosing (day 0), and on days 7 and 14 post­ dose. Body weights were recorded pre­ test, weekly during the study period and on FOB assessment days. Clinical signs were recorded at least once daily. At study termination all animals were sacrificed and fixed by whole body perfusion, designated tissues of the nervous system were processed for microscopic neuropathological evaluation. The NOAEL for neurotoxic effects was found to be 6 mg/ kg for females and the LOAEL was 20 mg/ kg based on increased forelimb grip strength and decreased grooming behavior and motor activity (MA). The NOAEL for neurotoxicity in males is 20 mg/ kg and the LOAEL for males is 60 mg/ kg based on tremors, convulsions, decreased MA, and increased forelimb grip strength. The Uncertainty Factor includes 10x for inter­ species variation, and10X for intra­ species extrapolation. The FQPA safety factor is reduced to 3X. Therefore, the acute Population Adjusted Dose (aPAD) is 0.02 mg/ kg/ day (NOAEL of 6 mg/ kg/ day ÷ 300 (UF of 100 x FQPA factor of 3). The acute dietary endpoint for the general population was considered sufficiently protective for the subpopulation of females 13­ 50. Although, there was evidence of increased susceptibility in the DNT, the offspring effects were not attributable to a single dose. A separate endpoint for this subpopulation was therefore not identified. The critical toxicology study for chronic non­ cancer dietary risk assessment is the chronic toxicity/ oncogenicity study in rats. In this chronic toxicity/ oncogenicity study, lindane was administered in the diet to groups of 115 male and 115 female Wistar rats per dose at concentrations of 0, 1, 10, 100, or 400 ppm for 2 years. Corresponding delivered doses were 0, 0.05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0. 06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. The systemic toxicity LOAEL for male and female rats is 100 ppm (4. 81 and 6.0 mg/ kg/ day, respectively) based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets. The systemic toxicity NOAEL is 10 ppm (0. 47 and 0. 59 mg/ kg/ day for males and females, respectively). The Uncertainty Factor includes 10X for inter­ species variation, and10x for intra­ species extrapolation. The FQPA safety factor is reduced to 3X. Therefore, the chronic Population Adjusted Dose (cPAD) was determined to be 0.0016 mg/ kg/ day (NOAEL of 0. 47 mg/ kg/ day ÷ 300 (UF of 100 x FQPA of 3). For occupational assessment, the dermal absorption rate for lindane was estimated to be approximately 10% in 10 hours of exposure in humans. The HIARC concurred with the TES 17 committee decision (HED Doc. # 013460) that the dermal absorption factor is 10% based on a published report by Feldman and Maibach (Toxicology and Applied Pharmacology 28, 126­ 132, 1974). Table 3. Doses and Toxicological Endpoints Selected for Risk Assessment of Lindane EXPOSURE SCENARIO DOSE (mg/ kg/ day) ENDPOINT STUDY TYPE/ MRID Acute Dietary­ general population NOAEL= 6 mg/ kg UF = 100 LOAELis20 mg/ kgbased on increasedgrip strength, increased motor activity Acute Neurotoxicity in Rats/ 44769201 Acute RfD = 0. 06 mg/ kg/ day aPAD = 0. 02 mg/ kg/ day Chronic Dietary NOAEL= 0. 47 mg/ kg/ day UF = 300 LOAEL is 100 ppm (4. 81 mg/ kg/ day) periacinar hepatocyte hypertrophy, increased liver/ spleen weight, decreased platelets Chronic Feeding and Carcinogenicity in Rats 41094101, 41853701 42891201 Chronic RfD = 0. 0047 mg/ kg/ day cPAD = 0.0016 mg/ kg/ day Short­ Term 1 (Dermal) NOAEL= 1. 2 mg/ kg/ day LOAEL is 50 ppm based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. Developmental Neurotoxicity Study in Rats (oral) 45073501 Intermediate­ Term 1 (Dermal) NOAEL= 1. 2 mg/ kg/ day LOAEL is 50 ppm based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. Developmental Neurotoxicity Study in Rats (oral) 45073501 Long­ Term 1 (Dermal) NOAEL= 0. 47 mg/ kg/ day LOAEL is 100 ppm (4. 81 mg/ kg/ day) periacinar hepatocyte hypertrophy, increased liver/ spleen weight, decreased platelets Chronic Feeding and Carcinogenicity in Rats 41094101, 41853701 42891201 Dermal Absorption Factor = 10% Short Term 1 (Inhalation) 0.13 mg/ kg/ day (0. 5 mg/ m 3 ) based on clinical signs (diarrhea, piloerection) seen at day 14 and continuing for 20 days 90­ Day Inhalation Toxicity / 00255003 Intermediate Term 1 (Inhalation) 0.13 mg/ kg/ day (0. 5 mg/ m 3 ) LOAEL is 5. 0 mg/ m 3 based on increased kidney weights of female rats and bone marrow effects. 90­ Day Inhalation Toxicity / 00255003 Long Term 2 (Inhalation) N/ A N/ A N/ A 1 An MOE of 100 was selected 2 Exposure thru this route for this duration is not expected 18 The Maibach study tested 12 pesticides and herbicides, including lindane, on human subjects (6 per chemical) to quantify their dermal penetration. C 14 ­labeled chemicals were applied topically (4 g/ cm 2 ) to the forearm or via the intravenous route (1 Ci). Excretion of the chemicals was then monitored by collecting and analyzing urine samples during the 5 day testing period. All results were calculated as percent of the injected or applied dose. Data obtained after IV dosing was used to correct the skin penetration data for incomplete urinary recovery. Lindane was shown to have a penetration factor of 9.3% ± 3. 7 (SD). The critical study selected for short­ and intermediate­ term dermal risk assessment was the Developmental Neurotoxicity Study in rats. A 90­ day dermal toxicity study in rabbits was available; the NOAEL was 10 mg/ kg/ day and the LOAEL was 60 mg/ kg/ day based on hepatic toxicity. The HIARC did not consider this study to be appropriate for risk assessment and instead selected an oral endpoint due to: 1) the concern for developmental effects as seen in pups in the developmental neurotoxicity study, 2) developmental effects are not evaluated in the dermal toxicity study, 3) the dermal toxicity study was conducted in the rabbit, while the increased susceptibility was seen in rat pups via an oral route, and 4) this endpoint will be protective of dermally exposed workers. For developmental toxicity, the NOAEL was 1. 2 mg/ kg/ day and the LOAEL was 5.6 mg/ kg/ day based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. The target MOE is 100 (10X for interspecies variation and 10X for intraspecies variation) for occupational exposure. Since an oral endpoint was selected, a 10% dermal absorption factor will be used for route to route extrapolation. The critical study selected for risk assessment for long­ term dermal exposure was the Chronic One­ Year Toxicity Study in rats, which is discussed above. The systemic toxicity LOAEL for male and female rats is 4. 81 and 6.0 mg/ kg/ day, respectively, based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets. The systemic toxicity NOAEL is 0.47 and 0. 59 mg/ kg/ day for males and females, respectively. The target MOE is 100 (10X for interspecies variation and 10X for intraspecies variation) for occupational exposure. Since an oral endpoint was selected, a 10% dermal absorption factor will be used for route to route extrapolation. The critical study for inhalation risk assessment for lindane is an 90­ Day Inhalation Toxicity. Lindane was administered by inhalation to groups of 12 male and 12 female Wistar rats at nominal concentrations of 0, 0.02, 0.10, 0.50, or 5.0 mg/ m 3 , 6 h/ day for 90 days. Lindane was detected in the brain, liver, fat, and serum of all exposed rats. The HIARC established a NOAEL of 0.5 mg/ m 3 for this risk assessment based on clinical signs (diarrhea and piloerection) seen at day 14 after exposure and continuing for 20 days at the highest concentration tested (5 mg/ m 3 ). This NOAEL is applicable and appropriate only for short­ term exposure risk assessment because the effects were seen during this period of exposure. For intermediate exposures, the NOAEL is 0.5 mg/ m 3 (0. 13 mg/ kg) based on increased kidney weights and bone marrow effects. For inhalation risk assessments for occupational exposure, the target MOE is 100 (10X for 19 intraspecies variation and 10X for interspecies variation). Long­ term inhalation exposure is not expected. iv. Endocrine Disruptor Effects EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). v. Incident Reports The Agency has conducted a review of reported poisoning incidents associated with human exposure to lindane. The Agency has consulted the following data bases for the poisoning incident data on the active ingredient lindane: Incident Data System, Poison Control Center Data ­ 1993 through 1998, California Data ­ 1982 through 1998, and the National Pesticide Telecommunications Network. The review only included lindane containing products currently registered for use as a seed treatment. Incidents due to all other types of lindane products were excluded. No incidents were located related to seed treatment use of lindane. None of the cases reported to Poison Control Centers from 1993 through 1998 concerned products identified as being used for seed treatment. However, it should be noted that nearly one­ third of the exposures involving lindane did not identify a specific product, but rather just exposure to lindane. Detailed descriptions of eight cases submitted to the California Pesticide Illness Surveillance Program (1982­ 1998) were reviewed. In three of these cases, lindane was deemed the primary cause of the illness. All three incidents occurred in 1984. All three cases involved driving and filling planter hoppers with treated cotton seed. Two of the cases, apparently involved in the same operation, were both treated in a hospital and off work for 7 days. The third case was not treated in a hospital but was off work for 2 days. Specific symptoms were not reported for any of these three cases. The National Pesticide Telecommunications Network did not report on incidents specifically related to lindane use for seed treatment. Relatively few incident of illness have been reported due to lindane used for seed treatment; therefore, no recommendations can be made based on the few incident reports available. 20 IV. Exposure and Risk Assessment A. Dietary Exposure (Food Sources) i. Background In 1993, CIEL offered to voluntarily cancel all crop uses of lindane except seed treatment and certain non­ food uses. The Agency considers lindane seed treatment as a food use requiring tolerances based on existing data from radiolabeled studies indicating uptake of residues from the treated seeds into the aerial portion of the growing crop. The only food/ feed use of lindane which is being supported for reregistration is seed treatment on cereal grains (excluding rice and wild rice). Seed treatment uses on broccoli, Brussels sprouts, cabbage, cauliflower, lettuce, radishes, and spinach are no longer being supported for reregistration by Inquinosa. In addition, the established tolerances for the following commodities will be revoked because no registrants have committed to support the foreign or domestic uses for: apples, apricots, asparagus, avocados, celery, cherry, collards, cucumbers, eggplants, grapes, guavas, kale, kohlrabi, mangoes, melons, mushrooms, mustard greens, nectarines, okra, onions (dry bulb only), peaches, pears, pecans, peppers, pineapple, plums (fresh prunes), pumpkins, quinces, squash, strawberries, summer squash, swiss chard and tomatoes. Tolerances for residues of lindane in/ on food and feed commodities are currently established under 40 CFR §180.133 and are expressed in terms of lindane per se. The nature of the residue in plants is not adequately understood. A new nature of the residue study from seed treatment are required for cereal grain. The nature of the residue in poultry and ruminants is adequately understood. The HED Metabolism Assessment Review Committee (T. Morton, 8/ 30/ 00, D267069) concluded that the total radiolabeled residues (TRRs) should be used for risk assessment purposes and calculation of dietary burdens, pending receipt of additional metabolism data. Table 4. Tolerance Reassessment Summary for Lindane. Commodity Tolerance Listed Under 40 CFR (ppm) Reassessed Tolerance (ppm) Comment Tolerance Listed Under 40 CFR §180.133 Apples 1 Revoke Not being supported for reregistration. Apricots 1 Revoke Not being supported for reregistration. Asparagus 1 Revoke Not being supported for reregistration. Avocados 1 Revoke Not being supported for reregistration. Broccoli 1 Revoke Not being supported for reregistration. Table 4. Tolerance Reassessment Summary for Lindane. Commodity Tolerance Listed Under 40 CFR (ppm) Reassessed Tolerance (ppm) Comment 21 Brussels sprouts 1 Revoke Not being supported for reregistration. Cabbage 1 Revoke Not being supported for reregistration. Cauliflower 1 Revoke Not being supported for reregistration. Lettuce 3 Revoke Not being supported for reregistration. Spinach 1 Revoke Not being supported for reregistration. Celery 1 Revoke Not being supported for reregistration. Collards 1 Revoke Not being supported for reregistration. Kale 1 Revoke Not being supported for reregistration. Kohlrabi 1 Revoke Not being supported for reregistration. Mustard greens 1 Revoke Not being supported for reregistration. Swiss chard 1 Revoke Not being supported for reregistration. Cherry 1 Revoke Not being supported for reregistration. Cucumbers 3 Revoke Not being supported for reregistration. Eggplants 1 Revoke Not being supported for reregistration. Fat of meat from cattle, goats, horses, and sheep 7 Revoke Current tolerances are based on direct dermal application. The need for livestock tissue tolerances will be reevaluated when the required nature of the residue study in plants is submitted Fat ofmeat from hogs 4 Grapes 1 Revoke Not being supported for reregistration. Guavas 1 Revoke Not being supported for reregistration. Mangoes 1 Revoke Not being supported for reregistration. Melons 3 Revoke Not being supported for reregistration. Mushrooms 3 Revoke Not being supported for reregistration. Nectarines 1 Revoke Not being supported for reregistration. Okra 1 Revoke Not being supported for reregistration. Onions (dry bulb only) 1 Revoke Not being supported for reregistration. Peaches 1 Revoke Not being supported for reregistration. Pears 1 Revoke Not being supported for reregistration. Pecans 0.01 Revoke Not being supported for reregistration. Peppers 1 Revoke Not being supported for reregistration. Pineapple 1 Revoke Not being supported for reregistration. Plums (fresh prunes) 1 Revoke Not being supported for reregistration. Pumpkins 3 Revoke Not being supported for reregistration. Quinces 1 Revoke Not being supported for reregistration. Squash 3 Revoke Not being supported for reregistration. Strawberries 1 Revoke Not being supported for reregistration. Summer squash 3 Revoke Not being supported for reregistration. Table 4. Tolerance Reassessment Summary for Lindane. Commodity Tolerance Listed Under 40 CFR (ppm) Reassessed Tolerance (ppm) Comment 22 Tomatoes 3 Revoke Not being supported for reregistration. ii. Sources of Lindane Residues on Foods The only food/ feed use of lindane which is being supported for reregistration is seed treatment on cereal grains (excluding rice and wild rice). Seed treatment uses on broccoli, Brussels sprouts, cabbage, cauliflower, lettuce, radishes, and spinach are no longer being supported for reregistration. There are no adequate nature of the residue studies for plants from seed treatment application; therefore, a new metabolism study is required for cereal grain. A seed treatment metabolism study was reviewed by HED; although it was deemed inadequate due to insufficient characterization/ identification of the radioactive residues, it was found to be useful in the determination of the TRR for use in this dietary exposure analysis. The corn grain and forage TRRs were translated to sorghum. Secondary residues in livestock commodities may result from livestock consuming treated food. The nature of the residue in poultry is understood. The nature of the residue in ruminants is adequately understood since the registrant recently submitted the required data (MRID 45224101, 45224102, and 45277201) to upgrade a ruminant metabolism study (MRID 44867104) which was deemed inadequate. The lindane equivalent residue values used in the dietary exposure analyses were derived using a ratio of total radioactive residue divided by the amount of lindane present in the metabolism studies (ruminant and poultry). Thiswould be worstcase estimatesince we areassuming thatallofthe TRRwould be residues of concern. The dietary exposure analyses using the total radioactive residues is a Tier 3 assessment since percent crop treated was used in the analyses. The dietary exposure analyses that were based on the adjustment of the lindane residues in the livestock feeding studies is a Tier 3 assessment. Percent market share was available for all crops included in the analyses. Since lindane is registered for seed treatments only, there is no difference in the percent crop treated between crops grown for the fresh market and those grown for processing. A processing study was available for canola only; the default DEEM™ processing factors were used for all other foods. iii. Residue Chemistry Studies for Lindane A tabular summary of the residue chemistry science assessments for reregistration of lindane is presented in Table A of the Revised Residue Chemistry Chapter (T. Morton, D279259, 12/ 11/ 01). When end­ use product DCIs are developed (e. g., at issuance of the RED), all end­ use product labels (e. g., MAI labels, SLNs, and products subject to the generic data exemption) should be amended such that they are consistent with the basic producers' labels. A 30­ day plant­ 23 back interval for leafy vegetables and a 12­ month plant­ back interval for all other unregistered crops is required on all end­ use product labels for lindane. Nature of the Residue ­ Plants (GLN 860.1300): The qualitative nature of lindane residues in plants reflecting seed treatment is inadequately understood. For the purpose of reregistration, the basic registrants are required to conduct new plant metabolism studies on lindane. These studies should be conducted on a representative cereal grain, as the registrants have indicated that the only food uses they are supporting are for seed treatment of these crops. The new studies should be conducted at rates which insure that sufficient 14 C­ residues are available for analysis. Crop samples should be harvested at the appropriate stage. Identification of 14 C­ residues should also be confirmed using more than one method, or by GC/ MS. Nature of the Residue ­ Animals (GLN 860.1300): No direct livestock treatments remain registered. Residues of lindane may occur in livestock as a result of feeding of lindane treated feed (secondary residues). The qualitative nature of the residue in ruminants is adequately understood. The basic registrants have recently submitted additional data for the ruminant metabolism study (MRID 44867104) which was deemed inadequate but upgradable. To upgrade the study, the registrant was required to identify the metabolite labeled LiV in goat liver's aqueous phase which accounted for 25.2 % of the total radioactivity (0.57 ppm). In addition, storage stability data was required. The registrant has recently submitted the required data (MRID 45224101, 45224102, and 45277201) thus, adequately addressing this deficiency. The total radioactive residues (TRR; expressed as lindane equivalents) in collected samples were 3. 46 ppm in fat, 2. 25 ppm in liver, 0. 48 ppm in kidney, 0. 20 ppm in muscle, and 0. 20 ppm in milk. The parent, lindane was the major residue identified in all goat matrices. The qualitative nature of the residue in poultry is adequately understood. A poultry metabolism study (MRIDs 40271301 and 44405404), submitted by the registrants in response to the 9/ 85 Lindane Reregistration Guidance Document, has recently been upgraded to acceptable status. A brief summary of the poultry metabolism study follows. Laying hens were dosed with [ 14 C] lindane at levels equivalent to 1.2 ppm or 120 ppm in the diet for four consecutive days. Radioactive residues accumulated to the greatest extent in fatty tissues. In high dose hens, TRR levels were highest in fat (96.98 ppm) and lowest in breast muscle (1.44 ppm). TRR levels were proportionally less in tissues of low­ dose hens (fat, 1. 26 ppm; breast muscle 0. 02 ppm). In eggs of high­ dose hens, 14 C­ residues peaked on Day 4 at 10.83 ppm in yolks and 0.21 ppm in whites. Lindane was the major residue component identified and accounted for approximately 95% of the TRR in egg yolks, 71­ 86% of the TRR in muscle, skin, and fat, and 52% of the TRR in liver. Other metabolites that were identified included: 1,2,4­ trichlorobenzene; 1,3,5­ trichlorobenzene and dichlorobenzene( s); tetrachlorobenzene (either 1,2,4,5­ or 1,2,3,4­); PCCH; 1, 2, 3, 4tetrachlorobenzene tetrachlorocyclohexene; 1,2,3,4,5­ pentachlorobenzene; and hexachlorocyclohexene. The results of the ruminant and poultry metabolism studies will be presented to HED's MARC for determination of terminal residue of concern in eggs, milk, and animal tissues once an adequate seed treatment metabolism study is submitted. If the Committee determines that lindane 24 is the only residue of concern requiring regulation, then the existing storage stability data for poultry commodities, the analytical method used for data collection, and the poultry feeding study will be upgraded to acceptable status. In the absence of acceptable metabolism studies, the HED MARC (T. Morton, 8/ 30/ 00, D267069) concluded that the total radioactive residues should be used for risk assessment purposes until adequate plant metabolism studies are submitted. Residue Analytical Methods (GLN 860.1340): Adequate methods are available for determination of residues of lindane per se in/ on plant and animal commodities. The Pesticide Analytical Manual (PAM) Vol. II lists Methods I and II for the analysis of mixed isomers of 1,2,3,4,5,6­ hexachlorocyclohexane in/ on plant and animal commodities. Method I is a multiresidue method (see "GLN 860.1360: Multiresidue Methods" section) for chlorinated compounds. Method II is based upon the official final AOAC method (1990, 15th edition of AOAC) and is suitable for determining residues of lindane in/ on AOAC Group I nonfatty foods (vegetables and fruits), dairy products, fish, and eggs. The stated limit of detection of Method II is 0.05 ppm for most commodities. Because the nature of the residue in plants resulting from seed treatment uses as well as the nature of the residue in ruminants have not been delineated, the adequacy of the available analytical methods cannot be determined. The registrants are reminded that radiovalidation of enforcement method( s) is a reregistration requirement; therefore, representative samples from the requested plant and ruminant metabolism studies should be used for validation and analyzed by the existing or proposed enforcement method( s) to determine whether total toxic residues are extracted from weathered samples. Adequate data­ collection methods have been submitted for detection of lindane per se in/ on cucumbers and spinach. The analytical procedures for detecting lindane in cucumbers and spinach are essentially the same. Based on acceptable method validation recoveries, the Agency has deemed the GC/ ECD method to be adequate for determining residues of lindane per se in nonfatty crops. A GC/ MS method (SOP# Meth­ 109) entitled "Determination of Lindane in Wheat and Canola Matrices" was utilized as the data­ collection method in a recently submitted wheat field study. Following extraction and purification, detection and quantitation were conducted using a gas chromatograph equipped with a mass selective detector (GC/ MS). The LOQ was 0. 005 ppm. A data­ collection method, based on the AOAC method, was also submitted for detection of lindane per se in eggs, milk, and animal tissues. The Agency previously required an EPA method validation for the submitted method if lindane tolerances for lean animal tissues were to be established because the AOAC method did not describe techniques which the registrant's method contained (e. g., gel permeation chromatography and rotary evaporation). The FDA method now utilizes these techniques; therefore, the requirement for a petition method validation 25 was conditionally waived provided HED's MARC determines that lindane per se is the only residue of concern in animal commodities. Multiresidue Methods (GLN 860.1360): The 10/ 99 PESTDATA database (PAM, Vol. I, Appendix I) contains data concerning the applicability of multiresidue methods to lindane. Lindane is completely recovered (> 80% recovery) using protocols 302 (Luke method), 303 (Mills, Onley, and Gaither method), and 304 (Mills method) for fatty and non­ fatty foods. Should the HED MARC determine that lindane metabolites other than the parent should be regulated, the Agency will require the registrants to submit additional multiresidue methods test data for the metabolites of concern. Storage Stability Data (GLN 860.1380): The specifics of reregistration requirements for storage stability data in plants and animals cannot be ascertained until an acceptable plant metabolism study is available, and the HED MARC has determined the terminal residues of concern. Assuming that lindane per se is the terminal residue of concern and provided the additional temperature information is submitted, the available storage stability data for lindane support the storage conditions and intervals of samples collected from existing crop field trials and livestock feeding studies. A summary of available storage stability data for lindane per se is summarized below. Raw agricultural and processed commodities: Residues of lindane per se are relatively stable under frozen (­ 20
C) storage conditions for up to 8 months in/ on cucumbers and spinach and for approximately 14 months in/ on tomatoes and wheat forage. Lindane residues are stable in wheat grain, wheat hay, and wheat straw for approximately 18 months when stored under frozen conditions. Lindane residues in canola seed were stable for up to 6. 5 months when stored under frozen conditions (no temperature given). Lindane residues were stable for up to 2 months in canola oil and 1. 5 months in canola meal when stored under frozen conditions (no temperature given). The registrant is required to submit additional storage stability data (temperature logs) specifying the storage conditions of the canola storage stability samples. Assuming that lindane per se is the terminal residue of concern, these data support the storage conditions and intervals of samples collected from existing crop field trials. Animal commodities: Residues of lindane per se are relatively stable in eggs, milk, and edible tissues of animals stored frozen (­ 18
C) for up to 9 months. Assuming that lindane per se is the terminal residue of concern, these data support the storage conditions and intervals of samples collected from existing ruminant and poultry feeding studies. Crop Field Trials (GLN 860.1500): A translocation study (MRID 40431207) formed the basis for food­ use classification of lindane when the pesticide is applied as a seed treatment. In this study, [ 14 C] lindane was applied as a seed treatment to corn (field and sweet), mustard, radish, spinach, sugar beet, and wheat at approximately 1x the label rate. The treated seeds were then planted outdoors in 55 gallon drum halves and allowed to grow under simulated normal agricultural practices. Samples of immature and mature crop commodities were analyzed for total 14 C, and some fractions were extracted with hexane and analyzed by a GC method for total 26 lindane. The study failed to adequately identify radioactive residues in/ on all commodities grown from treated seed. Nonetheless, with the possible exception of wheat grain and foliage, residues were characterized to be not associated with biological molecules (e. g., amino acid, sugar, etc.) that have incorporated the radiolabel. Should the HED MARC determine that lindane metabolites other than the parent should be regulated, the Agency will require the registrants to submit additional crop field trial data for all residues of concern. The registrant has submitted PP# 9F05057, for the establishment of time­ limited tolerances for residues of lindane per se in/ on the RACs of crops for which seed treatments are being proposed. The petition included a number of leafy and brassica vegetables, radish, and corn. The only crop in this petition which is now being supported by the registrant is corn. A revised Section F is required deleting all other crops from the petition. Tolerances cannot be established or reassessed until an adequate plant metabolism study for cereal grain is submitted. The registrants have also submitted PP# 9F6022, for the establishment of tolerances on lindane per se in/ on canola for which seed treatment is being proposed. Tolerances cannot be established or reassessed until an adequate plant metabolism study and additional residue data are submitted. In addition, the registrants recently submitted acceptable residue data reflecting seed treatment on wheat RACs. A representative formulation (lindane 30­ C flowable) was applied as a seed treatment to wheat at 0.52 oz. ai/ cwt (or 330 ppm lindane on the seed). Following treatment, the treated seeds were planted in 15 diverse geographic locations. Wheat forage samples were collected at or near the jointing stage, the hay samples at early flower to soft dough stage, and the grain and straw samples at normal harvest maturity. Residues of lindane were nondetectable (< 0.005 ppm) in/ on all treated wheat grain and straw samples. Residues of lindane ranged from <0.005 ppm (nondetectable) to 0. 04 ppm in/ on treated wheat forage and from <0.005 ppm (nondetectable) to 0. 02 ppm in/ on treated wheat hay. Additional residue data would be required if the HED MARC determines residues of concern include metabolites of lindane in addition to lindane per se. Processed Food/ Feed (GLN 860.1520): No data are available to determine whether lindane residues of concern concentrate in the processed fractions of cereal grains following seed treatment. A processing study on corn is required for the purpose of reregistration. A processing study on wheat would also be required if the HED MARC determines residues of concern include metabolites of lindane in addition to lindane per se. At this time, a processing study for wheat processed fractions is not being required if lindane per se is the only residue of concern (S. Funk, 10/ 31/ 95, D213401). In 1998, the U. S. Food and Drug Administration (FDA) monitoring program analyzed a total of 227 samples of milled grain products for lindane residues at an LOQ of 0. 01 ppm. Commodities analyzed included flour and other milled products, breakfast foods, and baked goods. Lindane was not detected in any sample. 27 The registrant submitted a canola processing study along with PP# 9F6022 where lindane residues in/ on canola refined oil, canola meal, and bleached/ deodorized canola oil were determined. Lindane in canola refined oil concentrated by a factor of at least 5. 2x. Lindane did not concentrate in canola meal and bleached/ deodorized canola oil. Meat, Milk, Poultry, Eggs (GLN 860.1480): The nature of the residue in plants is not understood. Upon receipt of the requested plant metabolism data, the Agency will: (i) determine the adequacy of established tolerances for animal commodities; (ii) calculate the expected dietary intake for beef cattle, dairy cattle, and swine; and (iii) re­ evaluate the need for additional feeding studies. It should be noted that ruminant (M. Kovacs, 9/ 20/ 88, CB No. 4037) and poultry feeding (G. Otakie, 8/ 31/ 88, RCB No. 4034) studies are available assuming that lindane per se is the only residue of concern in animals. Confined/ Field Accumulation in Rotational Crops (GLN 860.1850 and 860.1900): The basic registrants have submitted a confined rotational crop study which was deemed unacceptable and not upgradable because of inadequate characterization and identification of residues due to significant losses of organosoluble residues during analysis. Although the study is inadequate and the application rate used (0.75 lb ai/ A) greatly exceeds the level of soil residues that are likely to result from seed­ treatment uses, the data indicate that residues of lindane persist in the soil and can be taken up by rotational crops at intervals up to one year. For the purpose of reregistration, the Agency will not require a new confined rotational crop study provided the registrants propose a 30­ day plantback interval for leafy vegetables and a 12­ month plantback interval for all other unregistered crops on all end­ use product labels for lindane as recommended by the ChemSAC (memo, 10/ 5/ 00). Since this proposal has been accepted by the registrants, then limited rotational field trial data will not be required. B. Dietary Exposure Estimates Lindane acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model (DEEM™) software Version 7. 73, which incorporates consumption data from USDA's Continuing Surveys of Food Intake for Individuals (CSFII), 1989­ 1992. The 1989­ 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive days, and in total represent more than 30,000 unique "person days" of data. Foods "as consumed" (e. g., apple pie) are linked to raw agricultural commodities and their food forms (e. g., apples­ cooked/ canned or wheat­ flour) by recipe translation files internal to the DEEM software. Consumption data are averaged for the entire US population and within population subgroups (e. g., children one to six years old) for chronic exposure assessment, but are retained as individual consumption items for acute exposure assessment. For chronic exposure and risk assessment, estimates of average residues for foods (e. g., orange) or food­ forms (e. g., orange­ juice) of interest are multiplied by the averaged consumption estimate of each food/ food­ form of each population subgroup. Exposure estimates are expressed in mg/ kg body weight/ day and as a percent of the cPAD. 28 For acute exposure assessments, individual one­ day consumption data are used on an individual­ by­ individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic (Tier 1 or Tier 2) exposure assessment, or "matched" in multiple random pairings with residue values and then summed in a probabilistic (Tiers 3& 4) assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user (i. e., those who reported eating relevant commodities/ food forms) and a per­ capita basis. Seed treatment uses on broccoli, Brussels sprouts, cabbage, cauliflower, lettuce, radishes, and spinach are no longer being supported for reregistration by Inquinosa. Therefore, revised acute, chronic dietary exposure and risk analyses have been conducted with these commodities removed (T. Morton, 12/ 13/ 01, 279260). The HED Metabolism Assessment Review Committee concluded that the total radiolabed residues (TRRs) should be used for risk assessment purposes and calculation of dietary burdens, pending receipt of additional metabolism data (T. Morton, 8/ 30/ 00, D267069). The HED ChemSAC recommended comparing the results from the dietary exposure analysis using the TRRs as the residue input with results from a second dietary exposure analysis using lindane residues per se from the livestock feeding studies. Exposure to lindane was determined by using the ratio (ppm TRR/ ppm lindane parent) from the livestock metabolism studies. Only the commodities being supported by the registrant were included in the dietary exposure analysis; no import uses were included as all of these tolerances will be revoked. Additionally, FDA monitoring data show that residues of lindane are not being found in imported commodities. Some residues are reported for gamma­ BHC but these residues are associated with use of BHC, not lindane. The Biological and Economic Analysis Division (OPP/ BEAD) verified the registrant's percent market share estimate for lindane (I. Yusuf email, 7/ 17/ 00). A canola processing study for lindane was recently reviewed (T. Morton, D269388, 5/ 10/ 01). Lindane was not detected in bleached/ deodorized canola oil (< 0.005 ppm). Therefore, ½ LOQ (0. 0025 ppm) will be used as the DEEM™ adjustment factor 1. DEEM™ default concentrations factors (adjustment factor 1) will be used for all other concentration factors. The wheat grain and forage TRRs were translated to barley, oats, and rye. The corn grain and forage TRRs were translated to sorghum. Anticipated residues (DP Barcode D279260, T. Morton, 12/ 13/ 01) were provided for all commodities and have been used when calculating the dietary risk. Although the database for lindane is substantially complete, additional data are needed to eliminate the uncertainties associated with the exposure/ risk assessment. The anticipated residue values are the best estimates the Agency can provide using the residue data available at this time. These values have an inherent uncertainty associated with variations in analytical methods, geographical representation of field trials, seasonal variation of residue levels, etc. 29 C. Dietary Risk Estimates (Food Sources) The only food/ feed use of lindane which is being supported for reregistration is seed treatment cereal grains (excluding rice and wild rice). Seed treatment uses on broccoli, Brussels sprouts, cabbage, cauliflower, lettuce, radishes, and spinach are no longer being supported for reregistration. A revised DEEM™ analysis was performed to estimate acute and chronic dietary exposure and risk from lindane from all commodities supported for reregistration, i. e., seed treatment of cereal grains (T. Morton, 12/ 13/ 01, D279260). The HED Metabolism Assessment Review Committee concluded that the TRRs should be used for risk assessment purposes and calculation of dietary burdens, pending receipt of additional metabolism data (T. Morton, D267069, 8/ 30/ 00). Results of the dietary exposure analysis are presented in Table 5. i. Acute Dietary Exposure and Risk Estimates For lindane, the acute dietary exposure analysis was a tier 3 probabilistic assessment. Estimated acute dietary exposure is below HED's level of concern for all population subgroups at the 99.9 th percentile. The maximum dietary risk estimate is 17 % of the aPAD for the subpopulation all infants and 7 % of the aPAD for the U. S. population when the feeding studies were adjusted to include all lindane related residues using the metabolism studies. ii. Chronic Dietary Exposure and Risk Estimates Estimated chronic dietary risk is below HED's level of concern. The resulting risk estimates are 3 % of the cPAD for the U. S. population and 11 % of the cPAD for children 1­ 6 years of age (the most highly exposed population subgroup). The remaining population subgroups were <6 % of the cPAD when the feeding studies were adjusted to include all lindane related residues using the metabolism studies. Table 5. Estimated Acute and Chronic Dietary Exposure and Risk Population Subgroup Acute (99. 9th %ile) Chronic (mean exposure) Exposure (mg/ kg/ day) % aPAD Exposure (mg/ kg/ day) % cPAD U. S. Population 0. 001305 7 0. 000054 3 All infants (< 1 yr) 0.003320 17 0.000072 5 Children (1­ 6 yrs) 0. 001973 10 0.000173. 11 Children (7­ 12 yrs) 0.001088 5 0. 000096 6 Females (13­ 50 yrs) 0.000467 2 0. 000034 2 Males (13­ 19 yrs) 0.000670 3 0. 000061 4 Males (20+ yrs) 0.000458 2 0. 000034 2 Seniors (55+ yrs) 0.000409 2 0. 000030 2 30 iii. Chronic Dietary Exposure and Risk Estimates for Indigenous People The Indigenous Peoples of the Arctic region of the U. S. (Alaska) rely heavily on subsistence diets as their food source. HED performed a revised supplementary chronic dietary risk and exposure assessment to assess the risk to Indigenous People from worldwide use and manufacture of lindane (T. Morton, D282455, 4/ 17/ 02). Because the annual harvest rates were divided by 365 to obtain daily harvest rates, and the daily intake rates used in the assessment no acute dietary exposure analysis was conducted. The chronic analysis used subsistence food harvest amounts, total HCH residues in traditional foods, and adjusting the HCH exposure to obtain lindane exposure. Based on revised exposure estimates, the chronic dietary risk to adult male Indigenous People ranges from 0.000055 ­ 0. 0006 mg/ kg body weight/ day which is between 3 and 38 % of the cPAD. This is below HED's level of concern (cPAD = 0. 0016 mg/ kg bw/ day). The revised estimate of chronic dietary risk to adult female Indigenous People ranges from 0.000064 ­ 0. 0007 mg/ kg bw/ day or from 4 to 44 % of the cPAD, also below HED's level of concern. The revised lindane dietary risk estimates for children resulting from subsistence food consumption range from 0.0002 ­ 0. 0022 mg/ kg bw/ day or from 13% to 138% of the cPAD. For children 7­ 12 years old, the lindane residue amount was divided by 29 kg (7­ 12 year body weight) to obtain the % cPAD from subsistence foods. The resulting range of lindane dietary risk estimates from subsistence food consumption for children 7­ 12 is 4 to 48% of the cPAD. Table 6. Assumed Total Dietary Intake of Lindane (gamma­ HCH) and Estimated Chronic Dietary Risk for Indigenous Peoples Population Subgroup Body Weight (kg) Lindane Exposure (mg/ kg/ day) % cPAD Adult male 70 0. 000055 ­ 0. 0006 3­ 38 Adult female 60 0. 000064 ­ 0. 00071 4­ 44 Children 1­ 6 10 0.0002 ­ 0. 0022 13­ 138 Children 7­ 12 29 0. 00007­ 0.0008 4­ 48 iv. Cancer Dietary Risk Estimates No dietary cancer risks for lindane were estimated. D. Uncertainties in Dietary Exposure Assessment There are no adequate nature of the residue metabolism studies for plants from seed treatment application. New metabolism studies are required for three crops; however, a seed treatment metabolism study (which was classified as inadequate) was reviewed by the Agency and used in the determination of the TRR for use in this dietary exposure analysis. The corn grain and forage TRRs were translated to sorghum. The nature of the residue in poultry and ruminants is understood. The magnitude of the residue studies in poultry and cattle only analyzed for lindane per se. The total residue equivalents were derived using a ratio of total radioactive residue 31 divided by the amount of lindane present in the metabolism studies. This would be worst case estimate since we are assuming that all of the TRR would be residues of concern. The dietary exposure analyses using the total radioactive residues is a Tier 3 probabilistic assessment since percent crop treated was used in the analyses. Percent market share was available for all crops included in the analyses. Since lindane is registered for seed treatments only, there is no difference in the percent crop treated values between crops grown for the fresh market and those grown for processing. A processing study was available for canola only; the default DEEM™ processing factors were used for all other foods. E. Drinking Water Exposure Although the only current agricultural use of lindane is for seed treatment, lindane has been extensively used in the past as an insecticide on a variety of crops, for home termite control, and as a wood preservative. Fate studies show that lindane is both moderately mobile (mean Koc = 1368) and highly persistent (soil half life of 2. 6 years). Even considering lindane's very low use rate under the current use restriction to seed treatment (maximum of 0. 05 lb a. i./ acre), modeling studies show that lindane concentrations in both surface and ground water may reach environmentally significant levels (> MCL). This conclusion is based solely on lindane's use as a seed treatment and does not consider past uses of lindane. However, note that lindane continues to persist in the environment from past uses. Lindane is persistent and moderately mobile. It is resistant to photolysis and hydrolysis (except at high pH), and degrades very slowly by microbial actions. Degradates are predominantly isomers of benzene hexachloride, pentachlorocyclohexane, 1,2,4,­ trichlorobenzene, and 1, 2, 3­ trichlorobenzene. Also, lindane can possibly transform to the alpha and beta isomers of hexachlorocyclohexane by biological and phototransformation, although this issue remains to be conclusively resolved. Metabolites are not quantified since they comprise less than 10% of the total residue; they are also found in rat metabolism studies and have therefore been evaluated for their toxicologic effects. Lindane is transported through the environment by both hydrologic and atmospheric means. Lindane has often been detected in surface and ground water, and lindane and its isomers have been detected in areas of non use (e. g., the arctic), indicating global atmospheric transport. Most of these detections resulted from a combination of lindane's past widespread use and its extreme persistence. Currently, U. S. agricultural uses of lindane are restricted to seed treatments, and application rates are quite low. Even under these restriction, however, lindane may reach water resources at levels above the MCL of 0. 2 µg/ L. 32 i. Water Monitoring Data The presence of lindane in the environment, due to previous widespread agricultural use, is well documented in U. S. data bases. For example, In the U. S. EPA STORET data base, 720 detections in ground water were reported between the years 1968 and 1995, in nearly all regions of the country, with especially high numbers of detections in the South and West. For these 720 detections, the median and mean concentrations were 0.01 and 11 µg/ L, respectively. For surface waters, 8775 detections were reported with median and mean concentrations of 0.005 and 0. 18 µg/ L. STORET Detections were reported in nearly all regions of the conterminous U. S. In the USGS NAWQA study, lindane was detected in 2.58% of surface water samples (0. 67% at levels greater than 0.05 µ g/ L, maximum concentration reported was 0.13 µ g/ L). For groundwater, USGS NAWQA reported a detection frequency of 0. 1 % (0.07% at levels greater than 0.01 µ g/ L, maximum concentration reported was 0.032 µ g/ L). Mean and median concentrations from monitoring data are below HED's calculated Drinking Water Levels of Comparison (See Tables 10 and 11). ii. Ground Water EFED used the Screening Concentration in Ground Water (SCI­ GROW) model to estimate lindane concentrations in groundwater contaminated by terrestrial uses. SCI­ GROW is a regression­ based model that uses few input parameters: pesticide's organic carbon partition coefficient (Koc ), aerobic soil degradation half­ life, and product label application rate and frequency (Barrett, 1997). It provides a groundwater screening concentration for use in determining potential risk to human health from drinking water contaminated with a pesticide. The groundwater concentration is estimated based on the maximum application rates in areas where groundwater is exceptionally vulnerable to contamination. These vulnerable areas are characterized by high rainfall, rapidly permeable soil, and shallow aquifer. Input parameters and output and the resulting EEC are summarized in Table 7. Table 7. SCIGROW/ Groundwater Input Parameters and Results for Seed Treatment Application Rate: Wheat Canola 1 @ 0. 051 lb/ acre 1 @ 0. 116 lb/ acre Aerobic Soil Half Life 980 days (mean value) Organic Carbon Partitioning Coefficient (Koc ) 1367 mL/ g (median value) Peak EEC 0.011 µg/ L (wheat) 0.025 µg/ L (canola) Annual Average EEC 0.011 µg/ L (wheat) 0.025 µg/ L (canola) 33 iii. Surface Water Surface water concentrations from lindane use as a seed treatment were previously estimated using the Generic Estimated Environmental Concentrations (GENEEC) model. The GENEEC model is no longer used to estimate EECs for drinking water, however. Therefore, revised surface water concentrations were predicted with the assessment model, FIRST. FIRST is based upon the linked Pesticide Root Zone Model (PRZM) which simulates pesticides in field run­ off and Exposure Analysis Modeling System (EXAMs) which simulates pesticide fate and transport in an aquatic environment. FIRST uses an Index Reservoir which is based on Shipman City Lake in Illinois (13 acres in area, 9 feet deep, and a watershed area of 427 acres). FIRST is designed to produce more realistic estimates of pesticides in surface water that is used as a source of drinking water. Table 8 presents a summary of FIRST inputs and results. Table 8. FIRST/ Surface Water Input Parameters and Results for Lindane Seed Treatment. Parameter Value Application Rate and Number 0. 051 lb ai/ A x 1 application (Wheat) 0. 116 lb ai/ A x 1 application (Canola) Organic Carbon Partitioning Coefficient 942 ml/ g lowest of 4 values (MRID 00164346) Solubility 7 ppm Application Type Granular/ incorporated to 1.2 inches Percent Cropped Area 56% for Wheat and 87% for Canola Aerobic Soil Half­ life 980 days single value (MRID 406225­ 01)* Aerobic Aquatic Half­ life 1960 days (aerobic soil halflife x 2) Photolysis stable (MRIDs 0016457; 001645545; 447931) Hydrolysis stable (MRID 00161630) Peak EEC 0.98 µg/ L (wheat) 4.16 µg/ L (canola) Annual Average EEC 0.46 µg/ L (wheat) 1.95 µg/ L (canola) *In a 336­ day aerobic soil metabolism study, lindane degraded very slowly, with a registrant­ calculated half life of 980 days, thus the "3x" rule was not applied. iv. Drinking Water Estimate Environmental Concentrations The concentrations presented in Table 9 for drinking water EECs will be used for the purposes of this risk assessment. The drinking water EECs for surface water were based on the FIRST model simulations. Drinking water EECs for groundwater were based on SCIGROW model simulations. 34 Table 9. Drinking Water EECs for Lindane Drinking Water Source Acute Chronic Groundwater 0.025 µ g/ L 0. 025 µ g/ L Surface Water 4.16 µ g/ L 1. 95 µ g/ L F. Drinking Water Risk Estimates Drinking water levels of comparison (DWLOCs) associated with acute and chronic exposure to lindane in drinking water have been calculated. These DWLOCs are compared with the EECs of lindane in ground water and surface water. The DWLOC is the concentration of a chemical in drinking water that would be acceptable as an upper limit in light of total aggregate exposure to that chemical from food, water, and residential sources. The acute and chronic DWLOC for lindane includes aggregate exposure from food and water only. i. DWLOCs for Chronic Exposure Chronic DWLOCs were calculated based on the chronic dietary (food) exposure estimates using lindane TRR that had been adjusted using feeding and metabolism studies, along with default body weights and water consumption figures. The Agency's default body weights and water consumption values used to calculate DWLOCs are as follows: 70 kg/ 2L (adult male), 60 kg/ 2L (adult female), and 10 kg/ 1L (infant/ children). To calculate the chronic DWLOC, the chronic dietary food exposure was subtracted from the chronic PAD as shown in the following equation: DWLOCchronic = [chronic water exposure (mg/ kg/ day) x (body weight)] [consumption (L) x 10 ­3 mg/ g] where, chronic water exposure (mg/ kg/ day) = [cPAD ­ (chronic food (mg/ kg/ day)] The EECs for both surface water and groundwater were less than the chronic DWLOCs, indicating that chronic exposure to lindane in food and water is less than HED's level of concern. Calculated chronic DWLOCs and EECs are provided in Table 10. Table 10. Drinking Water Levels of Comparison for Chronic Dietary Exposure Population Subgroup Chronic PAD (mg/ kg/ day) Food Exposure (mg/ kg/ day) Max. Water Exposure (mg/ kg/ day) DWLOCchronic (ug/ L) Surface Water Annual Avg EECs (ug/ L) Ground Water Annual Avg EECs (ug/ L) US Population 0. 0016 0.000054 0.001546 54 1.95 0.025 All infants < 1 yr 0.0016 0.000072 0.001528 15 1.95 0.025 Children (1­ 6 yrs) 0. 0016 0.000173 0.001427 14 1.95 0.025 Children (7­ 12 yrs) 0.0016 0.000096 0.001504 15 1.95 0.025 Females (13­ 50 yrs) 0.0016 0.000034 0.001566 47 1.95 0.025 Males (13­ 19 yrs) 0.0016 0.000061 0.001539 54 1.95 0.025 Table 10. Drinking Water Levels of Comparison for Chronic Dietary Exposure Population Subgroup Chronic PAD (mg/ kg/ day) Food Exposure (mg/ kg/ day) Max. Water Exposure (mg/ kg/ day) DWLOCchronic (ug/ L) Surface Water Annual Avg EECs (ug/ L) Ground Water Annual Avg EECs (ug/ L) 35 Males 20+ 0.0016 0.000034 0.001566 55 1.95 0.025 Seniors 55+ 0.0016 0.000030 0.00157 55 1.95 0.025 ii. DWLOCs for Acute Exposure Acute DWLOCs were calculated based on the acute dietary exposure estimates that were determined using lindane TRR adjusted with feeding and metabolism studies, along with default body weights and water consumption figures. The Agency's default body weights and water consumption values used to calculate DWLOCs are as follows: 70 kg/ 2 L (adult male), 60 kg/ 2 L (adult female), and 10 kg/ 1 L (infant/ children). To calculate the DWLOC, the acute dietary food exposure was subtracted from the acute PAD using the equation: DWLOCacute = [acute water exposure (mg/ kg/ day) x (body weight)] [consumption (L) x 10 ­3 mg/ g] where, acute water exposure (mg/ kg/ day) = [aPAD ­ (acute food (mg/ kg/ day)] The EECs for both surface water and groundwater were less than the acute DWLOCs for all sub­ populations indicating that acute aggregate exposure to lindane in food and water is less than HED's level of concern. Acute DWLOCs and EECs are provided in Table 11. Table 11. Drinking Water Levels of Comparison for Acute Dietary Exposure Population Subgroup Acute PAD (mg/ kg/ day) Food Exposure (mg/ kg/ day) Max. Water Exposure (mg/ kg/ day) DWLOCacute (ug/ L) Surface Water Peak EEC (ug/ L) Ground Water Peak EEC (ug/ L) US Population 0. 02 0. 0013 0.019 665 4.16 0.025 All infants < 1 yr. 0. 02 0. 0033 0.017 170 4.16 0.025 Children 1­ 6 yrs. 0.02 0.002 0.018 180 4.16 0.025 Children 7­ 12 yrs. 0. 02 0. 0011 0.019 190 4.16 0.025 Females 13­ 50 yrs. 0.02 0.0005 0.019 570 4.16 0.025 Males 13­ 19 yrs 0. 02 0. 0007 0.019 665 4.16 0.025 Males 20+ 0.02 0.0005 0.019 665 4.16 0.025 Seniors 55+ 0.02 0.0004 0.019 665 4.16 0.025 36 iii. Non­ Dietary Exposure Occupational lindane exposure via dermal and inhalation routes can occur during handling, mixing, loading, and applying activities. There are currently no residential pesticidal uses being supported for lindane and therefore, there is no potential for residential exposure from pesticidal uses of lindane. Based on toxicological criteria and potential for exposure, HED has conducted separate dermal and inhalation exposure assessments for a variety of occupational scenarios. G. Occupational Exposure and Risk Estimates There are potential exposures to mixers, loaders, applicators, or other handlers associated with seed treatment uses of lindane. Based on the use patterns and potential exposures described above, 5 major exposure scenarios were identified as representative of lindane uses: (1) on farm seed treatment with dry formulations ­ open transfer system, (2) on farm seed treatment with liquid formulations ­ closed transfer system, (3) mixing/ loading and applying liquid with commercial seed­ treatment equipment, (4) bagging and otherwise handling treated seeds, (5) cleaning/ maintaining seed treatment equipment, and (6) loading/ planting treated seeds. To assess the exposures from on­ farm treatment of the liquid formulation with a closed transfer system (scenario 2) and commercial seed treatment activities with lindane (scenarios 3, 4a, 4b, and 5), the Agency considered all relevant data, including a study which was conducted at three seedtreatment plants in Alberta, Canada, during which lindane was one of the active ingredients being monitored (MRID 44731501). To refine this assessment, the Agency also used surrogate data from a commercial seed treatment facility (Helix study, MRID 45200002), from which median unit dermal and inhalation exposure measurements were available to assess risks to various commercial seed treatment workers, including baggers, sewers, stackers, forklift operators, and cleaners. Because the equipment used for on­ farm treatment with the liquid formulation has similar performance to the equipment used in the commercial facility, exposure data from the Helix study was also used to assess workers treating seeds for this scenario (scenario 2). In addition, the Agency used surrogate exposure data (Isophenfos study, MRID 42251901) to assess loading and planting treated seeds (scenario 6). Table 12 presents the exposure scenarios, application rates, and amount potentially handled that have been used for the exposure calculations. Exposures for handling treated seed before planting and planting treated seed use parameters for wheat and canola as representative crops. Therefore, the rates/ seed types presented in Table 12 are representative, rather than inclusive, and no attempt has been made to assess a range of application rates to ensure that all use rate/ exposure scenarios are included. Table 12: Exposure Variables for Uses of Lindane Exposure Scenario (Scenario #) Chemical Specific Monitoring Data Available? PHED Data? Application Rates (lb ai/ amount of seed) Daily lb Seed Treated/ Handled Lb ai Handled/ day (1) on farm seed treatment with dry formulations ­ open transfer system Yes Fenske Study MRID #44405802 No 0.023 lb ai/ bushel (60 lbs seed) for wheat 0.056 ­0. 125 lb ai/ 100 lb( corn) 12000­ 24000 lbs seed (wheat) 1500 2700 lbs seed (corn) 5.0 a ­9. 3 (wheat) 0.84­ 3. 4 (corn) Table 12: Exposure Variables for Uses of Lindane Exposure Scenario (Scenario #) Chemical Specific Monitoring Data Available? PHED Data? Application Rates (lb ai/ amount of seed) Daily lb Seed Treated/ Handled Lb ai Handled/ day 37 (2) on farm seed treatment with liquid formulations closed transfer system Yes Helix Study MRID #45200002 No 0. 043 lb ai/ 100 lb seed (wheat) 0. 75 ­ 1. 5 lb ai/ 100 lb seed (canola) 30000 lbs seed b (wheat) 2000 lbs seed (canola) 13 (wheat) 15/ 30 (canola) (3) mixing/ loading and applying liquid with a commercial seed­ treatment equipment Yes Helix Study MRID #45200002 No 0. 043 lb ai/ 100 lb seed (wheat) 0. 75 ­ 1. 5 lb ai/ 100 lb seed (canola) 176000 lbs seed (wheat and canola) 76 (wheat) 1320/ 2640 (canola) (4) handlerfor commercial seed­ treatment equipment (i. e. bagging and stacking and forklift operator) Yes Helix Study MRID #45200002 No 0. 043 lb ai/ 100 lb seed (wheat) 0.75­ 1.5 lb ai/ 100 lb seed (canola) 176000 lbs seed (wheat and canola) 76 (wheat) 1320/ 2640 (canola) (5) Cleanerfor commercial seed treatment Yes Helix Study MRID #45200002 No Cleaner daily inhalation exposures measured in mg/ kg/ day were taken directly from the HELIX study. (6) Loading and Planting treated seed Yes Isophenphos Study MRID #42251901 Yes 0. 043 lb ai/ 100 lb seed (wheat) 0. 75 ­ 1. 5 lb ai/ 100 lb seed (canola) 30000 lbs seed b (wheat) 2000 lbs seed (canola) 13 (wheat) 15/ 30 (canola) a Data are available from on farm treatment study; assumes 120 lbs wheat per acre, planting 100 ­200 acres per day; 15 lbs corn/ acre planting 100180 acres day b Daily amount treated based on HEDs estimates of acreage that would be reasonably expected to be planted in a day for commercially treated seed or seed treated with an on­ farm closed system. Assumes 120 lbs wheat/ acre, 8 lbs canola/ acre, planting an average of 250 acres/ day. i. Commercial Seed Treatment HED has revised its assessment of occupational exposure for commercial seed treatment. The previous assessment was based on a commercial seed treatment study (MRID 44731501) which was of a lesser quality and probably did not address changes in the technology that have occurred since the study was conducted . The revised assessment is based on a study measuring exposures of workers treating canola seed with HELIX 289S (a mixture of thimethozam, difenconazole, metalaxyl, and fludioxonil). The study was reviewed jointly by EPA and PMRA (MRID 45200002). The HELIX 289S Study is comprehensive occupational exposure study designed and conducted to quantify potential exposure to thiamethoxam, formulated as a flowable liquid, during commercial treatment of canola seed. Lindane end­ use products for canola use are liquids (flowable formulation). Lindane products for grower use on small grains, corn, and sorghum are dust and wettable powders and liquids. In the absence of more formulation specific data, HED believes the HELIX Study provides the best data available for assessing exposure/ risk from commercial seed treatment with lindane. HED has reevaluated the estimates of exposure and risk from treatment of wheat and canola seed with lindane using unit dermal and inhalation exposures provided in the HELIX 289FS Study. A detailed description of the study and the calculations for exposure assessment are provided in an April 23, 2002 memorandum from D. Jaquith (D282419). ii. On Farm Seed Treatment and Planting of Treated Seed Based on seed treatment surveys and conversations with experts in the field, the vast majority (98%) of lindane seed treatments are incorporated into the seed on farm; very little is 38 incorporated into the seed by seed processors. Corn and oats are exclusively treated on farm (BEAD's Impact Analysis of the Seed Treatment Uses of Lindane on Wheat, Barley, Oats, Rye, Corn, Sorghum, andCanola, D. Brassard, 2/ 5/ 00). HED'sevaluationofonfarmseedtreatment in an open system was based on a study of worker exposure to lindane during manual treatment of winter wheat (Fenske, MRID 44405802; D283397). HED also evaluated the exposures of workers using on­ farm seed treatment transfer systems for liquid formulations which provide a more enclosed environment. For the closed transfer system worker exposure analysis, HED used median unit dermal and inhalation exposures provided in the HELIX 289FS commercial seed treatment study to estimate exposure and risk from lindane treatment of wheat and canola seed. HED has also reevaluated exposures from the loading and planting of seed treated with lindane. These revisions are based on data provided in a study measuring exposures of workers to isophenphos during planting of oftanol­ treated canola seed (MRID No. 42251901). A detailed description of the study and the calculations for exposure assessment are provided in exposure assessment memoranda from D. Jaquith (D282418, D283397). The revised assessment also uses a higher seeding rate of 8 lb/ seed/ acre. The previous assessment assumed a seeding rate of 4 lb/ seed/ acre. iii. Occupational Exposure and Risk Occupational exposure scenarios assessed are summarized in Table 13. The daily exposures, as well as the resulting short and intermediate term MOEs are presented in Table 14. Short and intermediate (if applicable) term MOEs were calculated for dermal and inhalation exposure routes for a total of five worker exposure scenarios. The analysis indicates MOEs of concern (MOE< 100) for the following exposure scenarios/ pathways: dermal exposure from on farm seed treatment; inhalation exposure from commercial treatment (mixing/ loading/ application) of canola seed at both high and low­ end rates of 1. 5 and 0. 75 lb/ 100 lb seed; and inhalation exposure from commercial handling of canola treated at the high­ end application rate of 1. 5 lb/ 100 lb seed. All other exposure scenarios result in MOEs that are not of concern for either dermal or inhalation exposure pathways. Dermal MOEs for all scenarios range between 9 and 190000. Inhalation MOEs range from 30 to 16000. MOEs are not of concern for the on farm worker using a closed system and wearing protective clothing similar to that of commercial seed treatment plant workers. However, it must be noted that the exposure/ risk assessments presented in Table 13 for the on farm closed transfer system scenario are valid only if the type of equipment and protective clothing used in the surrogate HELIX study are employed. Therefore, this closed system exposure/ risk assessment can be used for regulatory purposes only if the personal protective measures assumed in the analysis are required on the label. Table 13. Exposure Scenario Descriptions for the Use of Lindane. Exposure Scenario Data Source Standard Assumptions a Comments On­ farm seed treatment with dry formulation ­ open transfer system (1) Rhone­ Poulenc Data Fenske Study MRID # 444058­ 02 Assumes enough seed treated and planted for 100 Acres per day low end, 180/ 200 Acres per day high­ end All data were for gloved hands; (see study, Appendix A, D283397) Table 13. Exposure Scenario Descriptions for the Use of Lindane. Exposure Scenario Data Source Standard Assumptions a Comments 39 On­ farm seed treatment with liquid formulation ­ closed transfer system (2) HELIX Study Data MRID # 45200002 Assumes 250 acres are planted per day at 120 lbs of wheat; 8 lbs of canola seed per acre See study review, based on Imazilil Assessment and BEAD data Mixing/ loading/ application of liquid formulation for commercial seed treatment (3) HELIX Study Data MRID # 45200002 Assumes throughput of seed for both wheat and canola is 176000 lbs per 8 hour day See study review; based on amounts of seed from study data Seed Handler for commercial seed treatment (4) HELIX Study Data MRID # 45200002 Assumes throughput of seed for both wheat and canola is 176000 lbs per 8 hour day See study review; based on amounts of seed from study data Cleaner for commercial seed treatment (5) HELIX Study Data MRID # 45200002 Based on practices used in the HELIX Study See study review; based on amounts of seed from study data Loading and Planting treated seed (6) Isophenphos Study Data MRID #42251901 Assumes 250 acres are planted per day at 120 lbs of wheat; 8 lbs of canola seed per acre See study review, based on Imazilil Assessment and BEAD data a All Standard Assumptions are based on an 8­ hour work day as estimated by HED. Table 14: Daily Exposures, Short and Intermediate MOEs of Workers to Lindane During Seed Treatment and Planting of Treated Seed. Exposure Scenario (Scenario #) Crop Application Rates ( lb ai/ 100 lbs seed or Lb/ A) Amount Handled per Day (lbs a. i.) Unit Exposure (mg/ lb ai) a Daily Exposure (mg/ kg/ day) Short­ Term & Intermediate Term b MOEs Dermal Inhalation Dermal c Inhalation e Dermal d Inhalation f On farm seed treatment with dry formulation ­ open transfer system (1) wheat 0.043 5 (100A planted) 9.4 0. 0016 0.70 0.0001 17 1100 0.043 10 (200 A planted) 9.4 0. 0016 1.39 0.0002 9 550 corn 0.056 low­ end 0.84( 100 A planted) 9.4 0. 0016 0.11 0.00002 92 6500 1.5 (180 A planted) 9.4 0. 0016 0.20 0.00003 60 3700 0.125 high­ end 1.9 (100 A planted) 9.4 0. 0016 0.25 0.00004 48 3000 3.4 (180 A planted) 9.4 0. 0016 0.45 0.00007 26 1700 On farm seed treatment with liquid formulation­ closed transfer system (2) wheat 0.043 13 0.00083 0.00012 0.0002 0.000022 67000 5900 canola 1.5 high­ end 30 0.00083 0.00012 0.0004 0.00005 29000 2500 0.75 low­ end 15 0.00083 0.00012 0.0002 0.000026 57000 5000 Mixing/ loading/ application of liquid formulation for commercial seed treatment Treater Closed Transfer chemical resistant coveralls over long­ sleeved shirt, longpants, chemical resistant gloves( 3) wheat 0.043 76 0.00083 0.00012 0.0010 0.00013 11000 1000 canola 1.5 high­ end 2640 0.00083 0.00012 0.036 0.0045 330 30 0.75 low­ end 1320 0.00083 0.00012 0.018 0.0023 660 60 Seed Handler for commercial seed treatment Bagger/ Sewer/ Stacker chemical resistant coveralls over long­ sleeved shirt, long pants, chemical resistant gloves (4a) wheat 0.043 76 0.00026 0.00006 0.00033 6.5E­ 05 37000 2000 canola 1.5 high­ end 2640 0.00026 0.00006 0.011 0.0023 1000 60 0.75 low­ end 1320 0.00026 0.00006 0.0057 0.0011 2100 120 Table 14: Daily Exposures, Short and Intermediate MOEs of Workers to Lindane During Seed Treatment and Planting of Treated Seed. Exposure Scenario (Scenario #) Crop Application Rates ( lb ai/ 100 lbs seed or Lb/ A) Amount Handled per Day (lbs a. i.) Unit Exposure (mg/ lb ai) a Daily Exposure (mg/ kg/ day) Short­ Term & Intermediate Term b MOEs Dermal Inhalation Dermal c Inhalation e Dermal d Inhalation f 40 Seed Handler for commercial seed treatment ­ Forklift Operator ­ cotton/ polyester coveralls over long­ sleeved shirt, long pants, chemical resistant gloves (4b) wheat 0.043 76 0.00008 8E­ 06 0. 00010 8.3E­ 06 119000 16000 canola 1.5 high­ end 2640 0.00008 8E­ 06 0. 0035 0.00029 3400 450 0.75 low­ end 1320 0.00008 8E­ 06 0. 0018 0.00015 6800 900 Cleaner* ­ chemical resistant coveralls over long­ sleeved shirt, long pants, chemical resistant gloves (5) wheat NA NA NA NA 0.0067 0.0012 1800 110 canola NA NA NA NA 0. 0067 0.0012 1800 110 Loading and Planting Treated Seed (6) wheat 0.043 13 0.06 0.0006 0.013 00011 920 1200 canola 1.5 high­ end 30 0.06 0.0006 0.03 0.00026 400 500 0.75 low­ end 15 0.06 0.0006 0.015 0.00013 800 1000 a Median unit dermal and inhalation unit exposures b Intermediate term MOEs are not applicable for Scenarios (1) On Farm Seed Treatment and (5) Planting Treated Seed. c Daily Dermal Exposure (mg/ kg/ day) = unit exposure (mg/ lb ai) x amount handled per day (lbs a. i.) / bw (60 kg). d Dermal MOE = Oral NOAEL (1. 2 mg/ kg) / [daily exposure (mg/ kg/ day) x dermal absorption factor (10%)]. e Daily Inhalation Exposure (mg/ kg/ day) = inhalation unit exposure (mg/ lb ai) x amount handled per day (lbs a. i.) / body weight (70 kg). *Cleaner daily inhalation exposures, measured in mg/ kg/ day, were taken directly from the HELIX study. f Inhalation MOE = NOAEL (0. 13 mg/ kg/ day) / daily exposure (mg/ kg/ day). V. Aggregate and Cumulative Exposure and Risk Characterization The Food Quality Protection Act amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA, Section 408( b)( 2)( A)( ii)) require that for establishing a pesticide tolerance "that there is reasonable certainty that no harm will result from aggregate exposure to pesticide chemical residue, including all anticipated dietary exposures and other exposures for which there are reliable information." Aggregate exposure is the total exposure to a single chemical (or its residues) that may occur from dietary (i. e., food, and drinking water), residential and other non­ occupational sources, and from all known or plausible exposure routes (oral, dermal and inhalation). Aggregate risk assessments are typically conducted for acute (1 day), short­ term (1­ 7 days), intermediate­ term (7 days to several months), and chronic (several months to lifetime) exposure. 41 A. Acute Aggregate Risk The acute aggregate risk estimate to lindane addresses exposures from food and drinking water only since there are no residential pesticide uses remaining. The lindane acute dietary risk estimates, including all sources of residues of lindane, range from 2% to 17% of the aPAD at the 99.9 th percentile of the population, with infants (< 1yr) being the highest exposed population subgroup. Thus, the acute dietary (food) risk estimate associated with lindane exposure is below the Agency's level of concern. Based on SCI­ GROW model simulations, the acute estimated concentration (EEC) of lindane in groundwater from seed treatment uses is 0.025 µg/ L. The acute surface water EECs resulting from the use of lindane are 4. 16 µg/ L based on FIRST modeling results. The EECs from the use of lindane are less than the DWLOCs for all populations, indicating that acute food and drinking water exposures do not exceed the Agency's level of concern. It should be noted that neither the model nor the monitoring data reflect concentrations after dilution (from source to treatment to tap) or drinking water treatment. HED concludes that acute aggregate lindane exposure in food and water from the use of lindane does not exceed the Agency's level of concern. B. Short­ and Intermediate­ Term Aggregate Risk The short­ and intermediate­ term aggregate risk estimate includes chronic dietary (food and water) from lindane uses, and intermediate­ term non­ occupational exposures (i. e., residential/ recreational uses). There are no residential/ recreational seed treatment uses with a short or intermediate­ term exposure scenario. Therefore, a short and intermediate­ term aggregate risk estimate were not evaluated. C. Chronic Aggregate Risk Chronic aggregate risk estimates do not exceed HED's level of concern. The aggregate chronic dietary risk estimates include exposure to lindane residues in food and water only since no chronic residential pesticide use scenarios were identified. The resulting risk estimates are 3 % of the chronic PAD (% cPAD) for the U. S. Population and 11 % of the cPAD for Children 1­ 6 years of age (the most highly exposed population subgroup). The remaining population subgroups were between 2% and 6 % of the cPAD when the feeding studies were adjusted using the metabolism studies. Using the FIRST model, the estimated average concentration of lindane in surface water resulting from seed treatment uses is 1.95 ppb. The chronic EEC for groundwater based on the SCI­ GROW model 0.025. Both surface and groundwater EECs are less than HED's respective drinking water level of comparison for exposure to lindane. Mean and median concentrations from monitoring data are also below HED's calculated DWLOCs. Based on the 42 available information, HED concludes with reasonable certainty that no harm to any population will result from chronic aggregate exposure to lindane. D. Cumulative Exposure and Risk The Food Quality Protection Act (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non­ occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low­ level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. HED did not perform a cumulative risk assessment as part of this reregistration review for lindane because HED has not yet initiated a review to determine if there are any other chemical substances that have a mechanism of toxicity common with that of lindane. For purposes of this reregistration decision , EPA has assumed that lindane does not have a common mechanism of toxicity with other substances. On this basis, the registrant must submit, upon EPA's request and according to a schedule determined by the Agency, such information as the Agency directs to be submitted in order to evaluate issues related to whether lindane shares a common mechanism of toxicity with any other substance and, if so, whether any tolerances for lindane need to be modified or revoked. If HED identifies other substances that share a common mechanism of toxicity with lindane, HED will perform aggregate exposure assessments on each chemical, and will begin to conduct a cumulative risk assessment. HED has recently developed a framework that it proposes to use for conducting cumulative risk assessments on substances that have a common mechanism of toxicity. This guidance was issued for public comment on January 16, 2002 (67 FR 2210­ 2214) and is available fromthe OPPWebsite at: http:// www. epa. gov/ pesticides/ trac/ science/ cumulative_ guidance. pdf In the guidance, it is stated that a cumulative risk assessment of substances that cause a common toxic effect by a common mechanism will not be conducted until an aggregate exposure assessment of each substance has been completed. Before undertaking a cumulative risk assessment, HED will follow procedures for identifying chemicals that have a common mechanism of toxicity as set forth in the "Guidance for Identifying Pesticide Chemicals and Other Substances that Have a Common Mechanism of Toxicity" (64 FR 5795­ 5796, February 5, 1999). 43 VI. Risk Characterization The lindane risk assessment contains strengths, weaknesses, and uncertainties based on the existing toxicological and exposure data, modeling methodologies, data gaps, and gaps in scientific knowledge. This assessment uses standard assumptions regarding human body weight, work life, and other exposure parameters; and interspecies extrapolation to estimate risks. Additional assumptions were made regarding route to route extrapolation. Strengths and uncertainties of the assessment are described below. The OPP/ Cancer Assessment Review Committee (CARC) has completed the review of newly submitted carcinogenicity study in CD­ 1 mice along with other data. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC has classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on an increased incidence of benign lung tumors in female mice only. The Committee, therefore, recommended that the quantification of human cancer risk is not required. Lindane is a neurotoxicant. In acute, subchronic and developmental neurotoxicity studies, it was found to cause neurotoxic effects including tremors, convulsions, decreased motor activity, increased forelimb grip strength, hypersensitivity to touch, hunched posture and decreased motor activity habituation. There also appears to be a greater susceptibility to exposure by offspring compared to parental animals in the developmental neurotoxicity study. Lindane has also been implicated as a possible endocrine disruptor in birds, mammals and possibly fish. Further studies to ascertain the validity of such evidence is necessary to make informed risk assessment decisions. Lindane is distributed to all organs at measurable concentrations within a few hours after oral administration. The highest concentrations are found in adipose tissue. The metabolism of lindane is initiated through one of several pathways: Dehydrogenation leading to gamma HCH, dehydrochlorination leading to formation of gamma hexchlorohexene or hydroxylation leading to formation of hexachlorocyclohexanol. Further metabolism leads to a large number of metabolites. Lindane is converted by enzymatic reactions, mainly in the liver. Lindane appears to affect the liver and kidney in male rats when administered through the oral, dermal or inhalation routes of exposure. Kidney lesions in males indicative of alpha 2µ globulin accumulation were observed in animals treated with  10 ppm, but are not considered relevant to human health risk assessment The liver effects include: incidence of periacinar hepatocytic hypertrophy which was significantly (p  0.01) increased in male and female rats dosed at 100 ppm (4. 81 and 6.00 mg/ kg/ day, respectively). In addition, increased liver and spleen weights, and decreased platelets were also noted. 44 Lindane is not considered teratogenic when administered orally or subcutaneously. Developmental NOAELs were found to be at levels equal to or greater than maternal NOAELs, except in the developmental neurotoxicity study. The developmental neurotoxicity LOAEL was 5.6 mg/ kg/ day (NOAEL was 1. 2 mg/ kg/ day) based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation compared to a maternal toxicity LOAEL of 13.7 mg/ kg/ day (NOAEL is 5.6 mg/ kg/ day) based on decreased body weight gains, decreased food consumption, and increased reactivity to handling. The data base for reproductive toxicity is considered complete. Both parental and offspring LOAELs are 13 mg/ kg; however there is a qualitative difference in the severity of effects. In the parental animals, toxicity was seen in the form of reduction in body weight gain during gestation while offspring toxicity was correlated with decreases in pup viability and pup body weight in the F1 and F2 generations as well as delayed maturation in the F2 generation. Evidence for quantitative increase in susceptibility could not be ascertained due to the wide spread in the doses tested. In a mammalian cell gene mutation assay and an in vivo sister chromatid exchange assay, no mutagenic response was detected. These studies were classified as unacceptable. The open literature suggests, however, that technical grade HCH (hexachlorohexane; 6. 5%
HCH) may induce some mutagenic activity as evidenced in a dominant lethal mutation assay and sister chromatid exchanges. It has been noted, however, by the IPCS that lindane does not appear to have a mutagenic potential. There are no adequate nature of the residue studies for plants from seed treatment application. A new metabolism study is required for cereal grains; however, a seed treatment metabolism study (which was classified as inadequate) was reviewed by the Agency and used in the determination of the TRR for use in the dietary exposure analysis. Additional residue data would be required if the HED MARC determines residues of concern include metabolites of lindane in addition to lindane per se. The lindane residue values were derived using a ratio of total radioactive residue divided by the amount of lindane present in the metabolism studies. This would be worstcase estimatesince we areassuming thatallofthe TRRwould be residues of concern. The dietary exposure analyses using the total radioactive residues is a Tier 3 assessment since percent crop treated was used in the analyses. The dietary exposure analyses that were based on the adjustment of the lindane residues in the feeding studies is a Tier 3 assessment. Percent market share was available for all crops included in the analyses. Since lindane is registered for seed treatments only, there is no difference in the percent crop treated values between crops grown for the fresh market and those grown for processing. A processing study was available for canola only; the default DEEM™ processing factors were used for all other foods. 45 No acute or chronic residential use scenarios were identified for lindane; therefore, aggregate risk estimates address exposures from food and drinking water only. The lindane acute dietary risk estimates, including all sources of residues of lindane, range from 7% to 17% of the aPAD at the 99.9 th percentile of the population, with infants (< 1yr) being the highest exposed population subgroup. Thus, the acute dietary (food) risk estimate associated with lindane exposure is below the Agency's level of concern. The aggregate chronic dietary risk estimates include exposure to lindane residues in food and water. The resulting risk estimates are 3 % of the chronic PAD (% cPAD) for the U. S. Population and 11 % of the cPAD for Children 1­ 6 years of age (the most highly exposed population subgroup). The remaining population subgroups were <6 % of the cPAD when the total radioactive residue is adjusted using the metabolism studies. Chronic aggregate risk estimates, therefore, do not exceed HED's level of concern. Exposure estimates for a number of occupational scenarios were derived from limited data from the submitted studies, scientific literature, and knowledge of cultural practices, in combination with models and literature studies. No residential exposure assessment was conducted by the Agency since pesticide uses have been limited to seed treatment only. The Agency considers the occupational exposure estimates to be the best available with current methodologies. The analysis indicates MOEs of concern (MOE< 100) for the following exposure scenarios/ pathways: dermal exposure from on farm seed treatment; inhalation exposure from commercial treatment (mixing/ loading/ application) of canola seed at both high and low­ end rates of 1. 5 and 0. 75 lb/ 100 lb seed; and inhalation exposure from commercial handling of canola treated at the high­ end application rate of 1. 5 lb/ 100 lb seed. All other exposure scenarios result in MOEs that are not of concern for either dermal or inhalation exposure pathways. Volatilization appears to be an important route of its dissipation under the high­ temperature conditions of tropical regions. The presence of lindane in the environment, due to previous widespread agricultural use, is well documented in U. S. data bases. For example, In the U. S. EPA STORET data base, 720 detections in ground water were reported between the years 1968 and 1995, in nearly all regions of the country, with especially high numbers of detections in the South and West. For these 720 detections, the median and mean concentrations were 0.01 and 11 µg/ L, respectively. For surface waters, 8775 detections were reported with median and mean concentrations of 0.005 and 0. 18 µg/ L. STORET Detections were reported in nearly all regions of the conterminous U. S. In the USGS NAWQA study, lindane was detected in 2.58% of surface water samples (0. 67% at levels greater than 0.05 µ g/ L, maximum concentration reported was 0.13 µ g/ L). For groundwater, USGS NAWQA reported a detection frequency of 0. 1 % (0.07% at levels greater than 0.01 µ g/ L, maximum concentration reported was 0. 032 µ g/ L). HCH and Lindane have been found in the tissues and fat of humans living in the Arctic. It appears that lindane is transported from regions where it is used to the Arctic and has been found at detectable levels in the food supply of the indigenous populations of Alaska and the Northwest Territories. Detectable levels of lindane along with other isomers of HCH have been documented in fish, elk, caribou and other aquatic and wildlife. It persists in the air, water, and 46 soil and continues to show patterns of long range atmospheric movement into areas where it has been banned or never been used. The continued worldwide use of lindane may pose an environmental, as well as a human toxicologic risk to the indigenous peoples of the Arctic. The Indigenous Peoples of the Arctic region of the U. S. (Alaska) rely heavily on subsistence diets as their food source. Thus, it is appropriate for the Agency to perform a supplementary dietary risk and exposure assessment to assess the risk to the Indigenous People from worldwide use and manufacture of lindane. HED performed a revised supplementary chronic dietary risk and exposure assessment to assess the risk to Indigenous People from worldwide use and manufacture of lindane (T. Morton, D222455, 4/ 17/ 02). Based on this revised exposure estimate, the chronic dietary risk to male and female adult Indigenous People is below HED's level of concern. Revised estimate of risks to a 10 kg child results in an estimated chronic dietary risk to an Indigenous child (1­ 6 years) of 0.0002 ­ 0. 0022 mg/ kg/ day (13 to 138% cPAD). Revised estimate of chronic dietary risk to a 7­ 12 year old indigenous child (29 kg body weight) is 0. 00007 ­0. 0008 mg/ kg/ day or 4­ 48% of the cPAD which is below HED's level of concern. It should be noted that factors such as bioaccumulation of lindane and the cumulative effects of combinations of chemicals which act through a common mode of action have not been incorporated into this assessment. As the Agency develops its cumulative risk assessment policies, if lindane is found to share a common mode of action with other chemicals, a more comprehensive evaluation of the contribution to public risk will be initiated. This risk assessment does not at this time include an assessment of risks from exposure to lindane from uses other than seed treatment (e. g., use of lindane to treat head lice or scabies). VII. Data Needs Most of the Reregistration data requirements for Lindane have been fulfilled. The few remaining data requirements are described below. A. Toxicology Data Requirements 870.3700b Prenatal developmental in rabbit 870.5300 Gene Mutation Mammalian Cell 870.5450 Dominant Lethal Assay 870.5915 In Vivo Sister Chromatid Exchange Although the prenatal developmental study in rabbits was found unacceptable, a new study is not being required at this time. The rationale for this decision is contained in the body of this document. No further genetic toxicity testing are required at this time. The mutagenic potential of lindane will be reevaluated in conjunction with the carcinogenicity review and a determination as to the need for further studies will occur at that time. 47 B. Product and Residue Chemistry Data Requirements Product Chemistry  All pertinent product chemistry data are satisfied for the Kanoria 99.5% T/ TGAIs except additional data are required concerning UV/ visible absorption (OPPTS 830.7050). Pertinent product chemistry data remain outstanding for the Inquinosa 99.5% T/ TGAI concerning product identity, starting materials and production process, preliminary analysis, certified limits, oxidation/ reduction, explodability, storage stability, corrosion characteristics, and UV/ visible absorption (OPPTS 830.1550, 1600, 1620, 1700, 1750, 6314, 6316, 6317, 6320, and 7050). These data have been submitted and are currently under review by HED (T. Morton, D276302). Technical products registered to Kanoria Chemicals & Industries were suspended effective 12/ 5/ 00 for failure to comply with a cost sharing agreement with Inquinosa. Therefore, all technicals registered which are repackages of the Kanoria products would be required to change suppliers. The Kanoria products are shown in data summary tables which are attached to the Revised Residue Chemistry Chapter (T. Morton, 12/ 11/ 01, D279259) for informational purposes only. The Prentiss, Drexel, and Amvac 99. 5% technicals are repackaged from EPA­ registered products, and all data requirements will be satisfied by data for the technical source products. Provided that the registrants submit the data required in the data summary tables for the lindane T/ TGAIs in the Product and Residue Chemistry Chapters (T. Morton, 279259) and either certify that the suppliers of beginning materials and the manufacturing processes have not changed since the last comprehensive product chemistry reviews or submit complete updated product chemistry data packages, the Branch has no objections to the reregistration of lindane with respect to product chemistry data requirements. Residue Chemistry ­ The Agency will not require a new confined rotational crop study provided the registrants propose a 30­ day plantback interval for leafy vegetables and a 12­ month plantback interval for all other unregistered crops on all of their end­ use product labels for lindane. ­ New nature of the residue study is required for application of lindane as a seed treatment to a cereal grain. ­ If, after submission of an acceptable cereal grain seed treatment metabolism study, the HED Metabolism Assessment Review Committee determines the residues of concern to include metabolites in addition to lindane, additional crop field trial data, magnitude of the residue in poultry and cattle, and processing studies will be required. In addition, an adequate residue analytical method and storage stability data will be required. 48

epa

2024-06-07T20:31:43.024812

regulations

EPA-HQ-OPP-2002-0202-0003

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Office of Prevention, Pesticides and Toxic Substances July 31, 2002 MEMORANDUM SUBJECT: Lindane; Chemical No. 009001. Revised Assessment of Risk from Use of Lindane for Treatment of Lice and Scabies DP Barcode: D284188; Submission No. S605841 Reregistration Case #: 0315 FROM: Becky Daiss Environmental Health Scientist Reregistration Branch 4 Health Effects Division (7509C) THROUGH: Susan Hummel Branch Senior Scientist Reregistration Branch 4 Health Effects Division (7509C) TO: Mark Howard Reregistration Branch 3 Special Review & Reregistration Division (7508C) This provides HED's revised assessment of risk from use of lindane for treatment of scabies and lice. The revised assessment incorporates additional information and comments provided by the Food and Drug Administration (FDA). 2 1.0 ASSESSMENT OF RISK FROM USE OF LINDANE TO TREAT SCABIES HED's assessment of risk from use of lindane to treat scabies uses data from both animal and human studies and provides a range of risk estimates. EPA conducted analyses using: 1) a Margin of Exposure (MOE) approach based on animal toxicity data, and 2) a comparison of lindane blood levels from one study which documents cases of accidental lindane ingestion by toddlers in which blood levels were determined after ingestion, and a second study which provides data on blood levels of lindane following application of lindane to treat scabies. HED based its assessment on directions provided in the current label for scabies treatment. It is important to note, however, that FDA is planning to make a number of changes to the label including statements that restrict the use to patients who have attained adult stature (i. e., > 60 kg body weight). Therefore, HED also considered pending label changes in its assessment of lindane as a scabies treatment. 1.1 MOE Approach Under this approach, an estimated MOE is calculated based on a toxicological endpoint recommended by HED's Hazard Identification and Assessment Committee (HIARC) and compared with the target MOE for short­ term dermal exposure/ risk to determine whether there is an exposure of concern. The MOE is the ratio of the appropriate No Observed Adverse Effect Level (NOAEL) to estimated exposure. For the short­ term dermal endpoint, a NOAEL of 6 mg/ kg/ day was selected from an acute oral neurotoxicity study in rats. For residential exposures, uncertainty factors are used to determine target MOEs. The target MOE for exposure to lindane from pharmaceutical use is 100 based on uncertainty factors (UF) used to account for differences among humans (intraspecies variability ­ UF of 10), and for differences between the test animals and humans (interspecies extrapolation ­ UF of 10). Since the NOAEL is based on an oral toxicity study, dermal absorption data are required to adjust the oral dose. Two different dermal absorption factors were used to calculate estimated exposure. One was taken from a 1989 article published in Journal of Toxicological and Environmental Health, which reported data from a dermal absorption study on rhesus monkeys to determine if lindane applied for treatment of lice and scabies is absorbed into the blood stream (1). A second was taken from a study in Toxicology and Applied Pharmacology, 1974, in which lindane was tested on human subjects to quantify dermal penetration (2). The monkey study involved topical application of 1% lotion, at label prescribed rates, to the forehead, forearm, or forepaw of monkeys for 24 hours. Percent absorption was determined based on urinary excretion of 14 C­ lindane. Study results indicated that 18, 34, and 54% of the applied dose was absorbed after application to the forearm, forehead, and palm, respectively. A weighted average of 20% was derived based on the body surface area corresponding to the applicable dermal absorption factor from the monkey study. For the human study, C 14 ­labeled lindane was applied topically (4 g/ cm 2 ) to the forearm and via the intravenous route (1 Ci). Excretion of the chemical was then monitored by collecting 3 and analyzing urine samples during the 5 day testing period. All results were calculated as percent of the injected or applied dose. Data from the IV dosing was used to correct the skin penetration data for incomplete urinary recovery. Lindane was shown to have a dermal penetration factor of 9.3% ± 3. 7 (SD). Results of the scabies MOE assessment for children and young adults using both monkey and human dermal absorption data are provided in Tables 1 and 2 respectively. The analysis indicates MOEs of concern (MOE< 100) from both high and low­ end treatment scenarios. Table 1. Assessment of Use of Lindane for Scabies ­ DAF from Product Specific Monkey Study Age Group Oral NOAEL (mg/ kg/ d) Applied Dose (mg) 1 Body Weight (kg) 2 Daily Dermal Dose (mg/ kg/ d) dermal absorption (%) MOE Target MOE 3 Young Adult 6 600 high end (1 oz) 60 10 20 3 100 Young Adult 6 300 low end (2 oz) 60 5 20 6 100 Child 4­ 6 6 250 high end 22 11 20 3 100 Child 4­ 6 6 150 low end 22 7 20 4 100 Toddler 1­ 3 6 200 high end 13 15 20 2 100 Toddler 1­ 3 6 100 low end 13 8 20 4 100 MOE = Oral NOAEL( mg/ kg/ day) daily dermal dose (mg/ kg/ day) x dermal absorption factor (%) where: Daily Dermal Dose = applied dose (mg) ÷ body weight (kg) Applied Dose = 20­ 60g of 1% lotion (high­ end); 10­ 30 g of 1% lotion (low­ end) depending on age group Dermal Absorption Factor = 20% (weighted avg) where: Palm Dermal Absorption Factor = 54% ­­ DAF from monkey study; Used for hands which are assumed to be 6% of Dosed Body Surface Area based on % of Surface Area/ Body Part from EPA Exposure Factor Handbook (EFH) Vol I Forearm Dermal Absorption Factor = 18% ­­ DAF from monkey study; Used for 94% of Dosed Body Surface Area (all but hands) based on % of Total Surface Area/ Body Part from EPA EFH Vol I Dosed Body Surface Area = entire body from neck down Table 2. Assessment of Lindane for Scabies ­ DAF from Pesticide Exposure in Human Study Age Group Oral NOAEL (mg/ kg/ d) Applied Dose (mg) 1 Body Weight (kg) 2 Daily Dermal Dose (mg/ kg/ d) dermal absorption (%) MOE Target MOE 3 Young Adult 6 600 high end 60 10 10 6 100 Young Adult 6 300 low end 60 5 10 12 100 Child 4­ 6 6 250 high end 22 11 10 5 100 Child 4­ 6 6 150 low end 22 7 10 9 100 Toddler 1­ 3 6 200 high end 13 15 10 4 100 Toddler 1­ 3 6 100 low end 13 8 10 8 100 MOE = Oral NOAEL( mg/ kg/ day) daily dermal dose (mg/ kg/ day) x dermal absorption factor (%) where: Daily Dermal Dose = applied dose (mg) ÷ body weight (kg) Applied Dose = 20­ 60 g of 1% lotion (high­ end); 10­ 30 g of 1% lotion (low­ end) depending on age group Dermal Absorption Factor = 10% from human pesticide application dermal absorption study 1 Application rates are based on pending label for young adults and current label/ estimated body sizes for small children. 2 Young adult BW is based on pending label changes. Child and toddler BW is avg from EPA EFH 3 Does not include an FQPA safety factor which, if applied, would increase the Target MOE to 300 for infants and children 4 Uncertainties Associated with the MOE Assessment Toxicity Endpoint ­ The toxicity endpoint used in the MOE assessment is based on an acute oral neurotoxicity study where the test material was administered by gavage. An oral gavage dose may be absorbed more rapidly than the dermal dose, producing a higher peak concentration of lindane in the blood and target tissues than a dermal dose. Use of a toxicity endpoint based on an oral dose (adjusted to reflect 10% or 20% dermal absorption) may therefore overestimate toxicity from a dermal dose. Since adult animals were used in the acute oral study and children are more susceptible to exposure than adults, use of a toxicity endpoint based on the acute study may underestimate risks to children who are exposed to lindane. Dermal Absorption ­ HED calculated MOEs assuming 20% and 10% dermal absorption. The 20% absorption value is derived from a study of the absorption of the scabies lotion applied to monkeys. The lotion was left on for 24 hours in the monkey assessment and therefore may overestimate dermal absorption for scabies treatment, which has a 12 hour exposure duration limit based on label restrictions. In addition, monkeys may not absorb the scabies lotion in the same manner as humans. The 10% absorption values is from a study of absorption of pesticides applied to humans. Humans may absorb the pesticide and lotion formulations at different rates. Since there are no data to evaluate the relative absorption of the scabies lotion by monkeys vs. humans or the relative absorption by humans of the pesticide vs. scabies lotion, it is not possible to assess whether these dermal absorption factors tend to overstate or understate potential risk. However, use of both studies provides a range of dermal absorption and probably provides an adequate bounding of potential exposure. Anticipated Label Changes ­ According to the FDA, the label for the 1% scabies treatment lotion will be revised to restrict use to, "patients who have attained adult stature, or approximately 60 kg". The label will also be revised to recommend only that a thin layer of lotion be applied. The current label prescribes the following; "Use only enough to cover the body in a thin layer. 1 ounce (half a 2 ounce container) should be all that is needed for children under 6 years of age: 1­ 2 ounces for older children and adults". HED conducted its scabies MOE assessment based on directions provided in the current label. Given anticipated label changes, use in accordance with the revised label would eliminate risks to young children (less than 60 kg). Also, according to FDA, pending label changes to the amount of lotion required should result in lower application rates for both older children and adults. 1. 2 Blood Level Comparison in Children HED also analyzed potential risk from lindane used as a scabies treatment based on data on lindane blood levels provided in two published literature studies. One study documents cases of accidental lindane ingestion by toddlers in which blood levels were determined after ingestion. The second study provides data on blood levels of lindane in children after application of 1% 5 lindane lotion to treat scabies. The blood level associated with acute accidental ingestion which resulted in short­ term adverse effects according to the accidental ingestion case study is 0.32 ug/ mL. The highest measured blood concentration from the clinical study of levels associated with prescribed uses of lindane to treat scabies was 0.064 ug/ mL. The studies are described in more detail below. Acute Accidental Lindane Ingestion Case reports published in the November, 1995, edition of the Annals of Emergency Medicine provide data on blood levels, adverse effects, and time and level of recovery resulting from acute accidental lindane ingestion in toddlers.( 3) As noted in the Annals publication, most cases reported in the literature involve dermal lindane toxicity; ingestion toxicity is infrequently documented and data on blood levels associated with ingestion are rare. The article presents three cases in which blood levels were obtained and documented after ingestion. The highest lindane blood concentrations documented in the case studies in which the patient exhibited full recovery was 0. 32 ug/ mL (Case 1). This case involved a 13 month old boy who accidently ingested part of the contents of a bottle of Kwell lotion. The following description of Case 1 is excerpted from the 1995 article. In this case, a 13 month old boy was brought to a local emergency department after being found with an open bottle of Kwell lotion. He was described as glassy eyed, he vomited twice, and had a generalized tonic­ clonic seizure. The child was transported to the hospital where he was somnolent. Shortly after arrival, he had another seizure. He was treated and laboratory analyses were conducted. Blood lindane concentrations were determined with the method of Dale et al in accordance with Environmental Protection Agency procedures. The lindane level was 0. 32 ug/ mL (4 hours after ingestion) and 0. 02 ug/ mL (20 hours after ingestion). The child was transferred to a children's hospital ICU, where his mental status progressively improved. The next day the child had slightly decreased activity. During observation over the next 2 days his condition progressively improved, and he was discharged home. The Physicians Desk Reference (PDR) provides the following statement on clinical pharmacology regarding 1% lindane cream, "Dale, et al reported a blood level of 290 ng/ ml associated with convulsions following the accidental ingestion of a lindane containing product". Lindane Blood Levels in Children Following Application of 1% Lotion for Scabies A 1977 article in The Journal of Pediatrics provides data from a study conducted in the Acute Care Clinic of Children's Medical Center, Dallas, Texas which documents blood levels of lindane in infants and children who were treated with 1% lindane lotion for scabies. (4) 6 In this study, serum concentrations of lindane were determined in infants and children with and without scabies infection following application of 1% lindane lotion. Studies were performed in 20 infected and noninfected patients who averaged 33 to 64 months of age with average weights ranging from 13 to 17 kg. After a pretreatment blood sample was obtained, 1% lindane product was applied to the body surface area prescribed by the label. Twenty four hours after application of the lotion, all patients were given a warm soapy bath. The current label for lindane lotion applied for scabies specifies that the lotion should not be left on for more than 12 hours. This may result in an overestimation of blood concentrations, however, it is likely not relevant to the risk assessment since the blood level measured at 6 hours was used for risk assessment purposes. Specimens of blood for determination of lindane concentrations were obtained at 0, 2, 4, 6, 8, 12, 24, and 48 hours after topical application of 1% lotion. Patient characteristics are presented in Table 3 and results are presented in Table 4. TABLE 3. Characteristics of Scabies Treatment Patients Infected Non­ Infected No. patients 12 8 Mean Age (months) 33 64 Mean Weight (kg) 13 17 Dose of 1% lotion (mg) 44 57 TABLE 4. Blood Concentrations of Lindane After Scabies Treatment Concentrations of Lindane in Blood (ug/ ml) Time (hr) Infected Noninfected Avg Range Avg Range 2 0. 013 0.005­ 0.038 0.007 0.001­ 0.017 4 0. 025 0.007­ 0.048 0.013 0.008­ 0.027 6 0. 028 0.013­ 0.039 0.024 0.007­ 0.064 8 0. 026 0.010­ 0.037 0.019 0.009­ 0.040 12 0.023 0.002­ 0.043 0.015 0.002­ 0.033 24 0.010 0.003­ 0.019 0.013 0.006­ 0.024 36 0.008 0.002­ 0.012 0.009 0.004­ 0.018 48 0.006 0.001­ 0.021 0.005 0.002­ 0.008 Blood half­ life 17.9 hr 21.4 hr Discussion of Uncertainties Associated with Blood Level Analysis Allowable Blood Level in Children (i. e., non­ exceedance levels based on evidence of adverse effects) ­ It is uncertain whether the levels of 320 ng/ mL and 290 ng/ mL represent the maximum levels of lindane in the subjects' blood. Given that the measured level of 320 ng/ mL in the cited clinical study was taken at least 4 hours after ingestion, it is likely that initial blood levels were higher. It is also uncertain what blood level is associated with the effects observed in the case study patient. To the extent that observed effects are attributable to higher than measured lindane blood levels, the assessment tends to overstate potential risk. To the extent that adverse effects may be associated with lindane blood levels lower than 320 ng/ mL, the assessment may tend to underestimate risk. 7 The subjects in the clinical study received a bath with warm soapy water prior to application of the lindane lotion. Wet skin tends to exhibit greater dermal absorption than dry skin. Use of the blood levels from the study may therefore overstate potential exposure for individuals who have dry skin at the time of application. In the clinical study, the lindane lotion was left on for 24 hours after application. The current label for scabies treatment specifies that the lotion should not be left on for more than 12 hours. This prolonged exposure may result in an overestimation of blood concentrations seen after 12 hours. However, it should not effect the 6 hour peak level used in the risk assessment. The potential contribution of other lotion components to observed effects is not known. Anticipated Label Changes ­ Based on the average age, the clinical scabies study looked only at infants and small children (up to 8 yrs old). Average amounts of lindane applied in the study were 129­ 158 mg. Given that the current label prescribes up to 300 mg (1 oz) for infants and up to 600 mg (2 oz) for children 6 and older, the amount of product applied in the study was 2­ 4 times less than the currently allowable amount. However, the label for the 1% scabies lotion will be revised to prescribe against use of the product for small children (i. e., children less than 60 kg). Given anticipated label changes, use in accordance with the revised label would eliminate risks to young children (< 60 kg). Also, according to FDA, pending label changes on the amount of lotion required should result in lower application rates for both older children and adults. Although there is insufficient data to indicate a correlation between amount applied dermally and corresponding blood levels, it is reasonable to assume that use of a lower amount of product will produce lower lindane blood levels. Finally, the new label will direct that lindane be applied to dry skin which will reduce the amount of lindane absorbed into the blood stream. Children vs. Adults ­ The blood level comparison analysis pertains and is applicable only to small children. HED has no data on blood levels associated with adverse effects in adults nor do we have data on blood levels associated with prescribed use of lindane to treat scabies in adults. Based on available toxicity data, children are more sensitive than adults. Therefore adverse effects would occur at higher blood levels in adults and older children than in young children. In addition, blood levels associated with prescribed use (under both current and revised labels) would be lower in older children and adults due to differences in weight to body surface area ratios between young children and adults/ young adults. 1.3 HED Conclusions HED's analysis using the MOE approach indicates MOEs of concern from both high and low­ end treatment scenarios for all ages assessed using either monkey or human dermal absorption data. For the blood concentration analysis, HED compared blood concentrations from the scabies study with the blood concentration associated with short­ term adverse effects in children. HED is concerned that there is an inadequate margin of safety between the blood levels associated with scabies treatment (0. 064 ug/ mL) and the blood levels resulting in short term 8 effects in children (0. 29 ­ 0. 32 ug/ mL). Given variability of responses in humans, an uncertainty factor of 10 is considered reasonable for this risk assessment. There is a 4­ 5 fold difference between blood levels in treated patients and allowable blood levels identified based on evidence of adverse effects. While this assessment does consider mitigation efforts being undertaken by FDA, it is important to note that it does not consider the medical benefits of scabies treatment. 1. 4 FDA Assessment and Conclusions FDA will approve a drug that it finds is safe and effective for a specific population with a specific condition when the drug is used in accordance with its proposed labeling. Safe and effective does not mean without risks, it means that the benefit of the treatment outweighs the risk for the patient group specified in the label. As described below, FDA conducted a risk/ benefit analysis of the use of lindane as second line prescription medication for scabies and concluded, based on that analysis, that lindane is safe and effective for treatment of scabies when used in a manner consistent with its labeling. Second line therapy is defined as a product that should be used only if another treatment has already failed, or if the patient cannot tolerate another available therapy. Risks Lindane has been on the market since 1947, but was labeled a second line therapy in 1995 after review by the FDA. It is similar in action to other approved therapies, but has a higher percutaneous absorption than other approved scabicides and pediculocides. This greater systemic exposure may translate to a greater potential for serious adverse events, such as seizure. This systemic exposure can be exaggerated in patients with an immature or compromised cutaneous barrier. Animal data have demonstrated that the young are more sensitive to the neurotoxic effects of lindane. FDA assessed the safety and potential risks from use of lindane as a drug based on safety information from the spontaneous adverse event reporting system (AERS) and current literature. The AERS database is a collection of spontaneous, voluntarily submitted reports of adverse events associated with drug products submitted by consumers, healthcare professionals, manufacturers, and others. One of the limitations of a voluntary system of reporting is a substantial amount of under­ reporting. FDA estimates that between one and 10% of all adverse events are reported to FDA. Other limitations include the variability in the quality and quantity of information reported. In spite of known limitations, the spontaneous system has value. The system is sensitive to rare, unexpected events, is simple to use, and is relatively inexpensive. However, the AERS database does not include the total number of patients who have been treated, with or without adverse events. Because of this, it is not possible to quantify the percentage of patients who have had adverse events. Most of the serious adverse events in the AERs database occurred in patients who had already labeled contraindications to the use of lindane, who used lindane in excessive amounts, or who ingested lindane. 9 Moreover, even though there appears to be a narrow therapeutic index, there isn't much evidence that labeled use leads to serious adverse events. The 290 ng/ ml plasma level in the Physician's Desk Reference (PDR) and the 320 ng/ ml plasma level from the Aks article are plasma levels that were obtained several hours after acute ingestion of the lindane product. The two levels are from pediatric patients who ingested lindane and had seizures. This information is helpful to a physician in determining if the patient's seizure was secondary to lindane ingestion, or if there is another etiology. The plasma levels may provide a tool to determine the etiology of a patient's seizure upon presentation to the Emergency Room but are not a "No observed adverse event level (NOAEL)." The data for lindane indicate that there is a two­ compartment pharmacokinetic model. After ingestion, there is a steep rise in the serum level, followed by a rapid decline during the disposition phase when some lindane distributes to lipid tissues and some is excreted. The disposition phase is followed by a prolonged beta elimination phase. Based on this model, it is probable that the patients'symptoms (seizure) occurred at a higher serum level than those levels obtained 4 hours after the initial ingestion. In addition, the marketed formulation contains other ingredients that may contribute to the toxicity in acute ingestions. Ingredients for lotion include: glycerol monostearate, cetyl alcohol, stearic acid, trolamine, carrageenan, 2­ amino­ 2­ methyl­ 1propanol methylparaben, butylparaben, perfume and water. Ingredients for shampoo include: trolamine lauryl sulfate, polysorbate 60, acetone and water It is important to emphasize that the blood levels listed in the PDR and the article by Aks are single cases following ingestion by toddlers of an unknown quantity of lindane. The young do appear to be more sensitive to the neurotoxic effects of lindane, as seen in studies across species. The serum lindane level that may lead to a seizure in a small child is most likely lower than the level that would cause an equal effect in an adult. The labeling is being changed to reflect this concern, indicating that lindane should be used only in patients who have achieved adult stature, or approximately 60 kilograms. Benefits FDA recognizes that all drugs have associated risks. Therefore, FDA must determine if the potential risks of adverse side effects associated with a drug treatment outweigh the overall health benefits of treating the condition. Although not life threatening, scabies can pose significant problems if left untreated, including severe itching and secondary infections. In underdeveloped areas of the world where treatments are not available or medical care is inaccessible, scabies can be pandemic and accounts for significant morbidity. FDA has concluded that there is no question that the standard of care for these patients is to administer scabicidal treatment for their infestation. FDA considers alternative therapies when evaluating the benefit of a drug. Although the FDA has determined that there are other products for the treatment of scabies that may have less risk and should be used first in a patient, FDA also recognizes that there are patients "who have 10 either failed to respond to adequate doses, or are intolerant of, other approved therapies." These patients would have documented failed prior treatment with other approved products, or documented reactions – either local or systemic, to those products or drugs that would be expected to cross­ react with those products. Although there are other therapies available for first­ line use in the treatment of scabies, FDA believes it is in the best interest of public health to have several alternatives available for this subset of patients. The approved treatment options for scabies are limited. They are: ­ permethrin cream, 5% (Acticin and Elimite), ­ lindane cream 1% (not marketed in the U. S.), lindane lotion 1%, and ­ crotamiton cream (Eurax). ­ Precipitated sulfur ointment, 5­ 10%, is occasionally compounded and used for scabies. For safety reasons, crotamiton and precipitated sulfur ointment are reasonable options for young children and pregnant women, but the efficacy of these products is much lower than other products, and re­ treatment is frequently necessary. There is information available on the internet about other alternative treatments that include soaking in borax. The efficacy of these therapies is unknown. Resistance to products must also be considered when evaluating drugs. There are currently only three approved treatments for scabies, and as mentioned earlier, crotamiton is not as effective as lindane or permethrin. Lindane is labeled for second line therapy and should only be used in the event that there is treatment failure or if the patient is intolerant to the other two treatments. If a patient has persistent infestation after one form of treatment, there should first be an assessment for appropriate use, and if it is determined that the failure wasn't due to misuse, then the patient should be retreated with an alternative agent. There is a public health benefit to having several treatment options for a condition where a patient may require re­ treatment with a different therapy, especially when there may be emerging or transient resistance. Lindane has been available since 1947, and there are some case reports that the scabies mite has recently developed resistance to it. A literature search did not reveal any reports of scabies mite resistance to permethrin, but it has been on the market for a much shorter period of time than lindane. There is one case report in the literature of resistance to crotamiton. It is not unreasonable to expect that resistance to permethrin will develop over time. If this resistance does occur, and lindane is not available, physicians would not have alternative approved and effective therapies for patients infested with scabies. Conclusions FDA has concluded that lindane is safe and effective for treatment of scabies when used in a manner consistent with its labeling. Although lindane is already labeled as a second line therapy, the current label is being revised to indicate that lindane is for use only in patients who have attained adult stature (approximately 60 kilograms). This emphasizes that it should not be used in young pediatric patients, and that patients should be post­ pubescent. In addition, physicians are 11 instructed to use caution when they are prescribing this product to patients who have underlying conditions (HIV/ AIDS) or are on medications that may result in a lowered seizure threshold, and patients who have skin conditions that may allow enhanced absorption. Extensive information will be provided for the physician and the patient regarding the potential risk of applying the product more than once. The new label also includes a medication guide that must, by law, be given to each patient with the lindane prescription. This medication guide explains in plain language the potential for harm if the lindane is used other than as instructed. It also includes clear instructions for use. The high volume container sizes are being discontinued to limit the amount per prescription. It is anticipated that this will decrease over­ use the product. 2.0 ASSESSMENT OF RISK FROM USE OF LINDANE TO TREAT LICE HED's assessment of risk from use of lindane to treat head lice relies on data provided in two published literature studies. One study documents cases of accidental lindane ingestion by toddlers in which blood levels were determined after ingestion. The second study provides data on blood levels of lindane in children and young adults following application of Kwell Shampoo to treat head lice. 2. 1 Blood Level Comparison in Children Acute Accidental Lindane Ingestion in Toddlers See case study and PDR data described above for scabies assessment. (3) Absorption of Lindane Following Application of Kwell Shampoo to Treat Lice EPA has a published study on blood levels of lindane in children and young adults following standard application of Kwell Shampoo. An 1983 article in Pediatric Dermatology provides data from a study conducted in the Outpatient Clinic of Children's Medical Center, Dallas, Texas. (4) In this study, serum concentrations of lindane were determined in children with pediculosis capititis following application of 1% Kwell shampoo. Studies were performed in 9 patients who were from 3.5 to 18 years of age with weights ranging from 13.6 to 35 kg, and heights ranging from 99 to 163 cm. After a pretreatment blood sample was obtained, 1% lindane product was applied to dry hair using a sufficient amount of medication to thoroughly saturate the hair and scalp. After 10 minutes, small quantities of water were added until a lather formed. Shampooing was continued for an additional 4 minutes after which the hair was rinsed and blown dry with a hair dryer. The current label for Kwell shampoo specifies that the shampoo should remain in place on dry hair for 4 minutes only before water is added to form lather. Consequently, the study may result in higher absorption than would occur following label directions. Four patients were 12 retreated because of persistence of living lice after 5 days. Specimens of blood were obtained at 0, 2, 4, 6, and 24 hours after topical application of Kwell shampoo. Patient characteristics are presented in Table 5 and results are presented in Table 6. TABLE 5. Characteristics of the Lice Patients Initial Treatment Retreatmemt No. patients 8 4 Mean Age (years) 7.8 8. 1 Mean Weight (kg) 27 29 Mean Height (cm) 122 124 Dose of 1% GBH Shampoo (mL) 44 57 Calculated Dose of lindane (mg) 420 530 TABLE 6. Blood Concentrations of Lindane After Lice Treatment Mean Concentrations of Lindane in Blood (ng/ mL) Time (hr) Initial Treatment Retreatment Avg Range Avg Range 0 0 0.29 0.25­ 0.3 2 1. 4 0.43­ 2.53 3.6 3. 26­ 3.88 4 0. 96 0. 38­ 1.52 3.3 1. 75­ 6.13 6 0. 72 0. 29­ 1.05 2.1 1. 64­ 2.64 24 0.41 0.26­ 0.69 1.1 0. 81­ 1.33 Discussion of Uncertainties Associated with Blood Level Analysis It is uncertain whether the levels of 320 ng/ mL and 290 ng/ mL represent the maximum levels of lindane in the subjects' blood. Given that the measured level of 320 ng/ mL in the cited clinical study was taken at least 4 hours after ingestion, it is likely that initial blood levels were higher. It is uncertain what blood level is associated with the effects observed in the case study patient. To the extent that observed effects are attributable to higher than measured lindane blood levels, the assessment tends to overstate potential risk. To the extent that adverse effects may be associated with lindane blood levels of 320 ng/ mL or lower, the assessment may tend to underestimate risk. The current label for Kwell shampoo specifies that the shampoo should remain in place on dry hair for 4 minutes only before water is added to form lather. In the clinical study, the shampoo was left in place for 10 minutes before water was added. Consequently, the study may result in higher absorption than would occur following label directions. 2.2 HED Conclusions The highest measured blood concentration obtained following single and double treatments of head lice at label rates but at longer than label specified treatment durations was 0.00613 ug/ mL. This is significantly lower than 0.32 ug/ mL, the blood level associated with acute accidental ingestion which resulted in short­ term adverse effects according to the cited case study 13 article. Therefore, HED does not believe that lindane pharmaceutical products used for treatment of lice pose human health risks of concern when used in accordance with directions provided on the label. 2. 3 FDA Assessment Based on its assessment of safety and potential risks from use of lindane as a prescription medication for scabies and lice, FDA has concluded that lindane is safe and effective for treatment of lice when used as labeled. 14 References (1) Moody, R. P., and Ritter, L., J. Tox and Env Hlth, 28: 161­ 169, 1989 (2) Feldman, R. J. and Maibach, H. I., Tox and Applied Pharmacology 28, 126­ 132, 1974 (3) Aks, S. E., KrantzA., Hryhorczuk, D. O., Wagner, S., andMock, J., AnnEmergMed, 26: 647­ 651, 1995 (4) Ginsburg, C. M. and Lowry, W., Pediatric Dermatology Vol 1. No. 1 74­ 76, 1983

epa

2024-06-07T20:31:43.045233

regulations

EPA-HQ-OPP-2002-0202-0004

Supporting & Related Material

December 13, 2001 MEMORANDUM SUBJECT: Lindane (009001) Reregistration Case No. 0315. Revised Anticipated Residues, Acute and Chronic Dietary Exposure and Risk Analyses for the HED Human Health Risk Assessment. DP Barcode D279260. FROM: Thurston G. Morton, Chemist Reregistration Branch 4 Health Effects Division (7509C) THROUGH: David Soderberg, Chemist Sheila Piper, Chemist Dietary Exposure Science Advisory Council and Susan V. Hummel, Branch Senior Scientist Reregistration Branch 4 Health Effects Division (7509C) TO: Rebecca Daiss, Risk Assessor Reregistration Branch 4 Health Effects Division (7509C) and Mark Howard/ Betty Shackleford Reregistration Branch 3 Special Review & Reregistration Division (7508C) Action Requested Prepare the revised anticipated residues and acute, chronic, and cancer dietary exposure and risk analyses for lindane (009001) incorporating comments from the public and deleting seed treatment uses on broccoli, Brussels sprouts, cabbage, cauliflower, lettuce, radishes, and spinach which are no longer being supported for reregistration by Inquinosa. The OPP/ Cancer Assessment Review Committee (CARC) has completed the reviewof newlysubmitted carcinogenicitystudyinCD­ 1 mice 2 along with other data. In accordance with the EPADraft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC has classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on an increased incidence of benign lung tumors in female mice only. The Committee, therefore, recommended that the quantification of human cancer risk is not required. Executive Summary ° Estimated acute dietary exposure is below HED's level of concern for all population subgroups at the 99.9 th percentile. The maximum dietary risk estimate is 17 % of the acute PAD (% aPAD) for the population subgroup All Infants (Table 18) and 7 % of the aPAD for the U. S. Population when the feeding studies were adjusted using the metabolism studies. ° Estimated chronic dietary risk is below HED's level of concern for all population subgroups. The resulting risk estimates are 3 % of the chronic PAD (% cPAD) for the U. S. Population and 11 % of the cPAD for Children 1­ 6 years of age (highest exposed population subgroup) and 6 % of the cPAD for Children 7­ 12 yrs. The remaining population subgroups were
5 %of the cPAD( Table 18) when the feeding studies were adjusted using the ratio of ppm TRR/ ppm lindane identified in the metabolism studies (Table 18). Toxicological Information Memoranda providing details of relevant toxicological information include the HIARC report dated 7/ 27/ 00 and the FQPA Safety Factor Committee report dated 8/ 2/ 00. The acute and chronic FQPA safety factors of 10X were reduced to 3X (see FQPA Safety Factor Document, 8/ 2/ 00). Areference dose (RfD) which includes the FQPA safety factor (10X, 3Xor 1X) is defined as the Population Adjusted Dose (PAD). Doses and endpoints for dietary risk assessment are presented in Table 1. The OPP/ Cancer Assessment Review Committee (CARC) has completed the review of newly submitted carcinogenicity study in CD­ 1 mice along with other data. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC has classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on an increased incidence of benign lung tumors in female mice only. The Committee, therefore, recommended that the quantification of human cancer risk is not required. 3 Table 1. Lindane: Toxicological Doses and Endpoints for Dietary Risk Assessment. EXPOSURE SCENARIO DOSE (mg/ kg/ day) ENDPOINT STUDY TYPE/ MRID Acute Dietary­ general population NOAEL= 6 mg/ kg UF = 100 FQPA = 3X LOAELis20 mg/ kgbased on increasedgrip strength, increased Motor Activity Acute Neurotoxicity in Rats/ 44769201 Acute RfD (Gen. Pop.) = 0. 06 mg/ kg/ day Acute Population Adjusted Dose (aPAD) = 0. 02 mg/ kg/ day Chronic Dietary NOAEL= 10 ppm (0. 47 mg/ kg/ day) UF = 100 FQPA = 3X LOAEL is 100 ppm (4. 81 mg/ kg/ day) periacinar hepatocyte hypertrophy, increased liver/ spleen weight, and increased platelets Chronic Feeding and Carcinogenicity in Rats 41094101 41853701 42891201 Chronic RfD = 0. 0047 mg/ kg/ day Chronic Population Adjusted Dose (cPAD) = 0. 0016 mg/ kg/ day Consumption Data HED conducts dietary risk assessments using the Dietary Exposure Evaluation Model (DEEM™), which incorporates consumption data generated in USDA's Continuing Surveys of Food Intakes by Individuals (CSFII), 1989­ 1992. For acute dietary risk assessments, the entire distribution of single day food consumption events is combined with either a single residue level (deterministic analysis, risk at 95th percentile of exposure reported) or a distribution of residues (probabilistic analysis, referred to as "Monte Carlo," with risk at 99. 9th percentile of exposure reported) to obtain a distribution of exposures in mg/ kg/ day. For chronic dietary risk assessments, the three­ day average of consumption for each sub­ population is combined with average residues in/ on commodities to determine an average exposure in mg/ kg/ day. Residue Information Tolerances for residues of lindane in/ on food and feed commodities are currently established under 40 CFR §180.133 and are expressed in terms of lindane per se. The nature of the residue in plants and ruminants is not adequately understood. New nature of the residue studies fromseed treatment are required for a cereal grain, leafy vegetable, and radish. Additional data are required for the ruminant metabolismstudy. The nature ofthe residue in poultry is adequately understood. The HED MetabolismAssessment ReviewCommittee(T. Morton, 8/ 30/ 00, D267069) concluded that theTRRs should be used for risk assessment purposes and calculation of dietary burdens, pending receipt of additional metabolismdata. The anticipated residues (ARs) were presented to the HED ChemSAC on 9/ 6/ 00. Exposure to lindane was determined by using the ratio (ppm TRR/ ppm lindane parent) fromthelivestock metabolismstudies. TheBiologicaland EconomicAnalysisDivision (OPP/ BEAD) verified the registrant's percent market share estimate for lindane (I. Yusuf email, 7/ 17/ 00). The usage data are provided as Attachment 1; inclusion of the data in dietary exposure analyses is discussed below. Acanola processing studyfor lindane wasrecentlyreviewed (T. Morton, D269388, 5/ 10/ 01). Lindane was not detected in bleached/ deodorized canola oil (< 0.005 ppm). Therefore, ½ 4 LOQ (0.0025 ppm) will be used as the DEEM™ adjustment factor 1. DEEM™ default concentrations factors (adjustment factor 1) will be used for all other concentration factors. The wheat grain and forage TRRs were translated to barley, oats, and rye. The corn grain and forage TRRs were translated to sorghum. The following metabolism and feeding studies were used to determine the appropriate residue values to be used in both the dietary burden calculation and the DEEM™ input files. Seed Treatment Metabolism Study (N. Dodd, 3/ 24/ 88, RCB 3259, MRID 40431207) Various seeds were treated with 14 C lindane. Spring wheat seeds were treated at 370 ppm (0. 3x), field corn seeds at 1800 ppm (0. 8x), and sweet corn seeds at 1400 ppm (0. 6x). Seeds were then planted outdoors. Samples were analyzed for radioactivity periodically by oxidative combustion and autoradiography. Samples were extracted and analyzed for 14 C by liquid scintillation counting (LSC) and for lindane by gas liquid chromatography (GLC) when significant residues were found by combustion. This study was deemed inadequate due to insufficient characterization/ identification of the radioactive residues. A new nature of the residue study from seed treatment is required for a cereal grain. The HED MARC (T. Morton, 8/ 30/ 00, D267069) concluded that the TRRs should be used for calculation of dietary burdens. The TRRs are summarized in the following table. Table 2. Summary of TRR in various crops after seed treatment with 14 C labeled lindane. Crop Matrix TRR (ppm) Field corn root 0. 340 Field corn foliage 0.064 Field corn grain < 0. 01 Sweet corn foliage 0.051 Sweet corn grain < 0.01 Wheat foliage 2.925 Wheat grain 0.052 The TRR used for barley, canola, oats, rye, and wheat grain was 0.052 ppm. The TRR value used for corn grain and sorghum grain was 0.01 ppm. Meat, Milk, Poultry, & Eggs 5 The following acute dietary burdens (Table 3) were calculated using the appropriate TRRs fromthe seed treatment metabolism study presented in the previous table (Table 2). The chronic dietary burdens (Table 4) have incorporated the percent market share of the feed item into the dietary contribution. Table 3. Lindane Acute Dietary Burden. 6 Feed Commodity % Dry Matter % Diet Anticipated Residue (ppm) Dietary Contribution (ppm) Beef Cattle Field corn grain 88 50 0.01 0.0057 Wheat forage 25 25 2. 925 2.925 Sorghum forage 35 15 0. 064 0.028 Wheat grain 89 10 0.052 0.006 Total 100 2.96 Dairy Cattle Field corn grain 88 40 0.01 0.0045 Wheat grain 89 10 0.052 0.006 Wheat forage 25 50 2. 925 5.85 Total 100 5.86 Poultry Field corn grain NA 20 0.01 0.002 Wheat grain NA 80 0.052 0.0416 Total 100 0.044 Swine Field corn grain NA 20 0.01 0.002 Wheat grain NA 80 0.052 0.0416 Total 100 0.044 Table 4. Lindane Chronic Dietary Burden. 7 Feed Commodity % Dry Matter % Diet Anticipated Residue (ppm) Percent Market Share Dietary Contribution (ppm) Beef Cattle Field corn grain 88 50 0.01 0.15 0.0009 Wheat forage 25 25 2. 925 0.03 0.0878 Sorghum forage 35 15 0. 064 0.03 0.0008 Wheat grain 89 10 0.052 0.03 0.0002 Total 100 0.0897 Dairy Cattle Field corn grain 88 40 0.01 0.15 0.0007 Wheat grain 89 10 0.052 0.03 0.0002 Wheat forage 25 50 2. 925 0.03 0.1755 Total 100 0.1764 Poultry Field corn grain NA 20 0.01 0.15 0.0003 Wheat grain NA 80 0.052 0.03 0.0012 Total 100 0.0015 Swine Field corn grain NA 20 0.01 0.15 0.0003 Wheat grain NA 80 0.052 0.03 0.0012 Total 100 0.0015 Ruminant Metabolism Study (MRID 44867104) 8 Lactating goats were orally administered 14 C­ Lindane capsules (via balling gun) immediately after the morning milking once per day for 7 days. The actual dose rat e was 13 mg/ kg. This dose rate is equivalent to approximately a 2x exaggerated rate for dairy cattle and approximately 4.4x for beef cattle based on an acute dietary burden as calculated by HED. The acute anticipated residues using the TRR alone for cattle and swine are summarized in Table 6 and 7. The chronic anticipated residues usingthe TRRalone forcattle andswine aresummarizedinTable 8 and 9. Table 5. Summary of TRR characterized/ identified in tissues of lactating goats orally dosed with 14 C­ Lindane at 13 ppm. Tissue Total Radioactive Residue (TRR) ppm Fat 3. 46 ppm Liver 2. 25 ppm Kidney 0. 48 ppm Muscle 0.20 ppm Milk Fat 0. 136 ppm Table 6. Cattle Acute Anticipated Residues From Nature of the residue study (M. Kovacs Jr., 9/ 20/ 88, RCB 4037). Tissue 13 ppm Feeding Level (4. 4X) a Cattle AR Fat 3. 46/ 4.4= 0.786 0.786 ppm Muscle 0.2/ 4.4= 0.045 0.045 ppm Milk Fat 0. 136/ 2= 0.068 0.068 ppm Liver 2. 25/ 4.4= 0.511 0.511 ppm b Kidney 0.48/ 4.4= 0.109 0.109 ppm a The 13 ppm feeding level represented 2x the dairy dietary burden. b Use for liver, meat byproducts, and other organ meats for beef, goat, horses, sheep, and veal. Table 7. Swine Acute Anticipated Residues based on metabolism data from the ruminant metabolism study. Tissue 13 ppm Feeding Level (295X) Swine AR Fat 3. 46/ 295= 0.012 0.012 ppm Muscle 0.2/ 295= 0.001 0.001 ppm Liver 2. 25/ 295= 0.008 0.008 ppm a Kidney 0.48/ 295= 0.002 0.002 ppm a Use for liver, meat byproducts, and other organ meats for pork. Table 8. Cattle Chronic Anticipated Residues From Nature of the residue study (M. Kovacs Jr., 9/ 20/ 88, RCB 4037). 9 Tissue 13 ppm Feeding Level (145X) a Cattle AR Fat 3. 46/ 145= 0.02 0.02 ppm Muscle 0.2/ 145= 0.001 0.001 ppm Milk Fat 0. 136/ 74= 0.002 0.002 ppm Liver 2. 25/ 145= 0.02 0.02 ppm b Kidney 0.48/ 145= 0.003 0.003 ppm a The 13 ppm feeding level represented 74x the chronic dairy dietary burden. b Use for liver, meat byproducts, and other organ meats for beef, goat, horses, sheep, and veal. Table 9. Swine Chronic Anticipated Residues based on metabolism data from the ruminant metabolism study. Tissue 13 ppm Feeding Level (8700X) Swine AR Fat 3. 46/ 8700= 0.0004 0.0004 ppm Muscle 0.2/ 8700= 0.00002 0.00002 ppm Liver 2. 25/ 8700= 0.0003 0.0003 ppm a Kidney 0.48/ 8700= 0.00006 0.00006 ppm a Use for liver, meat byproducts, and other organ meats for pork. Poultry Metabolism Study (MRID 40271301) Following 4 days of dosing with [ 14 C] lindane at levels equivalent to 120 (2700x) ppm in the acute diet, 14 C­ residues accumulated to the greatest extent in fatty tissues. In the high­ dose hens, TRRs were highest in fat (96.98 ppm) followed by skin (49.93 ppm), thigh muscle (11.81 ppm), liver (11.65 ppm), and breast muscle (1.44 ppm). 14 C­ Residues were readily extracted (80­ 141% TRR) fromyolks, thigh muscle, liver, skin, and fat of high­ dose hens using organic solvents, and 66.4­ 121.3% of the TRR was subsequently identified. Lindane was the principal 14 C­ residue identified in eggs and tissues, accounting for 94.5% of the TRR in egg yolks, 70.8­ 86.0% of the TRR in muscle, skin, and fat, and 51.5% of the TRR in liver. 1, 2, 4Trichlorobenzene was identified as accounting for 19.4% of the TRR in liver, and 0.6­ 3.5% of the TRR in egg yolks and other tissues. 1, 3, 5­ Trichlorobenzene and dichlorobenzene( s) were also detected in liver at 6.4 and 9.5% of the TRR, respectively. Tetrachlorobenzene (either 1,2,4,5­ or 1,2,3,4­) was detected in thigh muscle at 17.7% of the TRR and in other tissues at 2.2­ 3.1% of the TRR. Pentachlorocyclohexene was identified as accounting for 3. 8­ 6. 1% of the TRR in yolks and tissues. The remaining metabolites (1, 2, 3, 4­ tetrachlorobenzene/ tetrachlorocyclohexene; 1,2,3,4,5­ pentachlorobenzene; and hexachlorocyclohexene) detected intissues and/ or yolks each accounted for
4.4% of the TRR. The acute anticipated residues using the TRR alone for poultry are summarized in Table 10. The chronic anticipated residues using the TRR alone for poultry are summarized in Table 11. 10 Table 10. Summary of TRR characterized/ identified in tissues of laying hens orally dosed with 14 C­ Lindane at 120 ppm (2700x acute dietary burden) normalized to 1x the acute dietary burden. Tissue Total Radioactive Residue (TRR) ppm Acute Anticipated Residue (ppm) Fat 97.0 ppm/ 2700= 0.04 0.04 Liver 11.7 ppm/ 2700= 0.004 0.004 Skin 49.9 ppm/ 2700= 0.02 0.02* Thigh 11.8 ppm/ 2700= 0.004 0.004 Egg White 0.21/ 2700= 0.00008 0.00008 Egg Yolk 10.8 ppm/ 2700= 0.004 0.004 Whole Egg 0.7( 0.00008)+ 0. 3( 0. 004)= 0. 001 *Use for poultry meat byproducts Table 11. Summary of TRR characterized/ identified in tissues of laying hens orally dosed with 14 C­ Lindane at 120 ppm (80000x acute dietary burden) normalized to 1x the chronic dietary burden. Tissue Total Radioactive Residue (TRR) ppm Chronic Anticipated Residue (ppm) Fat 97.0 ppm/ 80000= 0.001 0.001 Liver 11.7 ppm/ 80000= 0.0001 0.0001 Skin 49.9 ppm/ 80000= 0.0006 0.0006* Thigh 11.8 ppm/ 80000= 0.0001 0.0001 Egg White 0.21/ 80000= 0.000003 0.000003 Egg Yolk 10.8 ppm/ 80000 0.0001 Whole Egg 0.7( 0.000003)+ 0. 3( 0. 0001)= 0. 00003 *Use for poultry meat byproducts Ruminant Feeding Study (M. Kovacs Jr., 9/ 20/ 88, RCB 4037) Dairy cattle were fed at three feeding levels of 20 ppm( 6. 7x acute beef cattle dietary burden), 60 ppm (20x acute beef cattle dietary burden), and 200 ppm (67x acute beef cattle dietary burden). The exaggerated feeding rates correspond to 3. 4x, 10x, and 34x for the acute dairy cattle dietary burden, respectively. The exaggerated feeding rates correspond to 450x, 1400x, and 4500x for the acute swine dietary burden, respectively. The acute anticipated residues for cattle and swine using the feeding studies along with information fromthe metabolismstudies are summarized in Tables 12 and 13. The chronic anticipated residues for cattle and swine using the feeding studies along with information from the metabolism studies are summarized in Tables 14 and 15. Table 12. Summary of lindane residues in cattle fed at 20, 60, and 200 ppm normalized to a 1x acute feeding level. 11 Sample 20 ppm (6.7x) a 60 ppm (20x) a 200 ppm (67x) a Average (ppm) * (ppm TRR/ ppm lindane) b Milk (Day 7) 0.41/ 3.4 = 0.120 1.64/ 10 = 0. 164 3.95/ 34 = 0. 116 0.133 * 1. 22 = 0.163 Liver 0. 10/ 6.7 = 0.015 0.19/ 20 = 0. 009 0.72/ 67 = 0. 011 0.012 * 6. 25 = 0.073 Kidney 0.34/ 6.7 = 0.051 1.07/ 20 = 0. 053 4.57/ 67 = 0. 068 0.057 * 2. 82 = 0.162 Muscle 0.97/ 6.7 = 0.145 1.80/ 20 = 0. 090 8.75/ 67 = 0. 130 0.122 * 1. 25 = 0.152 Fat 11.9/ 6.7 = 1.78 20.2/ 20 = 1. 01 58.1/ 67 = 0. 87 1. 22 * 1. 18 = 1.44 a First number in column is residue value from feeding study which is then divided by the exaggerated feeding rate. b Average residue value from three feeding levels multiplied by the ratio of (ppm TRR/ ppm lindane) in metabolism study. Table 13. Summary of lindane residues in swine translated from the cattle feeding study and normalized to 1x acute feeding level. Sample 20 ppm (450x) a 60 ppm (1400x) a 200 ppm (4500x) a Average (ppm) * (ppm TRR/ ppm lindane) b Liver 0. 10/ 450= 0.0002 0.19/ 1400= 0.0001 0.72/ 4500= 0.0002 0.0002 * 6. 25 = 0.001 Kidney 0.34/ 450= 0.0007 1.07/ 1400= 0.0008 4.57/ 4500= 0.001 0.0008 * 2. 82 = 0.002 Muscle 0.97/ 450= 0.002 1.80/ 1400= 0.001 8.75/ 4500= 0.002 0.002 * 1. 25 = 0.002 Fat 11.9/ 450= 0.026 20.2/ 1400= 0.014 58.1/ 4500= 0.013 0.018 * 1. 18 = 0.021 a First number in column is residue value from feeding study which is then divided by the exaggerated feeding rate. b Average residue value from three feeding levels multiplied by the ratio of (ppm TRR/ ppm lindane) in metabolism study. Table 14. Summary of lindane residues in cattle fed at 20, 60, and 200 ppm normalized to a 1x chronic feeding level. Sample 20 ppm (223x) a 60 ppm (669x) a 200ppm( 2230x) a Average (ppm) * (ppm TRR/ ppm lindane) b Milk (Day 7) 0.41/ 113= 0.004 1.64/ 340= 0.005 3.95/ 1134= 0.003 0.004 * 1. 22 = 0.005 Liver 0. 10/ 223= 0.0004 0.19/ 669= 0.0003 0.72/ 2230= 0.0003 0.0003 * 6. 25 = 0.002 Kidney 0. 34/ 223= 0.002 1.07/ 669= 0.002 4.57/ 2230= 0.002 0.002 * 2. 82 = 0.006 Muscle 0.97/ 223= 0.004 1.80/ 669= 0.003 8.75/ 2230= 0.004 0.004 * 1. 25 = 0.005 Fat 11.9/ 223= 0.05 20.2/ 669= 0.03 58.1/ 2230= 0.03 0.04 * 1. 18 = 0.05 a First number in column is residue value from feeding study which is then divided by the exaggerated feeding rate. b Average residue value from three feeding levels multiplied by the ratio of (ppm TRR/ ppm lindane) in metabolism study. Table 15. Summary of lindane residues in swine translated fromthe cattle feeding study and normalized to 1x chronic 12 feeding level. Sample 20 ppm (13300x) a 60 ppm (40000x) a 200 ppm (133000x) a Average (ppm) * (ppm TRR/ ppm lindane) b Liver 0. 10/ 13300= 0.000 008 0.19/ 40000= 0.0000 05 0.72/ 133000= 0.000005 0.000006 * 6. 25 = 0.00004 Kidney 0.34/ 13300= 0.000 03 1.07/ 40000= 0.0000 3 4.57/ 133000= 0.00003 0.00003 * 2. 82 = 0.00008 Muscle 0.97/ 13300= 0.000 07 1.80/ 40000= 0.0000 5 8.75/ 133000= 0.00007 0.00006 * 1. 25 = 0.00008 Fat 11.9/ 13300= 0.000 9 20.2/ 40000= 0.0005 58.1/ 133000= 0.0004 0.0006 * 1. 18 = 0.0007 a First number in column is residue value from feeding study which is then divided by the exaggerated feeding rate. b Average residue value from three feeding levels multiplied by the ratio of (ppm TRR/ ppm lindane) in metabolism study. Poultry Feeding Study (G. Otakie, 8/ 31/ 88, RCB 4034) Poultry were fed lindane at 1.5 (34x the acute dietary burden), 4. 5 (102x the acute dietary burden), and 15 (340x the acute dietary burden) ppmfeeding levels. The acute anticipated residues for poultry using the feeding study along with information from the metabolism study are summarized in Table 16. The chronic anticipated residues for poultry using the feeding study along with information from the metabolism study are summarized in Table 17. Table 16. Summary of lindane residues in poultry fed at 1.5, 4.5, and 15 ppm normalized to a 1x acute feeding level. Sample 1.5 ppm (34x) a 4.5 ppm (102x) a 15 ppm (340x) a Average (ppm) * (ppm TRR/ ppm lindane) b Eggs 0.216/ 34 = 0. 006 0.672/ 102 = 0. 006 2.357/ 340 = 0. 007 0.006 * 1. 06 = 0.006 Liver 0. 12/ 34 = 0. 003 0.51/ 102 = 0. 005 0.78/ 340 = 0. 002 0.003 * 1. 95 = 0.006 Heart 0. 33/ 34= 0. 010 0. 89/ 102= 0. 009 2. 26/ 340= 0. 007 0. 009 *1 =0. 009 c Thigh 0. 19/ 34 = 0. 005 0.36/ 102 = 0. 003 1.35/ 340 = 0. 004 0.004 * 1. 40 = 0.006 Fat 2. 54/ 34 = 0. 075 7.8/ 102 = 0. 076 27.7/ 340 = 0. 081 0.077 * 1. 17 = 0.090 a First number in column is residue value from feeding study which is then divided by the exaggerated feeding rate. b Average residue value from three feeding levels multiplied by the ratio of (ppm TRR/ ppm lindane) in metabolism study. c 100% of the TRR in the chicken heart was identified as lindane. This residue was used for chicken byproducts, chicken giblets (excl. liver), turkey byproducts, turkey other organ meats, and turkey giblets (excl. liver). Table 17. Summaryof lindane residues in poultry fed at 1.5, 4.5, and 15 ppm normalized to a 1x chronic feeding level. 13 Sample 1.5 ppm (1000x) a 4.5 ppm (3000x) a 15 ppm (10000x) a Average (ppm) * (ppm TRR/ ppm lindane) b Eggs 0.216/ 1000= 0.0002 0.672/ 3000= 0.0002 2.357/ 10000= 0.0002 0.002 * 1. 06 = 0.0002 Liver 0. 12/ 1000= 0.0001 0.51/ 3000= 0.0002 0.78/ 10000= 0.00008 0.0001 * 1. 95 = 0.0002 Heart 0. 33/ 1000= 0.0003 0.89/ 3000= 0.0003 2.26/ 10000= 0.0002 0.0003 *1 =0. 0003 c Thigh 0. 19/ 1000= 0.0002 0.36/ 3000= 0.0001 1.35/ 10000= 0.0001 0.0001 * 1. 40 = 0.0002 Fat 2. 54/ 1000= 0.003 7.8/ 3000= 0.003 27.7/ 10000= 0.003 0.003 * 1. 17 = 0.004 a First number in column is residue value from feeding study which is then divided by the exaggerated feeding rate. b Average residue value from three feeding levels multiplied by the ratio of (ppm TRR/ ppm lindane) in metabolism study. c 100% of the TRR in the chicken heart was identified as lindane. This residue was used for chicken byproducts, chicken giblets (excl. liver), turkey byproducts, turkey other organ meats, and turkey giblets (excl. liver). Uncertainties There are no adequate nature of the residue studies for plants fromseed treatment application. Anew metabolism study is required for a grain crop; however, a seed treatment metabolism study (which was classified as inadequate) was reviewed by HED and used in the determination of the TRR for use in this dietary exposure analysis. The wheat grain and forage TRRs were translated to barley, oats, and rye. The corn grain and forage TRRs were translated to sorghum. The nature of the residue in poultry is understood. The nature of the residue in livestock is adequately understood. The magnitude of the residue studies in poultry and cattle only analyzed for lindane. The lindane residue values were derived using a ratio of total radioactive residue divided by the amount of lindane present in the livestock metabolism studies. This would be worst case estimate since we are assuming that all of the TRR would be residues of concern and adjusting the lindane residues in the livestock magnitude of the residue studies accordingly to account for the TRR. The dietaryexposure analyses using the total radioactive residues is a Tier 3 assessment since percent crop treated was used in the analyses. The dietary exposure analyses that were based on the adjustment of the lindane residues in the feeding studies is a Tier 3 assessment. Percent market share was available for all crops included in the analyses. Since lindane is being supported for reregistration for seed treatments only, there is no difference in the percent crop treated values between crops grown for the fresh market and those grown for processing. A processing study was available for canola only; the default DEEM™ processing factors were used for all other foods. Results/ Discussion 14 Estimated acute dietary exposure is below HED's level of concern for all population subgroups at the 99.9 th percentile. The maximum dietary risk estimate is 17 % of the aPAD for All Infants when the feeding studies were adjusted using the metabolism studies (Table 18). Estimated chronic dietary risk is below HED's level of concern for all population subgroups. The resulting risk estimates are 3 % of the chronic PAD (% cPAD) for the U. S. Population and 11 % of the cPADfor Children 1­ 6 years of age (highest exposed population subgroup) and 6 %of the cPAD for Children 7­ 12 yrs. The remaining population subgroups were
5% ofthe cPAD (Table 18) when the feeding studies were adjusted using the ratio of ppm TRR/ ppm lindane identified in the metabolism studies (Table 18). Table 18. Estimated Acute and Chronic Dietary Exposure and Risk using the feeding studies and adjusting lindane residues using the metabolism studies. Population Subgroup Acute (99.9th %­ ile) Chronic Exposure (mg/ kg/ day) %aPAD Exposure (mg/ kg/ day) % cPAD U. S. Population 0. 001305 7 0. 000054 3 All infants (< 1 yr) 0.003320 17 0.000072 5 Children (1­ 6 yrs) 0. 001973 10 0.000173 11 Children (7­ 12 yrs) 0.001088 5 0. 000096 6 Females (13­ 50 yrs) 0.000467 2 0. 000034 2 Males (13­ 19 yrs) 0.000670 3 0. 000061 4 Males (20+ yrs) 0.000458 2 0. 000034 2 Seniors (55+ yrs) 0.000409 2 0. 000030 2 cc : Chem F, Chron F. Morton , L. Richardson RDI: Chemistry SAC (9/ 6/ 00); DE SAC (9/ 25/ 00) (S. Piper, 12/ 13/ 01 & D. Soderberg, 12/ 13/ 01); SVH: 12/ 13/ 01 TM, Thurston Morton, Rm. 816D CM2, 305­ 6691, mail code 7509C List of Attachments: Attachment 1: Quantitative Usage Analysis, 7/ 17/ 00 (I. Yusuf, BEAD/ OPP). Attachment 2: Residue Distribution Files. Attachment 3: Residue Information. Attachment 4: Acute Analysis. Attachment 5: Chronic Analysis. Attachment 1: Quantitative Usage Analysis, 7/ 17/ 00 (I. Yusuf, BEAD/ OPP). (Registrant submission approved by BEAD) 15 From the Small Grains petition, Page 79. B. Market share representing maximum percent of crop treated is 15% for field corn, 10% for canola, 1% for sweet corn, and 3% each for wheat, oats, barley, and grain sorghum. From the Small Grains petition, Page 35 MARKET SHARE Reasonable estimates for the percentage of seeds of wheat, barley, oats, rye, and sorghum treated with lindane i. e., the market share, are 1% to 3%. The market share on corn may be as high as 15%. Market share information was used in calculations of Maximum Theoretical Dietary Burdens for livestock, and was considered in some estimations of human dietary exposure. From the vegetables petition, Page 22. MARKET SHARE: Reasonable estimates for the percentage of acres employing lindane­ treated seeds are: corn 15%, brassica < 1%, leafy vegetables < 1%, and radishes < 1%. (Personal Communication: T. McArtle, Trace Chemical and Seed Treatment Coalition representative, December 1998). Attachment 2: RDFs Documentation: doc beef fat lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 16 TOTALFREQ= 1 15,1.44 Documentation: doc beef meat lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.152 Documentation: doc beef meat by products lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.162 Documentation: doc beef liver lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.073 Documentation: doc milk lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.163 Documentation: doc poultry eggs lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.006 Documentation: doc poultry meat byproducts lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.009 Documentation: doc poultry liver lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.006 17 Documentation: doc poultry giblets lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.009 Documentation: doc poultry fat lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.09 Documentation: doc poultry meat lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.006 Documentation: doc swine fat lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.021 Documentation: doc swine meat byproducts lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.002 Documentation: doc swine liver lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.001 Documentation: doc swine meat lindane DOC ASSUMING 15% crop treated for highest feed item TOTALZ= 85 TOTALFREQ= 1 15,0.002 Attachment 3: Residue Information Acute Analysis using feeding study 18 F i l e n a m e : C :\d e e m \ 9 1\R e v i s e d Analysis\ 12­ 11­ 1\ 12­ 11­ 1RevacuteTRR. RS7 Chemical: Lindane R D( Chronic): . 16 mg/ kg bw/ day NOEL( Chronic): . 47 mg/ kg bw/ day R D( Acute): . 2 mg/ kg bw/ day NOEL( Acute): 6 mg/ kg bw/ day Q*= 1. 1 Date created/ last modi ied: 12­ 3­ 2 1/ 5: 14: 17/ 8 Program ver. 7. 75 Comment: Re erence doses have 3X FQPA actored in. This is a dietary analysis using the total radioactive residues rom the plant and animal metabolism studies. ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­ RDL indices and parameters or Monte Carlo Analysis: Index Dist Parameter # 1 Param # 2 Param # 3 # Code ­­­­­ ­­­­ ­­­­­­­­­­­­ ­­­­­­­­ ­­­­­­­ 1 6 bee meat. rd 2 6 bee at. rd 3 6 bee liver. rd 4 6 bee mbyp. rd 5 6 poultryegg. rd 6 6 poultry at. rd 7 6 poultrygiblets. rd 8 6 poultryliver. rd 9 6 poultrymbyp. rd 1 6 poultrymeat. rd 11 6 swine at. rd 12 6 swineliver. rd 13 6 swinembyp. rd 14 6 swinemeat. rd 15 6 milk. rd Food Crop Food Name De Res Adj. Factors RDL Code Grp ( ppm) # 1 # 2 Pntr ­­­­ ­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­ ­­­­­ ­­­­­­ ­­ 265 15 Barley . 52 1. . 3 323 M Bee ­dried . 45 1. 92 .15 1 19 324 M Bee ­ at w/ o bones .786 1. .15 2 325 M Bee ­kidney .1 9 1. .15 4 327 M Bee ­lean ( at/ ree) w/ o bones . 45 1. .15 1 326 M Bee ­liver .511 1. .15 3 321 M Bee ­meat byproducts .511 1. .15 4 322 M Bee ­other organ meats .511 1. .15 4 3 1 O Canola oil ( rape seed oil) . 25 1. .1 366 P Chicken­ byproducts . 4 1. .15 9 368 P Chicken­ at w/ o bones . 4 1. .15 6 367 P Chicken­ giblets( liver) . 4 1. .15 8 385 P Chicken­ giblets ( excl. liver) . 4 1. .15 7 369 P Chicken­ lean/ at ree w/ o bones . 4 1. .15 1 267 15 Corn grain­ bran . 1 1. .15 266 15 Corn grain­ endosperm . 1 1. .15 289 15 Corn grain­ oil . 1 1. .15 268 15 Corn grain/ sugar/ h cs . 1 1. 5 .15 388 15 Corn grain/ sugar­ molasses . 1 1. 5 .15 237 15 Corn/ pop . 1 1. .15 238 15 Corn/ sweet . 1 1. . 1 364 P Eggs­ white only . 8 1. .15 5 363 P Eggs­ whole . 1 1. .15 5 20 365 P Eggs­ yolk only . 4 1. .15 5 33 M Goat­ at w/ o bone .786 1. .15 2 331 M Goat­ kidney .1 9 1. .15 4 333 M Goat­ lean ( at/ ree) w/ o bone . 45 1. .15 1 332 M Goat­ liver .511 1. .15 3 328 M Goat­ meat byproducts .511 1. .15 4 329 M Goat­ other organ meats .511 1. .15 4 334 M Horsemeat . 45 1. .15 1 398 D Milk­ based water . 68 1. .15 15 319 D Milk­ at solids . 68 1. .15 15 318 D Milk­ non at solids . 68 1. .15 15 32 D Milk sugar ( lactose) . 68 1. .15 15 399 15 Oats­ bran . 52 1. . 3 269 15 Oats . 52 1. . 3 344 M Pork­ at w/ o bone . 12 1. .15 11 345 M Pork­ kidney . 2 1. .15 13 347 M Pork­ lean ( at ree) w/ o bone . 1 1. .15 14 346 M Pork­ liver . 8 1. .15 12 342 M Pork­ meat byproducts . 8 1. .15 13 343 M Pork­ other organ meats . 8 1. .15 13 362 P Poultry­ other­ at w/ o bones . 4 1. .15 6 21 361 P Poultry­ other­ giblets( liver) . 4 1. .15 8 36 P Poultry­ other­ lean ( at ree) w/ . 4 1. .15 1 274 15 Rye­ lour . 52 1. . 3 273 15 Rye­ germ . 52 1. . 3 272 15 Rye­ rough . 52 1. . 3 338 M Sheep­ at w/ o bone .786 1. .15 2 339 M Sheep­ kidney .1 9 1. .15 4 341 M Sheep­ lean ( at ree) w/ o bone . 45 1. .15 1 34 M Sheep­ liver .511 1. .15 3 336 M Sheep­ meat byproducts .511 1. .15 4 337 M Sheep­ other organ meats .511 1. .15 4 275 15 Sorghum ( including milo) . 1 1. . 3 355 P Turkey­ byproducts . 4 1. .15 9 357 P Turkey­­ at w/ o bones . 4 1. .15 6 356 P Turkey­ giblets ( liver) . 4 1. .15 8 358 P Turkey­ lean/ at ree w/ o bones . 4 1. .15 1 449 P Turkey­ other organ meats . 4 1. .15 9 429 M Veal­ dried . 45 1. 92 .15 1 424 M Veal­ at w/ o bones .786 1. .15 2 426 M Veal­ kidney .1 9 1. .15 4 425 M Veal­ lean ( at ree) w/ o bones . 45 1. .15 1 22 427 M Veal­ liver .511 1. .15 3 43 M Veal­ meat byproducts .511 1. .15 4 428 M Veal­ other organ meats .511 1. .15 4 278 15 Wheat­ bran . 52 1. . 3 279 15 Wheat­ lour . 52 1. . 3 277 15 Wheat­ germ . 52 1. . 3 437 15 Wheat­ germ oil . 52 1. . 3 276 15 Wheat­ rough . 52 1. . 3 Chronic Analysis using feeding study F i l e n am e : C :\d e e m \ 9 1 \R e v i s e d Analysis\ 12­ 11­ 1\ 12­ 11­ 1RevchronicTRR. RS7 Chemical: Lindane R D( Chronic): . 16 mg/ kg bw/ day NOEL( Chronic): . 47 mg/ kg bw/ day R D( Acute): . 2 mg/ kg bw/ day NOEL( Acute): 6 mg/ kg bw/ day Q*= 1. 1 Date created/ last modi ied: 12­ 3­ 2 1/ 5: 15: 47/ 8 Program ver. 7. 75 Comment: Fe erence doses have 3X FQPA actored in. This is the dietary analysis using the metabolism and eeding studies. ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­ Food Crop De Res Adj. Factors Code Grp Food Name ( ppm) # 1 # 2 ­­­­ ­­­­ ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­ ­­­­­ ­­­­­ 265 15 Barley . 52 1. . 3 323 M Bee ­dried . 5 1. 92 1. 324 M Bee ­ at w/ o bones . 5 1. 1. 325 M Bee ­kidney . 6 1. 23 1. 327 M Bee ­lean ( at/ ree) w/ o bones . 5 1. 1. 326 M Bee ­liver . 2 1. 1. 321 M Bee ­meat byproducts . 6 1. 1. 322 M Bee ­other organ meats . 6 1. 1. 3 1 O Canola oil ( rape seed oil) . 25 1. .1 366 P Chicken­ byproducts . 3 1. 1. 368 P Chicken­ at w/ o bones . 4 1. 1. 367 P Chicken­ giblets( liver) . 2 1. 1. 385 P Chicken­ giblets ( excl. liver) . 3 1. 1. 369 P Chicken­ lean/ at ree w/ o bones . 2 1. 1. 267 15 Corn grain­ bran . 1 1. .15 266 15 Corn grain­ endosperm . 1 1. .15 289 15 Corn grain­ oil . 1 1. .15 268 15 Corn grain/ sugar/ h cs . 1 1. 5 .15 388 15 Corn grain/ sugar­ molasses . 1 1. 5 .15 237 15 Corn/ pop . 1 1. .15 238 15 Corn/ sweet . 1 1. . 1 364 P Eggs­ white only . 2 1. 1. 363 P Eggs­ whole . 2 1. 1. 365 P Eggs­ yolk only . 2 1. 1. 33 M Goat­ at w/ o bone . 5 1. 24 1. 331 M Goat­ kidney . 6 1. 1. 333 M Goat­ lean ( at/ ree) w/ o bone . 5 1. 1. 332 M Goat­ liver . 2 1. 1. 328 M Goat­ meat byproducts . 6 1. 1. 329 M Goat­ other organ meats . 6 1. 1. 334 M Horsemeat . 5 1. 1. 398 D Milk­ based water . 5 1. 1. 319 D Milk­ at solids . 5 1. 1. 318 D Milk­ non at solids . 5 1. 1. 32 D Milk sugar ( lactose) . 5 1. 1. 399 15 Oats­ bran . 52 1. . 3 269 15 Oats . 52 1. . 3 344 M Pork­ at w/ o bone . 7 1. 1. 345 M Pork­ kidney . 8 1. 1. 347 M Pork­ lean ( at ree) w/ o bone . 8 1. 1. 346 M Pork­ liver . 4 1. 1. 342 M Pork­ meat byproducts . 8 1. 1. 343 M Pork­ other organ meats . 8 1. 1. 362 P Poultry­ other­ at w/ o bones . 4 1. 1. 361 P Poultry­ other­ giblets( liver) . 2 1. 1. 36 P Poultry­ other­ lean ( at ree) w/ . 2 1. 25 1. 274 15 Rye­ lour . 52 1. . 3 273 15 Rye­ germ . 52 1. . 3 272 15 Rye­ rough . 52 1. . 3 338 M Sheep­ at w/ o bone . 5 1. 1. 339 M Sheep­ kidney . 6 1. 1. 341 M Sheep­ lean ( at ree) w/ o bone . 5 1. 1. 34 M Sheep­ liver . 2 1. 1. 336 M Sheep­ meat byproducts . 6 1. 1. 337 M Sheep­ other organ meats . 6 1. 1. 275 15 Sorghum ( including milo) . 1 1. . 3 355 P Turkey­ byproducts . 3 1. 1. 357 P Turkey­­ at w/ o bones . 4 1. 1. 356 P Turkey­ giblets ( liver) . 2 1. 1. 358 P Turkey­ lean/ at ree w/ o bones . 2 1. 1. 449 P Turkey­ other organ meats . 3 1. 1. 429 M Veal­ dried . 5 1. 92 1. 424 M Veal­ at w/ o bones . 5 1. 1. 426 M Veal­ kidney . 6 1. 1. 425 M Veal­ lean ( at ree) w/ o bones . 5 1. 1. 427 M Veal­ liver . 2 1. 1. 43 M Veal­ meat byproducts . 6 1. 26 1. 428 M Veal­ other organ meats . 6 1. 1. 278 15 Wheat­ bran . 52 1. . 3 279 15 Wheat­ lour . 52 1. . 3 277 15 Wheat­ germ . 52 1. . 3 437 15 Wheat­ germ oil . 52 1. . 3 276 15 Wheat­ rough . 52 1. . 3 Attachment 4: Acute Analysis Acute Analysis Using Feeding Studies U. S. Environmental Protection Agency Ver. 7. 74 DEEM ACUTE Analysis or LINDANE (1989­ 92 data) Residue ile: 12­ 11­ 1RevacuteTRR. RS7 Adjustment actor # 2 used. Analysis Date: 12­ 11­ 2 1/ 16: 9: Residue ile dated: 12­ 3­ 2 1/ 5: 14: 17/ 8 NOEL ( Acute) = 6. mg/ kg body­ wt/ day Daily totals or ood and ood orm consumption used. MC iterations = 5 MC list in residue ile MC seed = 1 281 Run Comment: " Re erence doses have 3X FQPA actored in. This is a dietary ana lysis using the total radioactive residues rom the plant and animal metabolism studies." ================================================================= ============== Summary calculations ( per capita): 27 95th Percentile 99th Percentile 99. 9th Percentile Exposure % aR D MOE Exposure % aR D MOE Exposure % aR D MOE ­­­­­­­­­­ ­­­­­­­ ­­­­­­­­ ­­­­­­­­­­ ­­­­­­­ ­­­­­­­­ ­­­­­­­­­ ­­­­­­­ ­­­­­­­ U. S. Population: . 16 .8 37614 . 516 2. 58 11627 . 13 5 6. 52 4598 U. S. Population ( spring season): . 16 .8 3739 . 5 3 2. 51 11934 . 129 6. 45 465 U. S. Population ( summer season): . 152 .76 39455 . 521 2. 6 11525 . 1434 7. 17 4185 U. S. Population ( autumn season): . 166 .83 36 52 . 563 2. 82 1 648 . 1294 6. 47 4636 U. S. Population ( winter season): . 161 .8 37353 . 478 2. 39 12541 . 1221 6. 1 4914 Northeast region: . 152 .76 39479 . 521 2. 61 1151 . 1414 7. 7 4243 Midwest region: . 181 .91 331 1 . 574 2. 87 1 452 . 1383 6. 92 4337 Southern region: . 151 .76 39732 . 457 2. 29 13125 . 11 6 5.53 5424 Western region: . 158 .79 37994 . 523 2. 62 11466 . 1376 6. 88 436 Hispanics: . 179 .89 336 4 . 616 3. 8 9745 . 1456 7. 28 4122 Non­ hispanic whites: . 159 .79 37742 . 5 9 2. 54 11795 . 1281 6. 41 4682 Non­ hispanic blacks: . 15 .75 4 4 . 474 2. 37 12662 . 13 7 6. 54 459 28 Non­ hisp/ non­ white/ non­ black: . 158 .79 38 1 . 591 2. 96 1 149 . 1593 7. 97 3765 All in ants: . 2 4 1. 2 29448 . 837 4. 19 7167 . 332 16. 6 18 7 Nursing in ants (< 1 yr old): . 64 .32 941 . 288 1. 44 2 823 . 698 3. 49 8599 Non­ nursing in ants (< 1 yr old): . 234 1. 17 25658 . 1521 7. 6 3945 . 3626 18. 13 1654 Children 1­ 6 yrs: . 668 3.34 8987 . 1264 6. 32 4748 . 1973 9. 86 3 41 Children 7­ 12 yrs: . 353 1. 76 17 17 . 642 3. 21 9342 . 1 88 5. 44 5513 Females 13+ ( preg/ not nursing): . 191 .95 31424 . 342 1. 71 17528 . 5 9 2. 54 11797 Females 13+ ( nursing): . 148 .74 4 598 . 352 1. 76 17 23 . 623 3. 11 9632 Females 13­ 19 ( not preg or nursing): . 16 .8 374 5 . 311 1. 55 19293 . 676 3.38 8874 Females 2 + ( not preg or nursing): . 99 .5 6 5 3 . 2 7 1. 4 28962 . 4 5 2. 2 14816 Females 13­ 5 yrs: . 111 .55 54255 . 245 1. 23 24444 . 467 2. 34 12844 Males 13­ 19 yrs: . 2 1 1. 29852 . 413 2. 6 14542 . 67 3.35 896 Males 2 + yrs: . 1 6 .53 56425 . 225 1. 13 26647 . 458 2. 29 131 4 Seniors 55+: . 99 .5 6 477 . 2 3 1. 1 29619 . 4 9 2. 4 14676 29 Paci ic: . 156 .78 38498 . 531 2. 66 11297 . 1344 6. 72 4462 30 Attachment 5: Chronic Analysis Chronic Analysis Using Feeding Study U. S. Environmental Protection Agency Ver. 7. 73 DEEM Chronic analysis or LINDANE (1989­ 92 data) Res i d u e i l e n a m e : C :\d e e m \ 9 1 \R e v i s e d Analysis\ 12­ 11­ 1\ 12­ 11­ 1RevchronicTRR. RS7 Adjustment actor # 2 used. Analysis Date 12­ 12­ 2 1/ 13: 26: 48 Residue ile dated: 12­ 3­ 2 1/ 5: 15: 47/ 8 Re erence dose ( R D, Chronic) = . 16 mg/ kg bw/ day COMMENT 1: Re erence doses have 3X FQPA actored in. This is the dietary analysis using the metabolism and eeding studies. ================================================================= ============== Total exposure by population subgroup ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ Total Exposure ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ Population mg/ kg Percent o Subgroup body wt/ day R d ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­ ­­­­­­­­­­­­­­ U. S. Population ( total) . 54 3. 4% U. S. Population ( spring season) . 54 3.3% U. S. Population ( summer season) . 53 31 3.3% U. S. Population ( autumn season) . 56 3.5% U. S. Population ( winter season) . 53 3.3% Northeast region . 53 3.3% Midwest region . 6 3. 7% Southern region . 51 3. 2% Western region . 53 3.3% Hispanics . 59 3. 7% Non­ hispanic whites . 54 3. 4% Non­ hispanic blacks . 49 3. 1% Non­ hisp/ non­ white/ non­ black . 56 3.5% All in ants (< 1 year) . 72 4. 5% Nursing in ants . 19 1. 2% Non­ nursing in ants . 94 5. 9% Children 1­ 6 yrs . 173 1 .8% Children 7­ 12 yrs . 96 6. % Females 13­ 19 ( not preg or nursing) . 46 2. 9% Females 2 + ( not preg or nursing) . 29 1. 8% Females 13­ 5 yrs . 34 2. 1% Females 13+ ( preg/ not nursing) . 49 32 3. % Females 13+ ( nursing) . 43 2. 7% Males 13­ 19 yrs . 61 3.8% Males 2 + yrs . 34 2. 1% Seniors 55+ . 3 1. 9% Paci ic Region . 53 3.3% ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­­­­­­­­­­

epa

2024-06-07T20:31:43.052528

regulations

EPA-HQ-OPP-2002-0202-0005

Supporting & Related Material

December 11, 2001 MEMORANDUM: SUBJECT: Lindane (009001): Reregistration Case 0315. Revised Product and Residue Chemistry Chapters for the Lindane Reregistration Eligibility Document (RED). DP Barcode: D279259. FROM: Thurston G. Morton, Chemist Reregistration Branch 4 Health Effects Division (7509C) THROUGH: Susan V. Hummel, Branch Senior Scientist Reregistration Branch 4 Health Effects Division (7509C) TO: Rebecca Daiss, Risk Assessor Reregistration Branch 4 Health Effects Division (7509C) And Mark Howard/ Betty Shackleford Reregistration Branch 3 Special Review & Reregistration Division (7508C) Attached are the revised Product and Residue Chemistry Chapters for the lindane RED. The chapters were assembled by Dynamac Corporation under supervision of HED. The data assessment has undergone secondary review in the branch and has been revised to reflect branch policies. This memorandum serves to update the Product and Residue Chemistry Chapter (T. Morton, 6/ 7/ 01, D274754) by incorporating comments from the public comment period and incorporating submissions reviewed by the Agency since 9/ 26/ 00. Only uses supported for reregistration by Inquinosa are included. 2 EXECUTIVE SUMMARY: Product Chemistry
Pertinent product chemistry data remain outstanding for the Inquinosa 99.5% T/ TGAI concerning product identity, starting materials and production process, preliminary analysis, certified limits, oxidation/ reduction, explodability, storage stability, corrosion characteristics, and UV/ visible absorption (OPPTS 830.1550, 1600, 1620, 1700, 1750, 6314, 6316, 6317, 6320, and 7050). Technical products registered to Kanoria Chemicals & Industries were suspended effective 12/ 5/ 00 for failure to comply with a cost sharing agreement with Inquinosa. Therefore, all technical products registered which are repackages of the Kanoria products would be required to change suppliers. The Prentiss, Drexel, and Amvac 99.5% Ts are repackaged from EPA­ registered products, and all data requirements will be satisfied by data for the technical source products. Provided that the registrants submit the data required in the attached data summary tables for the lindane T/ TGAIs, and either certify that the suppliers of beginning materials and the manufacturing processes have not changed since the last comprehensive product chemistry reviews or submit complete updated product chemistry data packages, the Branch has no objections to the reregistration of lindane with respect to product chemistry data requirements. Residue Chemistry
The Agency will not require a new confined rotational crop study provided the registrants propose a 30­ day plantback interval for leafy vegetables and a 12­ month plantback interval for all other unregistered crops on all of their end­ use product labels for lindane. The registrants have informed the Agency they will propose the specified plantback intervals.
A new nature of the residue study is required for application of lindane as a seed treatment to a cereal grain.
If the HED Metabolism Assessment Review Committee determines the residues of concern to include metabolites in addition to lindane, then additional crop field trial data, magnitude of the residue in poultry and cattle, and processing studies are required. In addition, an adequate residue analytical method and storage stability data will be required. 3 Dietary Exposure/ Risk Assessment
Anticipated residues (DP Barcode D279260, T. Morton, 12/ 4/ 01) will be provided for all commodities and should be used when calculating the dietary risk associated with the RED. Although the database for lindane is substantially complete, additional data are needed to eliminate the uncertainties associated with the exposure/ risk assessment. The anticipated residue values are the best estimates HED can provide using the residue data available at the time of the RED. These values have an inherent uncertainty associated with variations in analytical methods, geographical representation of field trials, seasonal variation of residue levels, use of TRR from metabolism studies, etc. cc : Chem F, Chron F. Morton , Shallal RDI: ChemSAC: 9/ 13/ 00; SVH: 12/ 11/ 01 TM, Thurston Morton, Rm. 816D CM2, 305­ 6691, mail code 7509C 4 LINDANE Case 0315; PC Code 009001 D279259 Reregistration Eligibility Decision: Product Chemistry Considerations December 11, 2001 Contract No. 68­ W­ 99­ 053 Submitted to: U. S. Environmental Protection Agency Arlington, VA Submitted by: Dynamac Corporation 2275 Research Boulevard Rockville, MD 22850­ 3268 5 Cl Cl Cl Cl Cl Cl LINDANE REREGISTRATION ELIGIBILITY DECISION: PRODUCT CHEMISTRY CONSIDERATIONS Case No. 0315; PC Code 009001 DESCRIPTION OF CHEMICAL Lindane (gamma isomer of benzene hexachloride, gamma isomer of hexachlorocyclohexane) is a broad­ spectrum organochlorine insecticide/ acaricide registered for control of insects and other invertebrates. The only registered food/ feed use is seed treatment for field and vegetable crops. Empirical Formula: C6 H6 Cl6 Molecular Weight: 290.9 CAS Registry No.: 58­ 89­ 9 PC Code: 009001 IDENTIFICATION OF ACTIVE INGREDIENT Lindane is a white crystalline solid with a melting point of 112­ 113 C, specific gravity of 1.85, octanol/ water partition coefficient (Kow ) of 3135, and vapor pressure of 9.4 x 10 ­6 mm Hg at 20 C. Lindane is soluble in water (10 ppm at 20 C) and most organic solvents, including acetone and aromatic and chlorinated hydrocarbons. Lindane is only slightly soluble in mineral oils. Lindane is stable to light, heat, air, and strong acids, but decomposes upon exposure to trichlorobenzenes and HCl in alkali. MANUFACTURING­ USE PRODUCTS According to a search of the Reference Files System (REFS) conducted 5/ 29/ 01, there are eight registered manufacturing­ use products (MPs) under PC Code 009001. The registered MPs subject to a reregistration eligibility decision are listed in Table 1. 6 Table 1. Registered lindane manufacturing­ use products. Formulation EPA Registry Number Registrant 99.5% T 655­ 28 1 Prentiss Incorporated 99.5% T 655­ 393 1 99.5% T 5481­ 225 1 Amvac Chemical Corporation 99.5% T 19713­ 61 1 Drexel Chemical Company 99.5% T 19713­ 191 1 99.5% T 40083­ 1 Inquinosa Internacional, S. A. 99.5% T 66951­ 1 Kanoria Chemicals & Industries Ltd. 99.5% T 66951­ 2 1 Repackaged from an EPA­ registered product. REGULATORY BACKGROUND The Lindane Reregistration Standard and the Addendum to the Lindane Reregistration Standard were issued 6/ 7/ 85 and 7/ 16/ 85, respectively, and required additional product chemistry data concerning lindane. The Lindane Guidance Document dated 9/ 85 reiterated the data gaps outlined under the Addendum to the Reregistration Standard. Data submitted in response to the Guidance Document for the lindane T/ TGAIs were evaluated in the Lindane Reregistration Standard Update dated 1/ 31/ 91 with regard to adequacy in fulfilling product chemistry requirements. The Centre International d'Etudes du Lindane (CIEL) members (Rhone­ Poulenc, Inc., EM Industries, Inc. (representing Celamerck GmbH and Company), and Inquinosa) have submitted data jointly. Kanoria Chemicals and Industries, Inc. became a member of CIEL in 1994 (Letter from McKenna and Cuneo on behalf of CIEL dated 11/ 30/ 94, in support of application to register a technical lindane product). Prentiss and Amvac previously entered into data sharing agreements with CIEL in accordance with the provisions of FIFRA §3( C)( 2)( B)( ii). Technical products registered to Kanoria Chemicals & Industries were suspended effective 12/ 5/ 00 for failure to comply with a cost sharing agreement with Inquinosa. The current status of the product chemistry data requirements for the lindane T/ TGAIs is presented in the attached data summary tables. Refer to these tables for a listing of the outstanding product chemistry data requirements. CONCLUSIONS Pertinent product chemistry data remain outstanding for the Inquinosa 99.5% T/ TGAI concerning product identity, starting materials and production process, preliminary analysis, certified limits, oxidation/ reduction, explodability, storage stability, corrosion characteristics, and UV/ visible absorption (OPPTS 830.1550, 1600, 1620, 1700, 1750, 6314, 6316, 6317, 6320, and 7050). 7 Technical products registered to Kanoria Chemicals & Industries were suspended effective 12/ 5/ 00 for failure to comply with a cost sharing agreement with Inquinosa. Therefore, all technical registered which are repackages of the Kanoria products would be required to change suppliers. The Kanoria products are shown in attached data summary tables for informational purposes only. The Prentiss, Drexel, and Amvac 99.5% Ts are repackaged from EPA­ registered products, and all data requirements will be satisfied by data for the technical source products. Provided that the registrants submit the data required in the attached data summary tables for the lindane T/ TGAIs, and either certify that the suppliers of beginning materials and the manufacturing processes have not changed since the last comprehensive product chemistry reviews or submit complete updated product chemistry data packages, HED has no objections to the reregistration of lindane with respect to product chemistry data requirements. AGENCY MEMORANDA CITED IN THIS DOCUMENT DP Barcode: D211047 Subject: RD Product Chemistry Review for EPA File Symbol Number 66951­ R, Kanoria Lindane Crystals From: S. Mathur To: G. Larocca Dated: 3/ 21/ 95 MRID( s): 43498201­ 43498203 DP Barcode: D211063 Subject: RD Product Chemistry Review for EPA File Symbol Number 66951­ E, Kanoria Lindane Powder From: S. Mathur To: G. Larocca Dated: 3/ 21/ 95 MRID( s): 43498201­ 43498203 PRODUCT CHEMISTRY CITATIONS Bibliographic citations include only MRIDs containing data which fulfill data requirements. References (cited): 00072468 Hooker Chemical & Plastics Corporation (19??) Product Chemistry Data: Lindane HGI. (Unpublished study received May 7, 1981 under 935­ 17; CDL: 245029­ A) 00102995 Zoecon Corp. (1981) [Study of the Chemical Lindane]. (Compilation; unpublished study received Sep 15, 1981 under 20954­ 107; CDL: 246026­ A) 00118712 Commerce Industrial Chemicals, Inc. (1969) Laboratory Report: [Lindane]: Lab No. C11,131, Supplement #1. (Unpublished study received May 12, 1969 under 10531­ 1; submitted by Petland Products, Inc., Chicago, IL; CDL: 026276­ A) 8 00118743 Makhteshim Beer­ Sheva Chemical Works, Ltd. (1976) [Chemistry of Lindane]. (Compilation; unpublished study received Jul 11, 1978 under 11678­ 16; CDL: 234441­ A) 00160127 Inquinosa (19??) Synthesis of Lindane. Unpublished study. 4 p. 00160129 Buys, M. (1986) Lindane... Product Identity and Composition... Discussion of the Formation of Impurities: Report AG/ CRLD/ AN/ MB/ ID/ 15274.86. Unpublished study prepared by Rhone­ Poulenc Agrochimie. 10 p. 00160130 Mirfakhrae, K.; Norris, F. (1986) Determination of the Octanol/ Water Partition Coefficient of Lindane: Ref. No. 86/ BHL/ 191/ AG: ASD No. 86/ 187. Unpublished study prepared by Rhone­ Poulenc Inc. 26 p. 00164782 Viziere, G. (1986) Lindane: Analysis and Certification of Product Ingredients: AG/ CRLD/ AN/ MB/ ID/ 15871.86. Unpublished study prepared by Rhone­ Poulenc Agrochimie. 57 p. 00164783 Buys, M. (1986) Lindane: Analytical Data for the Technical Grade Lindane Produced by Inquinosa: Report AG/ CRLD/ AN/ MB/ ID/ 158874.86. Unpublished study prepared by Rhone­ Poulenc Agrochimie. 9 p. 43498201 Brookman, D.; Curry, K. (1994) The Product Chemistry of Kanoria Lindane (Product Identity and Disclosure of Ingredients). Unpublished study prepared by Technology Sciences Group, Inc. 35 p. 43498202 Brookman, D.; Curry, K. (1994) The Product Chemistry of Kanoria Lindane (Analysis and Certification of Product Ingredients). Unpublished study prepared by Technology Sciences Group, Inc. 49 p. 43498203 Brookman, D.; Curry, K. (1994) The Product Chemistry of Kanoria Lindane (Physical and Chemical Characteristics). Unpublished study prepared by Technology Sciences Group, Inc. 18 p. 9 Case No. 0315 PC Code: 009001 Case Name: Lindane Registrant: Prentiss, Inc. Product( s): 99.5% Ts (EPA Reg. Nos. 655­ 28 and 655­ 393) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition Y CSF 4/ 21/ 97 (655­ 28) CSF 4/ 23/ 97 (655­ 393) 830.1600 Description of materials used to produce the product N/ A 830.1620 Description of production process N/ A 830.1670 Discussion of formation of impurities N/ A 830.1700 Preliminary analysis N/ A 830.1750 Certified limits Y CSF 4/ 21/ 97 (655­ 28) CSF 4/ 23/ 97 (655­ 393) 830.1800 Enforcement analytical method N/ A 830.6302 Color N/ A 830.6303 Physical state N/ A 830.6304 Odor N/ A 830.6313 Stability to normal and elevated temperatures, metals, and metal ions N/ A 830.6314 Oxidation/ reduction: chemical incompatability N/ A 830.6315 Flammability N/ A 830.6316 Explodability N/ A 830.6317 Storage stability N/ A 830.6319 Miscibility N/ A 830.6320 Corrosion characteristics N/ A 830.7000 pH N/ A 830.7050 UV/ visible absorption N/ A 830.7100 Viscosity N/ A 830.7200 Melting point/ melting range N/ A 830.7220 Boiling point/ boiling range N/ A 830.7300 Density/ relative density/ bulk density N/ A 830.7370 Dissociation constants in water N/ A 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 830.7840 Water solubility: column elution method; shake flask method N/ A 830.7950 Vapor pressure N/ A 1 Y = Yes; N = No; N/ A = Not Applicable. The Prentiss technical products are repackaged from EPA­ registered products; data requirements will be satisfied by data for the source products. 2 The CSFs were obtained from the product jackets. 10 Case No. 0315 PC Code: 009001 Case Name: Lindane Registrant: Amvac Chemical Corp. Product( s): 99.5% T (EPA Reg. No. 5481­ 225) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition N 3 CSF 6/ 19/ 86 830.1600 Description of materials used to produce the product N/ A 830.1620 Description of production process N/ A 830.1670 Discussion of formation of impurities N/ A 830.1700 Preliminary analysis N/ A 830.1750 Certified limits N 3 CSF 6/ 19/ 86 830.1800 Enforcement analytical method N/ A 830.6302 Color N/ A 830.6303 Physical state N/ A 830.6304 Odor N/ A 830.6313 Stability to normal and elevated temperatures, metals, and metal ions N/ A 830.6314 Oxidation/ reduction: chemical incompatability N/ A 830.6315 Flammability N/ A 830.6316 Explodability N/ A 830.6317 Storage stability N/ A 830.6319 Miscibility N/ A 830.6320 Corrosion characteristics N/ A 830.7000 pH N/ A 830.7050 UV/ visible absorption N/ A 830.7100 Viscosity N/ A 830.7200 Melting point/ melting range N/ A 830.7220 Boiling point/ boiling range N/ A 830.7300 Density/ relative density/ bulk density N/ A 830.7370 Dissociation constants in water N/ A 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 830.7840 Water solubility: column elution method; shake flask method N/ A 830.7950 Vapor pressure N/ A 1 Y = Yes; N = No; N/ A = Not Applicable. The available CSF indicates that the Amvac technical product is repackaged from EPA­ registered products which have been canceled (1/ 28/ 98). If the product is repackaged from a currently registered product, data requirements will be satisfied by data for the source product; otherwise, additional product chemistry data may be required. 2 The CSF was reviewed in the Lindane Reregistration Standard Update dated 1/ 31/ 91. 3 The CSF must be revised to cite the current registered source( s) of the technical product (PPIS Deficiency Notice, 11/ 1/ 99, J. Hinkle). 11 Case No. 0315 PC Code: 009001 Case Name: Lindane Registrant: Drexel Chemical Company Product( s): 99.5% Ts (EPA Reg. Nos. 19713­ 61 and 19713­ 191) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition Y CSFs 2/ 25/ 98 830.1600 Description of materials used to produce the product N/ A 830.1620 Description of production process N/ A 830.1670 Discussion of formation of impurities N/ A 830.1700 Preliminary analysis N/ A 830.1750 Certified limits Y 3 CSFs 2/ 25/ 98 830.1800 Enforcement analytical method N/ A 830.6302 Color N/ A 830.6303 Physical state N/ A 830.6304 Odor N/ A 830.6313 Stability to normal and elevated temperatures, metals, and metal ions N/ A 830.6314 Oxidation/ reduction: chemical incompatability N/ A 830.6315 Flammability N/ A 830.6316 Explodability N/ A 830.6317 Storage stability N/ A 830.6319 Miscibility N/ A 830.6320 Corrosion characteristics N/ A 830.7000 pH N/ A 830.7050 UV/ visible absorption N/ A 830.7100 Viscosity N/ A 830.7200 Melting point/ melting range N/ A 830.7220 Boiling point/ boiling range N/ A 830.7300 Density/ relative density/ bulk density N/ A 830.7370 Dissociation constants in water N/ A 830.7550 Partition coefficient (n­ octanol/ water), shake flask method N/ A 830.7840 Water solubility: column elution method; shake flask method N/ A 830.7950 Vapor pressure N/ A 1 Y = Yes; N = No; N/ A = Not Applicable. The Drexel technical products are repackaged from EPA­ registered products; data requirements will be satisfied by data for the source products. Data previously submitted by Drexel in support of the reregistration of these products are no longer applicable. 2 The CSFs were obtained from the product jackets. 3 The CSFs should be revised to propose certified limits for the active ingredient which reflect the actual levels in the technical products. 12 Case No. 0315 PC Code: 009001 Case Name: Lindane Registrant: Inquinosa Internacional, S. A. Product( s): 99.5% Ts (EPA Reg. No. 40083­ 1) PRODUCT CHEMISTRY DATA SUMMARY Guideline Number Requirement Are Data Requirements Fulfilled? 1 MRID Number 2 830.1550 Product identity and composition N 3 830.1600 Description of materials used to produce the product N 4 00160127 830.1620 Description of production process N 5 00160127 830.1670 Discussion of formation of impurities Y 00160129 830.1700 Preliminary analysis N 6 00164783 830.1750 Certified limits N 3 830.1800 Enforcement analytical method Y 7 00164782 830.6302 Color Y 00072468 830.6303 Physical state Y 00118743 830.6304 Odor Y 00102995 830.6313 Stability to normal and elevated temperatures, metals, and metal ions Y 00072468 830.6314 Oxidation/ reduction: chemical incompatability N 830.6315 Flammability N/ A 8 830.6316 Explodability N 830.6317 Storage stability N 830.6319 Miscibility N/ A 8 830.6320 Corrosion characteristics N 830.7000 pH N/ A 9 830.7050 UV/ visible absorption N 10 830.7100 Viscosity N/ A 8 830.7200 Melting point/ melting range Y 00118743 830.7220 Boiling point/ boiling range N/ A 8 830.7300 Density/ relative density/ bulk density Y 00072468 830.7370 Dissociation constants in water N/ A 9 830.7550 Partition coefficient (n­ octanol/ water), shake flask method Y 00160130 830.7840 Water solubility: column elution method; shake flask method Y 00118712 830.7950 Vapor pressure Y 00118743 1 Y = Yes; N = No; N/ A = Not Applicable. A CSF for the Inquinosa technical product was not available from the product jacket. Until a current CSF is available for comparison, the Agency cannot ascertain whether TGAI data (physical/ chemical data) from other CIEL members are applicable to the Inquinosa product. 2 Bolded references were reviewed in the Lindane Reregistration Standard dated 6/ 7/ 85 and all other references were reviewed in the Lindane Reregistration Standard Update dated 1/ 31/ 91. 3 An updated CSF is required for evaluation of the product chemistry data (Lindane Reregistration Standard Update dated 1/ 31/ 91). 13 4 Information is required concerning the relative amounts and order in which the starting materials are added. 5 Additional information is required concerning: (I) clarification as to whether the process is a batch or continuous process; (ii) the duration of each step and the entire process; (iii) description of the equipment used; and (iv) quality control measures used to ensure the integrity of the product. 6 Data demonstrating that the method used for analysis of dioxins and dibenzofurans can quantitate the 2, 3, 7, 8TCDD reference standard to 0. 1 ppb must be provided. 7 If the CIPAC normalized 4 gamma/ 1/ M/ 1 cryoscopic method is to be used for enforcement of certified limits of the active ingredient, then a complete description of the method, along with supporting validation data, is required. 8 Data are not required because the TGAI/ MP is a solid at room temperature. 9 Data were not required by the Lindane Registration Standard concerning pH and dissociation constant. 10 The OPPTS Series 830, Product Properties Test Guidelines require data pertaining to UV/ visible absorption for the PAI. 14 LINDANE Case 0315; PC Code 009001 D279259 Reregistration Eligibility Decision Residue Chemistry Considerations December 11, 2001 Contract No. 68­ W­ 99­ 053 Submitted to: U. S. Environmental Protection Agency Arlington, VA Submitted by: Dynamac Corporation The Dynamac Building 2275 Research Boulevard Rockville, MD 20850­ 3268 15 LINDANE REREGISTRATION ELIGIBILITY DECISION RESIDUE CHEMISTRY CONSIDERATIONS Case 0315; PC Code 009001 TABLE OF CONTENTS page INTRODUCTION ......................................................... 16 REGULATORY BACKGROUND ............................................. 16 SUMMARYOFSCIENCE FINDINGS ......................................... 17 GLN 860.1200: Directions for Use ........................................ 17 GLN 860.1300: Nature of the Residue ­ Plants ............................... 18 GLN 860.1300: Nature of the Residue ­ Animals .............................. 18 GLN 860.1340: Residue Analytical Methods ................................. 19 GLN 860.1360: Multiresidue Methods ..................................... 20 GLN 860.1380: Storage Stability Data ..................................... 21 GLN 860.1500: Crop Field Trials ......................................... 21 GLN 860.1520: Processed Food/ Feed ...................................... 23 GLN 860.1480: Meat, Milk, Poultry, Eggs .................................. 23 GLN 860.1400: Water, Fish, and Irrigated Crops ............................. 26 GLN 860.1460: Food Handling ........................................... 26 GLN 860.1850 and 860.1900: Confined/ Field Accumulation in Rotational Crops ..... 26 TOLERANCE REASSESSMENT SUMMARY ................................... 39 Tolerances Listed Under 40 CFR §180.133 .................................. 39 Tolerances To Be Proposed Under 40 CFR §180.133 ........................... 40 PendingTolerancePetitions .............................................. 40 CODEXHARMONIZATION................................................. 43 DIETARYEXPOSUREASSESSMENT ........................................ 45 AGENCYMEMORANDARELEVANTTOREREGISTRATION .................... 46 MASTERRECORDIDENTIFICATIONNUMBERS .............................. 50 16 Cl Cl Cl Cl Cl Cl LINDANE REREGISTRATION ELIGIBILITY DECISION RESIDUE CHEMISTRY CONSIDERATIONS Case 0315; PC Code 009001 INTRODUCTION Lindane (gamma isomer of benzene hexachloride, gamma isomer of hexachlorocyclohexane) is a broad spectrum organochlorine insecticide/ acaricide registered for control of insects and other invertebrates on a wide variety of field crops and vegetable crops (seed treatment only). According to a REFS search, conducted on 5/ 29/ 01, there are approximately 34 federally registered end­ use products (EPs) containing lindane as the active ingredient and three Section 24C registrations. Lindane end­ use products are formulated as dust (D), wettable powder (WP), emulsifiable concentrate (EC), flowable concentrate (FlC), and ready­ to­ use (RTU) solution. The reregistration of lindane is being supported by Centre International d'Etudes du Lindane (CIEL) and its member company holding U. S. registrations, Inquinosa, S. A. Currently, Inquinosa does not have any registered lindane end­ use products. In 1993, CIEL offered to voluntarily cancel all crop uses of lindane except seed treatment and certain non­ food uses. The Agency considers lindane seed treatment as a food use requiring tolerances based on existing data from radiolabeled studies indicating uptake of residues from the treated seeds into the aerial portion of the growing crop. REGULATORY BACKGROUND Lindane is a List A reregistration pesticide. A Reregistration Standard for Lindane was issued 9/ 85. The Residue Chemistry Chapter to the Reregistration Standard was issued on 6/ 7/ 85, an addendum on 9/ 5/ 85, and an Update on 1/ 31/ 91. The Reregistration Standard along with its Science Chapters summarized the available data for each residue chemistry guideline and specified what additional data are required for reregistration purposes. Data Call­ In (DCI) Notices for lindane were issued by the Agency on 9/ 30/ 91, 3/ 3/ 95, 10/ 13/ 95, and 3/ 31/ 97. The information contained in this document outlines the current Residue Chemistry Science Assessments with respect to supporting seed treatment uses of lindane, as well as the reregistration of the pesticide. 17 In 1983, EPA concluded a major Special Review effort of lindane based on carcinogenicity, fetotoxicity/ teratogenicity, reproductive effects, and acute effects on aquatic organisms. This effort resulted in the cancellation of indoor uses of smoke fumigation devices and greatly limited the use of pet dips on dogs. In addition, there were uses that were allowed to continue only if certain imposed restrictions were implemented. The restrictions were based on the degree of associated hazards, and included changes in warning labels, the wearing of protective clothing, and restrictions to limit uses to certified pest control operators. In 1995, EPA announced (FR Vol. 60, No. 143, 38329­ 38331, 7/ 26/ 95) its decision not to initiate a Special Review of lindane based on worker health concerns arising from studies showing irreversible renal effects in the rat. The Agency has determined that these effects occur only in the kidneys of male rat and are not relevant for human risk assessment. Tolerances are currently established under 40 CFR §180.133 for residues of lindane per se in/ on various raw agricultural commodities at 0.01 ppm (pecans) to 3 ppm (cucumbers, lettuce, melons, mushrooms, pumpkins, squash, summer squash, and tomatoes). Lindane tolerances are also established at 4 ppm in the fat of meat from hogs and at 7 ppm in the fat of meat from cattle, goats, horses, and sheep. No tolerances have been established for processed food/ feed commodities. Adequate methods are available for the enforcement of tolerances for residues of lindane per se in/ on plant and animal commodities. SUMMARY OF SCIENCE FINDINGS GLN 860.1200: Directions for Use The basic registrants, CIEL and its member company (Inquinosa) presently do not have any registered lindane end­ use products. However, it is noted that lindane remains registered by other companies for use on a wide variety of food/ feed crops such as fruit crops, field crops, and vegetable crops (including seed treatment) [Source: 5/ 29/ 01 search of EPA's REFS database]. CIEL and its member company have expressed intentions to support certain non­ food uses and seed treatment uses of lindane on cereal grains (including barley, corn, oats, rye, sorghum, and wheat but excluding rice and wild rice). The registrants have submitted PP# 9F05057, for the establishment of time­ limited tolerances for residues of lindane per se in/ on the RACs of crops for which seed treatments are being proposed. Tolerances cannot be established or reassessed until an adequate plant metabolism study is submitted. The registrants have also submitted PP# 9F6022, for the establishment of tolerances on lindane per se in/ on canola for which seed treatment is being proposed. Tolerances cannot be established or reassessed until an adequate plant metabolism study is submitted and additional residue data. A tabular summary of the residue chemistry science assessments for reregistration of lindane is presented in Table A. When end­ use product DCIs are developed (e. g., at issuance of the RED), RD should require that all end­ use product labels (e. g., MAI labels, SLNs, and products subject 18 to the generic data exemption) be amended such that they are consistent with the residue data which was submitted. A 30­ day plantback interval for leafy vegetables and a 12­ month plantback interval for all other unregistered crops is required on all of their end­ use product labels for lindane. GLN 860.1300: Nature of the Residue ­ Plants The qualitative nature of lindane residues in plants reflecting seed treatment is inadequately understood. For the purpose of reregistration, the basic registrants are required to conduct a new plant metabolism study on lindane. This study should be conducted on a representative cereal grain, as the registrants have indicated that the only food uses they are supporting are for seed treatment of these crops. The new studies should be conducted at an application rate which will insure that sufficient 14 C­ residues are available for analysis. Crop samples should be harvested at the appropriate stage. In addition, care should be taken to insure that radioactivity is not lost during analysis. Identification of 14 C­ residues should also be confirmed using more than one method, or by GC/ MS. The results of the requested plant metabolism study will be considered by HED's MARC for determination of terminal residues of concern in cereal grains. Although the nature of the residue in plants remains inadequately understood at this time, HED has no objection to proceeding with the Lindane RED and with risk assessments, given that acceptable enforcement and datacollection methods are available for determining residues of lindane per se in/ on plants and the proposed food/ feed uses of lindane are limited to seed treatment. The HED MARC (T. Morton, 8/ 30/ 00, D267069) concluded that the total radioactive residues should be used for risk assessment purposes until adequate plant metabolism studies are submitted. Plant metabolism studies reflecting postemergence foliar application on apples (MRID 40410902), cucumbers (MRID 40431204), and spinach (MRID 40431201) were previously submitted by the basic registrants in response to the requirements of the 9/ 85 Lindane Reregistration Guidance Document. These studies were deemed unacceptable and nonupgradable because of several deficiencies including inadequate characterization and identification of 14 C­ residues. GLN 860.1300: Nature of the Residue ­ Animals The qualitative nature of the residue in ruminants is adequately understood. The basic registrants had submitted a ruminant metabolism study (MRID 44867104) which was deemed inadequate but upgradable. To upgrade the study, the registrant was required to identify the metabolite labeled LiV in goat liver's aqueous phase which accounted for 25.2 % of the total radioactivity (0.57 ppm). In addition, storage stability data was required showing individual tissue sampling dates and final analysis dates. The registrant has recently submitted the required data (MRID 45224101, 45224102, and 45277201) thus, adequately addressing this deficiency. A brief summary of the recently reviewed goat metabolism study follows. Lactating goats were orally administered with [ 14 C] lindane capsules immediately after morning milking once per day for seven 19 days at a level equivalent to 13 ppm. Milk was collected twice daily and within 24 hours of the last dose, the animals were sacrificed. The total radioactive residues (TRR; expressed as lindane equivalents) in collected samples were 3. 46 ppm in fat, 2.25 ppm in liver, 0. 48 ppm in kidney, 0. 20 ppm in muscle, and 0. 20 ppm in milk. The parent, lindane was the major residue identified in all goat matrices and accounted for approximately 56% of the TRR in milk fat, 85% of the TRR in fat, 81% of the TRR in muscle, 36% of the TRR in kidney, and 16% of the TRR in liver. Other metabolites present were: gamma­ pentachlorocyclohexene (PCCH); 1,2,4­ trichlorobenzene; gamma­ tetrachlorocyclohexene (TCCH); 1,2­ dichlorobenzene, a glutathione conjugate of a dichlorophenol, and a conjugate of a monochlorophenol. The qualitative nature of the residue in poultry is adequately understood. A poultry metabolism study (MRIDs 40271301 and 44405404), submitted by the registrants in response to the 9/ 85 Lindane Reregistration Guidance Document, has recently been upgraded to acceptable status. A brief summary of the poultry metabolism study follows. Laying hens were dosed with [ 14 C] lindane at levels equivalent to 1.2 ppm or 120 ppm in the diet for four consecutive days. Radioactive residues accumulated to the greatest extent in fatty tissues. In high dose hens, TRR levels were highest in fat (96.98 ppm) and lowest in breast muscle (1.44 ppm). TRR levels were proportionally less in tissues of low­ dose hens (fat, 1. 26 ppm; breast muscle 0. 02 ppm). In eggs of high­ dose hens, 14 C­ residues peaked on Day 4 at 10.83 ppm in yolks and 0.21 ppm in whites. Lindane was the major residue component identified and accounted for approximately 95% of the TRR in egg yolks, 71­ 86% of the TRR in muscle, skin, and fat, and 52% of the TRR in liver. Other metabolites that were identified included: 1,2,4­ trichlorobenzene; 1,3,5­ trichlorobenzene and dichlorobenzene( s); tetrachlorobenzene (either 1,2,4,5­ or 1,2,3,4­); PCCH; 1, 2, 3, 4tetrachlorobenzene tetrachlorocyclohexene; 1,2,3,4,5­ pentachlorobenzene; and hexachlorocyclohexene. The results of the ruminant and poultry metabolism studies will be presented to HED's MARC for determination of terminal residue of concern in eggs, milk, and animal tissues when an acceptable plant metabolism study is submitted. If the Committee determines that lindane per se is the only residue of concern requiring regulation, then the existing storage stability data for poultry commodities, the analytical method used for data collection, and the poultry feeding study will be upgraded to acceptable status. The HED MARC (T. Morton, 8/ 30/ 00, D267069) concluded that the total radioactive residues should be used for risk assessment purposes until an adequate plant metabolism study is submitted. GLN 860.1340: Residue Analytical Methods Because the nature of the residue in plants resulting from seed treatment uses have not been adequately delineated, the adequacy of the available analytical methods cannot be determined. The registrants are reminded that radiovalidation of enforcement method( s) is a reregistration requirement; therefore, representative samples from the requested plant metabolism study should be used for radiovalidation and analyzed by the existing or proposed enforcement method( s) to determine whether total toxic residues are extracted from weathered samples. 20 Adequate methods are available for determination of residues of lindane per se in/ on plant and animal commodities. The Pesticide Analytical Manual (PAM) Vol. II lists Methods I and II for the analysis of mixed isomers of 1, 2, 3, 4, 5, 6­ hexachlorocyclohexane in/ on plant and animal commodities. Method I is a multiresidue method (see "GLN 860.1360: Multiresidue Methods" section) for chlorinated compounds. Method II is based upon the official final AOAC method (1990, 15th edition of AOAC) and is suitable for determining residues of lindane in/ on AOAC Group I nonfatty foods (vegetables and fruits), dairy products, fish, and eggs. The stated limit of detection of Method II is 0. 05 ppm for most commodities. Adequate data­ collection methods have been submitted for detection of lindane per se in/ on cucumbers and spinach. The analytical procedures for detecting lindane in cucumbers and spinach are essentially the same. Residues of lindane are extracted with acetonitrile, partitioned with hexane: acetonitrile, cleaned up using Florisil column chromatography, and analyzed by gas chromatography with electron capture detection (ECD); the reported detection limit was 0.01 ppm. Based on acceptable method validation recoveries, the Agency has deemed the GC/ ECD method to be adequate for determining residues of lindane per se in nonfatty crops. A GC/ MS method (SOP# Meth­ 109) entitled "Determination of Lindane in Wheat and Canola Matrices" was utilized as the data­ collection method in a recently submitted wheat field study. Briefly, residues in/ on wheat forage, hay, grain, and straw samples were extracted with acetonitrile and water. The water was salted out, and an aliquot of the remaining acetonitrile extract was purified by means of a hexane solvent partition, gel permeation chromatography, dichloromethane/ salt water solvent partition, and a carbon black solid phase extraction cartridge cleanup. Detection and quantitation were conducted using a gas chromatograph equipped with a mass selective detector (GC/ MS). The LOQ was 0. 005 ppm. A data­ collection method, based on the AOAC method, was also submitted for detection of lindane per se in eggs, milk, and animal tissues. The Agency previously required an EPA method validation for the submitted method if lindane tolerances for lean animal tissues were to be established because the AOAC method did not describe techniques which the registrant's method contained (e. g., gel permeation chromatography and rotary evaporation). The FDA method now utilizes these techniques; therefore, the requirement for a petition method validation was conditionally waived provided HED's MARC determines that lindane per se is the only residue of concern in animal commodities. GLN 860.1360: Multiresidue Methods The 10/ 99 PESTDATA database (PAM, Vol. I, Appendix I) contains data concerning the applicability of multiresidue methods to lindane. Lindane is completely recovered (> 80% recovery) using protocols 302 (Luke method), 303 (Mills, Onley, and Gaither method), and 304 (Mills method) for fatty and non­ fatty foods. Should the HED MARC determine that lindane metabolites other than the parent should be regulated, the Agency will require the registrants to submit additional multiresidue methods test data for the metabolites of concern. 21 GLN 860.1380: Storage Stability Data The specifics of reregistration requirements for storage stability data in plants and animals cannot be ascertained until acceptable plant metabolism studies are available, and the HED MARC has determined the terminal residues of concern. Assuming that lindane per se is the terminal residue of concern and provided the additional temperature information is submitted, the available storage stability data for lindane support the storage conditions and intervals of samples collected from existing crop field trials and livestock feeding studies. A summary of available storage stability data for lindane per se is summarized below. Raw agricultural and processed commodities: Residues of lindane per se are relatively stable under frozen (­ 20
C) storage conditions for up to 8 months in/ on cucumbers and spinach and for approximately 14 months in/ on tomatoes and wheat forage. Lindane residues are stable in wheat grain, wheat hay, and wheat straw for up to approximately 18 months when stored under frozen conditions. Lindane residues in canola seed were stable for up to 6. 5 months when stored under frozen conditions (no temperature given). Lindane residues were stable for up to 2 months in canola oil and 1. 5 months in canola meal when stored under frozen conditions (no temperature given). The registrant is required to submit additional storage stability data (temperature logs) specifying the storage conditions of the canola storage stability samples. Assuming that lindane per se is the terminal residue of concern, these data support the storage conditions and intervals of samples collected from existing crop field trials. Animal commodities: Residues of lindane per se are relatively stable in eggs, milk, and edible tissues of animals stored frozen (­ 18
C) for up to 9 months. Assuming that lindane per se is the terminal residue of concern, these data support the storage conditions and intervals of samples collected from existing ruminant and poultry feeding studies. GLN 860.1500: Crop Field Trials A translocation study (MRID 40431207) formed the basis for food­ use classification of lindane when the pesticide is applied as a seed treatment. In this study, [ 14 C] lindane was applied as a seed treatment to corn (field and sweet), mustard, radish, spinach, sugar beet, and wheat at approximately 1x the label rate. The treated seeds were then planted outdoors in 55 gallon drum halves and allowed to grow under simulated normal agricultural practices. Samples of immature and mature crop commodities were analyzed for total 14 C, and some fractions were extracted with hexane and analyzed by a GC method for total lindane. The above study failed to adequately identify radioactive residues in/ on all commodities grown from treated seed. Nonetheless, with the possible exception of wheat grain and foliage, residues were characterized to be not associated with biological molecules (e. g., amino acid, sugar, etc.) that have incorporated the radiolabel. The total residues found, the hexane­ extractable residues, and the residues attributable to lindane are summarized in the table below. Should the HED MARC determine that lindane metabolites other than the parent should be regulated, the Agency will require the registrants to submit additional crop field trial data for all residues of concern. 22 Table 1. Residues in Various Crops Grown from Seed Treated with Lindane. Crop Matrix TRR (ppm) Radioactivity in Hexane Extract Residues Attributed to Lindane Radish Root 0.056 0.038 ppm; 68% TRR 0. 030 ppm; 54% TRR Mustard Foliage 0.021 0.012 ppm; 57% TRR 0. 017 ppm; 81% TRR 1 Field Corn Root 0.340 0.307 ppm; 90% TRR 0. 165 ppm; 49% TRR Field Corn Foliage 0.064 0.016 ppm; 25% TRR 0. 008 ppm; 13% TRR Field Corn Grain <0. 01 ­­ Sweet Corn Foliage 0.051 0.060 ppm; 118% TRR 0. 012 ppm; 24% TRR Sweet Corn Grain <0.01 ­­ Sugar Beet Root (Immature) 0.297 0.175 ppm; 59% TRR 0. 090 ppm; 30% TRR Sugar Beet Foliage 0.181 0.174 ppm; 96% TRR 0. 035 ppm; 19% TRR Wheat Foliage 2.925 0.136 ppm; 4. 6% TRR 0.016 ppm; 0. 55% TRR Wheat Grain 0.052 ­­ 0.002 ppm; 3. 8% TRR Spinach Leaves 0. 020 ­­ 1 Lindane exceeds the TRR of extract. The registrants have submitted PP# 9F05057, for the establishment of time­ limited tolerances for residues of lindane per se in/ on the RACs of crops for which seed treatments are being proposed. Tolerances cannot be established or reassessed until adequate plant metabolism studies are submitted. The registrants have also submitted PP# 9F6022, for the establishment of tolerances on lindane per se in/ on canola for which seed treatment is being proposed. Tolerances cannot be established or reassessed until adequate plant metabolism studies are submitted. In addition, the registrants recently submitted acceptable residue data reflecting seed treatment on wheat RACs. A representative formulation (Lindane 30­ C) was applied as a seed treatment to wheat at 0.52 oz. ai/ cwt (or 330 ppm lindane on the seed). Following treatment, the treated seeds were planted in 15 diverse geographic locations. Wheat forage samples were collected at or near the jointing stage, the hay samples at early flower to soft dough stage, and the grain and straw samples at normal harvest maturity. Residues of lindane were nondetectable (< 0. 005 ppm) in/ on all treated wheat grain and straw samples. Residues of lindane ranged from <0.005 ppm (nondetectable) to 0. 04 ppm in/ on treated wheat forage and from <0.005 ppm (nondetectable) to 0.02 ppm in/ on treated wheat hay. Additional residue data would be required if the HED MARC determines residues of concern include metabolites of lindane in addition to lindane per se. 23 GLN 860.1520: Processed Food/ Feed No data are available to determine whether lindane residues of concern concentrate in the processed fractions of corn following seed treatment. A processing study on corn is required for the purpose of reregistration. A processing study on wheat would also be required if the HED MARC determines residues of concern include metabolites of lindane in addition to lindane per se. A processing study for wheat processed fractions is not being required if lindane per se is the only residue of concern (S. Funk, 10/ 31/ 95, D213401). In 1998, the U. S. Food and Drug Administration (FDA) monitoring program analyzed a total of 227 samples of milled grain products for lindane residues at an LOQ of 0.01 ppm. Commodities analyzed included flour and other milled products, breakfast foods, and baked goods. Lindane was not detected in any sample. The registrant submitted a canola processing study along with PP# 9F6022 where lindane residues in/ on canola refined oil, canola meal, and bleached/ deodorized canola oil were determined. Lindane in canola refined oil concentrated by a factor of at least 5. 2x. Lindane did not concentrate in canola meal and bleached/ deodorized canola oil. GLN 860.1480: Meat, Milk, Poultry, Eggs The nature of the residue in plants is not understood. Upon receipt of the requested plant metabolism data, the Agency will: (I) determine the adequacy of established tolerances for animal commodities; (ii) calculate the expected dietary intake for beef cattle, dairy cattle, and swine; and (iii) re­ evaluate the need for additional feeding studies. It should be noted that ruminant (M. Kovacs, 9/ 20/ 88, CB No. 4037) and poultry feeding (G. Otakie, 8/ 31/ 88, RCB No. 4034) studies are available (summarized below) assuming that lindane per se is the only residue of concern in animals. Ruminant Feeding Study Thirteen lactating Holstein cows were orally administered gelatin capsules containing lindane daily for 28 consecutive days. The cows were assigned to four groups (four cows per dose group plus one control). Three of the four cows in each dosing level were also dermally treated via a dip tank on day 21 and 28. Lindane residues in Table 2 are from the single cow which did not receive the dip treatment. Cows were housed in a common area. The administered dose levels were 20 ppm, 60 ppm, and 200 ppm which are equivalent to 143x, 426x, and 1,418x the maximum lindane dietary burden of 0. 141 ppm for dairy cattle (assuming lindane is the sole residue of concern). Using the total radioactive residues for feed items as required by the HED MARC, the feeding levels are equivalent to 3x, 10x, and 34x the maximum lindane dietary burden for dairy cattle (equivalent to 7x, 20x, and 67x the maximum lindane dietary burden for beef cattle). The calculation of expected dietary intake for beef and dairy cattle, using feed items derived from proposed seed treatment uses, is presented in Table 2. The daily dose was given to each cow after the morning milking. Milk subsamples were collected for analysis on days 0, 1, 3, 24 7, 14, 21, 25, and 28. Tissue samples were collected from each cow after sacrifice by exsanguination. All tissue samples were immediately frozen on dry ice and stored at ­15
C for 4 to 4½ months prior to residue analysis. Milk samples were stored at ­15
C for 1 to 3 months prior to analysis. The available storage stability data indicate that lindane per se is relatively stable in eggs, milk, and edible tissues of animals stored frozen (­ 18
C) for up to 9 months. These data support the storage conditions and intervals of samples collected from dairy cattle feeding study. Samples were analyzed for lindane residues by validated AOAC Multiresidue GLC methodology with electron capture detection. Table 2. Calculation of maximum dietary burdens of beef cattle, dairy cattle, and swine for lindane using feed items derived from seed treatment. Feed Commodity % Dry Matter % Diet Reassessed Tolerance (ppm) 2 Dietary Contribution (ppm) 1 Beef Cattle Corn forage 40 40 0.1 0. 100 Corn grain 88 60 0. 01 0. 007 Total Burden 0.107 Dairy Cattle Corn forage 40 50 0.1 0. 125 Corn grain 88 40 0. 01 0. 004 Corn stover 83 10 0. 1 0.012 Total Burden 0.141 Swine Corn grain NA 80 0. 01 0. 008 Wheat grain NA 20 0.005 0.001 Total Burden 0.009 1 Contribution = [reassessed tolerance / % DM] X % diet). 2 Reassessed tolerance if lindane per se is determined by the HED MARC to be the only residue of concern. The results of the dairy cattle feeding study are presented in Table 3. There appears to be a linear correlation between the dose level and the residue found for each tissue and for milk. Residues of lindane in milk plateaued on Day­ 7. By extrapolation of residue levels obtained at the 20­ ppm dosing levels, the maximum expected residues of lindane in dairy cattle milk and tissues are all below 0. 01 ppm except in the fat where the predicted maximum residue is 0.084 ppm. 25 Table 3. Residues of lindane in milk and meat of dairy cattle dosed with lindane in the diet at 20, 60 and 200 ppm for 28 consecutive days. Tissue Lindane Residues (ppm) Obtained at Various Dosing Levels 20 ppm 60 ppm 200 ppm Liver 0. 10 0. 19 0. 72 Kidney 0.34 1.07 4.57 Heart 1. 23 1. 56 10. 3 Muscle 0.97 1.80 8.75 Fat 11.9 20.2 158.1 Milk Day­ 7 0. 47 1. 08 5. 20 Day­ 14 0.17 0.75 3.12 Day­ 21 0.19 1.02 7.08 Day­ 25 0.31 1.19 5.49 Day­ 28 0.67 1.90 10.81 Poultry Feeding Study Sixty White Leghorn laying hens were orally administered gelatin capsules containing lindane daily for 28 consecutive days. The hens were assigned to fourteen groups (four hens per group, 4 groups per dose level plus two control groups). The administered dose levels were 1. 5 ppm, 4. 5 ppm, and 15 ppm which are equivalent to 15x, 45x, and 150x the maximum lindane dietary burden of 0.10 ppm for poultry as calculated by the registrant. The daily dose was given to each hen at the daily egg sampling and feeding. Egg samples were collected for analysis on days 0, 1, 3, 7, 14, 21, 25, and 28. Tissue samples were collected from each hen after sacrifice by exsanguination. Tissue samples were composited by group (four hens). All tissue samples were immediately frozen on dry ice and stored at ­15
C for a maximum of 5 months prior to residue analysis. Egg samples were stored at ­15
C for a maximum of 5 months prior to analysis. The available storage stability data indicate that lindane per se is relatively stable in eggs, milk, and edible tissues of animals stored frozen (­ 18
C) for up to 9 months. These data support the storage conditions and intervals of samples collected from the poultry feeding study. Samples were analyzed for lindane residues by validated AOAC Multiresidue GLC methodology with electron capture detection. The results of the poultry feeding study are presented in Table 4. There appears to be a linear correlation between the dose level and the residue found for eggs and each tissue. Residues of lindane in eggs plateaued by Day­ 14. By extrapolation of residue levels obtained at the 1. 5­ ppm dosing levels, the maximum expected residues of lindane in poultry eggs and tissues are all below 0.01 ppm except in the kidney, fat, and eggs where the predicted maximum residues are 0.011, 0.169, and 0. 014 ppm, respectively. 26 Table 4. Residues of lindane in eggs and tissues of laying hens dosed with lindane in the diet at 1. 5, 4. 5 and 15 ppm for 28 consecutive days. Tissue Lindane Residues (ppm) Obtained at Various Dosing Levels 1.5 ppm 4.5 ppm 15 ppm Liver 0. 12 0. 51 0. 78 Kidney 0.17 0.55 2.03 Heart 0. 33 0. 89 2. 26 Gizzard 0. 10 0. 32 0. 95 Thigh 0. 19 0. 36 1. 35 Breast 0.03 0.10 0.37 Fat 2. 54 7. 75 27.65 Eggs Day­ 7 0. 110 0.258 0.878 Day­ 14 0.216 0.609 2.14 Day­ 21 0.185 0.603 2.36 Day­ 25 0.189 0.672 2.10 Day­ 28 0.205 0.588 2.38 GLN 860.1400: Water, Fish, and Irrigated Crops Lindane is presently not registered for direct use on water and aquatic food and feed crops; therefore, no residue chemistry data are required under this guideline topic. GLN 860.1460: Food Handling Lindane is presently not registered for use in food­ handling establishments; therefore, no residue chemistry data are required under this guideline topic. GLN 860.1850 and 860.1900: Confined/ Field Accumulation in Rotational Crops The basic registrants have submitted a confined rotational crop study which was deemed unacceptable and not upgradable because of inadequate characterization and identification of residues due to significant losses of organosoluble residues during analysis. Although the study is inadequate and the application rate used (0.75 lb ai/ A) greatly exceeds the level of soil residues that are likely to result from seed­ treatment uses, the data indicate that residues of lindane persist in the soil and can be taken up by rotational crops at intervals up to one year. For the purpose of reregistration, the Agency will not require a new confined rotational crop study provided the registrants propose a 30­ day plantback interval for leafy vegetables and a 12­ month plantback interval for all other unregistered crops on all of their end­ use product labels for lindane. If this recommendation is not acceptable to the registrants, then limited rotational field trial data are required. The limited field trials should be conducted on a representative crop (as defined in 40 CFR 180.41) at two sites per crop for the following three crop groups: root and tuber vegetables, leafy vegetables and small grains (wheat, barley, oats, and rye) for a total of six 27 trials. As with confined studies (OPPTS 860.1850), soybeans may be substituted for the leafy vegetable. The six trials should be conducted on crops which a registrant intends to have as rotational crops on the label. In addition, some of the six trials could be conducted using other crops that are typically involved in crop rotation such as alfalfa and soybeans. The registrants have informed the Agency they will propose the specified plantback intervals. The results of the confined rotational crop study are summarized in the tables below. Table 5a. Summary of the characterization/ identification of radioactive residues in/ on barley forage grown in sandy loam soil treated with [ 14 C] lindane at 0. 75 lb ai/ A (22x the seed treated barley application rate). 30­ DAT Barley Forage (TRR = 0. 0991 ppm) 121­ DAT Barley Forage (TRR = 0. 3939 ppm) 365­ DAT Barley Forage (TRR = 0. 1082 ppm) Metabolite %TRR ppm %TRR ppm %TRR ppm Identified Lindane 15.79 0.0156 26.18 0.1031 3.17 0.0034 2,4­ Dichlorophenol 2.43 0.0024 1.02 0.0040 ­­ 2,4,5 Trichlorophenol 2. 96 0. 0029 2.89 0.0114 ­­ 2,3,4,6 Tetrachlorophenol ­­ ­­ 4. 45 0. 0175 ­­ Total identified 21.18 0.0209 34.54 0.1360 3.17 0.0034 Characterized Unidentified Residues 3. 65 0. 0036 0.05 0.0002 9.31 0.0101 Total identified/ characterized 24.83 0.0245 34.59 0.1362 12.48 0.0135 Nonextractable 51.36 0.0509 39.30 0.1548 40.39 0.0437 Table 5b. Summary of the characterization/ identification of radioactive residues in/ on barley straw and grain grown in sandy loam soil treated with [ 14 C] lindane at 0. 75 lb ai/ A. 30­ DAT Barley Straw (TRR = 0. 3866 ppm) 121­ DAT Barley Straw (TRR = 0. 9341 ppm) 30­ DAT Barley Grain (TRR = 0. 0478 ppm) Metabolite %TRR ppm %TRR ppm %TRR ppm Identified Lindane 0. 36 0. 0014 2.42 0.0226 ­­ 4 Chlorophenol 16.61 0.0642 0.90 0.0084 8.79 0.0042 2,4­ Dichlorophenol 3.80 0.0147 2.28 0.0213 2.09 0.0010 2,4,5­ Trichlorophenol 1. 82 0. 0070 1.06 0.0099 3.35 0.0016 Total identified 22.59 0.0873 6.66 0.0622 14.23 0.0068 Characterized Unidentified Residues 2. 58 0. 0100 1.73 0.0161 ­­ Acid hydrolysate ­­ ­­ 7. 37 0. 0688 ­­ Total identified/ characterized 25.17 0.0973 15.76 0.1471 14.23 0.0068 Nonextractable NR NR 78.21 0.7306 NR NR NR = not reported 28 Table 6a. Summary of the characterization/ identification of radioactive residues in/ on mature carrot root grown in sandy loam soil treated with [ 14 C] lindane at 0. 75 lb ai/ A. 30­ DAT Mature Carrot Root (TRR = 0. 4447 ppm) 121­ DAT Mature Carrot Root (TRR = 0. 4081 ppm) 365­ DAT Mature Carrot Root (TRR = 0. 3984 ppm) Metabolite %TRR ppm %TRR ppm %TRR ppm Identified Lindane 47.65 0.2119 83.12 0.3392 88.78 0.3537 Pentachlorocyclohexene ­­ ­­ 5.61 0.0229 3.21 0.0128 Total identified 47.65 0.2119 88.73 0.3621 91.99 0.3665 Characterized Unidentified Residues 2. 41 0. 0107 3.16 0.0129 2.81 0.0112 Total identified/ characterized 50.06 0.2226 91.89 0.3750 94.80 0.3777 Nonextractable 1.03 0.0046 2.50 0.0102 0.90 0.0036 Table 6b. Summary of the characterization/ identification of radioactive residues in/ on mature carrot tops grown in sandy loam soil treated with [ 14 C] lindane at 0. 75 lb ai/ A. 30­ DAT Mature Carrot Tops (TRR = 0. 0916 ppm) 121­ DAT Mature Carrot Tops (TRR = 0. 1857 ppm) 365­ DAT Mature Carrot Tops (TRR = 0. 0637 ppm) Metabolite %TRR ppm %TRR ppm %TRR ppm Identified Lindane 69.19 0.0634 91.12 0.1692 18.45 0.0118 Total identified 69.19 0.0634 91.12 0.1692 18.45 0.0118 Characterized Unidentified Residues 14.44 0.0132 2.80 0.0052 37.28 0.0237 Total identified/ characterized 83.63 0.0766 93.92 0.1744 55.73 0.0355 Nonextractable 13.21 0.0121 10.29 0.0191 29.04 0.0409 29 Table 7. Summary of the characterization/ identification of radioactive residues in/ on immature and mature lettuce grown in sandy loam soil treated with [ 14 C] lindane at 0. 75 lb ai/ A. a 30­ DAT Immature Lettuce (TRR = 0. 0207 ppm) 121­ DAT Immature Lettuce (TRR = 0. 0419 ppm) 30­ DAT Mature Lettuce (TRR = 0. 0429 ppm) Metabolite %TRR ppm %TRR ppm %TRR ppm Identified Lindane 137.57 0.0285 26.08 0.0109 42.80 0.0184 4­ Chlorophenol ­­ ­­ ­­ ­­ 7.56 0.0032 2,4,5­ Trichlorophenol ­­ ­­ ­­ ­­ 7. 02 0. 0030 2,3,4,6­ Tetrachlorophenol ­­ ­­ ­­ ­­ 4. 30 0. 0018 Total identified 137.57 0.0285 26.08 0.0109 61.68 0.0264 Characterized Unidentified Residues ­­ ­­ 5. 66 0. 0024 5.45 0.0023 Total identified/ characterized 137.57 0.0285 31.74 0.0133 67.13 0.0287 Nonextractable 32.37 0.0067 24.58 0.0103 35.20 0.0151 a Organosoluble 14 C­ residues were
0.01 ppm from 365­ day immature lettuce and 121­ and 365­ day mature lettuce samples and were not further characterized. (continued; footnotes follow) 30 Table A. Residue Chemistry Science Assessments for Reregistration of Lindane. GLN: Data Requirements Current Tolerances, ppm [40 CFR §180.133] Must Additional Data Be Submitted? References 1 860.1200: Directions for Use N/ A = Not Applicable Yes 2 REFS search of 5/ 29/ 01 860.1300: Plant Metabolism N/ A Yes 3 00025707, 00060143, 00060150, 00105413, GS­ 00010, GS­ 00012, GS­ 00013, GS­ 00019, 40410902 4 , 40431201 4 , 40431204 4 , 44383001 5 , 44383002 5 , 44405403 6 860.1300: Animal Metabolism N/ A No 7 GS­ 00014, GS­ 00015, GS­ 00016, 40271301 8 , 40271302 9 , 44405404 6 , 44867104 10 , 45224101 11 , 45224102 11 , 45277201 11 860.1340: Residue Analytical Methods ­ Plant commodities N/ A Reserved 12 05006312, GS­ 00018, 40431202 13 , 40431206 13 , 44383003 5 , 44383004 5 , 44909901 14 ­ Animal commodities N/ A Reserved 12 00025690, 00032233, 00099909, 05002348, 05003005, GS­ 00017, 40431208 15 , 44440601 16 , 44867105 10 860.1360: Multiresidue Methods N/ A Reserved 17 860.1380: Storage Stability Data ­ Plant commodities N/ A Yes 18 40431203 19 , 40431205 19 , 41699701 20 , 44440602 16 , 44909901 14 ­ Animal commodities N/ A Reserved 21 40660502 22 , 44440603 16 , 44867106 10 Table A (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR §180.133] Must Additional Data Be Submitted? References 1 (continued; footnotes follow) 31 860.1500: Crop Field Trials [NOTE: The basic registrants are supporting only seed treatment uses of lindane on cereal grains (including barley, corn, oats, rye, sorghum, and wheat but excluding rice and wild rice). The rows corresponding to these crops are shaded.] Root and Tuber Vegetables Group ­ Beet, sugar, root None established No 23 40431207 24 ­ Radish, root None established No 25 40431207 24 Leaves of Root and Tuber Vegetables Group ­ Beet, sugar, tops (leaves) None established No 23 40431207 24 ­ Radish, tops (leaves) None established No 25 40431207 24 Bulb Vegetables (Allium spp.) Group ­ Onions (dry bulb) 1 No 23 Leafy Vegetables (Except Brassica Vegetables) Group ­ Celery (seed treatment) 1 No 23 ­ Lettuce (seed treatment) 3 No 26 41289407 ­ Spinach (seed treatment) 1 No 26 40431207 24 ­ Swiss chard (seed treatment) 1 No 23 Brassica (Cole) Leafy Vegetables Group ­ Broccoli (seed treatment) 1 No 27 ­ Brussels sprouts (seed treatment) 1 No 27 ­ Cabbage (seed treatment) 1 No 27 41289403 ­ Cauliflower (seed treatment) 1 No 27 Table A (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR §180.133] Must Additional Data Be Submitted? References 1 (continued; footnotes follow) 32 ­ Collards (seed treatment) 1 No 23 ­ Kale (seed treatment) 1 No 23 ­ Kohlrabi (seed treatment) 1 No 23 ­ Mustard greens (seed treatment) 1 No 23 40431207 24 ­ Rape greens (seed treatment) None established No 23 Fruiting Vegetables (Except Cucurbits) Group ­ Eggplant 1 No 23 ­ Pepper 1 No 23 ­Tomato 3 No 23 41699701 20 , 41861201 28 Cucurbit Vegetables Group ­ Cucumber 3 No 23 41289404 ­Melons 3 No 23 ­ Pumpkin 3 No 23 ­ Squash 3 No 23 Pome Fruits Group ­ Apple 1 No 23 41289401 ­Pear 1 No 23 ­Quince 1 No 23 Stone Fruits Group ­ Apricot 1 No 23 Table A (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR §180.133] Must Additional Data Be Submitted? References 1 (continued; footnotes follow) 33 ­ Cherry 1 No 23 ­ Nectarine 1 No 23 ­ Peach 1 No 23 41289408 ­Plum( freshprune) 1 No 23 Tree Nuts Group ­ Pecan 0. 01 No 23 41289601, 41421001 Cereal Grains Group ­ Barley grain (seed treatment) None established No 29 ­ Corn grain (seed treatment) None established No 40431207 24 ­ Oats grain (seed treatment) None established No 29 ­ Rye grain (seed treatment) None established No 29 ­ Sorghum grain (seed treatment) None established No 32 40431207 24 ­ Wheat grain (seed treatment) None established No 29 40431207 24 , 44909901 14 ­ Canola grain (seed treatment) None established Yes 30 44864401 31 , 45310501 31 Forage, Fodder, and Straw of Cereal Grains Group (Excluding Rice and Wild Rice) ­ Barley hay and straw (seed treatment) None established No 29 ­ Corn forage and stover (seed treatment) None established No 40431207 24 ­ Oats forage, hay, and straw (seed treatment) None established No 29 ­ Rye forage and straw (seed treatment) None established No 29 Table A (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR §180.133] Must Additional Data Be Submitted? References 1 (continued; footnotes follow) 34 ­ Sorghum forage and stover (seed treatment) None established No 32 40431207 24 ­ Wheat forage, hay, and straw (seed treatment) None established No 29 40431207 24 , 44909901 14 ­ Canola forage, hay, and straw (seed treatment) None established Yes 30 44864401 31 , 45310501 31 Miscellaneous Commodities ­ Asparagus 1 No 23 ­ Avocado 1 No 23 ­ Grape 1 No 23 41289405 ­ Guava 1 No 23 ­ Mango 1 No 23 ­ Miscellaneous crops with seed treatments only None established No 23 40431207 24 ­ Mushroom 3 No 23 ­Okra 1 No 23 ­ Pineapple 1 No 23 ­ Strawberry 1 No 23 ­ Tobacco None established No 23 41289409 860.1520: Processed Food/ Feed ­ Apple None established No 23 41289402 ­ Canola None established Yes 18 44864401 31 , 45310501 31 Table A (continued). GLN: Data Requirements Current Tolerances, ppm [40 CFR §180.133] Must Additional Data Be Submitted? References 1 35 1. Bolded references were reviewed in the Residue Chemistry Chapter to the Lindane Reregistration Standard dated 6/ 7/ 85 and its 9/ 5/ 85 addendum. Italicized references were reviewed in the Lindane Product and Residue Chemistry Reregistration Standard Updates (CB No. 6961, 1/ 31/ 91, E. Zager). All other references were reviewed as noted. The basic registrants are supporting only seed treatment uses of lindane on cereal grains (including barley, corn, oats, rye, sorghum, and wheat but excluding rice and wild rice). The rows corresponding to these crops are shaded. 2. The registrants must submit a formal petition for the establishment of tolerances for all appropriate RACs being supported for seed treatment uses. The petition should include all requisite petition sections including a Section B specifying the maximum use rate (in terms of oz ai/ 100 lb of seeds or cwt) and information pertaining to recommended seeding rate per acre should be included in order to allow the Agency to calculate rates in terms of lb ai/ A. In addition, the registrants should formally request the cancellation of all ­ Cereal grains None established Yes 33 ­ Grape None established No 23 41289406 ­ Tomato None established No 23 41861202 28 860.1480: Meat, Milk, Poultry, Eggs ­ Milk, Fat, Meat, and Meat Byproducts of Cattle, Goats, Hogs, Horses, and Sheep 7( fat ofmeat from cattle, goats, horses, and sheep); 4( fat ofmeat from hogs) Reserved 40 00025685, 00045126, 00075989, 00088048, 00088165, 00089592, 00101478, 00104441, 00118722, 00118723, 00118724, 00118725, 00118739, GS­ 00018, GS­ 00021, GS­ 00022, GS­ 00023, 40660503 34 , 40660504 35 , 40660505 36 ­ Eggs and the Fat, Meat, and Meat Byproducts of Poultry None established Reserved 40 40660501 37 , 44440604 16 860.1400: Water, Fish, and Irrigated Crops None established No 860.1460: Food Handling None established No 860.1850: Confined Rotational Crops N/ A No 38 41967301 39 860.1900: Field Rotational Crops None established Reserved 38 Table A (continued). 36 food/ feed uses except seed treatment and requests that all labels for the agricultural use of formulated lindane be revised to allow only seed treatment uses. 3. A new plant metabolism study reflecting seed treatment are required. This study should be conducted on a representative cereal grain as the registrants have indicated that the only food/ feed uses they are supporting are for seed treatment of these crops. Crop samples should be harvested at the appropriate stage. In addition, care should be taken to insure that radioactivity is not lost during analysis. Identification of 14 C­ residues should also be confirmed using more than one method, or by GC/ MS. 4. CB No. 3267, 3/ 24/ 88, G. Otakie. 5. DP Barcode D239699, 12/ 16/ 97, S. Funk. 6. DP Barcode D240495, 12/ 14/ 99, T. Morton. 7. The qualitative nature of the residue in ruminants and poultry is adequately understood. The results of the ruminant and poultry metabolism studies will be presented to the HED Metabolism Assessment Review Committee (MARC) for determination of terminal residue of concern in eggs, milk, and animal tissues when an acceptable plant metabolism study is submitted. If the HED MARC determines that lindane is the only residue of concern requiring regulation, then the existing storage stability data for livestock commodities, the analytical method used for data collection, and the livestock feeding studies will be upgraded to acceptable status. 8. CB No. 3315, 3/ 24/ 88, J. Onley. 9. CB No. 3312, 3/ 24/ 88, C. Deyrup. 10. DP Barcode D257805, 12/ 14/ 99, T. Morton. 11. DP Barcode D271442 and D274158, 4/ 18/ 01, T. Morton. 12. Adequate methods are available for determination of residues of lindane per se in/ on plant and animal commodities. However, the adequacy of the available analytical methods cannot be determined until the registrants submit acceptable plant metabolism studies reflecting seed treatment, and the HED MARC has determined the total toxic residues of lindane that need to be included in the tolerance expression. The registrants are reminded that radiovalidation of enforcement method( s) is a reregistration requirement; representative samples from the requested plant metabolism study should be used for radiovalidation and analyzed by the existing or proposed enforcement method( s) to determine whether total toxic residues are extracted from weathered samples. 13. CB No. 3257, 3/ 24/ 88, N. Dodd. 14. DP Barcode D259318, 8/ 30/ 00, T. Morton. 15. CB No. 3261, 3/ 24/ 88, N. Dodd. 16. DP Barcode D242510, 12/ 14/ 99, T. Morton. 17. Should the HED MARC determine that lindane metabolites other than the parent should be regulated, the Agency will require the registrants to submit additional multiresidue methods test data for the metabolites of concern. Table A (continued). 37 18. Additional storage stability data (temperature logs) are required for the canola field trials and the canola processing study. Storage stability data are also required to support the requested corn processing study. Additional storage stability data may be required if the HED MARC determines that additional lindane metabolites of concern need to be included in the tolerance expression. 19. CB No. 3260, 3/ 24/ 88, N. Dodd. 20. CB No. 7470, 3/ 29/ 91, R. Perfetti. 21. Assuming that lindane per se is the terminal residue of concern in animal commodities, adequate storage stability data are available to support the storage conditions and intervals of samples collected from existing ruminant and poultry feeding studies. Additional storage stability data may be required if the HED MARC determines that additional lindane metabolites of concern need to be included in the tolerance expression. 22. CB No. 4035, 8/ 23/ 88 and 8/ 26/ 88 (addendum), S. Willett. 23. Because no registrants have committed to support use( s) of lindane on this crop, no residue data are required. The Agency recommends that this use site be deleted from all lindane end­ use products. The Agency also recommends the revocation of existing lindane tolerances, if established, on the RACs of crops which are not being supported. 24. CB No. 3259, 3/ 24/ 88, N. Dodd. 25. Because no registrants have committed to support use( s) of lindane on this crop, no residue data are required. The Agency recommends that this use site be deleted from all lindane end­ use products. The Agency also recommends the revocation of existing lindane tolerances, if established, on the RACs of crops which are not being supported. 26. Because no registrants have committed to support use( s) of lindane on this crop, no residue data are required. The Agency recommends that this use site be deleted from all lindane end­ use products. The Agency also recommends the revocation of existing lindane tolerances, if established, on the RACs of crops which are not being supported. 27. Because no registrants have committed to support use( s) of lindane on this crop, no residue data are required. The Agency recommends that this use site be deleted from all lindane end­ use products. The Agency also recommends the revocation of existing lindane tolerances, if established, on the RACs of crops which are not being supported. 28. CB No. 8075, DP Barcode D164898, 4/ 8/ 92, R. Perfetti. 29. Assuming that lindane per se is the terminal residue of concern in plants, the available residue data, reflecting seed treatment, for wheat grain, forage, hay, and straw may be translated to the RACs of barley, oats, and rye, provided the registrants propose identical use patterns and tolerances. The registrants may propose a maximum seed treatment rate of 0. 052 oz ai/ cwt (or 330 ppm lindane on the seed) on small cereal grains which is supported by adequate residue data. 30. Assuming that lindane per se is the terminal residue of concern in plants, two additional field trials are required for canola. 31. DP Barcode 269388 and D273830, 5/ 10/ 01, T. Morton. Table A (continued). 38 32. Assuming that lindane per se is the terminal residue of concern in plants, the available seed treatment data for corn may be translated to sorghum, provided the registrants propose identical use patterns and tolerances. 33. The registrants are required to submit processing data to determine whether lindane residues of concern concentrate in the processed fractions of corn following seed treatment. 34. CB No. 4036, 8/ 31/ 88, M. Kovacs. 35. CB No. 4038, 8/ 29/ 88, S. Willett. 36. CB No. 4037, 9/ 20/ 88, M. Kovacs. 37. CB No. 4034, 8/ 31/ 88, G. Otakie. 38. For the purpose of reregistration, the Agency will not require a new confined rotational crop study provided the registrants propose a 30­ day plantback interval for leafy vegetables and a 12­ month plantback interval for all other unregistered crops on all of their end­ use product labels for lindane. If this recommendation is not acceptable to the registrants, then limited rotational field trial data are required. The limited field trials should be conducted on a representative crop (as defined in 40 CFR 180.41) at two sites per crop for the following three crop groups: root and tuber vegetables, leafy vegetables and small grains (wheat, barley, oats, and rye) for a total of six trials. As with confined studies (OPPTS 860.1850), soybeans may be substituted for the leafy vegetable. The six trials should be conducted on crops which a registrant intends to have as rotational crops on the label. In addition, some of the six trials could be conducted using other crops that are typically involved in crop rotation such as alfalfa and soybeans. The registrant has informed the Agency they will propose the specified plantback intervals. 39. DP Barcodes D172626 and D198353, 8/ 30/ 00, T. Morton. 40. The nature of the residue in plants is not understood. Upon receipt of the requested plant metabolism data, the Agency will: (I) determine the adequacy of established tolerances for animal commodities; (ii) calculate the expected dietary intake for beef cattle, dairy cattle, and swine; and (iii) reevaluate the need for additional feeding studies. Assuming that lindane per se is the only residue of concern in animals, acceptable ruminant and poultry feeding studies are available. 39 TOLERANCE REASSESSMENT SUMMARY Tolerances for residues of lindane in/ on raw agricultural and animal commodities are established under 40 CFR §180.133 and expressed in terms of residues of lindane per se [gamma isomer of benzene hexachloride]. The residue definition for lindane is misleading and should be amended as follows to harmonize with IUPAC nomenclature: gamma isomer of 1, 2, 3, 4, 5, 6hexachlorocyclohexane Plant commodity tolerances for lindane were originally established based on registered uses which included preplant soil application, foliar applications, and seed treatments. Animal commodity tolerances were established based on uses which included direct livestock animal treatment as well as animal premise treatment. Refer to Table B for a list of established lindane tolerances. The only food/ feed use of lindane which is being supported for reregistration is seed treatment on cereal grains (excluding rice and wild rice). A definitive reassessment of the currently established tolerances for lindane cannot be made at this time due to major deficiencies in the residue chemistry database. The Agency tentatively concludes that no changes in the present tolerance expression are required at this time until the nature of the residue in plants and animals is adequately elucidated, and HED's MARC has determined the terminal residues of concern. Because of the Agency's concerns about the possibility of human health effects due to dietary exposure to lindane and the lack of data to support seed treatment uses, no additional tolerances other than those required to support the basic registrants' proposed seed treatment uses, will be considered until the data gaps identified in this Residue Chemistry Chapter are fulfilled. The listing of lindane tolerances under 40 CFR §180.133 should be subdivided into parts (a), (b), (c), and (d). Part (a) should be reserved for commodities with permanent tolerances, part (b) for Section 18 emergency exemptions, part © for tolerances with regional registrations, and part (d) for indirect or inadvertent residues. Tolerances Listed Under 40 CFR §180.133: Following resolutions of residue chemistry data deficiencies specified in this Residue Chemistry Science Chapter, a statement in 40 CFR §180.133 should be added to specify that the established tolerances result from seed treatment only. The established tolerances for the following commodities should be revoked because no registrants have committed to support their uses: apples, apricots, asparagus, avocados, broccoli, Brussels sprouts, cabbage, cauliflower, celery, cherry, collards, cucumbers, eggplants, grapes, guavas, kale, kohlrabi, lettuce, mangoes, melons, mushrooms, mustard greens, nectarines, okra, onions (dry bulb only), peaches, pears, pecans, peppers, pineapple, plums (fresh prunes), pumpkins, quinces, radish, spinach, squash, strawberries, summer squash, swiss chard, and tomatoes. 40 Tolerances To Be Proposed Under 40 CFR §180.133: Tolerances for lindane residues of concern need to be established for: barley, grain; barley, hay; barley, straw; corn, grain; corn, forage; corn, stover; oat, grain; oat, forage; oat, hay; oat, straw; rye, grain; rye, forage; rye, straw; sorghum, grain; sorghum, forage; sorghum, stover; wheat, grain; wheat, forage; wheat, hay; and wheat, straw once required data are submitted. In addition, the need for tolerances for livestock tissues, milk, poultry tissues and eggs will be reevaluated once additional plant metabolism data is submitted. Pending Tolerance Petitions: In 1993, CIEL proposed to delete all food/ feed uses except seed treatment. Concomitantly, CIEL proposed to establish tolerances of 0.1 ppm for residues of lindane per se in/ on several RACs as a result of seed treatment. In an initial Agency review (DP Barcode D213401, 10/ 31/ 95, S. Funk) of available residue data reflecting seed treatment, the Agency concluded that the proposed tolerances were adequate in some instances and inadequate or non­ acceptable in others. In those instances where the proposed tolerances were deemed inadequate, the reviewer proposed values that HED would consider as appropriate. In 1998, CIEL submitted a petition, PP# 9F05057, for the establishment of time­ limited tolerances for residues of lindane per se in/ on several commodities resulting from seed treatment. The Agency review (DP Barcodes D254236, 8/ 30/ 00, T. Morton) of these tolerance proposals concluded that tolerances could not be established until an adequate plant metabolism study was submitted. The registrants have also submitted PP# 9F6022, (D269388, T. Morton, 5/ 10/ 01) for the establishment of tolerances on lindane per se in/ on canola for which seed treatment is being proposed. Tolerances cannot be established or reassessed until an adequate plant metabolism study is submitted. 41 Table B. Tolerance Reassessment Summary for Lindane. Commodity Tolerance Listed Under 40 CFR (ppm) Reassessed Tolerance (ppm) Comment [Correct Commodity Definition] Tolerance Listed Under 40 CFR §180.133 Apples 1 Revoke Not being supported for reregistration. Apricots 1 Revoke Not being supported for reregistration. Asparagus 1 Revoke Not being supported for reregistration. Avocados 1 Revoke Not being supported for reregistration. Broccoli 1 Revoke Not being supported for reregistration. Brussels sprouts 1 Revoke Not being supported for reregistration. Cabbage 1 Revoke Not being supported for reregistration. Cauliflower 1 Revoke Not being supported for reregistration. Lettuce 3 Revoke Not being supported for reregistration. Spinach 1 Revoke Not being supported for reregistration. Celery 1 Revoke Not being supported for reregistration. Collards 1 Revoke Not being supported for reregistration. Kale 1 Revoke Not being supported for reregistration. Kohlrabi 1 Revoke Not being supported for reregistration. Mustard greens 1 Revoke Not being supported for reregistration. Swiss chard 1 Revoke Not being supported for reregistration. Cherry 1 Revoke Not being supported for reregistration. Cucumbers 3 Revoke Not being supported for reregistration. Eggplants 1 Revoke Not being supported for reregistration. Fat of meat from cattle, goats, horses, and sheep 7 To be determined (TBD) The Agency will re­ calculate the maximum theoretical dietary burden for livestock animals and re­ assess the adequacy of the available animal feeding studies when the requested residue data for livestock feed items have been received and evaluated. Fat ofmeat from hogs 4 Grapes 1 Revoke Not being supported for reregistration. Guavas 1 Revoke Not being supported for reregistration. Mangoes 1 Revoke Not being supported for reregistration. Melons 3 Revoke Not being supported for reregistration. Mushrooms 3 Revoke Not being supported for reregistration. Nectarines 1 Revoke Not being supported for reregistration. Okra 1 Revoke Not being supported for reregistration. Onions (dry bulb only) 1 Revoke Not being supported for reregistration. Peaches 1 Revoke Not being supported for reregistration. Pears 1 Revoke Not being supported for reregistration. Pecans 0.01 Revoke Not being supported for reregistration. Peppers 1 Revoke Not being supported for reregistration. Pineapple 1 Revoke Not being supported for reregistration. Table B (continued). Commodity Tolerance Listed Under 40 CFR (ppm) Reassessed Tolerance (ppm) Comment [Correct Commodity Definition] 42 Plums (fresh prunes) 1 Revoke Not being supported for reregistration. Pumpkins 3 Revoke Not being supported for reregistration. Quinces 1 Revoke Not being supported for reregistration. Squash 3 Revoke Not being supported for reregistration. Strawberries 1 Revoke Not being supported for reregistration. Summer squash 3 Revoke Not being supported for reregistration. Tomatoes 3 Revoke Not being supported for reregistration. Tolerance To Be Proposed Under 40 CFR §180.133 Barley, grain None established TBD A nature of the residue study for lindane residues resulting from seed treatment application to a cereal grain is required. Barley, hay TBD Barley, straw TBD Canola, seed TBD Corn, grain TBD Corn, forage TBD Corn, stover TBD Oat, grain TBD Oat, forage TBD Oat, hay TBD Oat, straw TBD Rape greens TBD Rye, grain TBD Rye, forage TBD Rye, straw TBD Sorghum, grain TBD Sorghum, forage TBD Sorghum, stover TBD Wheat, grain TBD Wheat, forage TBD Wheat, hay TBD Wheat, straw TBD TBD = To be determined. 43 CODEX HARMONIZATION The Codex Alimentarius Commission has established several maximum residue limits (MRLs) for lindane in/ on various plant and animal commodities. The Codex MRLs are expressed in terms of gamma HCH (fat­ soluble). With respect to tolerance expression, the Codex MRL and U. S. tolerance for lindane are presently in harmony. However, the nature of the residue in plants and ruminants remains inadequately understood, and the HED's MARC may determine that additional lindane metabolites should be included in the U. S. tolerance expression. A numerical comparison of the Codex MRLs and the corresponding reassessed U. S. tolerances resulting from seed treatment is presented in Table C. The established Codex MRLs and the recommended U. S. tolerances for Brussels sprouts, cabbage (Savoy), cabbages (head), cereal grains, lettuce (head), and radish are not in harmony presumably because of differences in good agricultural practices. Attempts to harmonize residue limits in animal commodities cannot be made at this time because of several residue chemistry data gaps. 44 (continued next page). Table C. Codex MRLs and applicable U. S. tolerances for lindane. Recommendations are based on conclusions following reassessment of U. S. tolerances (see Table B). Codex Reassessed U. S. Tolerance, ppm 1 Codex Comments Commodity, As Defined MRL in mg/ kg (Step) Apple 0. 5 (CXL) Revoke Not being supported for reregistration. Beans (dry) 1 (CXL) 2 None established Not being supported for reregistration. Brussels sprouts 0. 5 (CXL) Revoke Not being supported for reregistration. Cabbage, Savoy 0.5 (CXL) Revoke Not being supported for reregistration. Cabbages, Head 0.5 (CXL) Revoke Not being supported for reregistration. Cacao beans 1 (CXL) None established Not being supported for reregistration. Carrot 0. 2 (CXL) None established Not being supported for reregistration. Cauliflower 0. 5 (CXL) Revoke Not being supported for reregistration. Cereal grains 0. 5 (CXL) 2 TBD for the grains of barley, oats, rye, and wheat Cherries 0.5 (CXL) Revoke Not being supported for reregistration. Cocoa butter 1 (CXL) None established Not being supported for reregistration. Cocoa mass 1 (CXL) None established Not being supported for reregistration. Cranberry 3 (CXL) None established Not being supported for reregistration. Currant, Red, White 0.5 (CXL) None established Not being supported for reregistration. Eggs 0.1 (CXL) None established Endive 2 (CXL) None established Not being supported for reregistration. Grapes 0.5 (CXL) Revoke Not being supported for reregistration. Kohlrabi 1 (CXL) Revoke Not being supported for reregistration Lettuce, Head 2 (CXL) Revoke Not being supported for reregistration. Meat of cattle, pigs, and sheep 2 (CXL) To be determined (TBD) Milks 0. 1 (CXL) None established Pear 0.5 (CXL) Revoke Not being supported for reregistration. Peas (pods and succulent = immature seeds) 0.1 (CXL) None established Not being supported for reregistration. Plums (including prunes) 0. 5 (CXL) Revoke Not being supported for reregistration. Potato 0.05 (CXL) None established Not being supported for reregistration. Poultry meat 0. 7 (CXL) None established Radish 1 (CXL) Revoke Not being supported for reregistration. Rape seed 0.05 (CXL) None established Spinach 2 (CXL) Revoke Not being supported for reregistration. Strawberry 3 (CXL) Revoke Not being supported for reregistration. Codex Reassessed U. S. Tolerance, ppm 1 Codex Comments Commodity, As Defined MRL in mg/ kg (Step) 45 Sugar beet 0.1 (CXL) None established Not being supported for reregistration. Sugar beet leaves or tops 0.1 CXL) None established Not being supported for reregistration. Tomato 2 (CXL) Revoke Not being supported for reregistration. 1 Reassessed U. S. tolerances pending compliance by the registrants with the recommendations specified in "GLN 860.1200: Directions for Use" section of this Chapter. 2 Postharvest treatment of the commodity. TBD = To be determined. DIETARY EXPOSURE ASSESSMENT Anticipated residues of lindane were recently determined by HED (DP Barcode D279260, T. Morton, 12/ 4/ 01) using data from available plant and animal metabolism studies along with animal feeding studies. 46 AGENCY MEMORANDA RELEVANT TO REREGISTRATION CB No.: 3257 Subject: ID No. 359­ 686. Lindane Registration Standard Followup. Analytical Methods for Plants From: N. Dodd To: A. Rispin, G. LaRocca, and E. Budd Dated: 3/ 24/ 88 MRID( s): 40431202 and 40431206 CB No.: 3259 Subject: ID No. 359­ 686. Lindane Registration Standard Followup ­ Residues From Seed Treatment From: N. Dodd To: A. Rispin, G. LaRocca, and E. Budd Dated: 3/ 24/ 88 MRID( s): 40431207 CB No: 3260 Subject: Lindane Registration Standard Follow up. Storage stability. From: N. Dodd To: A. Rispin, G. LaRocca, and E. Budd Dated: 3/ 24/ 88 MRIDs: 40431203 and 40431205 CB No: 3261 Subject: Lindane Registration Standard Follow up ­ Analytical Methods for Animal Tissues, Eggs, and Milk. From: N. Dodd To: A. Rispin, G. LaRocca, and E. Budd Dated: 3/ 24/ 88 MRID: 40431208 CB No. 3267 Subject: Partial Response (November 10, 1987) by Centre International d'Etudes du Lindane (CIEL) to Data Gap 171­ 4 (Nature of the Residue in Plants as Identified in the Residue Chemistry Chapter of the September 30, 1985 Lindane Registration Standard From: G. Otakie To: A. Rispin, G. LaRocca, and E. Budd Dated: 3/ 24/ 88 MRID( s): 40410902, 40431201, and 40431204 CB No: 3312 Subject: Partial Response (7/ 21/ 87) by Centre International d'Etudes du Lindane (CIEL) to Data Gap 171­ 4 (Nature of the Residue in Livestock Ruminants) as Identified in the Residue Chemistry Chapter of the September 30, 1985 Lindane Registration Standard. From: C. Deyrup To: A. Rispin, G. LaRocca, and E. Budd Dated: 3/ 24/ 88 MRID: 40271302 47 DEB No. 3315 Subject: Partial Response (July 15, 1987) by Centre International d'Etudes du Lindane (CIEL) to Data Gap 171­ 4 (Nature of the Residue in Livestock Poultry) as Identified in the Residue Chemistry Chapter of the September 30, 1985 Lindane Registration Standard From: J. Onley To: A. Rispin, G. LaRocca, and E. Budd Dated: 3/ 24/ 88 MRID( s): 40271301 CB No: 4035 Subject: ID No. 52904­ C. Lindane Registration Standard Followup. Storage Stability Data. From: S. Willett To: R. Engler, G. LaRocca, and E. Budd Dated: 8/ 23/ 88 and 8/ 26/ 88 (addendum) MRID: 40660502 CB No: 4034 Subject: Partial Response (June 9, 1988) by Centre International d'Etudes du Lindane (CIEL) to Data Gap Section 171­ 4 (Magnitude of the Residue in Poultry and Eggs) as Identified in the Residue Chemistry Chapter of the September 30, 1985 Lindane Registration Standard. From: G. Otakie To: R. Engler, G. LaRocca, andE. Budd Dated: 8/ 31/ 88 MRID: 40660501 CB No.: 4038 Subject: ID No. 52904­ C. Lindane Registration Standard Followup. Residues in Swine From: S. Willett To: R. Engler, G. LaRocca, andE. Budd Dated: 8/ 29/ 88 MRID( s): 40660504 CB No.: 4036 Subject: Partial Response (April 7, 1988) by Centre International d'Etudes du Lindane (CIEL) to Data Gap Section 171­ 4 [Magnitude of Residue in Animals (Sheep)] as Identified in the Residue Chemistry Chapter of the September 30, 1985 Lindane Registration Standard. From: M. Kovacs To: R. Engler, G. LaRocca, andE. Budd Dated: 8/ 31/ 88 MRID( s): 40660503 CB No.: 4037 Subject: Partial Response (December 15, 1987) by Centre International d'Etudes du Lindane (CIEL) to Data Gap 171­ 4 [Magnitude of Residue in Animals (Dairy Cattle Meat and Milk)] as Identified in the Residue Chemistry Chapter of the September 30, 1985 Lindane Registration Standard From: M. Kovacs To: R. Engler, G. LaRocca, E. Budd Dated: 9/ 20/ 88 MRID( s): 40660505 48 CB No.: 7470 Subject: Rhone­ Poulenc AG Company: Response to the Lindane Reregistration Standard: Crop field Trials and Storage Stability Data From: R. Perfetti To: R. Engler and L. Rossi Dated: 3/ 29/ 91 MRID: 41699701 CB No. 8075 DP Barcode: D164898 Subject: CIEL: Response to the Lindane Reregistration Standard: Residue and Processing Data From: R. Perfetti To: W. Burnam and L. Rossi Dated: 4/ 8/ 92 MRID: 41861201 and 41861202 CB No. 15325 DP Barcode: D213401 Subject: Lindane (Case 0315, Chemical 009001, List A). Seed Treatment Uses. From: S. Funk To: L. Schnaubelt/ R. Richards Dated: 10/ 31/ 95 MRID: None DP Barcode: D239699 Subject: Lindane (Chemical 009001, List A): CIEL Submissions to Upgrade Plant Analytical Method, Nature of the Residue in/ on Cucumbers, Nature of the Residue in/ on Apples. Time Extension Request for Ruminant Feeding Study, Ruminant Commodity Storage Stability Study, and Ruminant Commodity Analytical Method Study. From: S. Funk To: S. Jennings/ W. Waldrop Dated: 12/ 16/ 97 MRID( s): 44383001 through 44383004 DP Barcode: D240495 Subject: Lindane (009001): Nature of the Residue in Spinach and Poultry (GLN 860.1300). From: T. Morton To: M. McDavit/ B. Shackleford Dated: 12/ 14/ 99 MRID( s): 44405403 and 44405404 DP Barcode: D242510 Subject: Lindane (009001): Nature of the Residue in Plants and Animals (GLN 860.1300), Storage Stability (GLN 860.1380), Residue Analytical Method (GLN 860.1340), and Meat, Milk, Poultry, Eggs (GLN 860.1480). From: T. Morton To: M. McDavit/ B. Shackleford Dated: 12/ 14/ 99 MRID( s): 44440601, 44440602, 44440603, and 44440604. 49 DP Barcode: D257805 Subject: Lindane (009001): Nature of the Residue in Livestock (GLN 860.1300), Residue Analytical Method (GLN 860.1340), and Storage Stability (GLN 860.1380). From: T. Morton To: M. McDavit/ B. Shackleford Dated: 12/ 14/ 99 MRID( s): 44867104, 44867105, and 44867106 DP Barcode: D259318 Subject: Lindane (009001): Magnitude of the Residue in/ on Wheat From: T. Morton To: M. Howard/ B. Shackleford Dated: 8/ 30/ 00 MRID( s): 44909901 DP Barcode: D254236 and D265919 Subject: PP# 9F05057. Lindane (009001): Time Limited Tolerances for Various Crops. From: T. Morton To: M. Howard/ B. Shackleford Dated: 8/ 30/ 00 MRID( s): None DP Barcode: D172626 and D198353 Subject: Lindane: Confined Rotational Crop Study. From: T. Morton To: M. Howard/ B. Shackleford Dated: 8/ 30/ 00 MRID( s): 41967301 DP Barcode: D269094 Subject: Lindane (009001): Waiver Request for Nature of the Residue in Plants Grown From Seed Treated With Lindane (GLN 860.1300). From: T. Morton To: M. Howard/ B. Shackleford Dated: 1/ 9/ 01 MRID( s): None DP Barcode: D272625 Subject: Lindane (009001): Clarification on Waiver Request for Nature of the Residue in Plants Grown From Seed Treated With Lindane (GLN 860.1300). From: T. Morton To: M. Howard/ B. Shackleford Dated: 2/ 13/ 01 MRID( s): None DP Barcode: D243547 Subject: Lindane (009001): Question on Applicability of Seed Treatment Data for Pre­ Plant Soil Treatment Uses. From: T. Morton To: M. Howard/ B. Shackleford Dated: 2/ 28/ 01 MRID( s): None 50 DP Barcode: D244798 Subject: Lindane (009001): Status on Residue Chemistry Requirements for Lindane Seed Treatment Uses. From: T. Morton To: M. Howard/ B. Shackleford Dated: 3/ 13/ 01 MRID( s): None DP Barcode: D258079 Subject: Lindane (009001): Magnitude of the Residue in Meat and Milk of Dairy Cattle (GLN 860.1480). From: T. Morton To: M. Howard/ B. Shackleford Dated: 3/ 13/ 01 MRID( s): 44877501 DP Barcode: D269388 and D273830 Subject: PP# 9F6022 Lindane (009001): Lindane in/ on Canola. From: T. Morton To: M. Howard/ B. Shackleford Dated: 5/ 10/ 01 MRID( s): 44864401 and 45310501 DP Barcode: D271442 and D274158 Subject: Lindane: Nature of the Residue in Livestock. From: T. Morton To: M. Howard/ B. Shackleford Dated: 4/ 18/ 01 MRID( s): 45224101, 45224102, 45277201 DP Barcode: D274313 Subject: Lindane (009001): Magnitude of the Residue in Wheat. From: T. Morton To: M. Howard/ B. Shackleford Dated: 5/ 10/ 01 MRID( s): 45330301 MASTER RECORD IDENTIFICATION NUMBERS References Used To Support Reregistration 00025685 Williams, S.; Mills, P. A.; McDowell, R. E. (1964) Residues in milk of cows fed rations containing low concentrations of five Chlorinated hydrocarbon pesticides. Journal of the Association of Official Analytical Chemists 47( 6): 1124­ 1128. (unpublished submission received Nov 5, 1970 under 1F1060; submitted by Velsicol Chemical Corp., Chicago, Ill.; CDL: 099195­ AK) 00025690 Cummings, J. G.; Eidelman, M.; Turner, V.; et al. (1967) Residues in poultry tissues from low level feeding of five Chlorinated hydrocarbon insecticides to hens. Journal of the Association of Official Analytical Chemists 50( 2): 418­ 425. (unpublished submission received Nov 5, 1970 under 1F1060; submitted by Velsicol Chemical Corp., Chicago, Ill.; CDL: 099195­ AQ) 00025707 Hill, K. R. (1970) Pesticide residues: IUPAC commission on terminal residues. Journal of the Association of Official Analytical Chemists 53( 5): 987­ 1003. (unpublished submission received Nov 5, 1970 under 1F1060; submitted by Velsicol Chemical Corp., Chicago, Ill.; CDL: 099195­ BH) 51 00032233 Dionne, E.; Cary, G. A.; Sleight, B. H., III (1980) Analytical Procedure for the Determination of Pesticides and PCB in Brine Shrimp Tissue. (Unpublished study received Feb 19, 1980 under 677­ 313; prepared by EG& G, Bionomics, submitted by Diamond Shamrock Agricultural Chemicals, Cleveland, Ohio; CDL: 099247­ K) 00045126 Claborn, H. V.; Radeleff, R. D.; Bushland, R. C. (1960) Pesticide Residues in Meat and Milk: A Research Report. (U. S. Agricultural Research Service, Entomology Research, Div. And Animal Disease and Parasite Research Div., unpublished study; CDL: 093429­ S) 00060143 Saha, J. G. (1969) Letter sent to P. E. Porter dated Mar 10, 1969 [Metabolism of Lindane­ 14C by wheat plants]. (Canada, Dept. of Agriculture, Research Branch, unpublished study; CDL: 091355­ S) 00060150 Lichtenstein, E. P.; Fuhremann, T. W.; Scopes, N. E. A.; et al. (1967) Translocation of insecticides from soils into pea plants: Effects of the detergent LAS on translocation and plant growth. Journal of Agricultural and Food Chemistry 15( 5): 864­ 869. (unpublished submission received Apr 5, 1969 under 9F0785; submitted by Shell Chemical Co., Washington, D. C.; CDL: 091355­ Z) 00075989 Chevron Chemical Company (1949) Milk Contamination Studies. (Unpublished study received Jul 24, 1952 under 239­ 399; CDL: 231161­ B) 00088048 Gyrisco, G. G.; Muka, A. A. comps. (1951) Report on a Preliminary Study on the Effects of Feeding Insecticide Treated Alfalfa Hay to Dairy Cattle. (Unpublished study received Feb 21, 1955 under PP0007; prepared by G. L. F. Soil Building Service and Cornell Univ., Depts. of Entomology, Animal Husbandry and Dairy Industry, submitted by Shell Chemical Corp., New York, N. Y.; CDL: 090081­ U) 00088165 National Agricultural Chemicals Association (1955?) Supplementary Petition for Lindane Residue Tolerance. (Unpublished study received Jan 25, 1956 under PP0058; CDL: 090056­ A) 00089592 California Spray Chemical Corporation (1959) Residues of Lindane on Raw Agricultural Commodities. (Compilation; unpublished study received Apr 27, 1959 under PP0190; CDL: 090218­ B) 00099909 Shell Development Co. (1964) Determination of Chlorinated Pesticide Residues in Water, Soils, Crops and Animal Products: GLC­ Electron Capture Method: Analytical Method MMS­ 43/ 64. (Unpublished study received Nov. 9, 1964 under unknown administrative number; CDL: 129668­ A) 00101478 Radeleff, R. (1951) Effects of various levels of lindane in the feed of beef cattle. Veterinary Medicine XLVI( 3): 105­ 106,119. (unpublished submission received Sep 14, 1955 under PP0045; submitted by National Agricultural Chemicals Assn., Falls Church, VA; CDL: 090042­ F) 00104441 Hornstein, I.; McGregor, W.; Sullivan, W. (1956) Lowering the volatility of lindane cattle sprays by addition of film­ forming material. Agricultural and Food Chemistry 4( 2): 148­ 149. (unpublished submission received May 14, 1970 under 0H2545; submitted by Hazleton Laboratories, Inc., Falls Church, VA for Paper Products, Inc.; CDL: 221691­ C) 00105413 Caro, J. (1969) Accumulation by plants of organochlorine insecticides from the soil. Phytopathology 59( 9): 1191­ 1197. (unpublished submission received Nov 1, 1970 under unknown admin. no.; submitted by Hercules, Inc., Agricultural Chemicals, Wilmington, DE; CDL: 005105­ AM) 00118722 National Agricultural Chemicals Assoc. (1955) [Residues of Lindane in Agricultural and Cow Products]. (Compilation; unpublished study received Jan 24, 1956 under PP0058; CDL: 092338­ A) 00118723 California Spray­ Chemical Corp. (1959) [Lindane Residues in Milk and Meat]. (Compilation; unpublished study received on unknown date under PP0190; CDL: 092466­ A) 52 00118724 Collett, J.; Harrison, D. (1968) Lindane residues on pasture and in the fat of sheep grazing pasture treated with lindane pills. N. Z. Jl Agric. Res. 11: 589­ 600. (unpublished submission received May 12, 1969 under 9E0833; submitted by Office of the Commissioner, Washington, DC; CDL: 093535­ A) 00118725 National Agricultural Chemicals Assoc. (1955) The Results of Tests on the Amount of Residue Remaining, Including a Description of the Analytical Method Used: [Lindane]. (Compilation; unpublished study received on unknown date under PP0058; CDL: 098733­ A) 00118739 Chevron Chemical Co. (1949) [BHC: Residues in Milk]. (Compilation; unpublished study received on unknown date under 239­ 229; CDL: 224548­ A) 05002348 Burke, J.; Johnson, L. (1962) Investigations in the use of the micro­ coulometric gas chromatograph for pesticide residue analysis. Journal of the Association of Official Agricultural Chemists 45( 2): 348­ 354 05003005 Kovacs, M. F., Jr. (1966) Rapid detection of chlorinated pesticide residues by an improved TLC technique: 3 1/ 4 X 4" micro slides. Journal of the Association of Official Analytical Chemists 49( 2): 365­ 370 05006312 Osadchuk, M.; Romach, M; McCully, K. A. (1971) Cleanup and separation procedures for multipesticide residue analysis in monitoring and regulatory laboratories. Pages 357­ 381, in Pesticide Chemistry: Proceedings of the International IUPAC Congress of Pesticide Chemistry, 2nd; Feb. 22­ 26, 1971, Tel­ Aviv, Israel. Vol. 4: Methods in Residue Analysis. Edited by A. S. Tahori. New York: Gordon and Breach 40271301 Merricks, D. (1987) Determining the Metabolic Fate of Radiolabeled Lindane Fed to Laying Hens: Laboratory Project No. 1503. Unpublished compilation prepared by Agrisearch Inc. 47 p. 40271302 Wilkes, L.; Mulkey, N.; Hallenbeck, S.; et al. (1987) Metabolism Study of Carbon 14­ Lindane Fed of Topically Applied to Lactating Goats: Laboratory Project No. ADC 957. Unpublished study prepared by Analytical Development Corp., in cooperation with Rhone­ Poulenc Inc. 304 p. 40410902 Gemma, A. (1987) Metabolism of Carbon 14­ Lindane in/ on Apple Leaves and Fruit after Treatment with Carbon 14­ Lindane 25% EC: Project No.: 799R14: File No.: 40152. Unpublished study prepared by Rhone­ Poulenc Inc. 89 p. 40431201 England, D. (1987) Insecticides: Lindane: Metabolism in Spinach Plants Following Post­ emergence Application: Laboratory Project ID: D. Ag. 571. Unpublished study prepared by May & Baker Ltd. 62 p. 40431202 Godward, P. (1987) Insecticides: Lindane: Analytical Procedure for the Determination of Residues in Spinach: Laboratory Project ID: D. Ag. 573. Unpublished study prepared by May & Baker Ltd. 41 p. 40431203 Godward, P. (1987) Insecticides: Lindane: Storage Stability Study on Fortified Spinach Samples: Laboratory Project ID: D. Ag 572. Unpublished study prepared by May & Baker Ltd. 20 p. 40431204 England, D. (1987) Insecticides: Lindane: Metabolism in Cucumber Plants Following Post­ emergency Application: Laboratory Project ID: D. Ag. 570. Unpublished study prepared by May & Baker Ltd. 96 p. 40431205 England, P. (1987) Insecticides: Lindane; Storage Stability Study on Fortified Cucumber Samples: Laboratory Project ID: D. Ag 569. Unpublished study prepared by May & Baker Ltd. 20 p. 40431206 Godward, P. (1987) Insecticides: Lindane: Analytical Procedure for the Determination of Residues in Cucumber: Laboratory Project ID: D. Ag. 568. Unpublished study prepared by May & Baker Ltd. 41 p. 53 40431207 Piznik, M. (1987) The Uptake and Translocation of Radioactive Residues in Plants Grown from Seeds Treated with a Carbon 14 Radiolabelled Lindane Emulsifiable Concentrate (EC) Formulation: ASD No. 87/ 243. Unpublished study prepared by Rhone­ Poulenc Inc. 107 p. 40431208 Piznik, M. (1987) An Analytical Method for the Determination of Lindane in Animal Tissues, Eggs and Milk: Laboratory Project ID: ASD No. 87/ 241. Unpublished study prepared by Rhone­ Poulenc Inc. 36 p. 40660501 Merricks, D. (1988) Lindane Tissue and Egg Residue Study in Poultry: Final Report: Agrisearch Project No. 1507. Unpublished study prepared by Agrisearch, Inc. 96 p. 40660502 Piznik, M.; Ziegelbein, J.; Margitics, I.; et al. (1988) Freezer Storage Stability of Lindane in Animal Tissues, Eggs, and Milk: Project No. 799R14. Unpublished study prepared by Rhone­ Poulenc Ag Co. 38 p. 40660503 Billings, T. (1988) Tissue Residue Study in Sheep Using Lindane: Laboratory Project No. 8705o. Unpublished study prepared by Southwest Bio­ Labs, Inc. 285 p. 40660504 Billings, T. (1988) Tissue Residue Study in Swine Using Lindane: Laboratory Project No. 8704s. Unpublished study prepared by Southwest Bio­ Labs, Inc. 259 p. 40660505 Billings, T. (1988) Tissue Residue Study in Swine Using Lindane: Laboratory Project No. 8704s. Unpublished study prepared by Southwest Bio­ Labs, Inc. 259 p. 41289401 Landis Associates, Inc. (1988) Lindane 25% WP: Raw Agricultural Commodity Field Residue Protocol on Apples in California, Michigan, New York, Pennsylvania, North Carolina, and Washington: Lab Project Number: HLA/ 6237/ 116A. Unpublished study prepared by Hazleton Laboratories America, Inc. 386 p. 41289402 Landis Associates, Inc. (1989) Lindane 25% WP: Processed Commodity Field Residue Protocol on Apples in California, Michigan, North Carolina, and Washington: Lab Project Number: HLA/ 6237/ 116PA. Unpublished study prepared by Hazleton Laboratories, America. 588 p. 41289403 Landis Associates, Inc. (1989) Lindane 25% WP & 40% F: Raw Agricultural Commodity Field Residue Protocol on Cabbage in California, New York, Florida, Georgia, Texas, and Wisconsin: Lab Project Number: HLA/ 6237/ 116CA. 417 p. 41289404 Landis Associates, Inc. (1989) Lindane 25% WP & Lindane 40% F: Raw Agricultural Commodity Field Residue Protocol on Cucumbers in California, Ohio, and Michigan: Lab Project Number: HLA/ 6237/ 116CU. Unpublished study prepared by Hazleton Laboratories, America 438 p. 41289405 Landis Associates, Inc. (1988) Lindane 20% EC: Raw Agricultural Commodity Field Residue Protocol on Grapes in California, Michigan, New York, and Washington: Lab Project Number: HLA/ 6237/ 116G. Unpublished study prepared by Hazleton Laboratories America, Inc. 333 p. 41289406 Landis Associates, Inc. (1988) Lindane 20% EC: Processed Commodity Field Residue Protocol on Grapes in California, New York, and Washington: Lab Project Number: HLA/ 6237/ 116PG. Unpublished study prepared by Hazleton Laboratories America, Inc. 367 p. 41289407 Landis Associates, Inc. (1989) Lindane 25% WP and 40% F: Raw Agricultural Commodity Field Residue Protocol on Lettuce in California, Texas, New York, and New Jersey: Lab Project Number HLA/ 6237/ 116L. Unpublished study prepared by Hazleton Laboratories America, Inc. 471 p. 41289408 Landis Associates, Inc. (1989) Lindane 25% WP: Raw Agricultural Commodity Field Residue Protocol on Peaches in California, Michigan, Washington, Pennsylvania, and Georgia: Lab Project Number: HLA/ 6237/ 116P. Unpublished study prepared by Hazleton Laboratories America, Inc. 345 p. 54 41289409 Landis Associates, Inc. (1989) Lindane 20% EC: Raw Agricultural Commodity Field Residue Protocol on Tobacco in Virginia and Georgia: Lab. Project No. HLA/ 6237/ 116P. Unpublished study prepared by Hazleton Laboratories America, Inc. 237 p. 41289601 Landis Associates, Inc. (1989) Lindane 20% EC: Raw Agricultural Commodity Field Residue Protocol on Pecans in Louisiana, Texas, and Oklahoma: Lab Project Number: 6237/ 116.Unpublished study prepared by Hazleton Laboratories America, Inc. 257 p. 41421001 Walker, K. (1990) Lindane 20 [Percent] EC: Raw Agricultural Commodity Field Residue Protocol on Pecans in Louisiana: Lab Project Number: 6237­ 116 PC. Unpublished study prepared by Hazleton Laboratories America, Inc. 153 p. 41699701 Landis International, Inc. (1990) Lindane 25% WP: Raw Agricultural Commodity Field Residue on Tomatoes in Florida, Pennsylvania, California, New Jersey, Indiana, Michigan, and South Carolina: Lab Project Number: HLA 6237­ 116PT: W714­ 89­ 44­ 04­ 15B­ 02. Unpublished study prepared by Hazleton Laboratories America, Inc. 568 p. 41861201 Landis International, Inc. (1990) Lindane 25( percent) WP and Lindane 40% F: Processed Commodity Field Residue Protocol on Tomatoes in California, New Jersey, Pennsylvania, and Michigan: Lab Project Number: 6237­ 116PT: 1717­ 89­ 44­ 04­ 15B­ 08: 1714­ 89­ 44­ 04­ 15B­ 04. Unpublished study prepared by Hazleton Laboratories America, Inc. 742 p. 41861202 Hattermann, D. (1991) Lindane 20% EC: Processed Commodity Residue Evaluation Study on Tomatoes in California: Lab Project Number: 714­ 90­ 44­ 01­ 15B­ 01: 6237­ 130. Unpublished study prepared by Hazleton Wisconsin, Inc. 65 p. 41967301 Hurshman, B.; Xiao, G. (1991) Confined Accumulation Studies on Rotational Crops for Lindane: Lab Project Number: 36976: EF­ 88­ 41.Unpublished study prepared by ABC Labs and Pan­ Agricultural Labs., Inc. 120 p. 44383001 Curry, K.; Brookman, D. (1997) Metabolism of (carbon 14)­ Lindane in/ on Apple Leaves and Fruit After Treatment With (carbon 14)­ Lindane 25% EC: Supplement: Lab Project Number: 799R14: 40152. Unpublished study prepared by Rhone­ Poulenc Inc. 40 p. 44383002 Curry, K.; Brookman, D. (1997) Insecticides: Lindane­­( carbon 14)­ Metabolism in Cucumber Plants Following Post­ Emergence Application: Supplement: Lab Project Number: 5738: 5812: EC/ 86/ 004/ 01. Unpublished study prepared by May & Baker Ltd. 68 p. 44383003 Curry, K.; Brookman, D. (1997) Insecticides: Lindane: Analytical Procedure for the Determination of Residues in Cucumber: Supplement: Lab Project Number: D. AG 568. Unpublished study prepared by May & Baker Ltd. 11 p. 44383004 Curry, K.; Brookman, D. (1997) Insecticides: Lindane: Analytical Procedure for the Determination of Residues in Cucumber: Supplement: Lab Project Number: D. AG 568. Unpublished study prepared by May & Baker Ltd. 11 p. 44405403 Curry, K.; Brookman, D. (1997) Insecticides: Lindane­­( carbon 14) Metabolism in Spinach Plants Following Post­ Emergence Application: Supplement Report: Lab Project Number: 5739: STUDY/ EC/ 86/ 001/ 01: STUDY/ EC/ 86/ 001/ 02. Unpublished study prepared by Technology Sciences Group Inc. 53 p. 44405404 Curry, K.; Brookman, D. (1997) Determining the Metabolic Fate of Radiolabeled Lindane Fed to Laying Hens: Supplement Report: Lab Project Number: 1503. Unpublished study prepared by Technology Sciences Group Inc. 308 p. 55 44440601 Curry, K.; Brookman, D. (1997) Insecticides: Lindane: Analytical Procedure for the Determination of Residues in Poultry Tissues and Eggs. Unpublished study Centre International d'Etudes du Lindane. 42 p. 44440602 Curry, K.; Brookman, D. (1997) Insecticides: Lindane: Freezer Storage Stability Study on Fortified Spinach and Cucumber Samples: Supplement: Lab Project Number: 572: 569. Unpublished study prepared by Technology Sciences Group, Inc. 21 p. 44440603 Curry, K.; Brookman, D. (1997) Freezer Storage Stability of Lindane in Animal Tissues, Eggs and Milk: Supplement. Unpublished study prepared by Technology Sciences Group, Inc. 28 p. 44440604 Curry, K.; Brookman, D. (1997) Freezer Storage Stability of Lindane in Animal Tissues, Eggs and Milk: Supplement. Unpublished study prepared by Technology Sciences Group, Inc. 28 p. 44864401 Willard, T. (1999) Magnitude of the Residue of Lindane in Canola Raw and Processed Agricultural Commodities Following Seed Treatment with Premiere Plus: Lab Project Number: AA980775. Unpublished study prepared by American Agricultural Services, Inc. 134 p. 44867104 Willems, H.; Pluijmen, M. (1999) Fate of Orally Administered (carbon­ 14) Lindane in the Lactating Goat: Lab Project Number: 212761: 76104. Unpublished study prepared by Notox BV. 211 p. 44867105 Curry, K.; Hemingway, R.; Brookman, D. (1999) Lindane: Analytical Method for Determination of Residues in Animal Tissues and Milk: Supplement­­ Response to DER: Lab Project Number: CIEL6/ 993. Unpublished study prepared by Technology Sciences Group, Inc. 48 p. 44867106 Curry, K.; Hemingway, R.; Brookman, D. (1999) Freezer Storage Stability of Lindane in Animal Tissues, Eggs and Milk Response to DER and Proposal for Study Upgrade: Supplement to MRID 406605­ 02: Lab Project Number: CIEL6/ 99 2. Unpublished study prepared by Technology Sciences Group, Inc. 18 p. 44877501 Hemingway, R., Curry, K., and Brookman, D. (1999) Lindane: Tissue and Milk Residue Study in Dairy Cows ­ Response to DER and Proposal for Study Upgrade, Supplement to MRID 40660505. A supplemental study prepared by Technology Science Group Inc., Washington, D. C. and submitted by CIEL. 40 p. 44909901 Willard, T. (1999) Magnitude of the Residue of Lindane in Wheat Raw Agricultural Commodities Following Seed Treatment: Lab Project Number: AA980775: AA970775: AA970775.IA1. Unpublished study prepared by American Agricultural Services, Inc. 247 p. 45224101 Pluijmen, M and Willems, H. (2000) Fate of Orally Administered 14 C­ Lindane in the Lactating Goat: Report Amendment 01; NOTOX Project Number 212761. Unpublished study prepared by NOTOX. 14 p. 45224102 Stewart, R. (2000) Fate of Orally Administered 14 C­ Lindane in the Lactating Goat: Unaudited Draft Report. Unpublished study prepared by Huntingdon Life Sciences. 10 p. 45277201 Aikens, P. (2000) Investigations Into The Identity Of A Radioactive Metabolite Detected In The Liver Of A Goat Dosed With 14 C­ Lindane: Project Number SCI/ 056. Unpublished study prepared by Huntingdon Life Sciences Ltd. 36 p. 45310501 Willard, T. (2000) Magnitude of the Residue of Lindane in Canola Raw and Processed Agricultural Commodities Following Seed Treatment with Premeire Plus: Lab Project Number: AA980775. Unpublished study prepared by American Agricultural Services, Inc. 151 p. 45330301 Willard, T. (2001) Magnitude of the Residue of Lindane in Wheat Raw Agricultural Commodities Following Seed Treatment: Lab Project Number: AA970775. Unpublished study prepared by American Agricultural Services, Inc. 58 p. 56 GS­ 00010: San Antonio, J. P. "Demonstration of Lindane and a Lindane Metabolite in Plants by Paper Chromatography." Ag. and Food Chem., 7, 322 (1959). GS­ 00012: Herbst M. and G. Leber. "Investigations on Lindane either in Progress or Planned." Presented at the EPA in Washington, 12/ 18/ 75. GS­ 00013: Itokawa, H., et al. "Beitrage zur Okologischen Chemie­ XXII, Metabolismus und Ruckverhalten von Lindan­ 14C in honeren Pflanzen, Tetrahedron, 26, 763­ 773, 1970. GS­ 00014: Lindane Position Document 2/ 3, 1980. GS­ 00015: Lindane Position Document 4, 1984. GS­ 00016: R. W. Chadwick, et al. "Enhanced Pesticide Metabolism, a Previously Unreported Effect of Dietary Fibre in Mammals." Fd. Cosmet. Toxicol., 16, 217­ 225 (1978). GS­ 00017: Ivey, M. C., et al. "Lindane Residue in Chickens and Eggs Following Poultry House Spray," J. of Ecom. Entomol., 54( 3): 487­ 488 (1961). GS­ 00018: BHC­ Lindane Report, Special Pesticide Review group. GS­ 00019 (Section 18 Exemption for the use of lindane on sugarcane in Puerto Rico, 4/ 14/ 80). GS­ 00021: PP #058, Acc. No. 113144. GS­ 00022: No citation available GS­ 00023: Oehler, D. D., et al. "Residues in Milk Following Treatment of Cows with Lindane or Ronnel to Control Screw­ worms," J. Econ. Entomol., 63, 1467 (1970).

epa

2024-06-07T20:31:43.063620

regulations

EPA-HQ-OPP-2002-0202-0006

Supporting & Related Material

1 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: April 30, 2002 MEMORANDUM SUBJECT: REVISED OCCUPATIONAL AND RESIDENTIAL EXPOSURE ASSESSMENT AND RECOMMENDATIONS FOR THE RE REGISTRATION ELIGIBILITY DECISION DOCUMENT FOR LINDANE FROM David Jaquith Reregistration Action Branch 4 Health Effect Division (7509C) TO: Becky Daiss Reregistration Branch 4 Health Effect Division (7509C) THRU Susan Hummel, Senior Scientist Reregistration Branch 4 Health Effects Division (7509C) Please find attached the occupational and residential exposure assessment for lindane DP BARCODE D282648 Pesticide Chemical Codes: 009001 EPA Reg Nos: EPA MRID Nos.: 452000­ 02, 444058­ 02, 422519­ 01 PHED: No 2 CONTENTS EXECUTIVE SUMMARY...................................................... 3 1.0 BACKGROUND ........................................................ 4 1.1 Summary of Toxicity Concerns Relating to Occupational Exposures ......... 5 1. 2 Summary of Use Pattern and Formulations.............................. 7 1.3 Method and Types of Equipment Used for Mixing/ Loading/ Applying ........ 8 1. 4 Incident Reports................................................... 8 2.0 OCCUPATIONAL EXPOSURES ........................................... 8 2.1 Handler Exposures & Assumptions .................................... 8 2.1.1 Submitted Studies ........................................... 8 2.1.2 Summary of Occupational Handler Exposures ..................... 9 2.1.3 Summary of Uncertainties ..................................... 9 2.1.4 Calculations of Exposure ..................................... 11 2.2 Risk From Handler Exposures ....................................... 12 2.2.1 Risk From Handler Exposures ................................ 12 2.2.2 Summary of MOEs ......................................... 13 2.2.3 Cancer Risks .............................................. 13 2.2.3 Insufficient Data ........................................... 13 REFERENCES .................................................. 16 Appendix A ........................................................... 17 Appendix B ........................................................... 22 Appendix C ........................................................... 29 3 Executive Summary This document presents the occupational exposure assessment for use of lindane. Lindane is the gamma isomer of 1,2,3,4,5,6­ hexachlorocyclohexane, an insecticide previously used in many situations but now restricted to seed treatment only. There are no current registered uses for recreational, residential or other public (non­ occupational) settings. All uses other than seed treatment have been cancelled. Lice and scabies treatment is considered in the risk assessment document. Acute Toxicity Categories Acute toxicity categories for technical grade lindane are in Toxicity Category II for oral, Toxicity Category II for dermal, and Toxicity Category II for inhalation. It is in Toxicity Category III for primary eye irritation. The endpoints used in this document to assess lindane hazards include short­ term and intermediate­ term dermal and inhalation endpoints. The exposure duration for short­ term assessments is 1 to30 days or up to 1 month. Intermediate­ term duration is greater than 1 month to six months. Although there is little information to determine what percentage of workers apply for more than one month, it is reasonable to believe that typical uses of lindane by commercial seed treatment facilities may encompass an intermediate­ term duration. On farm treatments are more likely to be of short­ term duration. An oral developmental neurotoxicity study (MRID 45073501) in rats was selected for both dermal assessments. A 90­ day inhalation toxicity study (MRID 00255003) was selected for inhalation assessment for all time periods. In the developmental neurotoxicity study the maternal toxicity NOAEL is 50 ppm (5.6 mg/ kg/ day) based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. The offspring toxicity NOAEL was 10 ppm (1.2 mg/ kg/ day). In the subchronic inhalation toxicity study (Accession No. 255003) Tte systemic toxicity NOAELs for short term exposure was 0.5 mg/ m 3 (0.13 mg/ kg/ day), based on lesions in the kidney and increased kidney weights.( 1). Exposure data on lindane are available but limited. An exposure study addressing on farm seed treatment has been conducted (MRID 444058­ 02). A detailed description along with the exposure calculations are presented in Appendix A. Another study addressing commercial seed treatment with another chemical has been reviewed by the Agency. The an excerpt of the review of that study (MRID 452000­ 02), along with the calculations for lindane exposure are presented in Appendix B. The results of the handler assessments indicate that the on farm seed treatment provide dermal MOEs less than 100 with the attire worn during the study (long pants, long sleeved shirts, gloves). The assessments, both dermal and inhalation, yielded MOEs of less than 100 for 4 mixing/ loading/ application and bagging/ sewing/ stacking during commercial seed treatment of canola. All other exposure scenarios provide MOEs greater than or equal to 100 when wearing the clothing used in the study (coveralls over single layer of clothing, gloves for commercial other seed treatment workers) or at baseline attire (single layer of clothing, gloves for mixer/ loaders) for loading seed for planting or for planting treated seed. Due to the method of seed treatment, HED has determined that soil­ incorporated, postapplication agricultural exposure is considered to be negligible as long as the soil is not directly contacted. The exception is farmers handling treated seed. An estimate of the inherent risk from handling treated seed was conducted using relatively conservative assumptions. There are no study data available on exposure to lindane from handling treated seed and therefore the exposure was estimated using surrogate data. An excerpt of that review of that study (MRID 422519­ 01) and exposure calculations are presented in Appendix C. 1.0 BACKGROUND Purpose This document is for use in development of the Reregistration Eligibility Decision Document (RED) for the insecticide lindane and presents a review of the potential human health effects of occupational exposure to lindane. Criteria for Conducting Exposure Assessments An occupational and/ or residential exposure assessment is required for an active ingredient if (1) certain toxicological criteria are triggered and (2) there is potential exposure to handlers (mixers, loaders, applicators, etc.) during use or to persons entering treated sites after application is complete. For lindane, both of these criteria are met. 5 1.1 Summary of Toxicity Concerns Relating To Occupational Exposures Acute Toxicology Categories Table 1 presents the acute toxicity categories as outlined in the Report of the Hazard Identification Assessment Review Committee (1). Table 1: Acute Toxicity Categories for Lindane (Technical) STUDY TYPE MRID CATEGORY RESULT 81­ 1 Acute oral 00049330 II LD50 88 mg/ kg ­ males 91 mg/ kg ­ females 81­ 2 Acute dermal 00109141 II LD50 1000 mg/ kg ­ males 900 mg/ kg ­ females 81­ 3 Acute inhalation Acc. 263946 III LC50 1.56 mg/ L both sexes 81­ 4 Eye irritation Acc. 263946 III PIS = 0.6 no corneal involvement irritation cleared after 24 hours 81­ 5 Dermal irritation Acc. 263946 IV PIS = 0 not an irritant 81­ 6 Dermal sensitization Acc. 263946 NA not a sensitizer Other Endpoints of Concern The Report of the Hazard Identification Assessment Review Committee (HIARC) for lindane, (1) indicates that there are toxicological endpoints of concern for lindane. The endpoints used in assessing the risks for lindane are presented in Table 2. 6 Table 2. Doses and Toxicological Endpoints Selected for Risk Assessment of Lindane EXPOSURE SCENARIO DOSE (mg/ kg/ day) ENDPOINT STUDY TYPE/ MRID Acute Dietary­ general population NOAEL= 6 mg/ kg UF = 100 LOAEL is 20 mg/ kg based on increased grip strength, increased motor activity Acute Neurotoxicity in Rats/ 44769201 Acute RfD = 0.06 mg/ kg/ day aPAD = 0.02 mg/ kg/ day Chronic Dietary NOAEL= 0.47 mg/ kg/ day UF = 300 LOAEL is 100 ppm (4.81 mg/ kg/ day) periacinar hepatocyte hypertrophy, increased liver/ spleen weight, decreased platelets Chronic Feeding and Carcinogenicity in Rats 41094101, 41853701 42891201 Chronic RfD = 0.0047 mg/ kg/ day cPAD = 0.0016 mg/ kg/ day Short­ Term 1 (Dermal) NOAEL= 1.2 mg/ kg/ day LOAEL is 50 ppm based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. Developmental Neurotoxicity Study in Rats (oral) 45073501 Intermediate­ Term 1 (Dermal) NOAEL= 1.2 mg/ kg/ day LOAEL is 50 ppm based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. Developmental Neurotoxicity Study in Rats (oral) 45073501 Long­ Term 1 (Dermal) NOAEL= 0.47 mg/ kg/ day LOAEL is 100 ppm (4.81 mg/ kg/ day) periacinar hepatocyte hypertrophy, increased liver/ spleen weight, decreased platelets Chronic Feeding and Carcinogenicity in Rats 41094101, 41853701 42891201 Dermal Absorption Factor = 10% Short Term 1 (Inhalation) 0.13 mg/ kg/ day (0.5 mg/ m 3 ) based on clinical signs (diarrhea, piloerection) seen at day 14 and continuing for 20 days 90­ Day Inhalation Toxicity / 00255003 Intermediate Term 1 (Inhalation) 0.13 mg/ kg/ day (0.5 mg/ m 3 ) LOAEL is 5.0 mg/ m 3 based on increased kidney weights of female rats and bone marrow effects. 90­ Day Inhalation Toxicity / 00255003 Long Term 2 (Inhalation) N/ A N/ A N/ A 1 Since an oral NOAEL was selected, the dermal absorption factor (10%) should be used in route­ to­ route extrapolation. 2 Exposure thru this route for this duration is not expected 7 1.2 Summary of Use Patterns and Formulations The only use remaining for lindane is for seed treatment. The use closure memorandum (4) allows the seed treatment of the following crops: barley, broccoli, Brussels sprouts, cabbage, cauliflower, corn, lettuce, oats, radishes, rye, sorghum, spinach, and wheat. The crops and application rates are presented in Table 3. Wheat and canola were used as a representative crops for all other seeds treated with lindane because of the relatively large farm size, application rate, and nature of the product treated. Table 3. Summary of Application Rates for Seed Treatment Using Lindane on Various Crops. Commodity Formulation/ Reg. No. Use Rate barley 0.0375 lb ai/ 100 pound seed corn dust (19713­ 262) EC (71096­ 2) 0.125 lb ai/ bushel seed 0.125 lb ai/ 100 pound seed oats 7501­ 38, 10107­ 121 0.03125 lb ai/ 100 pound seed rye 19713­ 401 554­ 144 19713­ 387 0.032813 lb ai/ 100 pound seed sorghum 42056­ 15 0.0628 lb ai/ 100 pound seed spinach dust (7501­ 38, 34704­ 653, 34704­ 658, 19713­ 262, 34704­ 658, 42056­ 14, 10107­ 121, 66330­ 19) 0.0625 lb ai/ 100 pound seed wheat dust, 2935­ 492 0.042578 lb ai/ 100 pound seed canola Not currently registered 1.5 lb ai/ 100 pounds seed (a rate of 0.75 lb/ 100 lbs seed has been proposed) 1.3 Method and Type of Equipment Used for Mixing/ Loading/ Applying The flowable concentrate, and emulsifiable concentrate formulations for commercial application all require mixing with water to the label­ specified dilution. This is usually performed by scooping or pouring the formulation into a mixing tank, often of 100 gallons or more in capacity, with mechanical agitation to keep the resulting emulsion homogenized and prevent variations in application strength. Smaller amounts may be handled using a tiller­ planter (or seed drill)­ mounted system. Large commercial operations, may have mechanical, automated, 8 metered pumps which require only connecting the formulation to the pump. Again, small seed treatment operations, such as seed box (or "hopper box") mixing, may be done by pouring small amounts in to a mixing device before planting the seeds in to the soil. Dry formulations may also be used, particularly for on farm treatment. Timing and Frequency of Application Generally, seed will be treated on an as needed basis. However, it is industry practice only to treat enough seeds as are needed to be used that season. 1.4 Incident Data No information regarding seed treatment incidents is available at this time. 2.0 OCCUPATIONAL EXPOSURES 2.1 Handler Exposures & Assumptions HED has determined that there are potential exposures to mixers, loaders, applicators, or other handlers during usual use­ patterns associated with lindane. Based on the use patterns and potential exposures described above, 5 major exposure scenarios were identified to represent the extent of lindane uses: (1) mixing/ loading/ application of formulations for on­ farm seed treatment, (2) mixing/ loading and applying liquid with commercial seed­ treatment equipment, (3) bagging and otherwise handling treated seeds, (5) forklift operation, (6) cleaning seed treatment equipment, (7) mixing/ loading/ planting of treated seed for planting. 2.1.1 Submitted Studies Mixer/ loader/ applicator exposure data for lindane were required since one or more toxicological criteria had been triggered. Requirements for applicator exposure studies are addressed by Series 875 Group A (formerly Subdivision U of the Pesticide Assessment Guidelines). Three exposure studies, one addressing on­ farm treatment have been provided (Appendix A), another addressing commercial seed treatment (Appendix B), a third addressing planting of treated seed (Appendix C) 2.1.2 Summary of Occupational Handler Exposures Table 5 presents the exposure scenarios, application rates, and amount potentially handled that have been used for the exposure calculations. These are restricted to canola and wheat for commercial seed treatment and wheat for on­ farm treatments as representative of typical applications. Exposures for handling treated seed before planting and planting treated seed use parameters for wheat and canola as representative crops. Therefore, the rates/ seed types presented in Table 5 are not all conclusive and no attempt has been made to assess a range of application rates to ensure that all use rates and exposure scenarios are represented. 9 2.1.3 Summary of Uncertainties The assumptions and uncertainties are identified below to be used in risk management decisions: C Application Rates: Based on wheat for on farm treatment and canola for commercial seed treatment. Other types of seed may have slightly different rates but these differences are unlikely to appreciably alter the exposure/ risk assessment. C Amount Handled: For commercial seed treatment the amounts handled are assumed to be equal to the amounts handled at the facilities used in the study described in the Appendices. On farm treatment exposures were estimated assuming that enough wheat seed could be treated and planted for 100 acres per day at a rate of 120 pounds of seed per acre. C Unit Exposures: The unit exposure values for commercial seed treatment and planting of treated seed were derived from surrogate studies. The median exposure value was used for commercial seed treatment (Appendix B) and the arithmetic mean was used for the loading/ planting task (Appendix C). 10 Table 4: Exposure Variables for Uses of Lindane Exposure Scenario (Scenario #) Are Chemical Specific Monitoring Data Available Are PHED Data Available? Application Rates (lb ai/ amt of seed) Daily lb Seed Treated/ Handled Lb ai Handled/ day Applicator/ Handler Exposure (1) mixing/ loading/ planting of dry formulations for on farm treatment Yes MRID #44440585­ 02 No 0.023 lb ai/ bushel (60 lbs seed) for wheat 12000 lbs seed, see Appendix A) 4.7 a (2) mixing/ loading and applying liquid with a commercial seedtreatment equipment No MRID #45200002 No Wheat: 0.043lb ai/ 100 lb seed treated 176000 76 Canola (low­ end): 0.75 lb ai/ 100 lb seed treated 176000 1320 Canola (high­ end): 1.5 lb ai/ 100 lb seed treated 176000 2640 (3) handler for commercial seedtreatment equipment (i. e. bagging, sewing, stacking) with chemical resistant coveralls over long sleeve shirt long pants, chemical resistant gloves No MRID #45200002 No Wheat: 0.043lb ai/ 100 lb seed treated 176000 76 Canola (low­ end): 0.75 lb ai/ 100 lb seed treated 176000 1320 Canola (high­ end): 1.5 lb ai/ 100 lb seed treated 176000 2640 (4) handler for commercial seedtreatment equipment (i. e. bagging, sewing, stacking) with cotton/ polyester coveralls over long sleeve shirt long pants, chemical resistant gloves No MRID #45200002 No Wheat: 0.043lb ai/ 100 lb seed treated 176000 76 Canola (low­ end): 0.75 lb ai/ 100 lb seed treated 176000 1320 Canola (high­ end): 1.5 lb ai/ 100 lb seed treated 176000 2640 (5) Forklift operator ­ chemical resistant coveralls over long sleeve shirt long pants, chemical resistant gloves No MRID #45200002 No Wheat: 0.043lb ai/ 100 lb seed treated 176000 76 Canola (low­ end): 0.75 lb ai/ 100 lb seed treated 176000 1320 Canola (high­ end): 1.5 lb ai/ 100 lb seed treated 176000 2640 (6) Worker Cleaning seed treatment equipment ­ chemical resistant coveralls over long sleeve shirt long pants, chemical resistant gloves No MRID #45200002 No Wheat: 0.043lb ai/ 100 lb seed treated NA NA Canola (low­ end): 0.75 lb ai/ 100 lb seed treated NA NA Table 4: Exposure Variables for Uses of Lindane Exposure Scenario (Scenario #) Are Chemical Specific Monitoring Data Available Are PHED Data Available? Application Rates (lb ai/ amt of seed) Daily lb Seed Treated/ Handled Lb ai Handled/ day 11 Canola (high­ end): 1.5 lb ai/ 100 lb seed treated NA NA (7) Planting treated seed Enclosed cab No MRID #42251901 No Wheat: 0.043lb ai/ 100 lb seed treated 3000 12.9 Canola (low­ end): 0.75 lb ai/ 100 lb seed treated 1000 7.5 Canola (high­ end): 1.5 lb ai/ 100 lb seed treated 1000 15 a Data are available from on farm treatment study (Appendix A) c Daily amount treated based on HEDs estimates of acreage that would be reasonably expected to be planted in a day for commercially treated seed. The acres per day assumed 120 lbs. of wheat per acre, planting an average of 250 acres per day (2). 2.2 Risk From Handler Exposures EPA calculated the potential risk to persons from handler exposures and planting of treated seed using the daily dermal exposure scenarios identified in the exposure section. Potential dermal and inhalation daily exposures for occupational handlers were calculated using the following formulas (10 percent dermal absorption was assumed): The inhalation and dermal daily doses were calculated using the following formulas: 12 2.2.1 Risk From Handler Exposures Margins of Exposure (MOEs) were calculated for handlers for short­ term (one to seven days) and intermediate­ term (one week to several months) durations for both dermal and inhalation exposures. The MOEs were calculated using the following formulas: 13 2.2.2 Summary of MOEs The daily exposures, resulting short and intermediate term MOEs are presented in Table 7. The exposure scenario descriptions are presented in Table 8. The results of the short­ term dermal exposure duration indicate that the MOEs range from 5.2 for on farm seed treatment to 34000 for the planting of treated seed . A total of 9 dermal and inhalation MOEs were calculated for the various scenarios. Based on the level of protection used in the studies, all of the MOEs for the application portion of seed treatment were less than 100. All other dermal MOEs were above 100. Inhalation MOEs for workers other than applicators for commercial treatment and seed handlers at large facilities are greater than 100. 2.2.3 Cancer Risks The OPP/ Cancer Assessment Review Committee (CARC) has completed the review of newly submitted carcinogenicity study in CD­ 1 mice along with other data. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC has classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on an increased incidence of benign lung tumors in female mice only. The Committee, therefore, recommended that the quantification of human cancer risk is not required. 2.2.4 Insufficient Data Other studies are undergoing review by HED personnel at this time and may alter our estimate of exposure. 14 Table 5­ Daily Exposures and MOEs for Commercial Seed Treatment Plant Worker Exposure Exposure Scenario (Scenario #) Application Rates ( lb ai/ 100 lbs seed or Lb/ A) Amount Handled per Day (lbs a. i.) Unit Exposure (mg/ lb ai) a Daily Exposure (mg/ kg/ day) Short­ Term MOEs & Intermediate Term MOES Dermal Inhalation Dermal b Inhalation s Dermal c Inhalation e Mixing/ loading /planting dry formulation for on farm seed treatment (1) 0.043 4.7 9.4 0. 0016 0.074 0.00011 16 1200 Treater ­ Closed Transfer chemical resistant coveralls over long­ sleeved shirt, long pants, chemical resistant gloves (2) 1.5 (canola high­ end) 76 0.00083 0.00012 0.036 0.0053 329 25 0.75 (canola low­ end) 1320 0.00083 0.00012 0.018 0.0026 657 49 0.043 (wheat) 2640 0.00083 0.00012 0.0010 0.00015 11462 859 Bagger/ Sewer /Stacker chemical resistant coveralls over long­ sleeved shirt, longpants, chemical resistant gloves ­ (3) 1.5 (canola high­ end) 76 0.00026 0.00006 0.011 0.0026 1049 49 0.75 (canola low­ end) 1320 0.00026 0.00006 0.0057 0.0013 2098 98 0.043 (wheat) 2640 0.00026 0.00006 0.00033 0.000076 36591 1718 Bagger/ Sewer /Stacker cotten/ polyester coveralls over long­ sleeved shirt, longpants, chemical resistant gloves (4) 1.5 (canola high­ end) 76 0.0003 0.00006 0.013 0.00264 909 49 0.75 (canola low­ end) 1320 0.0003 0.00006 0.0066 0.0013 1818 98 0.043 (wheat) 2640 0.0003 0.00006 0.00038 0.000076 31712 1718 Forklift Operator ­ chemical resistant coveralls over long sleeved shirt, longpants, chemical resistant gloves (5) 1.5 (canola high­ end) 76 0.00008 7.7E­ 06 0. 0035 0.00034 34091 384 0.75 (canola low­ end) 1320 0.00008 7.7E­ 06 0. 0018 0.00017 6818 767 0.043 (wheat) 2640 0.00008 7.7E­ 06 0. 00010 9.7E­ 06 118922 13385 Cleaner ­ chemical resistant coveralls over long­ sleeved shirt, longpants, chemical resistant gloves (6) 1.5 (canola high­ end) 76 0.00669 0.00119 0.00011 1.98E­ 05 107623 6555 0.75 (canola low­ end) 1320 0.00669 0.00119 0.00011 1.98E­ 05 107623 6555 0.043 (wheat) 2640 0.00669 0.00119 0.00011 1.98E­ 05 107623.3 6555 a Median unit dermal and arithmetic mean inhaltion unit exposures b Dermal Exposure (mg/ kg/ day) = unit exposure (mg/ lb ai) x amount handled per day (lbs a. i.) / bw (60 kg). c Dermal MOE = Dermal NOAEL (1. 2 mg/ kg) / [daily exposure (mg/ kg/ day) x dermal absorption factor (10%)]. d Inhalation Exposure (mg/ kg/ day) = inhalation unit exposure (mg/ lb ai) x amount handled per day (lbs a. i.) / body weight (70 kg). e Inhalation MOE = NOAEL (0. 13 mg/ kg/ day) / daily exposure (mg/ kg/ day). 15 Table 6. Exposure Scenario Descriptions for the Use of Lindane. Exposure Scenario (Scenario #) Data Source Standard Assumptions a Comments b Mixing/ loading /planting dry formulation for on farm seed treatment (1) Rhone­ Poulenc Data MRID # 444058­ 02 Assumes enough seed treated and planted for 100 Acres per day All data were for gloved hands; (see study, Appendix A. ) Mixing/ loading/ application of liquid formulation for commercial seed treatment (2) Uniroyal Data MRID # 447305­ 01 176000 lbs of seed per day See study review; based on geometric mean of data and amounts of seed from study data Seed Handler for commercial seed treatment (3, 4,5,6) Uniroyal Data MRID # 447305­ 01 176000 lbs of seed per day See study review; based on geometric mean of data and amounts of seed from study data Loading and planting treated seed for planting (7) MRID 422519­ 01 Assumes 250 acres are planted per day at 120 lbs of seed per acre for wheat; 4 lbs per acre for canola, commercially treated seed Appendix C a All Standard Assumptions are based on an 8­ hour work day as estimated by HED. 16 REFERENCES 1) Lindane ­ Report of the Hazard Identification Assessment Review Committee, July 27, 2000. 2) Memorandum from S. Tadayon (CEB1) to A. Khasawinah (RRB4) titled "Occupational and Residential Exposure Assessment and Recommendations for the Registration Eligibility Decision Document for Imazalil", dated April 15, 2,000. 3) EPA (1998) Surrogate Exposure Guide, Estimates of Worker Exposure from the Pesticide Handler Exposure Database Version 1.1 4) Memorandum from M. Howard (SRRD) to Lindane RED Team Members titled "Final Lindane Use Closure Memo" dated May 17, 2000 (EMAIL). cc: Lindane file (009001) Correspondence file R. Kent (RRB4/ 7509C) D. Jaquith (RRB4/ 7509C) 17 APPENDIX A. MANUAL SEED TREATMENT (at farm): CITATION: Fenske, R. A., A. M. Blacker, S. J. Hamburger, and G. S. Simon (1990) Worker Exposure and Protective Clothing Performance During Manual Seed Treatment with Lindane. Arch. Environ. Contam. Toxicol. 19, 190­ 196. Fenske, R. A. Reregistration of Lindane Technical Case No. 0315, Chemical No. 9001. Worker Exposure to Lindane During Manual Seed Treatment. MRID No. 444058­ 02 Dermal and respiratory exposures of 4 male workers with prior experience were monitored during the manual treatment of winter wheat at a commercial wheat farm in South Dakota. The operations are considered to be representative of manual seed treatments in the midwest. A dust formulation containing 18.75 percent lindane, packaged in 10 lb bags was applied at the label rate of 2 ounces per bushel of seed. A total of 720 bushels of seed were treated. The treatment procedure involved the addition of grain to a 4 compartment, 12 bushel grain drill. The label instructions indicate the user is to fill the drill box half full of seed and add half of the formulation. The seed and formulation are then mixed with a stick. The rest of the grain is then added and the procedure repeated. After thorough mixing the seed was removed by a vacuum. Workers monitored in this study did not participate in the vacuuming procedure. Each mixing consisted of the application of 24 oz (680 g) of the formulation to 12 bushels of grain. A plastic scoop, cut from a plastic bottle and determined to hold 12 oz of formulation, was used to remove the powder from the bag. The scoop was used to spread the formulation evenly over the seed. Each replicate consisted of five mixings conducted by each of the four workers, the mixing activity lasting 4­ 6 minutes. The mixing periods averaged 24 minutes and were separated by 10­ 20 minute breaks. This was considered to be equal to one "work period". During this time a worker handled 120 oz of formulation or 1.4 lb of active ingredient. Each volunteer performed the tasks three times (total of 60 mixings), yielding a total of 12 work periods. During treatments the workers wore the label required long sleeve shirt, long pants, Nitrile gloves, a baseball cap, and a pesticide respirator. All clothing was new and/ or prewashed to avoid confounding analytical problems. The workers did not remove their gloves during the procedure but did during breaks. Dermal exposures were monitored using gauze dosimeters encased in an envelope with a 5.6 cm diameter circle exposed to the environment (25 cm² total area). Dosimeters were either attached to the clothing or taped to the skin on the chest, back, shoulders, forearms, upper legs, or lower legs. Two sets of dosimeters were used, one outside the clothing and the other inside the work garments. Care was taken to avoid overlap of the dosimeters, which could confound the results of the inner monitors. Surface areas were assumed to be those outlined in the Agency's Guidance (OPPTS 875 Group A test guidelines, formerly Subdivision U). Dermal exposure of the hands was monitored by hand wash with 250 mL of 10 percent isopropanol in distilled water. A plastic bag was wrapped around the wrist and the bag shaken for about 30 seconds. This procedure was repeated 3 times, resulting in a pooled volume of 750 mL for each hand. Hand rinses were conducted for each hand immediately prior to the exposure period and again 18 immediately after. Approximately 75 mL was transferred to a glass jar for storage. Respiratory exposure was monitored using calibrated battery powered pumps attached to the belt with a 37 mm fiberglass filter attached to the collar in the breathing zone. The flow rate was approximately 2 liters per minute. Dermal dosimeters and air filter cassettes were removed immediately after the exposure period. Gauze pads were removed from their holders with solvent rinsed tweezers and placed in individual 4 ounce glass jars. Filter were sealed and replaced in their original packing containers. All samples were maintained at 4° C during shipment and storage. Samples arrived at the analytical laboratory within 6 days of collection and analyzed within the next 2 months. Fifty mL of hexane/ acetone (1/ 1, v/ v) was added to the dermal dosimeters jars and the jars shaken for 1 hour. A 100 : L aliquot of the extract was added to a 10 mL volumetric flask and 2 : L of internal standard/ surrogate chemical (aldrin and heptachlor, respectively). The resulting solution was brought to volume with hexane The results of exposure monitoring are presented in Table A1. 19 Table A1. Exposures of Workers Applying Lindane as a Seed Treatment at a Rate of 1.4 lb ai) Pounds of Active Ingredient per 60 Bushels of Grain (3600 lbs of seed, total. Values used for exposure estimation are in boldface. Body Region Monitor Location Exposure (mg) Exposure (mg/ lb ai) Mean Median Range Mean Median Chest Outer 3.21 2.43 0.92­ 7.84 2.3 1.7 Back Outer 2.48 2.48 0.85­ 4.58 1.8 1.8 Forearms Outer 17.75 15.25 5.57­ 51.79 13.0 11.0 Upper arms Outer 4.43 3.88 0.99­ 10.10 3.2 2.7 Upper legs Outer 33.96 20.46 2.90­ 132.55 24.0 15 Lower legs Outer 1.34 9.64 0.43­ 5.95 0.96 6.9 Chest Inner 0.45 0.44 0.07­ 0.71 0.32 0.31 Back Inner 0.71 0.52 0.11­ 2.59 0.51 0.37 Forearms Inner 5.43 3.46 1.31­ 16.70 3.9 2.5 Upper arms Inner 1.12 0.79 0.12­ 2.91 0.80 0.56 Upper legs Inner 2.88 2.18 0.08­ 9.32 2.1 1.6 Lower legs Inner 0.16 0.12 0­ 0.33 0.11 0.086 Hands 0.74 0.71 0.4­ 1.27 0.53 0.51 Head/ Neck 1.72 1.47 0.7­ 3.58 1.2 1.1 Total Dermal 13.21 9.69 9.4 7.1 Respiratory 0.0022 0 0­ 0.016 0.0016 0 mg/ lb ai = Exposure (mg) ÷ 1.4 lb ai 20 Calculation of Daily Exposures: Assumptions: 1) An average worker weighs 60 kg for dermal risk assessment and 70 kg for inhalation exposure and has standard body surface areas and respiration rates as presented in the Pesticide Assessment Guidelines (OPPTS 875 Group A test guidelines). 2) Examination of the Census of Agriculture data for Kansas yielded a median farm sizes of in the 100 to 249 acre range. Three other wheat producing states (North Dakota, Washington, and Montana) had median farm sizes in the 250 to 499 acre range. A farm size of 500 acres was assumed. Workers were assumed to treat and plant enough seed for 250 Acres per day, yielding a short term exposure scenario. 3) Workers are assumed to wear the same clothing as those participating in the study. Typical clothing consists of a long sleeved shirt, long pants, and chemical resistant gloves. 4) Wheat is planted at a rate of 120 pounds of seed per acre and each bushel of seed weighs 60 pounds (Hanson, A. A. (Ed) (1989) Practical Handbook of Agricultural Science. CRC Press, Inc., Boca Raton, FLA.) and BEAD report. 5) While the application rate varies somewhat for various types of seeds, the application rate/ farm size is considered typical for lindane seed treatment products. Amount of seed treated per 8 hour day: Seed treated (lbs) = 100 A/ day x 120 lbs seed/ A l = 12000 lb seed/ day Amount of lindane handled per day: Lbs ai handled per day = 2 oz/ bushel x 0.1875 x 200 bushels seed/ day x 1 lb/ 16 oz = 4.7 lbs ai/ day 21 Estimation of Exposure (manual seed treatment): Dermal: Dermal Exposure (mg/ kg/ day) = 9.4 mg/ lb ai x 4.7 lbs ai/ day ÷ 60 kg x 0.1 = 0.074 mg/ kg/ day Respiratory: Respiratory Exposure (mg/ kg/ day) = 0.0016 mg/ lb ai x 12 lbs ai/ day ÷ 70 kg = 0.00011 mg/ kg/ day The resulting Dermal MOE is: MOED = 1.2 mg/ kg/ day ÷ 0.074 mg/ kg/ day = 16 The resulting Inhalation MOE is: MOEI = 0.13 mg/ kg/ day ÷ 0.00011 mg/ kg/ day = 1200 22 APPENDIX B UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Date: April 23, 2002 MEMORANDUM SUBJECT: LINDANE: REVISION OF EXPOSURE ASSESSMENT FOR COMMERCIAL SEED TREATMENT PLANT WORKER (MRID 45200002, DP Barcode D282419) (Excerpt) FROM David Jaquith Reregistration Action Branch 4 Health Effect Division (7509C) TO: Rebecca Daiss Reregistration Branch 4 Health Effect Division (7509C) 2.2 Revised Exposure and Risk Estimates HED has reevaluated the estimates of exposure and risk from treatment of wheat and canola seed with lindane using median unit dermal and inhalation exposures provided in the HELIX 289FS Study. Unit exposures used for this assessment are summarized in Table 2. Unit exposure data from the HELIX study are presented in detail in Appendix A. Table 2. Unit Dermal and Inhalation Exposures of Workers During Seed Treatment and Handling of Treated Seed 1 Median Unit Dermal and Inhalation Exposures Treater ­ Closed Transfer ­ Chemical­ Resistant coveralls over long­ sleeve shirt, long pants; chemical resistant gloves Dermal (n= 17) 0.83 : g/ lb/ ai Inhalation (n= 17) 0.12 : g/ lb/ ai Cleaner ­ Chemical­ Resistant coveralls over long­ sleeve shirt, long pants; chemical resistant gloves Dermal (n= 7) 6.70 : g/ kg bw Inhalation (n= 7) 1.20 : g/ kg bw Bagger/ Sewer/ Stacker ­ Chemical­ Resistant coveralls over long­ sleeve shirt, long pants; chemical resistant gloves Dermal ­ chemical resistant coveralls (n= 34) 0.26 : g/ lb/ ai Dermal ­ Cotton/ polyester coveralls (n= 19) 0.30 : g/ lb/ ai Table 2. Unit Dermal and Inhalation Exposures of Workers During Seed Treatment and Handling of Treated Seed 1 Median Unit Dermal and Inhalation Exposures 23 Inhalation (n= 53) 0.06 : g/ lb/ ai Forklift Operator ­ cotton/ polyester coveralls over long­ sleeve shirt, long pants; chemical resistant gloves Dermal (n= 12) 0.08 : g/ lb/ ai Inhalation (n= 12) 0.008 : g/ lb/ ai 1 Commercial Seed Treatment Plant Worker Exposure Study with Helix 289FS Seed Treatment on Canola (MRID 452000­ 02) The application rate in the HELIX study was 400 gm thiamethoxam/ 100 kg seed (0.88 lb/ 220000 lb seed). The throughput of seed of 7000 kg/ hr (15400 lb/ hr), 6800 kg /hr( 14960 lb/ hr), 5000 kg/ hr (11000 lb/ hr), 5000 kg/ hr (11000 lb/ hr), 10000 kg/ hr (22000 lb/ hr) for sites 1 to 5, respectively. The following assumptions were used to estimate exposure: 6) The throughput of seed for both wheat and canola is 22000 lb/ per hour or 176000 lbs per 8 hour day. 7) The application rate for wheat is 0.043 lb ai per hundred weight of seed. The application rate for canola is 1.5 lb (high­ end) and 0.75 lb (low­ end) ai per hundredweight of seed. 3) Pounds handled per day for wheat: lbs handled per day wheat = 176000 lbs/ day x 0.043 ÷ 100 lbs = 76 lbs/ day lbs handled per day canola (high­ end) = 176000 lbs/ day x 1.5 ÷ 100 lbs = 2640 lbs/ day lbs handled per day canola (low­ end) = 176000 lbs/ day x 0.75 ÷ 100 lbs = 1320 lbs/ day 4) Median unit dermal and inhalation exposures were used based on data distribution. 5) Worker body weight for dermal exposure = 60 kg (female body weight used for developmental endpoint) Worker body weight for inhalation exposure = 70 kg 24 APPENDIX C Date: April 24, 2002 MEMORANDUM SUBJECT: REVISION OF EXPOSURE ASSESSMENT FOR PLANTING OF SEED TREATED WITH LINDANE DP BARCODE D282418, MRID 42251901 (Excerpt) FROM David Jaquith Reregistration Action Branch 4 Health Effect Division (7509C) TO: Becky Daiss Reregistration Branch 4 Health Effect Division (7509C) THRU Susan Hummel, Senior Scientist Reregistration Branch 4 Health Effects Division (7509C) 2.0 CONCLUSIONS HED has reevaluated the estimates of exposure and risk from planting of wheat and canola seed with lindane using a study specifically addressing this scenario rather than using PHED as a model for planting seeds. Using an oral NOAEL of 1.2 mg/ kg/ day to assess dermal risk and an inhalation NOAEL of 0.13 mg/ kg/ day the MOEs are : 25 Estimation of Dermal and Respiratory Exposures or Risksof Workers Planting Wheat and Canola Seed Treated with Lindane Dermal Exposure (mg/ kg/ day) Respiratory Exposure (mg/ kg/ day) MOE Dermal Respiratory Wheat 0.0013 0.00011 920 1200 Canola 0.0015 0.00013 800 1000 Examination of the data from the revised assessment, derived from a planting study (not included in PHED) and the previous assessment from PHED indicates that there are a large number of non detect samples in both of the data sets. Since the original PHED­ derived estimates, which separated loading from planting showed large numbers of non detects for the planting function, it is evident that the loading contributes the majority of the exposure and that the actual planting task contributes relatively little to the total exposure. 3.0 CALCULATION OF EXPOSURES In order to estimate the exposures of workers planting seed treated with lindane a number of assumptions regarding amount of seed planted and other parameters were required. 6) It is assumed that 250 acres of wheat or canola can be planted in a day (2). 7) An average worker has a body weight of 60 kg (a change from the previous assessment due to changes in the toxicological parameters) for dermal assessment. A weight of 70 kg is used for inhalation assessments. 8) Wheat is planted at a rate of 120 lbs of seed per acre. Canola is planted at a rate of 4 lbs seed per acre. 9) The application rate of lindane on wheat seed is 0.68 oz/ cwt (0.043 lb/ cwt). For canola the rate is 23.3 oz/ cwt (1.5 lb ai/ cwt). See Appendix B. 10) The dermal absorption of lindane is 10 percent (1). 3.1 Exposure Assessment for Wheat Amount of lindane handled per day: 26 Lbs ai/ day = 250 A/ day x 120 lb seed/ A x 0.043 lb ai/ 100 lbs seed = 12.9 lb ai/ day The resulting dermal exposure using arithmetic mean values from Appendix A is: Dermal Exposure (mg/ kg/ day) = 0.0597 mg/ lb ai x 12.9 lb ai/ day x 0.1 (abs) ÷ 60 kg bw = 0.0013 mg/ kg/ day The resulting dermal MOE using a NOAEL of 1.2 mg/ kg/ day is: MOE = 1.2 mg/ kg/ day/ 0.0013 mg/ kg/ day = 920 The respiratory exposure is: Respiratory Exposure (mg/ kg/ day) = 12.9 lb ai/ day x 0.0006 mg/ lb ai ÷ 70 kg = 0.00011 mg/ kg/ day The resulting respiratory MOE using a NOAEL of 0.13 mg/ kg/ day is: MOE = 0.13 mg/ kg/ day/ 0.00011 mg/ kg/ day = 1200 3.1 Exposure Assessment for Canola Amount of lindane handled per day: Lbs ai/ day = 250 A/ day x 4 lb seed/ A x 1.5 lb ai/ 100 lbs seed = 15 lb ai/ day The resulting dermal exposure using arithmetic mean values from Appendix A is: Dermal Exposure (mg/ kg/ day) = 0.0597 mg/ lb ai x 15 lb ai/ day x 0.1 (abs) ÷ 60 kg bw = 0.0015 mg/ kg/ day The resulting dermal MOE using a NOAEL of 1.2 mg/ kg/ day is: MOE = 1.2 mg/ kg/ day/ 0.0015 mg/ kg/ day = 800 The respiratory exposure is: Respiratory Exposure (mg/ kg/ day) = 15 lb ai/ day x 0.0006 mg/ lb ai ÷ 70 kg = 0.00013 mg/ kg/ day The resulting respiratory MOE using a NOAEL of 0.13 mg/ kg/ day is: 27 MOE = 0.13 mg/ kg/ day/ 0.00013 mg/ kg/ day = 1000 28

epa

2024-06-07T20:31:43.077097

regulations

EPA-HQ-OPP-2002-0202-0007

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: April 24, 2002 MEMORANDUM SUBJECT: REVISION OF EXPOSURE ASSESSMENT FOR PLANTING OF SEED TREATED WITH LINDANE FROM David Jaquith Reregistration Action Branch 4 Health Effect Division (7509C) TO: Becky Daiss Reregistration Branch 4 Health Effect Division (7509C) THRU Susan Hummel, Senior Scientist Reregistration Branch 4 Health Effects Division (7509C) Please find attached the occupational and residential exposure assessment for lindane DP BARCODE D282418 Pesticide Chemical Codes: 009001 EPA Reg Nos: EPA MRID Nos.: 42251901 PHED: No 1.0 INTRODUCTION In March 2001 HED provided an exposure/ risk assessment for seed treatment use of lindane (1). The document included on­ farm treatments (using wheat as the typical treatment), planting the treated seed, and commercial seed treatment facilities. The treatment of seeds using on farm technology has not changed. The assessment of exposure during planting was derived from PHED V1.1 using the assumption that exposure from planting treated seed would be similar to that received from application of granular formulations of pesticides. Since that time HED has received a study actually measuring exposure during planting. The seed planting exposure assessment has been reviewed by HED personnel. The results and review of this study are presented in Appendix A. 2.0 CONCLUSIONS HED has reevaluated the estimates of exposure and risk from planting of wheat and canola seed with lindane using a study specifically addressing this scenario rather than using PHED as a model for planting seeds. Using an oral NOAEL of 1.2 mg/ kg/ day to assess dermal risk and an inhalation NOAEL of 0.13 mg/ kg/ day the MOEs are : Estimation of Dermal and Respiratory Exposures or Risksof Workers Planting Wheat and Canola Seed Treated with Lindane Dermal Exposure (mg/ kg/ day) Respiratory Exposure (mg/ kg/ day) MOE Derma l Respiratory Wheat 0.0013 0.00011 920 1200 Canola 0.0015 0.00013 800 1000 Examination of the data from the revised assessment, derived from a planting study (not included in PHED) and the previous assessment from PHED indicates that there are a large number of non detect samples in both of the data sets. Since the original PHED­ derived estimates, which separated loading from planting showed large numbers of non detects for the planting function, it is evident that the loading contributes the majority of the exposure and that the actual planting task contributes relatively little to the total exposure. 3.0 CALCULATION OF EXPOSURES In order to estimate the exposures of workers planting seed treated with lindane a number of assumptions regarding amount of seed planted and other parameters were required. 1) It is assumed that 250 acres of wheat or canola can be planted in a day (2). 2) An average worker has a body weight of 60 kg (a change from the previous assessment due to changes in the toxicological parameters) for dermal assessment. A weight of 70 kg is used for inhalation assessments. 3) Wheat is planted at a rate of 120 lbs of seed per acre. Canola is planted at a rate of 4 lbs seed per acre. 4) The application rate of lindane on wheat seed is 0.68 oz/ cwt (0.043 lb/ cwt). For canola the rate is 23.3 oz/ cwt (1.5 lb ai/ cwt). See Appendix B. 5) The dermal absorption of lindane is 10 percent (1). 3.1 Exposure Assessment for Wheat Amount of lindane handled per day: Lbs ai/ day = 250 A/ day x 120 lb seed/ A x 0.043 lb ai/ 100 lbs seed = 12.9 lb ai/ day The resulting dermal exposure using arithmetic mean values from Appendix A is: Dermal Exposure (mg/ kg/ day) = 0.0597 mg/ lb ai x 12.9 lb ai/ day x 0.1 (abs) ÷ 60 kg bw = 0.0013 mg/ kg/ day The resulting dermal MOE using a NOAEL of 1.2 mg/ kg/ day is: MOE = 1.2 mg/ kg/ day/ 0.0013 mg/ kg/ day = 920 The respiratory exposure is: Respiratory Exposure (mg/ kg/ day) = 12.9 lb ai/ day x 0.0006 mg/ lb ai ÷ 70 kg = 0.00011 mg/ kg/ day The resulting respiratory MOE using a NOAEL of 0.13 mg/ kg/ day is: MOE = 0.13 mg/ kg/ day/ 0.00011 mg/ kg/ day = 1200 3.1 Exposure Assessment for Canola Amount of lindane handled per day: Lbs ai/ day = 250 A/ day x 4 lb seed/ A x 1.5 lb ai/ 100 lbs seed = 15 lb ai/ day The resulting dermal exposure using arithmetic mean values from Appendix A is: Dermal Exposure (mg/ kg/ day) = 0.0597 mg/ lb ai x 15 lb ai/ day x 0.1 (abs) ÷ 60 kg bw = 0.0015 mg/ kg/ day The resulting dermal MOE using a NOAEL of 1.2 mg/ kg/ day is: MOE = 1.2 mg/ kg/ day/ 0.0015 mg/ kg/ day = 800 The respiratory exposure is: Respiratory Exposure (mg/ kg/ day) = 15 lb ai/ day x 0.0006 mg/ lb ai ÷ 70 kg = 0.00013 mg/ kg/ day The resulting respiratory MOE using a NOAEL of 0.13 mg/ kg/ day is: MOE = 0.13 mg/ kg/ day/ 0.00013 mg/ kg/ day = 1000 REFERENCES 1) Memorandum from D. Jaquith (RRB4) to S. Shallal (RRB4) titled "OCCUPATIONAL AND RESIDENTIAL EXPOSURE ASSESSMENT AND RECOMMENDATIONS FOR THE RE REGISTRATION ELIGIBILITY DECISION DOCUMENT FOR LINDANE", dated March 16, 2001. 2) Memorandum from S. Tadayon (CEB) to A. Khasawinah (RRB4) titled "OCCUPATIONAL AND RESIDENTIAL EXPOSURE ASSESSMENT AND RECOMMENDATIONS FOR THE RE REGISTRATION ELIGIBILITY DECISION DOCUMENT FOR IMAZALIL" dated April 15, 2,000. cc: Lindane file (009001) R. Kent (RRB4/ 7509C) Correspondence file D. Jaquith (7509C) APPENDIX A. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES March 03, 2002 Memorandum SUBJECT: Exposures of Workers to Isofenphos During Planting of Oftanol­ Treated Canola FROM: Seyed Tadayon, Chemist Chemistry Exposure Branch Health Effect Division (7509C) TO: Jeff Evans, Biologist Chemistry Exposure Branch Health Effect Division (7509C) DP Barcode: D281351 EPA MRID No: 42251901 Attached is a review of the applicator exposure during planting of treated seed with Oftanol® which was submitted by Mobay Inc. This review was completed by Versar, Inc. on February 15, 2002, under supervision of HED. It has undergone secondary review in the HED and has been revised to reflect Agency policies. Executive Summary Oftanol® Technical is an insecticide incorporated into a seed­ coating material that forms a hard, dry, shell­ like layer on the outside of the canola seed. The purpose of this study was to quantify inhalation and dermal exposure to workers planting treated seed using the active ingredients isofenphos. The study met most of the criteria specified in Subdivision K (currently referred to as Series 875 .1100 and 875.1300 Group B). Summary This study was conducted in Domain, Manitoba. Oftanol® Technical was applied to canola seeds prior to this study at a rate of 12 g ai (isofenphos) per kg of seed. Four workers were monitored four times, for a total of 16 replicates, as they opened and poured both the contents of the treated seed bags (25 kg) and fertilizer into their plant hoppers. The workers then drove a tractor, pulling the planter around the field planting between six and eight pounds of seed per acre. The workers used closed cab tractors with a ground speed ranging between 5 to 7 mph. Both seed and fertilizer traveled down a tube to the ground, where they were immediately covered with soil by a disc. Each replicate lasted an average of 3.22 hours and each worker handled an average of 4.33 lbs active ingredient per replicate All workers wore long­ sleeved shirts, coveralls, and chemical resistant gloves, in addition to their normal clothing. Air temperatures ranged from 69 o F to 82 o F and relative humidity ranged from 30 to 73%. Exposure to the treated seed was quantified by the following methods: a) Dermal exposure was estimated by 10 dermal patches. Dosimeters were attached to the worker's coverall at 10 locations: With this arrangement, the coveralls represented a single layer of normal clothing and the inner dosimeters collected the isofenphos that could reach the workers'skin if they were wearing only a single layer of clothing. b) Exposure to the workers' hands was determined by the hand­ rinse method. c) Inhalation exposure was monitored by attaching a quartz microfiber (QMA) filters in polystyrene cassettes to the workers' lapels. d) Cholinesterase activity was monitored by collecting blood samples. Exposure values for both potential (based on exterior patches) and actual (based on interior patches) dermal exposures was calculated. The Registrant corrected all data for field fortification recoveries, including recoveries above 90%. For those values below the LOD, the Registrant used ½ the recovery corrected LOD value. Versar only corrected data for field fortification recoveries less <90% and reported non­ detect values as ½ LOD. Total potential dermal exposures ranged from 0.0095 to 1.2369 mg/ lb ai handled. The primary body region contributors were the lower arm (0.1110 mg/ lb ai handled) and the lower leg (0.0712 mg/ lb ai handled). The overall average total potential dermal exposure was 0.3326 ± 0.3555 mg/ lb ai handled. The actual dermal exposure estimates ranged from 0.0028 to 0.1053 mg/ lb ai handled with an overall average actual dermal exposure of 0.0296 ± 0.0314 mg/ lb ai handled. Total dermal exposure estimates included both actual dermal exposures and hand exposures and averaged 0.0597 ± 0.1001 mg/ lb ai handled. Total exposure was calculated by taking the sum of all exposure routes (dermal­ hands, dermal­ body, and inhalation). The Registrant calculated a geometric mean total exposure of 0.15 mg/ lb ai applied. Versar's calculated total exposure is presented in Table 8 and averaged 0.060 ± 0.101 mg/ lb ai handled. Conclusions Dermal and inhalation exposures were assessed during the planting of treated canola seed. The workers performed both loading of the treated seed into seed hoppers and planting of the seed. Table 1 provides a summary of the total exposure to isofenphos during loading and planting of treated seed, as calculated by Versar. Versar's calculated average total exposure was 0.060 ± 0.101 mg/ lb­ ai handled. The geometric mean total exposure, as calculated by the Registrant, to isofenphos during planting of treated canola seed was 0.15 mg/ lb ai applied. The study author also reported total exposure in mg/ replicate and assumed that a worker is able to complete three replicates per day. The study author estimated an average daily exposure of 1.9 mg, but noted that a worker would probably not routinely work what is equivalent to three replicates per day during the planting season so that actual daily exposure would likely be less than 1.9 mg/ day. Table 1: Summary of Total Exposure to Oftanol During Loading and Planting Treated Canola. Replicate Exposure (mg/ lb ai handled) Dermal­ body Dermal­ hands Dermal­ Total Inhalation Inhalation + Dermal Total 1 0. 0731 0.0104 0.0835 0.0011 0.085 2 0. 1053 0.0069 0.1122 0.0018 0.114 3 0. 0033 0.0034 0.0067 0.0002 0.007 4 0. 0053 0.0046 0.01 0.0002 0.01 5 0. 0249 0.0046 0.0295 0.029 6 0. 016 0.0056 0.0216 0.0002 0.022 8 0. 0028 0.0028 0 0. 003 9 0. 0411 0.3333 0.3745 0.0024 0.377 11 0.0108 0.0068 0.0176 0.0004 0.018 13 0.058 0.0043 0.0623 0 0. 062 14 0.0124 0.0051 0.0174 0 0. 017 15 0.0199 0.0032 0.0231 0.0002 0.023 16 0.0117 0.0037 0.0153 0.0002 0.016 Average 0. 0296 0.0327 0.0597 0.0006 0.06 Standard Deviation 0.101 9 Attachment Versar Review Memo dated Febuary 15, 2002 10 Reviewer: Kelly McAloon/ Marit Espevik Date February 15, 2002 STUDY TYPE: Applicator Passive Dosimetry Study Using Patch Dosimetry, Hand Washes, Inhalation Monitoring, and Cholinesterase Monitoring. TEST MATERIAL: OFTANOL® Technical insecticide, a viscous liquid material formulation containing 90% isofenphos as the active ingredient. SYNONYMS: 1­ Methylethyl­ 2­[[ ethoxy[( 1­ methylethyl) amino] phosphinothioyl] oxy] benzoate (CAS # 25311­ 71­ 1); Isofenphos (ISO­ E, BSI); Isophenphos (ISO­ F) CITATION: Author: V. C. Dean Title: Exposures of Workers to Isofenphos During Planting of Oftanol­ Treated Canola Seeds Report Date: January 20, 1990 Performing Organization: Mobay Corporation Corporate Occupational and Product Safety Agricultural Chemicals Division P. O. Box 4913, Hawthorn Rd. Kansas City, MO 64120 Identifying Codes: MRID 422519­ 01; Report Number 99799; SPONSOR: Mobay Corporation Agricultural Chemicals Division Research & Development Department EXECUTIVE SUMMARY: The purpose of this study was to quantify inhalation and dermal exposure of workers handling canola seed treated with OFTANOL® Technical, containing 90% isofenphos as the active ingredient. The seeds had been treated with OFTANOL® Technical prior to this study and 25 kg bags of treated seed were provided for this exposure study. The study was conducted in Domain, Manitoba from May 16­ 23, 1989. Four workers were monitored four times, for a total of 16 replicates, as they loaded the treated seed into seed hoppers and drove tractors, planting between six and eight pounds of seed per acre. Each replicate lasted an average of 3.22 hours and each worker handled an average of 4.33 lbs active ingredient per replicate. Dermal exposure was estimated by handwashes and by dermal patches attached to the inner and outer clothing of each worker. Total dermal exposure was calculated by adding the dermal exposure to the hand exposure values. Inhalation exposure was measured using a conventional industrial hygiene methodology. The Registrant provided exposure values expressed in mg/ hr, mg/ replicate, and mg/ lb ai applied. Total dermal exposure to isofenphos, determined by the Registrant, ranged from 0.076 mg/ lb ai applied to 0.42 mg/ lb ai applied. The geometric mean total dermal exposure was estimated as 0.15 mg/ lb ai applied. The geometric mean inhalation exposure to isofenphos was estimated as 0.0003 mg/ lb ai applied. Total exposure to isofenphos ranged from 0.076 mg/ lb ai applied to 0.43 mg/ lb ai applied and the geometric mean was 0.15 mg/ lb ai applied. The study author also reported an average daily total exposure of 1.9 mg/ day, assuming that a worker is able to complete three replicates per day. Versar calculated exposure estimates in mg/ lb ai handled, as per EPA's request. Raw residue data were corrected using the field fortification recoveries. Versar only corrected for field recoveries less than 90%. Versar calculated a mean potential 11 inhalation exposure of 0.0006 ± 0.0008 mg/ lb ai handled. The overall average dermal exposure and the average hand exposure, as calculated by Versar, were 0.0296 ± 0.0314 and 0.0327 ± 0.0947 mg/ lb ai handled, respectively. Total dermal exposure was calculated as the sum of the overall dermal exposure and hand exposure and averaged 0.0597 ± 0.1001 mg/ lb ai handled. Versar also calculated total exposure as the sum of all exposure routes. The average total exposure was estimated 0.060 ± 0.101 mg/ lb ai handled. The Study Report also included cholinesterase monitoring results. These results show that the isofenphos exposures to the workers were well within the acceptable limits. The greatest deviations observed were 7.7% in the plasma and 3.7 % in the erythrocytes. The study author attributed these deviations to natural variations. The study met most of the Series 875.1100 and 875.1300 Guidelines. The major issues of concern were: (1) this study was performed at only one test site, (2) raw field data were corrected for all recoveries, even those greater than 90%, (3) concurrent laboratory fortification recoveries were not provided in the Study Report, (4) the limit of quantification was not provided for any media, only the limit of detection, (5) the analysis dates were not provided for any of the samples in this study in order to verify storage stability results, (6) individual field blank results were not provided in the Study Report, (7) there was only one field fortification level for air filter samples, (8) the Registrant used ½ the recovery corrected sample quantification limits for non­ detect values, rather than ½ the method limit of detection for that media, (9) method validation recoveries were not provided for handwash samples, (10) information on the individuals who participated in this study was not provided, (11) the inhalation methodology was calibrated with an airflow of 1L/ min instead of 2L/ min, (12) the Registrant used the inhalation geometric mean for replicate 5 since no sample was collected, (13) the Registrant used values slightly different from the NAFTA recommended body region surface areas, and (14) the Registrant calculated face exposures from head exposures. COMPLIANCE: A signed and dated Data Confidentiality statement was provided. The study sponsor waived claims of confidentiality within the scope of FIFRA Section 10( d) (1) (A), (B), or (C). The study sponsor stated that the EPA Good Laboratory Practice Standards (40 CFR part 160) did not apply to the study. GUIDELINE OR PROTOCOL FOLLOWED: A study protocol was provided with the Study Report. OPPTS Series 875, Occupational and Residential Exposure Test Guidelines, Group A: 875.1100 (dermal exposure), and 875.1300 (inhalation exposure) were followed for the compliance review of this study. I. MATERIALS AND METHODS A. MATERIALS 1. Test Material: Formulation: OFTANOL® Technical insecticide contains 90% (by weight) of isofenphos as the active ingredient (ai). This product is a viscous liquid material that is used as a seed treatment. Lot/ Batch # technical: 8­ 00­ 5270A Lot/ Batch # formulation: Not provided. Purity in technical: The OFTANOL® Technical was assayed during production at 91.8% isofenphos. CAS #( s): 25311­ 71­ 1 Other Relevant Information: EPA Registration number is 3125­ 326. 2. Relevance of Test Material to Proposed Formulation( s): The product label was not provided for the test material used in this study. Versar was able to locate a product label with the same product name as the one used in this study. . 3. Packaging: 12 The packaging of the test product was not reported in the study. All seed coating was performed prior to this study and 25 kg bags of treated seed were provided for this study. B. STUDY DESIGN There were 3 deviations to the protocol: (1) in addition to the analyses of plasma and erythrocyte levels, whole blood levels were also evaluated. Mobay Corporation's cholinesterase analysis procedure includes whole blood and it was, therefore, routinely included in the analysis, (2) one blood sample was collected the morning after a worker completed his monitored work cycle rather than immediately afterwards, and (3) for replicate sampling, three of the sixteen replicates monitored were not included in the data evaluation. No adverse effects due to these deviations were reported in the Study Report. 1. Number and type of workers and sites: Four individuals participated in the study at one test site, each serving as a subject four times, for a total of sixteen replicates. Each test subject was a private grower. The number of years of experience per worker was not provided. Each participant signed an informed consent form prior to the initiation of the study after being provided the proper information regarding the study, products being used, and proper precautions. The seed treatment was performed on canola seed prior to this study in Nisku, Alberta, Canada, from January 17­ 19, 1989. This study took place in Domain, Manitoba where the treated canola seeds were planted from May 16­ 23, 1989. 2. Meteorology: Air temperatures, relative humidity, and wind speed and direction were reported for the four sampling days. Air temperatures ranged from 69 o F to 82 o F and relative humidity ranged from 30 to 73%. Wind speed was reported as gusty for the first two sampling days, with wind speeds ranging from 10­ 30 mph. Wind speed on the remaining two sampling days ranged from 0­ 10 mph. Wind direction was reported as variable. 3. Replicates: Each of the four workers were monitored for four replicates as they opened and poured both the contents of the seed bags and fertilizer into their plant hoppers. The workers then drove a tractor, pulling the planter around the field planting between six and eight pounds of seed per acre. Table 1 presents a summary of the hours worked and the lb ai handled for all of the replicates. Table 1. Summary of Replicates 13 Date Replicates * Worker ID Hours Worked lb ai handled 37391 1 A 2.73 1.92 37391 2 A 2.25 2.88 37391 3 B 4.33 5.95 37391 4 B 3.08 4.32 37391 5 C 3.03 4.32 37391 6 C 3.08 3.6 37392 8 D 1.83 4.32 37392 9 A 4.75 5.76 37392 11 B 3. 62 2. 94 37393 13 D 2. 87 4. 62 37393 14 D 2. 58 3. 96 37398 15 C 4. 62 6. 24 37398 16 C 3. 13 5. 46 * Replicates 7, 10, and 12 not used. 4. Protective clothing: All workers wore long­ sleeved 65% polyester/ 35% cotton work shirts, 65% polyester/ 35% cotton coveralls, and chemical resistant (nitrile, Best No. 730) gloves, in addition to their normal clothing (denim trousers, cotton shirts, boots or tennis shoes, and baseball caps). The long­ sleeved shirts, coveralls and caps were supplied by Mobay Corporation and served as attachment sites for dermal dosimeters. The gloves, also supplied by Mobay Corporation, were used only as protective equipment. 5. Planting method: Worker A: Worker A used an International 310 Diskall pulled by a closed cab tractor at a ground speed of 7 mph. The worker opened the bags of treated seed and poured them into the seeder hopper. Fertilizer was also loaded into a hopper. Both seed and fertilizer dropped to the ground and were immediately covered with soil by a disc. This equipment arrangement provided for a 45 ft swath. Worker B: Worker B used a Coop­ Implements ­ G­ 100 Disker pulled by a John Deer 8630 close cab tractor at a ground speed of 5 mph. The worker cut the bags open with a pocket knife, stood on the back of the seeder and poured the 25 kg bag of treated seed into the trough of the seeder. Fertilizer was also poured into the seeder. Both seed and fertilizer traveled down a tube to the ground, where they were immediately covered with soil by a disc. This equipment arrangement provided for a 30 ft swath. Worker C: Worker C used an Air System 1502 Concord seeder, pulled by a Steiger/ Cougar 1000 closed cab tractor at a ground speed of 6 mph. The Concord Air tank is attached to an EZZE­ On Cultivator. The worker loaded the bags of treated seed into the back of a fertilizer truck. The truck was driven to the field and poured into the hopper of the seeder. Fertilizer was conveyed from the truck by an auger to a hopper on the seeder. Both seed and fertilizer were conveyed by air up to the planter, where they were deposited into the soil. This equipment arrangement provided for a 36 ft swath. Worker D: Worker D used a Chinook 1203, pulled by a Steiger CP 1360 closed cab tractor at a ground speed of 6 mph. The Chinook 1203 has two hoppers, one for seed and one for fertilizer. The worker opened the 25 kg bags of treated seed and poured them into the seed hopper of the Chinook 1203. Seed and fertilizer traveled from the hoppers through tubing to the ground and were deposited into the soil. This equipment arrangement provided for a 40 ft. swath. 6. Application Rate: 14 OFTANOL® Technical is an insecticide incorporated into a seed­ coating material that forms a hard, dry, shell­ like layer on the outside of the canola seed. According to the study author, the coated seeds are virtually dust­ free, when applied in this manner. The insecticide protects newly sprouted canola plants against the flee beetle. OFTANOL® Technical was applied to canola seeds prior to this study at a rate of 12 g ai (isofenphos) per kg of seed. All of the seed coating was done in Nisku, Alberta, Canada, from January 17­ 19, 1989. A product label was not provided in the Study Report. Versar was able to obtain a product label, but the label did not provide a recommended application rate. Since OFTANOL® Technical is not registered in Canada, this study was conducted under Research Permit Sub. No. 89­ 007. 7. Exposure monitoring methodology: Dermal dosimeters: Dermal exposure was estimated by 10 dermal patches. Dosimeter units consisted of a 3­ inch by 3­ inch 12­ ply gauge surgical sponge enclosed in an aluminized paperboard holder. Dosimeters were attached to the worker's coverall at 10 locations: both upper arms, both palmar forearms three inches above the wrists, right chest just above the pocket, left back at the shoulder blade, the front of both thighs, and both shins. Each paperboard holder had a circular opening, 5.6 cm in diameter, which faced away from the body to allow isofenphos to collect on the gauze sponge. One dosimeter was also attached to the worker's cap just above the bill and a second set of dosimeters was attached to the worker's clothing inside the coveralls at the following locations: both upper arms, both palmar forearms, left chest, right back, both thighs, and both shins. With this arrangement, the coveralls represented a single layer of normal clothing and the inner dosimeters collected the isofenphos that could reach the workers' skin if they were wearing only a single layer of clothing. Dosimeters were worn until the completion of the monitoring period, including maintenance, checking seed and fertilizer levels, and changing sites. At the end of the monitoring interval, the dosimeters were removed from the clothing and placed on a table. When all the dosimeters were removed, the gauze sponges were removed from their paperboard holders with tweezers and placed in labeled 1­ ounce glass bottles which were capped with polyseal­ lined screw caps and stored on dry ice. Hand: Exposure to the workers' hands was determined by the hand­ rinse method. At the end of the monitoring period, and at intermediate times when hands would normally be washed, the worker's hands were rinsed using the following procedure: 200 mL portion of absolute ethanol was placed into a 42­ oz Whirl­ Pak bag. The worker placed one hand into the bag and the bag was held tightly around the wrist. The hand and bag were shaken 50 times. The ethanol was stored in the plastic bag and used for subsequent washes during the monitoring period until the final wash. After the final wash, it was transferred into a 800 mL bottle for storage. Each hand was washed twice, for a total of four washed per replicate. After each of the four washes, the solution was transferred into a 800 mL bottle and vigorously shaken 50 times. An aliquot of the combined solution (left and right hand) was then transferred into a one­ ounce labeled sample bottle and placed on dry ice. The remaining solution was discarded. On seven occasions, the outsides of the workers' gloves were washed by the same method to provide a comparison of the amounts of isofenphos residues on hands and gloves. Inhalation: Inhalation exposure was monitored using a conventional industrial hygiene methodology. Quartz microfiber (QMA) filters in polystyrene cassettes were attached to the workers' lapels. Air was drawn through the filters at approximately 1 L/ min by a portable, battery­ powered pump (Gilian HFS 113A) attached to the workers' belt and connected to the filter cassette with PVC tubing. The filters removed particulates and aerosols containing isofenphos from the air during exposure sampling. When sampling was complete, the cassette was removed, capped, placed in a Whirl­ Pak and stored on dry ice. Cholinesterase: Blood samples were collected by venipuncture for determination of cholinesterase activity in the erythrocyte and plasma fractions. The puncture site was washed thoroughly with alcohol before sampling to sterilize and remove any isofenphos contamination that could affect the cholinesterase results. The following schedule was used: 1) Three pre­ exposure samples were collected to establish the baseline value for each participant. They were collected during the week before planting began. Participants and Chemargro Ltd. technical personnel gave assurances that participants had not 15 worked with cholinesterase­ inhibiting materials for a two­ week period prior to the baseline sampling; and 2) one sample was collected at the end of each workday, when all work with isofenphos was completed. All samples were collected by a locally licensed nurse. They were shipped by overnight express to the Mobay Corporation Toxicology Laboratory in Stilwell, Kansas. The samples were analyzed the following morning, using an automated modified Ellman method. Results were communicated by telephone to the study site at mid­ day on the day following sample collection. All samples collected during mornings were stored in ice chests on dry ice for approximately four hours until field collection activities for the afternoon replicates were complete. All samples were then repacked on dry ice for shipping to the Mobay Corporation Analytical Laboratory in Kansas City, Missouri. At the analytical laboratory, the samples were stored in freezers at ­7 degrees Celsius. 8. Analytical Methodology: Extraction method( s): Dermal Exposure Patches ­ 15 mL of ethanol was pipetted into sample vials and the vials were recapped. The sample vials were placed in a vertical position on a rotator and spun for 30 minutes to ensure complete absorption. Five mL of the sample solution was pipetted into a clean 15­ mL vial and 0.5 mL of a 0.5% carbowax solution was added. The solvent was evaporated from the sample solution using a stream of dry nitrogen and a heating block at 43 o C. The sample residue was reconstituted by pipetting 5 mL of t­ butyl methyl ether (MTBE) into the sample vial. The vial was capped with a polyseal and shaken for 30 seconds. Handrinse Samples ­ The samples were shaken vigorously and then a portion was filtered using a LID/ X filter. A portion of the filtered solution was immediately transferred into an autosampler vial and the vial was capped. Air Filters­ Filters were transferred to 0.5­ ounce vials and 2.0 mL of MTBE was added. The vial was sealed with a polyseal lid and gently swirled to wet the filter thoroughly. The sample vial was placed on a rotator, the rotator wheel was put in a vertical position, and the vial was spun for 30 minutes to ensure complete desorption. Detection method( s): See Table 2. 16 Table 2. Summary of GC Chromatographic and HPLC Conditions Media Air Filters Dermal pads Hand Rinses Instrument Varian Model 3400 Varian Model 3400 Shimadzu CR­ 3A /Varian 4270 Column J& W, 0.541mm i. d. x 15m length DB­ Wax fused­ silica capillary column with a 1.0 : m film thickness J& W, 0.541mm i. d. x 15m length DB­ Wax fused­ silica capillary column with a 1.0 : m film thickness DuPont Zorbax C­ 8 column, 4.6mm i. d. x 25 cm length with a 0.45 : m pore size Detector Nitrogen/ phosphorous detector Nitrogen/ phosphorous detector Temperatures Column: Initial: 100 o C Final: 185 o Injector: 250 o C Detector: 300 o C Column: Initital: 100 o C Final: 185 o Injector: 250 o C Detector: 300 o C Column: Ambient Injection Volume 9 µL 9 µL 100 µL Retention Time Isofenphos: 12.3 min Isofenphos oxygen analog: 13.5 min Isofenphos: 11.6 min Isofenphos oxygen analog: 12.7 min Isofenphos: 10.5 min Isofenphos oxygen analog: 3.8 min Quantitative Range 0.0025­ 0.05 ng/ : L 0. 0025­ 0.05 ng/ : L 0. 2­ 10 ng/ : L Method validation: The limit of detection (LOD) for air filters, gauze pads, and handwash samples was approximately 5ng/ sample, 38 ng/ sample, and 40 : g/ sample, respectively. For method validation, five air filter samples were fortified at the 0.2 : g level for both isofenphos and its oxygen analog. Fourteen dermal gauze samples were fortified at loadings of 1.0, 10, 100, and 1000 : g of isofenphos under field conditions. Handwash samples were fortified at loadings of 100 and 1000 : g using field samples. Method validation recoveries for the air filter samples averaged 109.0% ± 3.6% for isofenphos and 94.4% ± 7.3% for its oxygen analog. Recoveries for the dermal gauze pads averaged 96.9%± 6% and 94.2%± 3%, for the 1.0 and 1000 : g loadings respectively. Method validation recoveries for handwash samples were not reported in the Study Report. Instrument performance and calibration: According to the Study Report, analytical calibration standard curve data were generated before and after each set of samples analyzed. Standard concentrations were chosen to bracket the sample concentrations. Only concentrations within the validated range for each media were used. Quantification: Sample concentrations were calculated using the linear regression function of a chromatography software. Concentrations of isofenphos in the samples were determined directly from the standard curve. 9. Quality Control: Lab Recovery: Laboratory recoveries were not reported in the Study Report. Field blanks: Field blanks were collected for each media. All values were reported to be less than the LOD, except for 2 gauze pad samples (0.170 and 11.7 : g). Field recovery: Handwash Samples: Duplicate handwash samples were fortified at 200 and 2000 : g levels each sampling 17 day at the site by spiking a 200 mL ethanol portion with isofenphos formulation solutions. The spiked solutions were transferred into separate polyethylene bags and shaken 50 times. A portion of each sample was transferred from the plastic bags into 1­ oz bottles and the bottles were capped with polyseal lids to simulate the procedure for collecting field samples. Air Filters: Seven replicate filter samples were prepared each day by spiking 37­ mm, acetonitrile washed Whatman QM­ A filters with isofenphos formulation solution at a loading of approximately 0.2 : g of isofenphos. The spiked filters were then placed in separate filter cassettes. Each filter was supported by a stainless steel screen. Each cassette was then sealed tight with a cellulose shrink band and the two open ends were capped. To simulate the collection of field samples, the caps of each cassette were removed immediately before sampling and each filter unit was connected to a sampling pump which had been calibrated to a sampling rate of 1.0 L per minute. In addition, two blank filters were prepared at the same time to determine potential interference or contamination problems. Dermal samples: Seven replicate samples were generated at loading levels of approximately 1.0, 10, 100, and 1000 : g of isofenphos to simulate anticipated exposure levels for the outer gauze and 1.0, and 10 : g to simulate inner gauze pads. To spike the outer gauze pads, 0.5 mL of spiking solutions containing approx 2.0, 20, 200, and 2000 : g/ mL of isofenphos was pipetted onto separate gauze pads. Once the gauze pads were spiked, the solvent was allowed to evaporate. The spiked pads were placed in direct sunlight and exposed to the environment for approximately the same duration as the field samples. The inner pads were spiked in the same manner, but were placed under coverall material and were not exposed to sunlight. Field fortification recoveries for isofenphos are presented in Table 3. 18 Table 3. Field Fortification Recoveries for Isofenphos Sample Type Fortification Level ( : g) Sampling Day Average Fortification Recovery per Day (%) Average Isofenphos Recovery per Level (%) Overall Average (%) Standard Deviation Handwash samples 200 1234 111.3 109.1 97.5 98.3 104.1 102.4 6. 6 2000 1234 108.1 103.4 98.2 92.8 100.6 Filters 0.2 1234 100.1 69.9 86.0 93.9 88.1 88.1 12.2 Outer Gauze Pads 1 1234 107.3 73.3 100.8 88.9 92.6 90.1 12.1 10 1234 98.2 73.0 84.2 97.0 88.2 100 1234 87.0 86.1 78.4 110.4 90.9 1000 1234 82.7 89.8 85.4 96.2 88.6 Inner Gauze Pads 1 1234 112.7 78.2 84.8 116.3 98.5 96.3 17.1 10 1234 92.9 75.8 92.8 114.6 94.1 Formulation: The test products used were not characterized for this study. Storage Stability: The Study Report indicated that storage stability experiments were performed prior to the commencement of this study. Air filters: Approximately 0.2 : g isofenphos and its oxygen analog were field spiked onto QM­ A filters. Air 19 was pulled through the spiked filters at 1.0 L/ min ± 5% for 3.5 hours. The samples were then shipped to the Environmental Analysis Laboratory in Kansas City and stored in the freezer at ­7 o C for up to 72 days. Average recoveries ranged from 91.9% ± 12 to 110% ± 24. Gauze pads: A field study was conducted at Vero Beach, Florida, using isofenphos canola seed formulation to fortify gauze pads. Seven pads were fortified at 0.990 : g isofenphos and exposed to outdoor environmental conditions for 4.5 hours. The samples were shipped to the Environmental Analysis Laboratory in Kansas City and stored in the freezer for 40 days prior to analysis. The average total recovery from the gauze pad samples was 104% ± 2%. Three indoor sampling field studies were also conducted at a seed coating facility in Nisku, Alberta, Canada. Gauze pads were fortified with isofenphos canola seed formulation and exposed to the indoor environment of the seed coating facility for 8 hours. The samples were shipped to the Environmental Analysis Laboratory in Kansas City and stored for up to 159 days. Average recoveries ranged from 94.0% ± 1.7% to 118% ± 4%. Hand Rinses: The study author reported an average storage recovery of 110% ± 5% for storing samples of isofenphos in absolute ethanol at a 100­ : g loading for 117 days at ­7 o C. The study author also reported average recoveries for storing samples spiked with 203 or 2031 : g isofenphos at ­7 o C for 158 days of 112% ± 1% and 110% ± 3%, respectively. 10. Relevancy of Study to Proposed Use: The study monitored workers performing their normal duties during planting of treated canola seed. II. RESULTS AND CALCULATIONS: A. EXPOSURE CALCULATIONS: The study author provided exposure values expressed as mg/ replicate, mg/ hour, and mg/ lb ai applied for both dermal and inhalation exposure. The total amount of isofenphos recovered from the air filters was divided by the total volume of air sample, multiplied by the respiration rate and hours worked per replicate to provide the amount of isofenphos in mg/ replicate. The dermal gauze pad values were multiplied by the location area in cm 2 to provide the exposure in mg isofenphos per location. These values were summed to provide dermal gauze exposure values in mg/ replicate. Handwash samples were calculated using the same calculations as dermal exposures, assuming an area of 410 cm 2 . Versar estimated exposure values as mg/ lb ai handled as per EPA's request. Versar calculated both potential (based on exterior patches) and actual (based on interior patches) dermal exposures. The Registrant corrected all data for field fortification recoveries, including recoveries above 90%. For those values below the LOD, the Registrant used ½ the recovery corrected LOD value. Versar only corrected data for field fortification recoveries less <90% and reported non­ detect values as ½ LOD. Inhalation Exposure Inhalation exposures were calculated by both the Registrant and Versar from the breathing­ zone air concentrations determined from the amount of isofenphos found on the air­ sampling filters and the volume of air sample. A moderate workrate respiratory rate of 0.029 m 3 /min was assumed by the Registrant for the duration of the sampling period. Versar used the NAFTA recommended inhalation rate of 0.029 m 3 /min for moderate activities. According to the Registrant's calculations, the geometric mean of the inhalation exposure was 0.0003 mg/ lb ai with a geometric standard deviation of 3.7. Since no sample was collected for replicate 5, the Registrant used the geometric mean of all inhalation exposures as the value for replicate 5 in their calculations. Table 4 provides the Versar­ calculated potential inhalation exposures. The average exposure was 0.0006 ± 0.0008 mg/ lb ai handled. Potential Dermal Exposure Potential dermal exposure estimates were calculated by extrapolating values from exterior patches to the total surface area of the appropriate region. The Registrant did not report potential dermal exposures, although exterior dermal patches were analyzed and raw data were reported in the Study Report. Versar calculated potential dermal estimates for each region of the 20 body using the exterior patches (see Table 5). The total surface area of the exposed surfaces of the dermal patches was 24.63 cm 2 . Versar used the default NAFTA surface areas to calculate the potential dermal exposure for each body region. Total potential dermal exposures ranged from 0.0095 to 1.2369 mg/ lb ai handled. The primary body region contributors were the lower arm (0.1110 mg/ lb ai handled) and the lower leg (0.0712 mg/ lb ai handled). The overall average total potential dermal exposure was 0.3326 ± 0.3555 mg/ lb ai handled. Actual Dermal Exposure Actual dermal exposure estimates were calculated by extrapolating patch values from interior patches to the total surface area of the appropriate region. The Registrant extrapolated these values using recommended surface area estimates found in the EPA Pesticide Registration Guidelines, Subdivision U, Applicator Exposure. The surface area of the exposed surfaces of the dermal patches was 24.63 cm 2 . For actual dermal exposure to the head, the Registrant used the interior head patch value multiplied by a penetration factor of 0.13. This factor was calculated from the gauze dosimeter data by dividing the amount on an inner dosimeter by the amount on the adjacent outer dosimeter, in every case where both dosimeters had measurable amounts. The Registrant reported total dermal exposure as the sum of the values for covered skin, head and neck, and hands. The Registrant calculated hand exposures assuming an exposed area of 410 cm 2 and followed the same calculations as those used for dermal exposure. According to the Registrant's calculations, hand exposures ranged from 0.059 to 0.42 mg/ lb ai applied, with an average hand exposure of 0.11 mg/ lb ai applied. Versar's calculated hand exposures are reported in Table 6. These exposures ranged from 0.003 to 0.333 mg/ lb ai handled. The overall average hand exposure was 0.033 ± 0.095 mg/ lb ai handled. The Registrant calculated a geometric mean total dermal exposure of 0.15 mg/ lb ai applied. Versar calculated actual dermal estimates for each region of the body using the interior patches (except for the head) (see Table 7). Versar used the default NAFTA surface areas to calculate the actual dermal exposure for each body region. The actual dermal exposure estimates ranged from 0.0028 to 0.1053 mg/ lb ai handled with an overall average actual dermal exposure of 0.0296 ± 0.0314 mg/ lb ai handled. Total dermal exposure estimates included both actual dermal exposures and hand exposures and averaged 0.0597 ± 0.1001 mg/ lb ai handled. Total Exposure Total exposure was calculated by taking the sum of all exposure routes (dermal­ hands, dermal­ body, and inhalation). The Registrant calculated a geometric mean total exposure of 0.15 mg/ lb ai applied. Versar's calculated total exposure is presented in Table 8 and averaged 0.060 ± 0.101 mg/ lb ai handled. 21 III DISCUSSION A. LIMITATIONS OF THE STUDY: The study met most of the Series 875.1100 and 875.1300 Guidelines. The major issues of concern were: (1) this study was performed at only one test site, (2) raw field data were corrected for all recoveries, even those greater than 90%, (3) concurrent laboratory fortification recoveries were not provided in the Study Report, (4) the limit of quantification was not provided for any media, only the limit of detection, (5) the analysis dates were not provided for any of the samples in this study in order to verify storage stability results, (6) individual field blank results were not provided in the Study Report, (7) there was only one field fortification level for air filter samples, (8) the Registrant used ½ the recovery corrected sample quantification limits for non­ detect values, rather than ½ the method limit of detection for that media, (9) method validation recoveries were not provided for handwash samples, (10) information on the individuals who participated in this study was not provided, (11) the inhalation methodology was calibrated with an airflow of 1L/ min instead of 2L/ min, (12) the Registrant used the inhalation geometric mean for replicate 5 since no sample was collected, (13) the Registrant used values slightly different from the NAFTA recommended body region surface areas, and (14) the Registrant calculated face exposures from head exposures. B. CONCLUSIONS: Dermal and inhalation exposures were assessed during the planting of treated canola seed. The workers performed both loading of the treated seed into seed hoppers and planting of the seed. Table 8 provides a summary of the total exposure to isofenphos during loading and planting of treated seed, as calculated by Versar. Versar's calculated average total exposure was 0.060 ± 0.101 mg/ lb­ ai handled. The geometric mean total exposure, as calculated by the Registrant, to isofenphos during planting of treated canola seed was 0.15 mg/ lb ai applied. The study author also reported total exposure in mg/ replicate and assumed that a worker is able to complete three replicates per day. The study author estimated an average daily exposure of 1.9 mg, but noted that a worker would probably not routinely work what is equivalent to three replicates per day during the planting season so that actual daily exposure would likely be less than 1.9 mg/ day. 22 Table 4. Potential Inhalation (mg/ lb ai handled) Based on Residue Levels Found on Air Filters. Replicate Residue ( : g/ sample) Corrected Value ( : g/ sample) b Replicate length (min) Volume of air sampled (L) Concentration (mg/ m 3 ) c lb ai handled Respiration Rate (m 3 /min) Inhalation exposure (mg/ lb ai handled) d 1 0. 0664 0.0754 164 164 0.00046 1.92 0.029 0.00114 2 0. 1530 0.1737 135 135 0.00129 2.88 0.029 0.00175 3 0. 0339 0.0385 260 286 0.00013 5.95 0.029 0.00017 4 0. 0289 0.0328 185 203.5 0. 00016 4.32 0.029 0.00020 6 0. 0219 0.0249 185 203.5 0. 00012 3.60 0.029 0.00018 8 a 0.0050 110 107.8 0. 00002 4.32 0.029 0.00002 9 0. 2260 0.1793 285 107.8 0. 00166 5.76 0.029 0.00239 11 0.0608 0.0482 217 238.7 0. 00020 2.94 0.029 0.00043 13 a 0. 0050 172 189.2 0. 00001 4.62 0.029 0.00001 14 a 0. 0050 155 170.5 0. 00001 3.96 0.029 0.00002 15 0.0426 0.0454 277 304.7 0. 00015 6.24 0.029 0.00019 16 0.0460 0.0490 188 206.8 0. 00024 5.46 0.029 0.00024 Mean 0.0006 Geometric Mean 0.0002 Standard Deviation 0.0008 Coefficient of Variance (%) 138.58 a Residue was not detected. Therefore, ½ the LOD (0. 005 : g/ sample) was used. b Corrected for average field fortification recovery (88.1%) c Concentration (mg/ m 3 ) = (Residue ( : g/ sample) x 0.001)/( sample volume (L) x m 3 /1000L) d Exposure (mg/ lb ai handled) = [( Concentration (mg/ m 3 ) x Respiration rate (m 3 /min) x replicate length (min)]/ lb ai handled 23 Table 5. Potential Dermal Exposure (mg/ lb ai handled) Based on Exterior Patches Replicate Residues (ug/ cm 2 ) a Body Region Exposure (mg/ lb ai handled) c Head Back Chest Upper Arm Lower Arm Upper Leg Lower Leg lb ai applied Head (1300 cm 2 ) Back (3550 cm 2 ) Chest (3550 cm 2 ) Upper Arm (2910 cm 2 ) Lower Arm (1210 cm 2 ) Upper Leg (382 cm 2 ) Lower Leg (2380 cm 2 ) Total 1 0. 008 0.007 0.016 0.026 0.333 0.510 0.069 1.92 0.0054 0.1306 0.0302 0.0388 0.2096 0.1014 0.0856 0.6015 2 0. 041 0.007 0.229 0.107 1.473 0.327 0.096 2.88 0.0185 0.0856 0.2828 0.1085 0.6188 0.0434 0.0794 1.2369 3 0. 001 b 0.001 b 0.014 0.017 0.140 0.353 0.093 5.95 0 0. 005 0.009 0.0083 0.0284 0.0227 0.0373 0.1101 4 0. 001 b 0.001 b 0.001 b 0.011 0.029 0.294 0.037 4.32 0 0. 006 0 0. 0077 0.0083 0.026 0.0201 0.0693 5 0. 008 0.006 0.147 0.003 0.190 0.308 0.519 4.32 0.0025 0.05 0.1211 0.002 0.0531 0.0272 0.2861 0.5421 6 0. 020 0.001 b 0.097 0.013 0.043 0.179 0.161 3.6 0. 0071 0.008 0.0961 0.0103 0.0143 0.019 0.1066 0.2609 8 0. 001 b 0.001 b 0.001 b 0.001 b 0.007 0.001 b 0.001 b 4.32 0 0. 006 0 0. 001 0.002 0 0 0.0103 9 0. 050 0.024 0.217 0.074 0.353 0.522 0.036 5.76 0.0113 0.1491 0.1339 0.0373 0.0742 0.0346 0.0148 0.4552 11 0.010 0.001 b 0.001 b 0.007 0.038 0.073 0.035 2.94 0.0044 0.009 0 0. 0072 0.0158 0.01 0.028 0.0751 13 0.008 0.008 0.073 0.029 1.469 0.327 0.183 4.62 0.0021 0.0608 0.0565 0.0184 0.3847 0.027 0.0941 0.6437 14 0.001 b 0.001 b 0.001 b 0.001 b 0.001 0.004 0.001 b 3.96 0 0. 007 0 0. 001 0 0 0 0. 0095 15 0.008 0.006 0.026 0.047 0.143 0.184 0.299 6.24 0.0017 0.0321 0.0133 0.022 0.0278 0.0113 0.1139 0.2222 16 0.001 b 0.001 b 0.014 0.001 b 0.024 0.127 0.134 5.46 0 0. 005 0.009 0 0. 0053 0.009 0.0585 0.0877 Average 0.012 0.005 0.064 0.026 0.326 0.247 0.128 4.33 0.0042 0.0427 0.0581 0.0202 0.111 0.0255 0.0712 0.3326 Standard Deviation 0.3555 a Residue ( : g/ cm 2 ) = Residue ( : g/ sample)/ Patch surface area (24.63 cm 2 ) b Residue was not detected. Therefore, ½ the LOD (0. 038 : g/ sample) was used. c Body Region Exposure (mg/ lb­ ai)= (Exposure ( u g/ cm 2 ) x Body Region (cm 2 )/ lb ai applied) x 0.001 24 Table 6. Summary of Hand Exposure (mg/ lb ai handled) based on Hand Washes Replicate Residue ­ both hands ( : g/ sample ) lb ai handled Hand exposure ( : g /lb ai handled) Hand exposure (mg/ lb ai handled) 1 0. 33333333333 1.92 10.4 0. 010 2 0. 33333333333 2.88 6.9 0. 007 3 0. 33333333333 5.95 3.4 0. 003 4 0. 33333333333 4.32 4.6 0. 005 5 0. 33333333333 4.32 4.6 0. 005 6 0. 33333333333 3.60 5.6 0. 006 9 1920 5.76 333.3 0. 333 11 0.33333333333 2.94 6.8 0. 007 13 0.33333333333 4.62 4.3 0. 004 14 0.33333333333 3.94 5.1 0. 005 15 0.33333333333 6.24 3.2 0. 003 16 0.33333333333 5.46 3.7 0. 004 Mean 0.033 Geometric Mean 0.007 Standard Deviation 0.095 Coefficient of Variance (%) 289.98 a Residue value not detected. Therefore, ½ the LOD (40 : g/ sample) was used. Table 7. Actual Dermal Exposure (mg/ lb ai handled) Based on Interior Patches (except for Head) 25 Replicate Residues (ug/ cm 2 ) a Body Region Exposure (mg/ lb ai handled) c Neck b Head Back Chest Upper Arm Lower Arm Upper Leg Lower Leg lb ai applied Neck b Head (1300 cm 2 ) Back (3550 cm 2 ) Chest (3550 cm 2 ) Upper Arm (2910 cm 2 ) Lower Arm (1210 cm 2 ) Upper Leg (382 cm 2 ) Lower Leg (2380 cm 2 ) Total 1 0. 023 0.008 0.001 0.001 0.001 0.081 0.033 0.004 1.92 0.002 0.005 0 0 0 0.05 0.007 0.004 0.073 2 0. 236 0.041 0.001 0.022 0.006 0.076 0.036 0.004 2.88 0.0122 0.0185 0 0. 03 0 0.03 0.005 0.003 0.1053 30. 0150. 0010. 0010. 0010. 0010. 0010. 0160. 0015. 95000 0 0 00. 00100 40. 0020. 0010. 0010. 0010. 0010. 0060. 0130. 0014. 32000 0 0 00. 00100. 01 50. 1540. 0080. 0010. 0010. 0010. 0170. 0240. 0154. 320. 0050. 0030 0 0 00. 0020. 0080. 025 60. 0980. 0200. 0010. 0010. 0010. 0010. 0040. 0033. 60. 0040. 0070 0 0 000. 0020. 016 8 0. 0015 0.001 0.001 0.001 0.001 0.001 0.001 0.001 4.32 0 0 0 0 0 0000 9 0. 241 0.030 0.001 0.014 0.003 0.020 0.061 0.012 5.76 0.006 0.0113 0 0 0 00. 0040. 0050. 041 11 0.0015 0.010 0.001 0.001 0.001 0.004 0.010 0.001 2.94 0 0. 004 0 0 0 00. 00100. 011 13 0.081 0.008 0.016 0.003 0.016 0.030 0.059 0.029 4.62 0.003 0.002 0.01 0 0. 01 0 0.005 0.0152 0.058 14 0.0015 0.001 0.005 0.001 0.001 0.001 0.010 0.009 3.96 0 0 0 0 0 00. 0010. 0050. 012 15 0.0291 0.008 0.001 0.007 0.001 0.041 0.023 0.009 6.24 0 0. 002 0 0 0 00. 0010. 0030. 02 16 0.0152 0.001 0.001 0.001 0.008 0.003 0.011 0.010 5.46 0 0 0 0 0 000. 0040. 012 Average 0. 0690. 0120. 0020. 0040. 0030. 0220. 0230. 0084. 330. 0030. 0040 0 0 00. 0020. 0040. 03 Standard Deviation 0.031 a Residue ( : g/ cm 2 ) = Residue ( : g/ sample)/ Patch surface area (24.63 cm 2 ) b Sum of the calculations for both front and back neck (Areas: 150 and 110 cm 2 , respectively) c Body Region Exposure (mg/ lb ai handled)= (Exposure (ug/ cm 2 ) x Body Region (cm 2 )/ lb ai applied) x 0.001 26 Table 8. Total Exposure (mg/ lb ai handled) Replicate Exposure (mg/ lb ai handled) Dermal­ body Dermal­ hands Dermal­ Total Inhalation Inhalation + Dermal Total 1 0. 0731 0.0104 0.0835 0.0011 0.085 2 0. 1053 0.0069 0.1122 0.0018 0.114 3 0. 0033 0.0034 0.0067 0.0002 0.007 4 0. 0053 0.0046 0.01 0.0002 0.01 5 0. 0249 0.0046 0.0295 0.029 6 0. 016 0.0056 0.0216 0.0002 0.022 8 0. 0028 0.0028 0.00002 0.003 9 0. 0411 0.3333 0.3745 0.0024 0.377 11 0.0108 0.0068 0.0176 0.0004 0.018 13 0.058 0.0043 0.0623 0.00001 0.062 14 0.0124 0.0051 0.0174 0.00002 0.017 15 0.0199 0.0032 0.0231 0.0002 0.023 16 0.0117 0.0037 0.0153 0.0002 0.016 Average 0.0296 0.0327 0.0597 0.0006 0.06 Standard Deviation 0.101 27 _______ ___________________________ Name: Name: Evaluator Peer Reviewer Occupational Exposure Assessment Section Occupational Exposure Assessment Section __________________ ____________________ Date Date _________________________ Name: Head, Occupational Exposure Assessment Section _________________________ Date 28 Compliance Checklist Compliance with OPPTS Series 875, Occupational and Residential Exposure Test Guidelines, Group A: Guidelines, 875.1300 (inhalation), and 875.1100 (dermal) is critical. The itemized checklist below describes compliance with the major technical aspects of OPPTS 875.1300, and 875.1100. 875.1300 S Investigators should submit protocols for review purposes prior to the inception of the study. This criterion was probably met. 3) Expected deviations from GLPs should be presented concurrently with any protocol deviations and their potential study impacts. The study sponsor stated that GLP's did not apply to this study. 4) The test substance should be a typical end use product of the active ingredient. This criterion was met. 5) The application rate used in the study should be provided and should be the maximum rate specified on the label. However, monitoring following application at a typical application rate may be more appropriate in certain cases. It is uncertain whether this criterion was met. A product label was not provided in the study and the label obtained by Versar did not provide a maximum application rate. 6) Selected sites and seasonal timing of monitoring should be appropriate to the activity. It is uncertain whether these criteria were met. The study site was located in Canada and the study occurred during the month of May. 7) A sufficient number of replicates should be generated to address the exposure issues associated with the population of interest. For outdoor exposure monitoring, each study should include a minimum of 15 individuals (replicates) per activity. This criterion was met. Four individuals participated in this study, for a total of 16 replicates. 8) The quantity of active ingredient handled and the duration of the monitoring period should be reported for each replicate. This criterion was met. 9) Test subjects should be regular workers, volunteers trained in the work activities required, or typical homeowners. This criterion was met. 10) The monitored activity should be representative of a typical working day for the specific task in order to capture all related exposure activities. This criterion was met. 11) When both dermal and inhalation monitoring are required, field studies designed to measure exposure by both routes on the same subjects may be used. This criterion was met. 12) The analytical procedure must be capable of measuring exposure to 1 µg/ hr (or less, if the toxicity of the material under study warrants greater sensitivity). This criterion was met. 13) A trapping efficiency test for the monitoring media chosen must be documented. This criterion was not met. Trapping efficiency tests were not documented for any of the media used in this study. 14) Air samples should also be tested for breakthrough to ensure that collected material is not lost from the medium during sampling. It is recommended that at least one test be carried out where the initial trap contains 10X the highest amount of residue expected in the field. This criterion was not met. There was no mention of any breakthrough tests being run on the air filters used in the study. 15) The extraction efficiency of laboratory fortified controls is considered acceptable if the lower limit of the 95% confidence interval is greater than 75%, unless otherwise specified by the Agency. At a minimum, seven determinations should be made at each fortification level to calculate the mean and standard deviation for recovery. Total recovery from field­ fortified samples must be greater than 50% for the study. These criteria were partially met. The number of laboratory fortified controls and types of laboratory controls were not provided in the Study Report. 29 Field fortification results were provided and all were greater than 50%. 16) If trapping media or extracts from field samples are to be stored after exposure, a stability test of the compound of interest must be documented. Media must be stored under the same conditions as field samples. Storage stability samples should be extracted and analyzed immediately before and at appropriate periods during storage. The time periods for storage should be chosen so that the longest corresponds to the longest projected storage period for field samples. This criterion was met. A storage stability test was conducted. The Registrant, however, did not provide the actual dates of analysis. 17) A personal monitoring pump capable of producing an airflow of at least 2 L/ min. should be used and its batteries should be capable of sustaining maximum airflow for at least 4 hours without recharging. Airflow should be measured at the beginning and end of the exposure period. This criterion was probably not met. Personal monitoring pumps were calibrated to 1 L/ min and it was not reported if airflow was measured at the beginning and/ or end of the exposure period. 18) Appropriate air sampling media should be selected. The medium should entrap a high percentage of the chemical passing through it, and it should allow the elution of a high percentage of the entrapped chemical for analysis. This criterion was met. The study utilized personal air samplers containing air filters and absorption tubes. 19) If exposed media are to be stored prior to extraction, storage envelopes made from heavy filter paper may be used. The envelope must be checked for material that will interfere with analysis. Unwaxed sandwich bags should be used to contain the filter paper envelopes to help protect against contamination. This criterion was probably met. The Registrant states that after collection of the fiberglass filters, the air filter cassettes were removed, capped, and place in Whirl­ Pak bags. 20) Personal monitors should be arranged with the intake tube positioned downward, as near as possible to the nose level of the subject. This criterion was met. The cassette containing the air filter was attached to the worker's lapel. 21) Field calibration of personal monitors should be performed at the beginning and end of the exposure period. It is uncertain whether this criterion was met. There was no mention of calibration procedures in the Study Report. 22) Field fortification samples and blanks should be analyzed for correction of residue losses occurring during the exposure period. Fortified samples and blanks should be fortified at the expected residue level of the actual field samples. Fortified blanks should be exposed to the same weather conditions. These criteria were met. The Registrant mentioned that both field fortified samples and field blanks were collected. 23) Data should be corrected if any appropriate field fortified, laboratory fortified or storage stability recovery is less than 90 percent. This criterion was met. The Registrant corrected all data for field recoveries, even those greater than 90%. 24) Respirator pads should be removed using clean tweezers and placed in protective white crepe filter paper envelopes inside sandwich bags. The pads should be stored in a chest containing ice until they are returned to the laboratory, where they should be stored in a freezer prior to extraction. This criterion was not applicable to this study. 25) Field data should be documented, including chemical information, area description, weather conditions, application data, equipment information, information on work activity monitored, sample numbers, exposure time, and any other observations. These criteria were partially met. Brief descriptions of the test product used, the work activities being monitored, the planting equipment used, the application rate, the location of the study, and weather conditions were provided in the Study Report. However, no information regarding the individuals used in the study was provided. 26) Analysis methods should be documented and appropriate. This criterion was met. 27) A sample history sheet must be prepared by the laboratory upon receipt of samples. This criterion was not met. 875.1100 30 28) Investigators should submit protocols for review purposes prior to the inception of the study. This criterion was probably met. 29) Expected deviations from GLPs should be presented concurrently with any protocol deviations and their potential study impacts. The study sponsor stated that GLP's did not apply to this study. 30) The test substance should be a typical end use product of the active ingredient. This criterion was met. 31) The application rate used in the study should be provided and should be the maximum rate specified on the label. However, monitoring following application at a typical application rate may be more appropriate in certain cases. It is uncertain whether this criterion was met. A product label was not provided in the study and the label obtained by Versar did not provide a maximum application rate. 32) Selected sites and seasonal timing of monitoring should be appropriate to the activity. It is uncertain whether these criteria were met. The study site was located in Canada and the study occurred during the month of May. 33) A sufficient number of replicates should be generated to address the exposure issues associated with the population of interest. For outdoor exposure monitoring, each study should include a minimum of 15 individuals (replicates) per activity. This criterion was met. Four individuals participated in this study, for a total of 16 replicates. 34) The quantity of active ingredient handled and the duration of the monitoring period should be reported for each replicate. This criterion was met. 35) Test subjects should be regular workers, volunteers trained in the work activities required, or typical homeowners. This criterion was met. 36) Any protective clothing worn by the test subjects should be identified and should be consistent with the product label. This criterion was met. The protective clothing worn by the test subjects was identified and was consistent with the product label obtained by Versar. 37) The monitored activity should be representative of a typical working day for the specific task in order to capture all related exposure activities. This criterion was met. 38) Dermal exposure pads used for estimating dermal exposure to sprays should be constructed from paper­ making pulp or similar material (i. e., alpha­ cellulose), approximately 1 mm thick, that will absorb a considerable amount of spray without disintegrating. The alpha­ cellulose material should not typically require preextraction to remove substances that interfere with residue analysis. This should be determined prior to using the pads in exposure tests .This criterion is not applicable to this study. 39) Dermal exposure pads used for estimating dermal exposure to dust formulations, dried residues, and to dust from granular formulation should be constructed from layers of surgical gauze. The pad should be bound so that an area of gauze at least 2.5 inch square is left exposed. The gauze must be checked for material that would interfere with analysis and be preextracted if necessary. These criteria were partially met. The exposure pads were constructed from a surgical sponge and had a circular opening 5.6 cm (2.2 in) in diameter. It was not stated whether the gauze was checked for material that would interfere with analysis. 40) A complete set of pads for each exposure period should consist of 10 to 12 pads. If the determination of actual penetration of work clothing is desired in the field study, additional pads can be attached under the worker's outer garments. Pads should be attached under both upper and lower outer garments, particularly in regions expected to receive maximum exposure. Pads under clothing should be near, but not covered by, pads on the outside of the clothing. This criterion was met. 41) If exposed pads are to be stored prior to extraction, storage envelopes made from heavy filter paper may be used. The envelope must be checked for material that will interfere with analysis. Unwaxed sandwich bags should be used to contain the filter paper envelopes to help protect against contamination. This criterion was not met. Gauze pads were stored in 1­ ounce glass bottles capped with poly­ seal screw caps and stored on dry ice. 31 42) Hand rinses should be performed during preliminary studies to ensure that interferences are not present. Plastic bags designed to contain 0.5 gal and strong enough to withstand vigorous shaking (i. e., at least 1 mil inch thickness) should be used. During preliminary studies, plastic bags must be shaken with the solvent to be used in the study to ensure that material which may interfere with analysis is not present. It is unknown if this criterion was met. The study author made no mention of preliminary hand rinse studies. 43) The analytical procedure must be capable of quantitative detection of residues on exposure pads at a level of 1 ug/ cm 2 (or less, if the dermal toxicity of the material under study warrants greater sensitivity). It is unknown if this criterion was met. The limit of quantification was not provided in the study. The limit of detection for exposure pads was reported as 38 ng/ sample. 44) The extraction efficiency of laboratory fortified controls is considered acceptable if the lower limit of the 95% confidence interval is greater than 75%, unless otherwise specified by the Agency. At a minimum, seven determinations should be made at each fortification level to calculate the mean and standard deviation for recovery. Total recovery from field­ fortified samples must be greater than 50% for the study. These criteria were partially met. The number of laboratory fortified controls and types of laboratory controls were not provided in the Study Report. Field fortification recovery results were provided and all were greater than 50%. 45) If the stability of the material of interest is unknown, or if the material is subject to degradation, the investigator must undertake and document a study to ascertain loss of residues while the pads are worn. It is recommended that collection devices be fortified with the same levels expected to occur during the field studies. The dosimeters should be exposed to similar weather conditions and for the same time period as those expected during field studies. These criteria were met. A storage stability test was conducted. The Registrant, however, did not provide the actual dates of analysis. 46) Data should be corrected if any appropriate field fortified, laboratory fortified or storage stability recovery is less than 90 percent. This criterion was met. The Registrant corrected all raw residue data for field recoveries. 47) Field data should be documented, including chemical information, area description, weather conditions, application data, equipment information, information on work activity monitored, sample numbers, exposure time, and any other observations. These criteria were partially met. Brief descriptions of the test produce used, the work activities being monitored, the planting equipment used, the application rate, the location of the study, and the weather conditions were provided in the Study Report. However, no information regarding the individuals used in the study was provided. 48) A sample history sheet must be prepared by the laboratory upon receipt of samples. This criterion was not met. 32 APPENDIX B Comparison of Application Rates of Lindane Among Registered Crops Group Crop Ounce ai/ cwt Max Seed Lb ai/ acre Max Seed cwt/ acre Max Ounce ai/ acre Max Pound ai/ acre Root & Tuber Radish 0.53 20 0.2 0. 106 0.0066 Leafy Veggies Celery 1.31 2 0. 02 0. 0262 0.0016 Lettuce 1.31 3 0. 03 0. 0393 0.0025 Swiss 1. 31 8 0.08 0.1048 0.0066 Spinach 1. 31 15 0. 15 0. 1965 0.0123 Cereal Grains Corn 2 18 0. 18 0. 36 0. 0225 Barley 0.5 96 0. 96 0. 48 0. 0300 Oats 0.6 128 1.28 0.768 0.0480 Rye 0. 5 112 1.12 0.56 0.0350 Soughum 1.13 75 0.75 0.8475 0.0530 Wheat 0.68 120 1.2 0. 816 0.0510 Misc. Canola 23.3 4 0.04 0.932 0.0583 Brassica Broccoli 1.91 1.5 0. 015 0.02865 0.0018 Brussels 1.91 1.5 0. 015 0.02865 0.0018 Cabbage 1.91 1.5 0. 015 0.02865 0.0018 Cauli 1. 91 1. 5 0.015 0.02865 0.0018 Collards 1. 91 4 0.04 0.0764 0.0048 Kale 1.91 4 0. 04 0. 0764 0.0048 Kohlrabi 1.91 5 0. 05 0. 0955 0.0060 Mustard 1.91 5 0. 05 0. 0955 0.0060 Source for Maximum Lb Seed per Acre: Martin, J. H., W. H. Leonard, and D. L. Stamp, "Principles of Field Crop Production, Third Edition:, Macmillan Publishing Co., Inc., 1976.

epa

2024-06-07T20:31:43.084510

regulations

EPA-HQ-OPP-2002-0202-0008

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES September 28, 2000 MEMORANDUM SUBJECT: Lindane; P. C. Code 009001. The HED Toxicology Chapter for the Risk Assessment for the Reregistration Eligibility Decision Document (RED), Case # 818566. DP Barcode: D269338 From: Suhair Shallal, Toxicologist Reregistration Branch 4 Health Effects Division (7509C) Thru: Sanjivani Diwan, Senior Toxicologist Reregistration Branch 4 Health Effects Division (7509C) and Susan V. Hummel, Branch Senior Scientist Reregistration Branch 4 Health Effects Division (7509C) To: Suhair Shallal, Risk Assessor Reregistration Branch 4 Health Effects Division (7509C) Attached is the Toxicology Chapter for lindane, for purposes of issuing a Reregistration Eligibility Decision (RED) Document. 2 LINDANE PC Code: 009001 Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision Document Date: September 28, 2000 TABLE OF CONTENTS 1. 0 HAZARDCHARACTERIZATION........................................ 4 2. 0 REQUIREMENTS .................................................... 5 3. 0 DATAGAP( S) ....................................................... 6 4. 0 HAZARDASSESSMENT............................................... 6 4. 1 AcuteToxicity............................................... 6 4. 2 SubchronicToxicity........................................... 6 4. 3 PrenatalDevelopmentalToxicity................................ 10 4. 4 ReproductiveToxicity........................................ 14 4. 5 ChronicToxicity ............................................ 16 4. 6 Carcinogenicity ............................................. 21 4. 7 Mutagenicity ............................................... 23 4. 8 Neurotoxicity .............................................. 24 4. 9 Metabolism................................................ 28 5. 0 TOXICITYENDPOINTSELECTION.................................... 30 5. 1 SeeSection9. 2for EndpointSelectionTable. ...................... 30 5. 2 DermalAbsorption.......................................... 30 5. 3 ClassificationofCarcinogenicPotential ........................... 30 6. 0 FQPACONSIDERATIONS ............................................ 31 6. 1 SpecialSensitivitytoInfantsandChildren......................... 31 6. 2 RecommendationforaDevelopmentalNeurotoxicityStudy............ 32 7. 0 REFERENCES ...................................................... 33 8. 0 APPENDICES....................................................... 36 8. 1ToxicityProfileSummaryTables ................................ 37 8. 1. 1AcuteToxicityTable ............................ 37 8. 1. 2 Subchronic, ChronicandOther ToxicityTables ........ 37 Lindane/ September 2000 RED Toxicology Chapter 4 1.0 HAZARD CHARACTERIZATION Lindane is a moderately toxic compound in EPA toxicity class II. Labels for products containing it must bear the Signal Word WARNING. It is neither an eye nor dermal sensitizer. Some formulations of lindane are classified as Restricted Use Pesticides (RUP), and as such may only be purchased and used by certified pesticide applicators. Lindane is no longer manufactured in the U. S., and most agricultural and dairy uses have been canceled by the EPA because of concerns about the compound's potential to cause cancer. The primary effect of lindane is on the nervous system; as seen in both acute, subchronic, and developmental neurotoxicity studies, as well as, combined chronic and carcinogenicity study, lindane appears to cause neurotoxic effects including tremors, convulsions and hypersensitivityto touch. This is further corroborated by the published literature in which human exposure has been seen to produce neurologic effects. Lindane also causes renal and hepatic toxicity via the oral, dermal and inhalation routes of exposure as seen in subchronic, reproduction and chronic toxicity studies in the rat. Indevelopmental toxicitystudies, no developmental effects were seen at levels where maternal toxicity was evident. In the rat developmental study, the developmental effects (extra rib and total skeletal variations) were seen at dose levels (20 mg/ kg/ day) greater than those that elicit maternal toxicity (10 mg/ kg/ day). In the reproduction study, both systemic and developmental LOAELs are 13 mg/ kg; however a qualitative difference in maternal and offspring effects (reduced body weight of maternal animals and reduced viability and delayed maturation in pups) indicates an increased pup susceptibility to exposure to lindane. This is further corroborated by a developmental neurotoxicity study in which a qualitative and quantitative increase in susceptibility is seen. At the high dose (13. 7 mg/ kg/ day) , parental animals have a reduced body weight and body weight gain while at the mid­ dose (5.6 mg/ kg/ day) offspring have a reduced survival rate, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation as compared to controls. The FQPA factor was therefore reduced to 3X. The toxicity endpoints have been selected by the Hazard Identification Assessment Review Committee (HIARC, 7/ 00) and can be found in Section 8­ Appendices. They include acute and chronic reference doses (RfDs), and short­, intermediate­ and long­ term dermal and inhalation no observable adverse effect levels (NOAELs). A reassessment of the cancer classification will occur after a review of the new mouse carcinogenicity report due in December 2000. Currently, according to the TES committee report (1994), lindane has not been classified by the HED Cancer Peer Review Committee. The RfD/ Peer Review Committee (1993) concluded that: "The mouse carcinogenicity data were considered insufficient because of major deficiencies associated with all studies available." Lindane however had been previously( 1985) classified bythe Cancer Assessment Group of the Office of Research and Development as a group B2/ C carcinogen based on increased incidence of mouse liver tumors. The upper­ bound slope of the dose­ response as reported in the memorandum is Q1* = 1. 1 (mg/ kg/ day) ­1 . Lindane does not appear to be mutagenic. The available mutagenicity studies are negative; they include a dominant lethal mutation assay, sister chromatid exchange assay and mammalian cell culture gene mutation in V79 cells. IPCS (1991) reported that lindane does not appear to have Lindane/ September 2000 RED Toxicology Chapter 5 mutagenic potential. There is some evidence that lindane may act as an endocrine disruptor; further investigation is necessary to ascertain the relevance and impact of such findings on public health. 2.0 REQUIREMENTS The requirements (CFR 158.340) for food­ use for LINDANE are in Table 1. Table 1. A Test Technical Required Satisfied 870.1100 Acute Oral Toxicity ............................. 870.1200 Acute Dermal Toxicity ........................... 870.1300 Acute Inhalation Toxicity ......................... 870.2400 Primary Eye Irritation ............................ 870.2500 Primary Dermal Irritation ......................... 870.2600 Dermal Sensitization ............................ yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ......................... Oral Subchronic (nonrodent) ...................... 870.3200 21­ Day Dermal ................................ 870.3250 90­ Day Dermal ................................ 870.3465 90­ Day Inhalation ............................... yes yes yes yes 870.3150 yes yes 870.3700a Developmental Toxicity (rodent) ................... 870.3700b Developmental Toxicity (nonrodent) ................ 870.3800 Reproduction .................................. yes yes yes yes yes yes 870.4100a Chronic Toxicity (rodent) ......................... 870.4100b Chronic Toxicity (nonrodent) ...................... 870.4200a Oncogenicity (rat) .............................. 870.4200b Oncogenicity (mouse) ............................ 870.4300 Chronic/ Oncogenicity ............................ yes yes yes yes yes yes no 870.5100 Mutagenicity C GeneMutation­ bacterial ............. 870.5300 Mutagenicity C GeneMutation­ mammalian........... 870.5915 Mutagenicity C Other GenotoxicEffects .............. yes yes yes yes 870.6100a Acute Delayed Neurotox. (hen) .................... 870.6100b 90­ Day Neurotoxicity (hen) ....................... 870.6200a Acute Neurotox. Screening Battery (rat) .............. 870.6200b 90 Day Neuro. Screening Battery (rat) ............... 870.6300 Develop. Neuro ................................ no no yes yes yes yes yes yes 870.7485 General Metabolism ............................. 870.7600 Dermal Penetration ............................. yes yes Special Studies for Ocular Effects AcuteOral (rat) ................................ SubchronicOral( rat) ............................ Six­ monthOral (dog) ............................ no no no A Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. 3.0 DATA GAP( S) A Mouse Carcinogenicity Study is expected in December 2000. Lindane/ September 2000 RED Toxicology Chapter 6 4.0 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of data base for acute toxicity: The data base for acute toxicity is considered complete. No additional studies are required at this time. Lindane is a moderately toxic compound in EPA toxicity class II. It is neither an eye nor dermal sensitizer. The vehicle used when administering lindane can determine its toxicity. It appears that oily solutions of lindane are more toxic than ones suspended in water. Clinical signs including convulsions, spasms as well as death have been found to occur after administration of lindane. The acute toxicity data on LINDANE is summarized below in Table 2. Table 2. Acute Toxicity Data on LINDANE Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity 00049330 LD50 88 mg/ kg ­ males 91 mg/ kg ­ females II 870.1200 Acute dermal toxicity 00109141 LD50 1000 mg/ kg ­ males 900 mg/ kg ­ females II 870.1300 Acute inhalation toxicity Acc. 263946 LC50 1.56 mg/ L both sexes III 870.2400 Acute eye irritation Acc. 263946 PIS = 0.6 no corneal involvement irritation cleared after 24 hours III 870.2500 Acute dermal irritation Acc. 263946 PIS = 0 not an irritant IV 870.2600 Skin sensitization Acc. 263946 not a sensitizer NA 4.2 Subchronic Toxicity Adequacy of data base for subchronic toxicity: The data base for subchronic toxicity is considered complete due to the availability of chronic studies and subchronic neurotoxicitystudy. No additional studies are required at this time. Lindane appears to affect the liver and kidneyin male rats when administered through the oral, dermal or inhalation routes of exposure. In addition, in an oral neurotoxicity study, hypersensitivity to touch and hunched posture were the basis for a neurotoxicity LOAEL of 28.1 mg/ kg. 870.3100 90­ Day Oral Toxicity ­ Rat The requirements for subchronic oralstudies are satisfied by chronic oral studies. See chronic oral section for executive summaries. Lindane/ September 2000 RED Toxicology Chapter 7 870.3100 90­ Day Oral Toxicity ­ Mouse The requirements for subchronic oral studies are satisfied by chronic oral studies. See chronic oral section for executive summaries. 870.3150 Oral Toxicity ­ Dog Chronic studies in two species, rat and rabbit, are available. See chronic oral section for executive summaries. 870.3200 90­ Day Dermal Toxicity B Rat EXECUTIVESUMMARY: Ina subchronic dermal toxicitystudy( MRID41427601), groups of 40 male and 40 female New Zealand white rabbits were treated with lindane (99.5% a. i.) in 5% aqueous carboxymethyl cellulose at doses of 0, 10, 60, or 400 mg/ kg/ day. Due to excessive toxicity the high dose was reduced to 350 mg/ kg/ day from week nine and to 320 mg/ kg/ day from week eleven. Animals were treated by dermal occlusion for 6 hours/ day, 5 days/ week. Within each dose group, 10 animals/ sex were used for interim sacrifice at week 6, 20 animals/ sex were used for the main study and dosed for 13 weeks, and 10 animals/ sex were dosed for 13 weeks and allowed a 6 week recovery period. Tremors and convulsions were observed in high­ dose animals beginning after day 16 in males and after day 19 in females. One mid­ dose female displayed these clinical signs on day 50 only. Clinical signs of toxicity were not observed in low­ dose animals. Reactions at the site of application were not reported. In the high­ dose group, 17 males and 8 females died prior to scheduled sacrifice. Deaths were first observed after week 5. All animals in the control, low­, and mid­ dose groups survived to scheduled sacrifice. Body weights and body weight gains by the low­ and mid­ dose males and females were similar to the controls throughout the study. High­ dose males and females began to lose weight after the first week of the study resulting in absolute body weights 3­ 7% and 3­ 10%, respectively, lower than the controls during the 13 weeks of treatment. During recovery, body weights of the males remained 3­ 8% below the controls while females recovered to 1­ 3% lower than the controls. Body weight data were not analyzed statistically. Body weight loss by the high­ dose groups correlated with generally reduced food consumption during treatment. No treatment­ related effects were observed on ophthalmology, urinalysis, or white blood cell parameters. Alkaline phosphatase activity was significantly increased in high­ dose animals at interim sacrifice for females (+ 34%; p
0. 05), and at main study sacrifice for males (+ 44%; p
0.01) and females (+ 53%; p
0. 01). High­ dose females also had significantly increased
­ glutamyl transferase activity (+ 38%; p
0. 01) at main study sacrifice. For high­ dose males, significant (p
0.05 or 0.01) reductions in hemoglobin (­ 7%), RBC (­ 8. 6%), and PCV (­ 5. 7%) were observed at main study sacrifice. These red cell parameters were comparable to the controls after recovery. Red cell parameters in females were not affected. At main study sacrifice, high­ dose males and females had slightly increased absolute kidney weights and significantly (p
0.01) increased relative kidney weights as compared with the controls. Lindane/ September 2000 RED Toxicology Chapter 8 Absolute and relative kidney (left and right) weights were 104­ 106% and 112­ 114%, respectively, for males and 105­ 106% and 115­ 116%, respectively, for females. High­ dose females also had significantly (p
0.01) increased absolute (+ 27.01 to 27.24%) and relative (+ 30.53 to 44.985) liver weights at both interim and main study sacrifice which remained slightly (+ 13 to 17.31%; n. s.) elevated after recovery. Relative liver weights were significantly (+ 36.77%; p
0.01) increased for high­ dose males at main study sacrifice. Absolute adrenal weights (left and right) were significantly (p
0.05 or 0.01) increased at main study sacrifice for mid­ dose males (+ 19.5 to 23.4%), high­ dose males (+ 40.5 to 46.3%), and high­ dose females (+ 33 to 34%). Relative adrenal weights were increased (p
0.05 or 0.01) +19 to 21.6% for mid­ dose males and +46 to 56.9% for high­ dose males and females. Following the recovery period, organ weights of the treated groups were similar to the control group. No treatment­ related gross or histopathological lesions were observed in the kidneys, adrenals, or skin. The incidence and severity of centrilobular hypertrophy of the liver was increased in mid­ and high­ dose males and females at the interim, main, and recovery sacrifice times. At both the interim and main sacrifices, centrilobular hypertrophy was observed in 20% of mid­ dose males, 25­ 30% of mid­ dose females, 80­ 100% of high­ dose males and 73­ 90% of high­ dose females. Following recovery this lesion was seen in 30% and 40% of mid­ dose males and females, respectively, and in 50% and 29% of high­ dose males and females, respectively. Therefore, the dermal toxicity LOAEL is >400 mg/ kg/ day and the dermal toxicity NOAEL is not identified. The systemic toxicity LOAEL is 60 mg/ kg/ day based on histopathological lesions of the liver in males and females and increased adrenal weights of males. The systemic toxicity NOAEL is 10 mg/ kg/ day. This study is classified as Acceptable/ guideline and does satisfy the guideline requirements for a repeated­ dose dermal study (82­ 2) in rabbits. 870.3465 90­ Day Inhalation B Rat EXECUTIVE SUMMARY: In a subchronic inhalation toxicity study (Accession No. 255003), lindane (99.9% a. i., Batch no. 79044/ 174) was administered by inhalation to groups of 12 male and 12 female Wistar rats at nominal concentrations of 0, 0.02, 0.10, 0.50, or 5.0 mg/ m 3 ,6 h/ day for 90 days. Additional control and high concentration groups, 12 rats/ sex, were treated for 90 days and allowed to recover for 6 weeks before sacrifice. Analytically measured atmospheric concentrations were 0, 0.02, 0.12, 0.60, and 4. 54 mg/ m 3 , respectively. The arithmetic mean particle size of the aerosol was 1. 11± 0.39 µm and the geometric mean was 1. 03± 1.45 µm. Lindane was detected in the brain, liver, fat, and serum of all exposed rats. The chemical accumulated in fat with levels reaching 127,120 µg/ g and 58, 260 µg/ g in high­ dose females and males, respectively. After the recovery period, traces of lindane were still detectable in the tissues. All rats survived to scheduled sacrifice. "Slight" diarrhea and piloerection were observed in all males and females exposed to the highest concentration, but the time to onset and duration were Lindane/ September 2000 RED Toxicology Chapter 9 not included. No exposure­ related effects were noted for bodyweight gain, food consumption, water consumption, or urinalysis parameters. Although hematology parameters did not appear to be affected by treatment, no individual animal data were included and the statistics could not be verified. Clinical chemistry results, especially for Na + ,K + ,andCa ++ , were highly variable. Cytochrome p­ 450 in males and females exposed to 5 mg/ m 3 was 338% and 174%, respectively, of the control values after 90 days, but similar to the control levels after the recovery period. Bone marrow myelograms from animals exposed to 5 mg/ m 3 showed significantly (p
0.05) increased reticulocytes (+ 108%), stemcells (+ 31%), and myeloblasts (+ 33%) in males, and increased reticulocytes (+ 55) in females, and decreased (­ 45%) lymphocytes in females. However, these changes in bone marrow cannot be definitively attributed to treatment since bone marrow from the other exposed groups was not assayed. Males exposed to 5 mg/ m 3 had significantly (p
0.05 or 0.01) increased absolute (+ 7.8% to +11.7%) and relative (+ 19.1% to 19.2%) kidney weights as compared with the controls. Absolute and relative kidney weights in the males exposed to 0. 5 mg/ m 3 were increased by 8­ 9.8% and 6. 98.2 respectively. Although not statistically significant, the increases in kidney weights for these groups were considered biologically significant. After the recovery phase, kidney weights from the exposed males were similar to the controls. In females exposed to 5 mg/ m 3 absolute and relative kidney weights were increased (p
0.05) by 9.2­ 9.9% and 7. 9­ 8. 2%, respectively, as compared with the controls. In high­ dose males, absolute liver weights were not affected, but relative liver weights were slightly (6. 9%) higher than the controls. For females exposed to the highest dose, absolute and relative liver weights were 12.2% and 11.0% higher, respectively, than the controls. No differences in absolute and relative liver weights were noted between the exposed and control groups after the recovery period. Kidney lesions in males exposed to 0, 0. 02, 0.10, 0.50, or 5.0 mg/ m 3 , were observed in 17%, 0, 25%, 83% and 82%, respectively, of the animals. These lesions included cloudy swelling of the tubule epithelia, dilated renal tubules with protein containing contents, and proliferated tubules. After the recovery phase, only cloudy swelling of the tubule epithelia was observed in two control animals and one high­ concentration animal. Therefore, the systemic toxicity LOAEL is 0.50 mg/ m 3 (0. 13 mg/ kg) based on transient microscopic lesions in the kidney and increased kidney weights of male rats. The systemic toxicity NOAEL is 0. 1 mg/ m 3 (0. 025 mg/ kg). This study is considered Acceptable/ guideline and satisfies the requirement for a subchronic inhalation toxicity study in rats [82­ 4]. 870.6200 Subchronic oral neurotoxicity B Rat See Section 4. 8 Neurotoxicity for Executive Summary Lindane/ September 2000 RED Toxicology Chapter 10 4.3 Prenatal Developmental Toxicity Adequacy of data base for Prenatal Developmental Toxicity: The data base for prenatal developmental toxicity is considered complete. No additional studies are required at this time. Lindane is not considered teratogenic when administered orally or subcutaneously. Developmental NOAELs were found to be at levels equal to or greater than maternal NOAELs, except in the Developmental Neurotoxicity Study. The neurotoxicity LOAEL was 5. 6 mg/ kg/ day (NOAEL is 1.2 mg/ kg/ day) based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation compared to a maternal toxicity LOAEL of 13.7 mg/ kg/ day (NOAEL is 5.6 mg/ kg/ day) based on decreased body weight gains, decreased food consumption, and increased reactivity to handling. 870.3700a Prenatal Developmental Toxicity Study ­ Rat EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 42808001), 20 presumed pregnant CFY( derived fromCharles River CD) rats per group were administered technical lindane (purity not given; Batch No. 6801/ 403) by gavage in 0.5% carboxymethyl­ cellulose at doses of 0, 5, 10, and 20 mg/ kg/ day on gestation days (GD) 6­ 15, inclusive. On GD 20, dams were sacrificed by CO2 , subjected to gross necropsy, and all fetuses examined externally. Approximately one­ third of each litter was processed for visceral examination and the remaining two­ thirds was processed for skeletal examination. Deaths of two high­ dose dams were attributed bythe authors to treatment although the cause of death was not reported. No treatment­ related clinical signs of toxicity were observed in any animal. Body weight gains and food consumption by the mid­ and high­ dose groups were decreased during the treatment interval as compared with the controls. Body weight gains by the mid­ and high­ dose dams were 70% and 46%, respectively, of the control values during GD 6­ 14. Food consumption by the mid­ and high­ dose groups was 72% of the control level during GD 7­ 10 and 92% and 65%, respectively, during GD 11­ 14. It should be noted that data were not available for the entire dosing interval and that statistical analyses were not provided for these data. Maternal necropsy was unremarkable. Organ weights were similar between the treated and control groups. Therefore, the maternal toxicity LOAELis 10 mg/ kg/ day based on reduced body weight gain and food consumption. The maternal toxicity NOAEL is 5 mg/ kg/ day. No significant differences were observed between the control group and the treated groups for number of corpora lutea, number of implantation sites, live fetuses/ dam, pre­ and postimplantation losses, fetal body weights, or fetal sex ratios. No treatment­ related effects were found at external or visceral examination of the fetuses. The percentage of litters in the control, low­, mid­, and high­ dose groups containing fetuses with extra (14th) ribs was 12.7, 21.0, 31.7, and 40.6% (p
0.05), respectively. The total incidences of litters containing fetuses with skeletal variants were 43.4, 52.7, 59.5, and 68. 0% (p
0.01), respectively. Although the response rates in the high­ dose group for extra ribs and total variants are Lindane/ September 2000 RED Toxicology Chapter 11 within the upper limit of historical control data, they were considered treatment­ related due to the dose­ related manner of increase. Therefore, the developmental toxicity LOAEL is 20 mg/ kg/ day based on increases in extra ribs and total skeletal variants; a trend for increases in these endpoints at the lower doses is recognized. The developmental toxicity NOAEL is 10 mg/ kg/ day. Although, this study was conducted prior to implementation of current guidelines but is considered sufficient for the purpose for which it was intended. This study is classified as Acceptable/ nonguideline and satisfies the requirements for a developmental toxicity study (83­ 3a) in rats. Several deficiencies were noted in the conduct of this study: percent purity of the test article wast not given, less than 20 litters/ group were available, dosing solutions were not analyzed for concentration, stability, or homogeneity, and much of the individual animal data were not included. EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 00062656), groups of presumed pregnant Sprague­ Dawley rats were administered lindane (purity not given; Lot No. 36346) by subcutaneous injection in corn oil (1 ml/ kg) at doses of 0, 5, 15, or 30 mg/ kg/ day on gestation days (GD) 6­ 15, inclusive. On GD 19, dams were sacrificed and the fetuses removed. Approximately one­ third of the fetuses from each litter were sectioned and examined for visceral malformations/ variations. The remaining two­ thirds of each litter were "examined externally" and processed and examined for skeletal malformations/ variations. Two high­ dose animals died prematurely. Clinical signs of toxicity, including tremors, convulsions, urine stains, excit ability, and anorexia, were reported for one high­ dose animal. However, it was not possible to correlate clinical signs with death since individual animal data were not included. No other clinical signs of toxicity were reported. Body weight gains by the mid­ and high­ dose dams were 76% and 23%, respectively, of the control levels during the treatment interval with both groups attaining statistical significance (p
0. 05). Overall body weight gain by the highdose group was 69% (p
0.05) of the controls. Food consumption by the high­ dose group was 47% of the control level during GD 6­ 11. Body weight gains by the low­ dose group and food consumption for the low­ and mid­ dose groups were similar to the controls throughout the study. Gross necropsy data, other than uterine data, for the dams were not provided. Therefore, the maternal toxicity LOAEL is 15 mg/ kg/ day based on decreased body weight gain. The maternal toxicity NOAEL is 5 mg/ kg/ day. No treatment­ related effects were observed between the control group and the treated groups for number of corpora lutea, number of implantation sites, live fetuses/ dam, pre­ and postimplantation losses, fetal body weights, or fetal crown­ rump lengths. No treatment­ related visceral or skeletal malformations/ variations were observed in any of the fetuses. Results of external examination were not reported. Therefore, the developmental toxicity NOAELis >30 mg/ kg/ day and the developmental toxicity LOAEL was not identified. Lindane/ September 2000 RED Toxicology Chapter 12 This study is classified as Unacceptable/ nonguideline and does not satisfy the requirements for a developmental toxicity study (83­ 3a) in rats. Several deficiencies were noted in the conduct of this study: the subcutaneous route is not the preferred method of administration, percent purity of the test article was not given, dosing solutions were not analyzed for concentration, stability, or homogeneit y, less than 20 litters/ group were available for evaluation, and much of the individual maternal and fetal data were not included. However, this data may be used as supplemental information. 870.3700b Prenatal Developmental Toxicity Study ­ Rabbit EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 42808002), 13 presumed pregnant NewZealand white rabbits per group were administered lindane (puritynot given; Batch No. 6801/ 403) by gavage in 0. 5% carboxymethyl­ cellulose at doses of 0, 5, 10, or 20 mg/ kg/ day on gestation days (GD) 6­ 18, inclusive. On GD 29, dams were sacrificed, subjected to gross necropsy, and all fetuses examined for visceral and skeletal malformations/ variations. Data from external examination of the fetuses was not included. All does survived to scheduled sacrifice. No treatment­ related clinical signs of toxicity were observed. Maternal body weight and food consumption were similar between the treated and control groups. Gross necropsy was unremarkable. Organ weights were similar between the treated and control groups. Therefore, the maternal toxicity NOAEL is >20 mg/ kg/ day and the maternal toxicity LOAEL was not identified. No treatment­ related effects were observed in any dose group for number of corpora lutea, number of implantation sites, live fetuses/ dam, pre­ and post­ implantation losses, fetal body weights, or fetal sex ratios. No treatment­ related visceral or skeletal malformations/ variations were observed in any of the fetuses. Therefore, the developmental toxicity NOAELis >20 mg/ kg/ day and the developmental toxicity LOAEL was not identified. This study is classified as Unacceptable/ not upgradable and does not satisfy the requirements for a developmental toxicity study (83­ 3b) in rabbits. Maternal and developmental toxicity LOAELs were not identified and the highest dose did not approach the limit dose. Therefore, dose selection was considered inadequate. Doses were based on the results of a subcutaneous study in the rabbit (MRID 00062658) which is not a valid method for selecting doses for an oral study. Several other deficiencies were noted in the conduct of this study: percent purity of the test article was not given, dosing solutions were not analyzed for concentration, stability, or homogeneity, and much of the individual animal data were not included. EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 00062658), 15 presumed pregnant New Zealand white rabbits per group following artificial insemination were administered lindane (purity and Batch No. not given) by subcutaneous injection in corn oil Lindane/ September 2000 RED Toxicology Chapter 13 (0. 5 ml/ kg) at doses of 0, 5, 15, or 45 mg/ kg/ day on gestation days (GD) 6­ 18, inclusive. Due to excessive toxicity, the high dose was reduced to 30 mg/ kg/ day after GD 9. On GD 29, dams were sacrificed, subjected to gross necropsy, and all fetuses examined for visceral and skeletal malformations/ variations. Data from external examination of the fetuses was not included. One mid­ dose damaborted and died on GD21 and 14/ 15 high­ dose animals died between GD10 and 26. The high­ dose group was then discontinued due to excessive mortality. Decreased activity and immobilized rear quarters were observed in the mid­ dose group (frequency and number affected not reported). No clinical signs of toxicity were observed in the low­ dose group. During GD 6­ 20, does in the mid­ dose group had a body weight loss of 126.7 g as compared with a body weight gain of 218.0 g by the controls. Body weight loss was accompanied by "markedly lower" food consumption by the mid­ dose animals. Body weight changes and food consumption for the low­ dose group were similar to the controls throughout the study. It appeared that does in the mid­ and high­ dose group had differences in the texture of the liver, however, data from gross necropsy were difficult to interpret due to poor copy quality of the original report. Therefore, the maternal toxicity LOAEL is 15 mg/ kg/ day based on clinical signs of toxicity, death, and reduction in body weight. The maternal toxicity NOAEL is 5 mg/ kg/ day. No treatment­ related effects were observed between the control group and the treated groups for number of corpora lutea, number of implantation sites, live fetuses/ dam, pre­ and postimplantation losses, fetal body weights, or fetal crown­ rump distances. No treatment­ related visceral or skeletal malformations/ variations were observed in any of the fetuses. Abortion by one mid­ dose doe was assumed to be due to excessive maternal toxicity and not to a direct effect on the embryos or fetuses. Therefore, the developmental toxicity NOAELis >15 mg/ kg/ day and the developmental toxicity LOAEL was not identified. This study is classified as Unacceptable/ not upgradable and does not satisfy the requirements for a developmental toxicity study (83­ 3b) in rabbits. Several deficiencies were noted in the conduct of this study: the subcutaneous route is not the preferred method of administration, excessive toxicity occurred at the high­ dose, percent purity of the test article wast not given, dosing solutions were not analyzed for concentration, stability, or homogeneity, and much of the individual maternal and fetal data were not included. However, these study results may be used in conjunction with the oral developmental toxicitystudyin rabbits (MRID42808002) as supplemental information. 870.6300 Developmental Neurotoxicity Study ­ Rat See Section 4. 8 Neurotoxicity for Executive Summary 4.4 Reproductive Toxicity Lindane/ September 2000 RED Toxicology Chapter 14 Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered complete. No additional studies are required at this time. Both parental and offspring LOAELs are 13 mg/ kg; however there is a qualitative difference in the severity of effects. In the parental animals, toxicity was seen in the form of reduction in body weight gain during gestation while offspring toxicity was correlated with decreases in pup viability and pup body weight in the F1 and F2 generations as well as delayed maturation in the F2 generation. Evidence for quantitative increase in susceptibility could not be ascertained due to the wide spread in the doses tested. 870.3800 Reproduction and Fertility Effects ­ Rat EXECUTIVE SUMMARY: In a multigeneration reproductive toxicity study (MRID 42246101), lindane (99.5% a. i.; Batch No. DA433) was administered to groups of 30 male and 30 female Charles River CD rats at dietary concentrations of 0, 1, 20, or 150 ppm (0. 087, 1.71, and 13.05 mg/ kg/ day, respectively) during the per mating period for two generations. One litter was produced in each generation. F1 pups chosen as parental animals were weaned onto the same diet as their parents. Test or control diets were administered to the F0 and F1 parental animals for 71 and 70 days, respectively, before the animals were mated within the same dose group. All animals were continuously exposed to test material either in the diet or during lactation until sacrifice. Premature sacrifices or intercurrent deaths of two F0 animals and five F1 animals were considered incidental to treatment; all other F0 and F1 males and females survived to terminal sacrifice. No treatment­ related clinical signs of toxicity were observed in males or females of either generation at any time during the study. No treatment­ related effects on body weights, body weight gains, food consumption, or food efficiency were observed for the F0 and F1 males and females during premating. Gross necropsy and histopathology of females was unremarkable. During gestation days 10­ 13, mean body weight gain by the high­ dose F0 females was significantly reduced (11%). Mean body weight gains by the high­ dose F0 females were also significantly lower on lactation day 1 (interval not specified) as compared to the controls, but recovery was apparent by weaning. No treatment­ related changes in body weights or body weight gains were observed in the F1 females during gestation or lactation. High­ dose male rats of both generations had a significantly (p
0.01) increased incidence of pale kidneys (10/ 29 F0 males and 10/ 30 F1 males) as compared with the controls (0/ 30 and 0/ 28, respectively). Areas of change on the kidneys (not defined) were observed in 7/ 29 high­ dose F0 males compared with 2/ 30 controls and in 4/ 30 mid­ dose F1 males and 5/ 30 high­ dose F1 males compared with 1/ 28 controls. Significantly (p < 0.01) increased incidence of hydronephrosis was observed in high dose F1 males (7/ 30) as compared to controls (0/ 28). Absolute and relative kidney weights of the mid­ and high­ dose F0 males and the high­ dose F1 males were significantly (p
0.01) increased as compared with the controls. F0 and F1 males in the mid­ and high­ dose groups had significantly (p
0.01) increased incidences of chronic interstitial nephritis, cortical tubular cell regeneration, hyaline droplets in proximal tubules, tubular necrosis with exfoliation and cellular casts, and cortical tubular casts (n. s.). These changes are characteristic of alpha 2 globulin accumulation, which is specific to male rats. Lindane/ September 2000 RED Toxicology Chapter 15 Increased absolute and relative liver weights, accompanied by hepatocellular hypertrophy, in the mid­ and high­ dose males and females of both generations were considered adaptive and of no biological significance. Therefore, the LOAEL for systemic toxicity is 150 ppm (13.05 mg/ kg/ day) based on decreased body weight gains by the F0 females during gestation. The systemic toxicity NOAEL is 20 ppm. In addition, the LOAEL for male rats is 20 ppm (1. 71 mg/ kg/ day) based on increased kidney weights and histopathological lesions in the kidney characteristic of alpha 2µ globulin accumulation; the NOAEL for males is 1 ppm (0. 087 mg/ kg/ day). Mating, fertility, gestation survival (postimplantation index), and liveborn indices, mean precoital interval, and mean gestation length were similar between the treated and control groups of both generations. The sex distribution was not affected by the test material. Mean litter sizes of the treated groups were not different from the controls throughout lactation for both generations. Viability indices for the high­ dose F1 and F2 pups were 81% and 85%, respectively, compared with  96% for the controls. This reduction in survival on lactation day 4 was due to the death or sacrifice (for humane reasons) of three F1 litters and two F2 litters. No treatment­ related clinical signs of toxicity were observed in the pups of either generation during lactation. Pup necropsy was unremarkable. Body weights of the low­ and mid­ dose F1 and F2 pups were similar to the controls throughout lactation. Body weights of the high­ dose pups of both generations were significantly (p
0.01) less than the controls on lactation days 1 and 25. In high­ dose F2 pups, the onset and completion of tooth eruption and completion of hair growth were significantly (p
0.01) delayed 10.5%, 11.6%, and 24%, respectively, as compared with the controls. Therefore, the LOAEL for reproductive toxicity is 150 ppm (13.05 mg/ kg/ day) based on reduced pup body weights and decreased viability in both generations and delayed maturation of the F2 pups. The reproductive toxicity NOAEL is 20 ppm (1.71 mg/ kg/ day). This study is classified as Acceptable/ guideline and satisfies the guideline requirements for a reproduction study (83­ 4) in rats. No major deficiencies were identified in the conduct of this study. 4.5 Chronic/ Carcinogenicity Toxicity Adequacy of data base for chronic toxicity: The data base for chronic toxicity is considered complete. No additional studies are required at this time. The liver appears to be the major target organ. The incidence of periacinar hepatocytic hypertrophy was significantly (p
0.01) increased in the 100­ and 400­ ppm (4. 81 and 6.00 mg/ kg/ day, respectively) males and the 400­ ppm females at 30 days and 26 weeks. In addition, increased liver and spleen weights, and decreased platelets were also noted. Kidney lesions in males indicative of alpha 2µ globulin accumulation were observed in animals treated with  10 ppm, but are not considered relevant to human health risk assessment. Lindane/ September 2000 RED Toxicology Chapter 16 870.4100a (870.4300) Chronic Toxicity B Rat EXECUTIVE SUMMARY: Results from interim sacrifice of 15 rats/ sex/ group, at 30 days and 26 weeks, of an ongoing chronic/ oncogenicity study are presented in this report (MRID 41094101). In the chronic toxicity/ oncogenicity study (MRID41853701), lindane (99.75% a. i., Lot no. DA433) was administered in the diet to groups of 115 male and 115 female Wistar rats at concentrations of 0, 1, 10, 100, or 400 ppmfor 2 years. Corresponding delivered doses were 0, 0. 05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0. 06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. No clinical signs of toxicity were observed. Mortalities in the 0, 1, 10, 100, and 400 ppm groups included 1, 2, 2, 2, and 0 males, respectively, and 2, 0, 1, 1, and 8 females, respectively. Deaths in high­ dose females occurred during weeks 2­ 4 and the cause of death was not determined. Body weights were slightly less than the controls for the high­ dose males (­ 6%) and females (­ 8%) during weeks 1­ 5 of the study, but gradually increased to within 2% of the control level by week 26 for males and week 9­ 10 for females. Food consumption was "marginally lower" in high­ dose males and females and water consumption was "marginallyhigher" in high­ dose males (63 ml/ kg/ day versus 50 ml/ kg/ day for controls). High­ dose females had significantly (p
0.01) decreased hemoglobin (­ 4 to ­7%) at weeks 3, 12, and 24, decreased RBC counts (­ 6 to ­6. 3%) at weeks 3 and 24, and decreased PCV (­ 4. 2 to ­9. 1%) at weeks 3 and 24. These red cell parameters were "marginally lower" for high­ dose males, but statistical significance was not reached. Platelet counts were increased by up to 13­ 14% in mid not defined) and high­ dose males (week 12) and females (week 24). White cell counts were significantly (p
0.05) increased 27.5% in mid­ dose (not defined) and 23.5% in high­ dose females due to increases in neutrophils. Statistically significant (p
0.05 or 0.01) changes in clinical chemistry parameters were observed in high­ dose males and females during the first 24 weeks. Inorganic phosphorous was increased by 7.3­ 29% and calcium was increased by 3.5­ 10%. Females in the 1, 10, and 100 ppm groups also had significantly (+ 6 to +8%; p
0.01) increased calcium levels at week 3 as compared with the controls. Differences in urea and total cholesterol by the high­ dose males and females were not consistent over time and did not appear to be dose­ related. Urinalyses were conducted by routine analysis, after water deprivation, and after water loading. Differences in urinalysis parameters between treated and control females were considered random and not treatment­ related. No clear evidence of an effect on kidney function was observed in males. Absolute kidney weights were significantly (p
0.05 or 0.01) increased in high­ dose males by 12.9% and 39.3%, and relative kidney weights were increased by 27.3% and 43.0% at 30 days and 26 weeks, respectively. Absolute and relative kidney weights from the 100­ ppm males were increased by 16. 9% and 23. 6%, respectively, at 30 days, but were similar to the controls at 26 weeks. Absolute liver weights were significantly (p
0.01) increased by 40.8% in high­ dose males at 26 weeks and by 29.3% and 32.3% in high­ dose females at 30 days and 26 weeks, respectively. Lindane/ September 2000 RED Toxicology Chapter 17 Relative liver weights of the high­ dose males and females were significantly (p
0.05 or 0.01) were greater (14.0­ 37.2%) than the controls at both sacrifice times. Increases in the incidence of pale kidneys in 100­ and 400­ ppmmales were noted at necropsy. At both 30 days and 26 weeks hyaline droplets in the proximal tubules were observed in the kidneys of all males (10/ 10; p
0.01) receiving 10, 100, and 400 ppm compared with none of the controls. Tubular regeneration (p
0.01) was observed after 30 days in 9­ 10/ 10 males treated with  10 ppm, but at 26 weeks was seen in only 8/ 10 males given 100 ppm and 7/ 10 given 400 ppm. In the 100 and 400 ppm groups, interstitial chronic nephritis occurred in 5­ 6 males at 30 days and 26 weeks and cortical tubular necrosis was observed in 9­ 10 males at 30 days. At 26 weeks cortical tubular necrosis was seen in only 2 100­ ppmmales and 5 (p
0.05) 400­ ppmmales. These treatment­ related kidney lesions were not observed in control males or in females at any dose level. The incidence of periacinar hepatocytic hypertrophy was significantly (p
0.01) increased in the 100­ and 400­ ppm males and the 400­ ppm females at 30 days and 26 weeks. At 30 days the incidences were 7/ 10 and 10/ 10 for males, respectively, and 9/ 9 for females. After 26 weeks of treatment, the incidences were 8/ 10 and 10/ 10 for males, respectively, and 9/ 9 for females. This lesion was not seen in control animals of either sex. No treatment­ related histopathological lesions were observed in the spleen, adrenals, brain, or thymus. Bone marrow data presentation was inadequate for assessment. Therefore, the systemic toxicity LOAEL is 10 ppm (0. 59 mg/ kg/ day) based on microscopic lesions in the kidney of male rats. The systemic toxicity NOAEL is 1 ppm (0.06 mg/ kg/ day). This study is considered Acceptable/ nonguideline as an interim report for a combined chronic toxicity/ oncogenicity study in rats [83­ 5]. It is sufficient for the purpose for which it was intended as an interim report. EXECUTIVE SUMMARY: In a chronic toxicity/ oncogenicity study (MRID 41853701), lindane (99. 75% a. i., Lot no. DA433) was administered in the diet to groups of 50 male and 50 female Wistar rats at concentrations of 0, 1, 10, 100, or 400 ppm for 2 years. Corresponding delivered doses were 0, 0. 05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0. 06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. An additional 15 rats/ sex/ group were designated for interimsacrifices at 30 days and 26 weeks (the results fromthese interimsacrifices are presented separately (MRID 41094101); more sacrifices were performed at 52 and 78 weeks. Clinical signs of toxicity consisted of convulsions in 11 high­ dose females. No other clinical signs were observed. Survival at the end of the study was 36, 36, 31, 20, and 16% for males and 49, 38, 44, 35, and 18% for females in the 0, 1, 10, 100, and 400 ppm groups, respectively. Survival of high­ dose males was similar to the controls through week 93. For females, however, survival was significantly decreased in the high­ dose group with 50% survival reached at week 89 compared to week 104 for the control group. Body weight gains were significantly (p
0.01) decreased for the 100­ and 400­ ppm males during the first few weeks of the study as compared to the controls. Because final body weights of Lindane/ September 2000 RED Toxicology Chapter 18 t he 100 ppm males were similar to the controls, the initial reduction in weight gain was not considered biologically significant. Final body weights of the high­ dose males were significantly 14 p
0. 05) less than the controls. Body weights and body weight gains for the treated females were similar to the controls throughout the study. Food consumption by the high­ dose groups was decreased 15% in males and 19% in females during the first week of the study, however, total food consumption for the entire study was similar to the control levels. Platelet counts were significantly (p
0.05 or 0.01) increased (20% or less ) in the 100­ and 400­ ppm males at week 12 and in 100­ and 400­ ppm males and females at week 24, but not at later time points. High­ dose males and females had significant (p
0.05 or 0.01) decreases in red blood cell parameters at week 104 as compared with the controls: hemoglobin was ­15.6% and ­17.6%, respectively, erythrocyte counts were ­14.1% and ­21%, respectively, and PCV was ­15.9% and 18.2 respectively. Significant (p
0.05 or 0.01) changes in clinical chemistry parameters were observed in highdose males and females during the first year of the study. Inorganic phosphorous was increased by 7.3­ 38.5% and calcium was increased by 3.4­ 10% in males and females; cholesterol was increased by 45­ 110% and urea was increased by 20­ 54% in females; and the albumin/ globulin ratio was decreased by 8. 3­ 18. 2% in females. All parameters were similar to the control levels by week 104. High­ dose males and females had increased absolute and relative liver weights at all interim sacrifices, although statistical significance was not always reached. At study termination, absolute and relative liver weights were significantly (p
0.01) increased by 21.2% and 38.5%, respectively, in high­ dose males and by 31.6% and 33.5%, respectively, in high­ dose females. At 100 ppm, absolute liver weights were increased by 8.6­ 11.2% (n. s.) and relative liver weights were increased by 14.4­ 17.6% (p
0.05 or 0.01) for both sexes at week 104. Significant (p
0.05 or 0.01) increases in absolute and relative spleen weights at week 52 and in relative spleen weights at week 104 were also noted, but the sex was not identified. The incidence rate of periacinar hepatocytic hypertrophy was significantly increased in the 100­ and 400­ ppmgroups with 25/ 50 males and 19/ 50 females affected at 100 ppm and 40/ 50 males and 43/ 50 females affected at 400 ppm. No treatmentrelated histopathological lesions were observed in the spleen or bone marrow. Kidney lesions in males indicative of alpha 2µ globulinaccumulation were observed in animals treated with  10 ppm, but are not considered relevant to human health risk assessment. Therefore, the systemic toxicity LOAEL for male and female rats is 100 ppm (4. 81 and 6.00 mg/ kg/ day, respectively) based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets. The systemic toxicity NOAEL is 10 ppm. Among high­ dose males, there was an apparent increase in adrenal pheochromocytomas. The percentage of animals with tumors (benign and malignant) was 14, 12, 19, 14, and 26% in the 0, 1, 10, 100, and 400 ppm groups, respectively. Statistical significance can be shown depending on the test used. Based on the data presented in this study, an assessment of the carcinogenic potential of lindane cannot be made. Additional histopathological examination of the adrenals from animals in Lindane/ September 2000 RED Toxicology Chapter 19 the 1, 10, and 100 ppm groups, as well as historical control data for this tumor type, are required. These data were submitted as a separate study (MRID 42891401). This chronic toxicity/ oncogenicity study in the rat is Unacceptable/ upgradable and does not satisfy the guideline requirement for a combined chronic toxicity/ oncogenicity study in rats [83­ 5]. Additional data on adrenal pheochromocytomas is necessary to complete the assessment. EXECUTIVE SUMMARY: The current study (MRID 42891201) was submitted as supplemental information to the combined chronic toxicity/ oncogenicity study. Data fromadditional microscopic examination of the adrenal gland from males in the low­ and two mid­ dose groups and historical control data are included. In a chronic toxicity/ oncogenicity study (MRID 41853701), lindane (99.75% a. i., Lot no. DA433) was administered in the diet to groups of 50 male and 50 female Wistar rats at concentrations of 0, 1, 10, 100, or 400 ppm for 2 years. Corresponding delivered doses were 0, 0. 05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0. 06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. An additional 15 rats/ sex/ group were designated for interimsacrifices at 30 days and 26 weeks; the results fromthese interimsacrifices are presented separately (MRID 41094101). Clinical signs of toxicity consisted of convulsions in 11 high­ dose females. No other clinical signs were observed. Survival at the end of the study was 36, 36, 31, 20, and 16% for males and 49, 38, 44, 35, and 18% for females in the 0, 1, 10, 100, and 400 ppm groups, respectively. Survival of high­ dose males was similar to the controls through week 93. For females, however, survival was significantly decreased in the high­ dose group with 50% survival reached at week 89 compared to week 104 for the control group. Body weight gains were significantly (p
0.01) decreased for the 100­ and 400­ ppm males during the first few weeks of the study as compared to the controls. Because final body weights of the 100 ppm males were similar to the controls, the initial reduction in weight gain was not considered biologically significant. Final body weights of the high­ dose males were significantly 14 p
0. 05) less than the controls. Body weights and body weight gains for the treated females were similar to the controls throughout the study. Food consumption by the high­ dose groups was decreased 15% in males and 19% in females during the first week of the study, however, total food consumption for the entire study was similar to the control levels. Platelet counts were significantly (p
0.05 or 0.01) increased (20% or less) in the 100­ and 400­ ppm males at week 12 and in 100­ and 400­ ppm males and females at week 24, but not at later time points. High­ dose males and females had significant (p
0.05 or 0.01) decreases in red blood cell parameters at week 104 as compared with the controls: hemoglobin was ­15.6% and ­17.6%, respectively, erythrocyte counts were ­14.1% and ­21%, respectively, and PCV was ­15.9% and 18.2 respectively. Significant (p
0.05 or 0.01) changes in clinical chemistry parameters were observed in highdose males and females during the first year of the study. Inorganic phosphorous was increased by Lindane/ September 2000 RED Toxicology Chapter 20 7.3­ 38.5% and calcium was increased by 3.4­ 10% in males and females; cholesterol was increased by 45­ 110% and urea was increased by 20­ 54% in females; and the albumin/ globulin ratio was decreased by 8. 3­ 18. 2% in females. All parameters were similar to the control levels by week 104. High­ dose males and females had increased absolute and relative liver weights at all interim sacrifices, although statistical significance was not always reached. At study termination, absolute and relative liver weights were significantly (p
0.01) increased by 21.2% and 38.5%, respectively, in high­ dose males and by 31.6% and 33.5%, respectively, in high­ dose females. At 100 ppm, absolute liver weights were increased by 8.6­ 11.2% (n. s.) and relative liver weights were increased by 14.4­ 17.6% (p
0.05 or 0.01) for both sexes at week 104. Significant (p
0.05 or 0. 01) increases in absolute and relative spleen weights at week 52 and in relative spleen weights at week 104 were also noted, but the sex was not identified. The incidence rate of periacinar hepatocytic hypertrophy was significantly increased in the 100­ and 400­ ppm groups with 25/ 50 males and 19/ 50 females affected at 100 ppm and 40/ 50 males and 43/ 50 females affected at 400 ppm. No treatment­ related histopathological lesions were observed in the spleen or bone marrow. Kidneylesions in males indicative of alpha 2µ globulin accumulation were observed in animals treated with  10 ppm, but are not considered relevant to human health risk assessment. Therefore, the systemic toxicity LOAEL for male and female rats is 100 ppm (4. 81 and 6.00 mg/ kg/ day, respectively) based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets. The systemic toxicity NOAEL is 10 ppm (0. 47 and 0.59 mg/ kg/ day, males and females, respectively). Eight additional males were identified as having adrenal pheochromocytomas. The revised percentages of animals with adrenal tumors in the 0, 1, 10, 100, and 400 ppm groups are 14, 16, 16, 6, and 24% for benign tumors, respectively, and 0, 0, 6, 8, and 2% for malignant tumors, respectively. Statistical significance was not reached by relevant tests. For comparison, historical control data fromCharles River and publications in the open literature were submitted. The 10 and 100 ppm groups had malignant tumor incidence rates greater than the historical control rate (0­ 2%). The high­ dose group also had a slight excess of benign and combined tumor rates as compared with the historical control rates (8­ 22% benign, combined could not be calculated), but this same net tumor incidence was the same as the control group of a published study. In the current study, pheochromocytomas were not considered the cause of death for any animal with the exception of a single animal in the 100 ppm group. Therefore, no evidence dose­ related and statisticallysignificant increase inadrenal tumors was observed in this study. The study was conducted at adequate dose levels. This chronic toxicity/ oncogenicity st udy in the rat is Acceptable/ guideline (revised) and satisfies the guideline requirement for a combined chronic toxicity/ oncogenicity study in rats [83­ 5]. Lindane/ September 2000 RED Toxicology Chapter 21 870.4100b Chronic Toxicity ­ Dog Chronic studies in two species, rat and rabbit, are available. See chronic oral section for executive summaries. 4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The data base for carcinogenicity is considered incomplete. According to the TES committee report (1994), lindane has not been classified by the HED Cancer Peer Review Committee. It was determined by the RfD/ Peer Review Committee (1993) that: "The mouse carcinogenicity data were considered insufficient because of major deficiencies associated with all studies available." Lindane however had been previously (1985) classified by the Cancer Assessment Group of the Office of Research and Development as a group B2/ C carcinogen based on increased incidence of mouse liver tumors. The upper­ bound slope of the dose­ response was given in that memorandumas Q1* = 1.1 (mg/ kg/ day) ­1 . Amouse carcinogenicity study is expected to be submitted in December 2000. 870.4200a Carcinogenicity Study ­ rat See the chronic toxicity section for executive summaries 870.4200b Carcinogenicity (feeding) ­ Mouse A new study is expected in December 2000. EXECUTIVE SUMMARY: In a special study, (MRID none) three strains of female mice, agouti, pseudoagouti, and black, were administered lindane at dietary concentrations of 0 or 160 ppm. The doses were selected based on a preliminary st udy where no deaths occurred after one month. Groups of 36­ 96 animals per strain were continuously fed treated or control diets for up to 24 months. Additional groups of 48­ 96 agouti and black mice were fed treated or control diets for 6 months then fed control diet for 6 or 18 months (recovery). No clinical signs of toxicity and no survival information were reported. No apparent effects on body weights or food consumption were observed, but only limited data were presented. When compared with untreated controls at 6 and 12 months, benzo( a) pyrene monooxygenase activity in the liver was increased 1.61­ 1.84x in the agouti, 2.71­ 2.78x in the pseudoagouti, and 2.07­ 2.09x in the black strains. Liver weights were increased 14.7­ 31.2% in the agouti, 13.5­ 22.0% in the pseudoagouti, and 12.2­ 16.4% in the black strains at interval sacrifices up to 24 months. Following the recovery period, liver weights of the treated mice were similar to the controls. No evidence for increased incidence or decreased latency of liver tumors was observed for the black strain at any time during the study (24 months) or for the pseudoagouti strain through the 18 month sacrifice. At 18 months, 0/ 34 control and 12/ 36 (33%) of the treated agouti mice Lindane/ September 2000 RED Toxicology Chapter 22 developed hepatocellular adenomas; one carcinoma each in the treated and control groups was noted. Both the treated agouti and pseudoagouti strains had clear increases in adenomas and slight increases in carcinomas at 24 months. The incidence rates for the control and treated agouti groups were 9% and 35%, respectively, for adenomas and 13% and 17%, respectively, for carcinomas. The incidence rates for the control and treated pseudoagouti groups were 5% and 12%, respectively, for adenomas and 2% and 5%, respectively, for carcinomas. Increases in Clara cell hyperplasia were noted in the lung at all sacrifice intervals for each strain and the incidence of lung tumors was increased in later months for the agouti and pseudoagouti strains. The percentage of mice with Clara cell hyperplasia in the control and treated groups was 631 and 72­ 92%, respectively, for the agouti; 6­ 17% and 50­ 79%, respectively, for the pseudoagouti; and 0­ 14% and 56­ 90%, respectively, for the black. Lung tumors for the agouti strain occurred in 0% of the control and 17% of the treated animals at 18 months and 4% of the control and 19% of the treated animals at 24 months. Lung tumors in the pseudoagouti strain occurred in 6% of the controls and 14% of the treated animals at 24 months. After recovery, the incidences of Clara cell hyperplasia (agouti and black) and lung tumors (agouti) remained slightly elevat ed as compared with the controls. In conclusion, dietary administration of lindane resulted in the induction of liver and lung tumors in the agouti and pseudoagouti mouse strains and caused increased liver weights, increased enzyme activity, and irreversible Clara cell hyperplasia in the lung of all three mouse strains tested. This study is considered Acceptable/ nonguideline as a special study in mice. The study deficiencies include: only females tested, only one dose level tested, histopathology data provided for lung and liver only, lack of analytical chemistry data, and no individual animal data. These study results can be used as supplementary information to the chronic/ oncogenicity study in rats. 4.7 Mutagenicity Adequacy of data base for Mutagenicity: The data base for Mutagenicity is considered adequate based on submitted studies and reports in the open literature. Lindane does not appear to be mutagenic. In a mammalian cell gene mutation assay and an in vivo sister chromatid exchange assay, no mutagenic response was detected. The open literature suggests, however, that technical grade HCH (hexachlorohexane; 6. 5%
­ HCH) may induce some mutagenic activity as evidenced in a dominant lethal mutation assay and sister chromatid exchanges. Overall, based on the results of acceptable studies on lindane, it does not appear to have mutagenic potential. Gene Mutation Lindane/ September 2000 RED Toxicology Chapter 23 cell gene mutation assay MRID 00144500 Unacceptable/ Guideline In a mammalian cell gene mutation assay conducted in Chinese hamster V79 cells, lindane was tested in the absence of metabolic activation at dose levels of 2.5, 5, 10, 25, 50, 70, 100, and 150 µg/ ml and in the presence of metabolic activation at dose levels of 5, 10, 25, 50, 100 250 and 500 µg/ ml. The S9 fraction used for metabolic activation was obtained from Aroclor 1254­ induced mouse liver. Tests with and without activation were conducted under aerobic and anaerobic conditions. Under anaerobic conditions, lindane without S9 was cytotoxic to the V79 cells at dose levels above 10 µg/ ml and with S9 at dose levels above 150 mg/ ml. No mutagenic activity of lindane was observed in V79 cells under any combination of conditions up to cytotoxic doses. Cytogenetics sister chromatid exchange MRID 00024504 Acceptable/ Guideline In a mammalian in vivo sister chromatid exchange (SCE) assay, 50µg tablets of bromodeoxy­ uridine were implanted into male and female CF­ 1 mice. Two hours after implantation, lindane was administered ip in arachis oil at dose levels of 1.3, 6.4 and 32.1 mg/ kg. For each dose level and control group, 30 bone marrow cells from each of 5 animals of each sex were examined for SCEs. No toxicity was reported in any treatment group. When results for male and female animals were pooled, only the highest dose produced a significant increase in SCEs over the controls. Positive control values were appropriate. ,dominant lethal assay MRID 00062657 Unacceptable/ Guideline In a mammalian dominant lethal assay, 10 male Sprague­ Dawley rats of unspecified age per group were exposed to lindane administered by subcutaneous injection in corn oil at doses of 0, 1, 3, and 10 mg/ kg five time per week for 10 weeks. Uteri were examined for live and dead implants and abnormalities. Males were also sacrificed and gross pathological analysis performed. The incidence of dead implants was significantly increased at the lowest dose but not at the two higher doses in the first week of mating but this increase was not observed during the second week. The authors conclude that lindane did not cause an increase in the incidence of dominant lethals inthis study. 4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: Neurotoxicity studies (acute, subacute and developmental) have been submitted. Lindane is a neurotoxicant. In acute, subchronic and developmental neurotoxicity studies, it was found to cause neurotoxic effects including tremors, convulsions, decreased motor activity, increased forelimb grip strength, hypersensit ivity to touch, hunched posture and decreased motor activity habituation. There also appears to be a greater susceptibility to exposure by offspring compared to parental animals. The LOAEL for offspring toxicity is 50 ppm (5. 6 mg/ kg/ day) based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation compared to a LOAEL of 120 ppm (13.7 mg/ kg/ day) based on decreased body weight gains, Lindane/ September 2000 RED Toxicology Chapter 24 decreased food consumption, and increased reactivity to handling for maternal toxicity. 870.6100 Delayed Neurotoxicity Study ­ Hen Not required 870.6200 Acute Neurotoxicity Screening Battery EXECUTIVE SUMMARY: In an acute oral neurotoxicity study (MRID44769201), groups of 10 Crl: CD® BR rats/ sex/ dose were administered single dose of lindane (Batch No. HLS96/ 1, Purity 99.78%) by gavage at concentrations of 0 (control), 6, 20, or 60 mg/ kg. Functional observational battery (FOB) and motor activity (MA) testing were performed prior to administration and within 3 hours (time of peak effect) of dosing (day 0), and on days 7 and 14 post­ dose. Body weights were recorded pre­ test, weekly during the study period and on FOB assessment days. Clinical signs were recorded at least once daily. At study termination all animals were sacrificed and fixed by whole body perfusion, designated tissues of the nervous system were processed for microscopic neuropathological evaluation. All animals survived to scheduled termination. One male in the 60 mg/ kg group was observed to convulse on the day of treatment within 2. 75 hours after dosing. Clinical signs were also observed in females treated at 60 mg/ kg within 24 hours of dosing and included: staining of the fur, stained urogenital region, hunched posture, and piloerection. These effects in females persisted for four days. Significant treatment­ related decreases in body weight gains were observed for males in the 60 mg/ kg group compared to the control group for the first week of the study. Females administered this concentration also had slightly lower body weight gains throughout the study. Food consumption for males and females administered 60 mg/ kg was significantly decreased compared to controls for Week 1 of the study. Food conversion ratios in the treated groups were not changed compared to control groups. At the first FOB assessment on Day 0 (3 hours after dosing) males and females in the 60 mg/ kg group exhibited piloerection (1
,2  ), decreased rectal temperature (1
,1  ), increased hindlimb foot splay and hunched posture (4
,7  ). Among males dosed at 60 mg/ kg, increased respiration (3
,1  ) and one observation of tremor/ twitching were observed. Females administered 60 mg/ kg were observed to have increased incidences of walking on tip toes (10), licking behavior (3), decreased foot splay (3) and an absence of grooming (8) behavior. Females in the 20 mg/ kg also had decreased grooming (3) behavior and increased forelimb grip strength. Motor activity was significantly decreased for males and females treated with 60 mg/ kg as well as among females treated with 20 mg/ kg three hours post­ treatment. The 6 mg/ kg group remained comparable to controls in FOB assessment parameters and MA. No neuropathological endpoints were observed during the histological examinations of the peripheral or central nervous systems of these animals at any exposure concentration. The NOAEL for systemic toxicity is 20 mg/ kg for males and 6 mg/ kg for females. Based on the substance­ related effects on body weight, body weight gain, food consumption, and clinical signs of toxicity the LOAEL for systemic toxicity in males is 60 mg/ kg. The LOAEL for females is 20 mg/ kg based on a lower incidence of grooming behavior and decreased Lindane/ September 2000 RED Toxicology Chapter 25 locomotor activity immediately after dosing, in addition to the parameters mentioned above. The NOAEL for neurotoxic effects is 6 mg/ kg for females and the LOAEL is 20 mg/ kg based on increased forelimb grip strength and decreased grooming behavior and motor activity (MA). The NOAEL for neurotoxicity in males is 20 mg/ kg and the LOAEL for males is 60 mg/ kg based on tremors, convulsions, decreased MA, and increased forelimb grip strength. This study is classified Acceptable/ guideline and satisfies the Subdivision F guideline requirement for an acute oral neurotoxicity study (§ 81­ 8) in rats. 870.6200 Subchronic Neurotoxicity Screening Battery EXECUTIVE SUMMARY: In a subchronic oral neurotoxicity study (MRID 44781101), groups of 10 Crl: CD® BR rats/ sex/ group were administered lindane (Batch No. HLS96/ 1, Purity 99.78%) in the diet for 13 weeks at concentrations of 0 (control), 20, 100, or 500 ppm. Due to severe toxic reactions to treatment at 500 ppm, the dose was reduced to 400 ppm on day 11 of treatment thereafter. These doses resulted in average daily intake values of 0, 1.4, 7.1, and 28.1 mg/ kg/ day for males and 0, 1.6, 7.9, and 30.2 mg/ kg/ day in females for 0, 20, 100, and 500/ 400 ppm, respectively. Functional observational battery (FOB) and motor activity (MA) tests were performed prior to administration and after 4, 8, and 13 weeks of treatment. Body weights were recorded pretest weekly during the study period and on FOB assessment days. Clinical signs were recorded at least once daily. At study termination all animals were sacrificed and fixed by whole body perfusion and designated tissues of the nervous system were processed for microscopic neuropathological evaluation. Three females in the 500/ 400 group died prior to scheduled termination. These deaths were attributed to treatment with lindane. One death was recorded on Day 11 of the study, one during week 10 and one during week 13. Clinical signs prior to death included weight loss, swollen muzzle with scabbing, hunched posture, piloerection, and staining of the anogenital region. Observations in surviving females treated at 500/ 400 ppmwere hypersensitivity to touch, staining of the urogenital region, and scabbing of the toes. Significant treatment­ related decreases (p< 0.05 or p< 0.01) in body weight were observed among males and females treated with 500/ 400 ppm of 14% and 23%, respectively. Decreases in body weight gains (70%
and 180%  , p< 0.01), food consumption (35%
and 50%  ,p< 0. 05or p< 0.01, respectively), and food conversion ratios were observed for males and females in the 500 ppm groups compared to the control group for the first week of the study. Male rats tended to recover from these effects after the dose was lowered. Females, however, did not exhibit this same level of recovery as their food consumption remained slightly depressed throughout the remainder of the study. Females in the 100 ppm group had significantly decreased body weight gains (40%, p< 0.05) compared to the control group during the first week of the study and this effect continued, although not at a level of significance throughout the remainder of the study. Females in the 100 ppm group had significantly decreased food consumption (16%, p< 0.01) for the first week of the study and this Lindane/ September 2000 RED Toxicology Chapter 26 trend continued throughout the study. Liver weights were also found to be increased at 500/ 400 ppm for both sexes; no additional information was given. During the FOB assessment (table A is attached at t he end of this document), males and females treated at the highest dose (500/ 400 ppm) were perceived as difficult to handle. They also were observed to have piloerection and hunched posture. Females in the highest dose group had missing claws (3), tended to urinate more often than controls, had a higher incidence of grooming behavior, rearing, motor activity, and one female was observed to convulse. Females across the dose groups were observed walking on tiptoes (5­ 7) and these incidences were significantly increased compared to the control (1) for the highest dose group. Females (5) in the 100 ppm group also had increased incidences of grooming behavior at the Week 4 evaluation and one animal in this group was extremely difficult to handle. The assessments of forelimb and hindlimb grip strength as well as hindlimb splay revealed no differences for any of the treated groups compared to the control groups. Colburn motor activity was also similar among treated groups compared to the control groups. No neuropathological endpoints attributable to lindane administration were observed during the histological examinations of the peripheral or central nervous systems of these animals at any exposure concentration. The NOAEL for systemic toxicity is 100 ppm for males (7. 1 mg/ kg) and 20 ppm for females (1.6 mg/ kg). Based on the substance­ related effects on body weight, body weight gain, food consumption, and clinical signs of toxicity the LOAELlevels for systemic toxicity in males is 500/ 400 ppm (28.1 mg/ kg) and 100 ppm for females (7. 9 mg/ kg). The NOAEL for neurotoxic effects is 100 ppm for males (7. 1 mg/ kg) and females (7. 9 mg/ kg). The neurotoxicity LOAEL is 500/ 400 ppm based on hypersensitivity to touch and hunched posture. This study is classified Acceptable/ guideline and satisfies the Subdivision F guideline requirement for an acute oral neurotoxicity study (§ 81­ 8) in rats. 870.6300 Developmental Neurotoxicity Study EXECUTIVE SUMMARY: In a developmental neurotoxicity study (MRID 45073501), lindane (Batch No. HLS 96/ 1; 99.78% a. i.) was administered to presumed pregnant Hsd Brl Han: Wist (Han Wistar) rats in the diet at concentrations of 0, 10, 50, or 120 ppm fromgestation day (GD) 6 through lactation day 10. These concentrations resulted in F0 maternal doses of 0. 8­ 0. 9, 4. 24.6 and 8. 0­ 10.5 mg/ kg/ day, respectively, during gestation and 1. 2­ 1. 7, 5. 6­ 8. 3, and 13.7­ 19.1 mg/ kg/ day, respectively, during lactation. The developmental neurotoxicityof lindane was evaluated in the F1 offspring. F1 animals (10/ sex) were evaluated for FOB, motor activity, auditory startle response, and learning and memory as well as developmental landmarks such as vaginal perforation and balanopreputial separation, and brain weights and histopathology on days 11 and 65, including Lindane/ September 2000 RED Toxicology Chapter 27 morphometrics. Small differences in absolute maternal body weights (7­ 8%) were observed between the high dose and control groups during gestation and early lactation (through day 11). Body weight gains by the high­ dose dams from GD 6 through GD 20 were 64­ 79% (p
0. 01) of the control level. Body weight changes during lactation were similar between the treated and control groups. During gestation, food consumption by the high­ dose group was significantly( p
0.01; 74­ 92% of controls) less than the control group for the intervals of GD 10­ 13, 14­ 17, and 18­ 19. Food consumption by the low­ and mid­ dose groups during gestation and by all treated groups during lactation was similar to the controls. Absolute body weights of the treated male and female pups in mid and high dose groups during lactation were 12­ 18% and 16­ 20% less than controls, respectively on days 4­ 11 of lactation with recovery to less than 10% by day 21. Body weight gains (p
0.05 or 0.01) on lactation days 1­ 4 and 1­ 11 were 76% and 84%, respectively, of the control levels for mid­ dose males, 79% and 79%, respectively, for mid­ dose females, 60% and 73%, respectively for highdose males, and 63 and 75%, respectively, for high­ dose females. Body weight gains by all treated groups were similar to the controls during lactation days 11­ 21. Except for mid and high dose females, postweaning, body weight gains were similar between the treated and control groups. Body weight differences for high dose dams were 10% less at the beginning of lactation and recovered to 6% less by the end of the study. The high­ dose group had a greater number of stillborn pups as indicated by a live birth index of 77% compared with 99% for the control group. In addition, nine high­ dose litters either died or were sacrificed moribund on lactation days 1­ 4. This resulted in a viability index for the high­ dose group of 71% compared with 89% for the controls. Pup mortality in the mid and high­ dose groups in litters surviving to weaning was greater before day 4 than in controls [ 3 pups in 2/ 20 controls; 18 pups in 8/ 22 litters, mid dose; 14 pups in 4/ 15 litters, high dose]. Survival was not affected at any time in the low dose group as compared with the control group. No dose­ or treatment­ related differences were observed between treated and control groups for duration of gestation, number of pups/ litter on day 1, or per cent male offspring. At necropsy, no treatment­ related gross abnormalities were observed in the dams or offspring. Absolute and relative liver and kidney weights of the offspring were not affected by treatment. A few clinical signs were observed in high dose dams and pups; increased reactivity to handling in dams on weeks 2 and 3 of dosing, and slower surface righting in pups on day 4. There were no effects on measures of physical or sexual development. There was an increase in motor activity at the mid and high dose during lactation in both sexes. Some decrease in habituation of motor activity in females on day 22 was also seen. While there was no effect on auditory startle reflex amplitudes, there was a clear reduction in auditory startle response habituation in both sexes at the high dose on day 28 and on day 60. Slight decreases in absolute, but not relative, brain weights in mid and high dose female pups were observed on postnatal day 11 (9­ 10%) but narrowed to 3­ 5% less by day 65. Brain lengths and widths were Lindane/ September 2000 RED Toxicology Chapter 28 similar between the treated and control pups. Morphometric brain measurements did not show any significant differences in the sizes of the neocortex, hippocampus, corpus callosum, or cerebellum on days 11 or 65. There were no effects on histopathology of the nervous system. The maternal toxicity LOAEL is 120 ppm (13.7 mg/ kg/ day) based on decreased body weight gains, decreased food consumption, and increased reactivity to handling. The maternal toxicity NOAEL is 50 ppm (5. 6 mg/ kg/ day). The offspring toxicity LOAEL is 50 ppm (5.6 mg/ kg/ day) based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. The offspring toxicity NOAEL is 10 ppm (1.2 mg/ kg/ day). This study is classified as Unacceptable/ Guideline [870.6300 (§ 83­ 6)] since laboratory validation studies of the neurobehavioral tests were not included, but it may be upgraded and found acceptable if this information is obtained. The number of animals tested at the highest dose is only 6 compared to the required number of 10 animals per dose. 4.9 Metabolism Adequacy of data base for metabolism: The data base formetabolismis considered tobe complete. No additional studies are required at this time. Lindane is distributed to all organs at measurable concentrations within a few hours after oral administration. The highest concentrations are found in adipose tissue. The metabolism of lindane is initiated through one of pathways: Dehydrogenation leading to
­ HCH, Dehydrochlorination leading to formation of
­ PCCH, Dechlorination leading to formation of
­ tetrachlorohexene, or Hydroxylation leading to formation of hexachlorocyclohexanol. Further metabolismleads to a large number of metabolites. Volatilizalion appears to be an important route of its dissipation under the high­ temperature conditions of tropical regions. Lindane is converted by enzymatic reactions, mainly in the liver. In mammals, including humans, lindane is excreted very rapidly in urine and faeces after metabolic degradation; only small amounts are eliminated unchanged. The half­ life of lindane administered to rats is 2­ 4 days depending on the frequency of exposures, single or repeated. 870.7600 Dermal Absorption ­ Rat EXECUTIVE SUMMARY: In a dermal absorption study, (MRID 40056107) 24 male Crl: CD ® (SD) BRrats per group received dermal applications of lindane 20% emulsifiable concentrate ([ 14 C]­ Lindane and unlabeled Lindane) at doses of 0. 1, 1. 0, or 10 mg/ rat. Four animals/ group were bled and sacrificed at intervals of 0. 5, 1, 2, 4, 10, or 24 hours after application of the test article. Quantities absorbed increased with dose and duration of exposure while percent absorbed Lindane/ September 2000 RED Toxicology Chapter 29 increased with time and decreased with dose. Percents of the low­, mid­, and high­ doses absorbed were 0.6, 0.96, and 0. 66% after 0. 5 hours; 18.07, 8.31, and 2. 81% after 10 hours; and then, increased to 27.72, 20.86, and 5. 05% after 24 hours. The total amount of test article absorbed after 24 hours, as calculated from urine, feces, and carcass, was 0. 028, 0.21, and 0. 51 mg for the low­, mid­, and high­ dose groups, respectively. The process appears to be approaching saturation at the high dose. Recovered radioactivity (absorbed, skin, skin rinse, filter paper and spreader) was 74.19, 70.19 and 58.35% of the applied dose after 24 hours of exposure in the low­, mid­, and high­ dose, respectively. This study is considered Acceptable/ guideline and satisfies the requirements for a dermal absorption study in rats [85­ 2]. EXECUTIVE SUMMARY: In a dermal absorption study, (MRID 40056108) 24 male Hra:( NZW) SPF rabbits per group received dermal applications of lindane 20% emulsifiable concentrate ([ 14 C]­ Lindane and unlabeled Lindane) at doses of 0. 5, 5. 0, or 50 mg/ rabbit. Four animals/ group were bled and sacrificed at intervals of 0. 5, 1, 2, 4, 10, or 24 hours after application of the test article. Quantities absorbed increased with dose and duration of exposure while percent absorbed increased with time and decreased with dose. Percentages of the low­, mid­, and high­ doses absorbed were 5.97, 6.68, and 1. 99% after 0. 5 hours ; 51.68, 23.76 and 10.96% after 10 hours; and then increased to 55.68, 39.99, and 16.56% after 24 hours. The total amount of test article absorbed after 24 hours, as calculated fromurine, feces, and carcass, was 0. 28, 2.00, and 8. 46 mg for the low­, mid­, and high­ dose groups, respectively. The original DER states that no evidence of saturation of the absorption process was observed; however upon further examination it appears that there is evidence of saturation at the highest dose (50 mg/ rabbit) tested. Recovered radioactivity (absorbed, skin, skin rinse, filter paper and spreader) was 82.01, 78.27 and 66.34% of the applied dose after 24 hours of exposure in the low­, mid­, and high­ dose, respectively. This study is considered Acceptable/ guideline and satisfies the requirements for a dermal absorption study in rabbits [85­ 2]. However, it should be noted that the rabbit is not the preferred species for dermal absorption studies as it grossly overestimates absorption compared to man. 5. 0 TOXICITY ENDPOINT SELECTION 5.1 See Section 9. 2 for Endpoint Selection Table. 5.2 Dermal Absorption Dermal Absorption Factor: 10 % The HIARC concurred with the TES committee decision (HED Doc. # 013460) that the dermal absorption factor is 10% based on a published report by Feldman and Maibach (Toxicology and Applied Pharmacology 28, 126­ 132, 1974). Lindane/ September 2000 RED Toxicology Chapter 30 The Maibach study tested 12 pesticides and herbicides, including lindane, on human subjects (6 per chemical) to quantitate their dermal penetration. C 14 ­labeled chemicals were applied topically (4 g/ cm 2 ) to the forearm or via the intravenous route (1 Ci). Excretion of the chemicals was then monitored by collecting and analyzing urine samples during the 5 day testing period. All results were calculated as percent of the injected or applied dose. Data obtained after IV dosing was used to correct the skin penetration data for incomplete urinary recovery. Lindane was shown to have a penetration factor of 9.3% ± 3. 7 (SD). The dermal absorption factor is required for dermal exposure for all durations of exposure risk assessment since oral doses were selected for these exposure periods. 5.3 Classification of Carcinogenic Potential The classification of carcinogenic potential will be re­ evaluated upon receipt of a new mouse carcinogenicity study, expected in December 2000. Currently, according to the TES committee report (1994, Doc 013460), lindane has not been classified by the HED Cancer Peer Review Committee. The RfD/ Peer Review Committee in 1993 concluded that: "The mouse carcinogenicity data were considered insufficient because of major deficiencies associated with all studies available." Lindane however had been previously (1985) classified by the Cancer Assessment Group of the Office of Research and Development as a group B2/ C carcinogen based on increased incidence of mouse liver tumors. Although the animal data was limited, the presence of a carcinogenic metabolite, 2,4,6­ trichlorophenol, in meaningful quantities in the urine of humans exposed to lindane and the structural similarity with a rodent carcinogen, alpha­ hexachlorocyclohexane, elevated the classification above a "C" to "B2". The upper­ bound slope of the dose­ response was Q1* = 1. 1 (mg/ kg/ day) ­1 . 6.0 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children Although the developmental study in rats provided no indication of a quantitative increased susceptibility/ sensitivity following in utero exposure to lindane, evidence of a qualitative increase in susceptibility was noted in the developmental neurotoxicity study and the 2­ generation reproductive study in rats. Therefore, the FQPAcommittee decided to reduce the safety factor to 3X for lindane. In the prenatal developmental toxicity studies in rats, developmental effects were observed only at or above doses causing maternal toxicity. The prenatal developmental study in rabbits is classified as Unacceptable (not upgradable) since maternal and developmental toxicityLOAELs were not identified and the highest dose did not approach the limit dose. Therefore, dose selection was considered inadequate. Doses were based on the results of a subcutaneous studyin the rabbit (MRID 00062658) which is not a valid method for selecting doses for an oral study. Several other deficiencies were noted in the conduct of this study, included: percent purity of the test article was Lindane/ September 2000 RED Toxicology Chapter 31 not given, dosing solutions were not analyzed for concentration, stability, or homogeneity, and much of the individual animal data were not included. Although the developmental toxicitystudyin rabbits was classified unacceptable, the HIARC concluded that a new study is not required because: 1) The developmental toxicity study in rabbits and rats using a subcutaneous route of administration shows no developmental effects at the maternally toxic dose; 2) The incidences of skeletal effects observed in the developmental toxicity study in rats, with gavage as the route of administration, are within historical controls; 3) More severe maternal effects are seen in the rabbit study with subcutaneous administration; 4) The rat appears to be the more sensitive species for developmental effects; 5) Adevelopmental neurotoxicity study has already been submitted. There was, however, evidence of qualitative increased susceptibility in the rat multi­ generation reproduction study: Both parental and offspring LOAELS are 13 mg/ kg; however there is a qualitative difference in the severity of effects. In the parental animals, toxicity was seen in the form of reduction in body weight gain during gestation while offspring toxicity was correlated with decreases in pup viability and pup body weight in the F1 and F2 generations as well as delayed maturation in the F2 generation. Evidence for quantitative increase in susceptibility could not be ascertained due to the wide spread in the doses tested. There is also quantitative increased susceptibility demonstrated in the rat developmental neurotoxicity study: Maternal toxicity observed at 120 ppm (13.7 mg/ kg/ day, LOAEL) is based on decreased body weight gains, decreased food consumption, and increased reactivity to handling (maternal NOAEL is 50 ppm; 5. 6 mg/ kg/ day). Offspring toxicity was observed at 50 ppm (5. 6 mg/ kg/ day, LOAEL) and is based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation (NOAEL is 10 ppm; 1. 2 mg/ kg/ day). The offspring effects seen in the developmental neurotoxicity study were the same as those seen in the the two­ generation reproduction study ­ no additional functional or morphological changes in the nervous system were noted. In the open literature, lindane is found in mother's milk and metabolites of lindane have been shown to cross the placental barrier. 6.2 Recommendation for a Developmental Neurotoxicity Study A developmental neurotoxicity study has already been conducted. Lindane/ September 2000 RED Toxicology Chapter 32 7. 0 REFERENCES MRID 00024504. Anonymous (1984). In vivo sister chromatid exchange assay in CF1­ mouse bone marrow cells with Lindane (interperitoneal injection): Lindane (gamma benzene hexachloride U. S. P.). Research and Consulting Company AG (RCC). Study No. 025716, July 17, 1984. 00062656. Reno, F. E. (1976) Teratology study in rats: Lindane (gamma benzene hexachloride, U. S. P.). Hazleton Laboratories America. Study No. 405­ 104. July 13, 1976. Unpublished. 00062657. Reno, F. E. and Medford, ?.?. (1976) Teratology study in rats: Lindane (gamma benzene hexachloride, U. S. P.). Hazleton Laboratories America, Inc. Study No. 405­ 107. November 12, 1976. Unpublished. 00062658. Reno, F. E. (1976) Teratology study in rabbits: Lindane (gamma benzene Lindane/ September 2000 RED Toxicology Chapter 33 hexachloride, U. S. P.). Hazleton Laboratories America. Study No. 450­ 103. August 6, 1976. Unpublished. 00144500. Glatt H. R. (1985). Mammalian cell (V79) mutagenicity test on Lindane using anaerobic exposure conditions. Institute of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D­ 6500 Mainz, FRG. Study No. 540­ VT21­ b. October 18, 1985. 255003. Anonymous. 1983. 90­ day inhalation study in rats with Lindane. Frauenhofer Institut fur Toxikologies und Aerosolforschung, D­ 5948 Schmollenberg, Germany. Project No. 104264. February 28, 1983. Unpublished. (Translated from German) 40056107. Bosch, A. L. 1987. Dermal absorption of 14 C­ lindane in male rats. Hazleton Laboratories America, HLA. Study No. 6188­ 103. January 13, 1987. Unpublished. 40056108. Bosch, A. L. 1987. Dermal absorption of 14 C­ lindane in male rabbits. Hazleton Laboratories America. HLA Study No. 6188­ 104. January 7, 1987. Unpublished. 40873501. Klonne, D. R. and Kintigh, W. J. 1988. Lindane technical fourteen­ week dust aerosol inhalation study on mice. Bushy Run Research Center, Export, PA. Study Nos. BRCC #51­ 524; Metpath #14014. October 7, 1988. Unpublished. 41094101. Aymes, S. J. 1989. Lindane: Combined oncogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks ­ Interim report week 0­ 26. Life Sciences Research, England. Study No. 88/ CIL002/ 816. March 7, 1989. Unpublished. 41427601. Brown, D. (1990) Lindane: 13 week dermal toxicity study (with interim kill and recovery period) in the rabbit. Hazleton, Inc., North Yorkshire, England. Study No. 6164­ 580/ 6. February 22, 1990. Unpublished. 41853701. Aymes, S. J. 1989. Combined oncogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks. Life Sciences Research, England. Study No. 90/ CIL002/ 0839. November 7, 1989. Unpublished. 42246101. King, V. C.. (1991) Lindane: Reproductive performance study in rats treated continuously through two successive generations. Life Sciences Res. Ltd., Suffolk, England. Study No. 91/ CIL004/ 0948. September 12, 1991. Unpublished. 42808001. Palmer, A. K. and Lovell, M. R. (1971) Effect of lindane on pregnancy of the rat. Huntingdon Research Centre, England. Study No. 4307/ 71/ 463. December 3, Lindane/ September 2000 RED Toxicology Chapter 34 1971. Unpublished. 42808002. Palmer, A. K. and Neuff, A. M. (1971) Effect of lindane on pregnancy of the New Zealand white rabbit. Huntingdon Research Centre, England. Study No. 4308/ 71/ 464. December 2, 1971. Unpublished. 42891201. Aymes, S. J. 1993. Lindane: Combined oncogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks. Addendum to final report (Adrenal histopathology ­ additional investigations). Life Sciences Research, England. Study No. 90/ CIL002/ 0839. June 2, 1993. Unpublished. 44769201 Hughes, E. W., 1999. Neurotoxicity study by a single oral gavage administration to CD rats followed by a 14­ day observation period. Huntingdon Life Sciences Ltd., P. O. Box 2, Huntingdon, Cambridgeshire, PE186ES, England. Project Identity CIL/ 011 February 25, 1999, Unpublished. 44781101 Hughes, E. W., 1999. 13­ week neurotoxicity study in rats by dietary administration. Huntingdon Life Sciences Ltd., P. O. Box 2, Huntingdon, Cambridgeshire, PE18 6ES, England. Project Identity CIL/ 012, March 5, 1999, Unpublished. 45073501. Myers, D. P. (1999) Lindane: Developmental neurotoxicity study in the Han Wistar rat by dietary administration. Huntingdon Life Sciences Ltd. Eye, Suffolk, IP23 7PX, England. Laboratory Project No. CIL/ 022, September 21, 1999. Unpublished. TOX DOCUMENT # 013460 Copley, Marion, Toxicology Endpoint Selection Document, November 4, 1994 014263 Shallal, Suhair, Lindane­ Report of the Hazard Identification Assessment Review Committee, July 27, 2000. 014272 Tarplee, Brenda, Lindane­ Report of the FQPA Safety Factor Committee, August 2, 2000 014275 Lindane­ Revision of dermal absorption factor, August 1, 2000. International Programme on Chemical Safety (IPCS), Environmental Health Criteria 124, Lindane, WHO, Geneva, 1991 Feldmann, RJ and HI Maibach, Percutaneous penetration of some pesticides and herbicides in man, Toxicology and Applied Pharmacology, 28: 126­ 132 (1974). Lindane/ September 2000 RED Toxicology Chapter 35 Wolff, G. L., Roberts, D. W., Morrissey, R. L., Greenman, D. L., Allen, R. R., Campbell, W. L., Bergman, H., Nesnow, S., and Firth, C. H. Tumorigenic responses to lindane in mice: potentiation by a dominant mutation. National Center for Toxicological Research, Jefferson, AK. MRID none. As published in Carcinogenesis 8: 1889­ 1897 (1987). Lindane/ September 2000 RED Toxicology Chapter 36 8. 0 APPENDICES Tables for Use in Risk Assessment Lindane/ September 2000 RED Toxicology Chapter 37 8.1 Toxicity Profile Summary Tables 8.1.1 Acute Toxicity Table ­ See Section 4. 1 8.1.2 Subchronic, Chronic and Other Toxicity Tables Table 1 Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3250 90­ Day dermal toxicity 41427601 acceptable/ guideline 1990 NOAEL = 60 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on lesion in the liver in males and females and adrenal gland weight increases in males 870.3465 90­ Day inhalation toxicity 00255003 acceptable/ guideline 1983 NOAEL = 0. 025 mg/ kg/ day LOAEL = 0. 13 mg/ kg/ day based on transient microscopic lesions in the kidney and increased kidney weights in the males. 40873501 acceptable/ guideline 1988 NOAEL = 0. 08 mg/ kg/ day LOAEL = 0. 25 mg/ kg/ day based on death of one male and one female 870.3700a Prenatal developmental in rat 00062656 (Subcutaneous) unacceptable/ nonguideline 1976 Maternal NOAEL = 5 mg/ kg/ day LOAEL = 15 mg/ kg/ day based on reduced body weight Developmental NOAEL = >30 mg/ kg/ day LOAEL = not identified 42808001 acceptable/ guideline 1971 Maternal NOAEL = 5 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on reduced body weight and food consumption Developmental NOAEL = 10 mg/ kg/ day LOAEL = 20 mg/ kg/ day based on skeletal variation. 870.3700b Prenatal developmental in rabbit 00062658 (Subcutaneous) unacceptable/ nonguideline 1976 Maternal NOAEL = 5 mg/ kg/ day LOAEL = 15 mg/ kg/ day based on clinical signs, mortality, reduced body weight Developmental NOAEL
15 mg/ kg/ day LOAEL = not identified 42808002 unacceptable/ nonguideline 1971 Maternal NOAEL
20 mg/ kg/ day LOAEL = not identified Developmental NOAEL
20 mg/ kg/ day LOAEL = not identified Lindane/ September 2000 RED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 38 870.3800 Reproduction and fertility effects 42246101 acceptable/ guideline 1991 NOAEL = 1. 7 mg/ kg/ day
; 0. 09mg/ kg/ day  LOAEL = 13 mg/ kg/ day based on reduced body weight
; 1. 7 mg/ kg/ day based on increased kidney weight and alpha­ 2 globulin accumulation  870.4100a Chronic toxicity rodents 870.4200 Carcinogenicity rats 41094101 41853701 42891201 acceptable/ guideline 1993 NOAEL =0. 6 mg/ kg/ day LOAEL = 4. 8 mg/ kg/ day  ; 6 mg/ kg/ day
based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets no evidence of carcinogenicity 870.4300 Carcinogenicity mice special study 1987 NOAEL = not identified LOAEL = 23 mg/ kg/ day based on induction of tumors, increased liver weights, increased enzyme activity, and irreversible Clara cell hyperplasia in lung evidence of carcinogenicity­ liver and lung tumors 870.5300 Gene Mutation Mammalian Cell 00144500 unacceptable/ guideline 1985 negative 870.5915 In Vivo Sister Chromatid Exchange 00024504 unacceptable guideline 1984 negative 870.5450 dominant lethal assay 00062657 unacceptable guideline negative 870.6200a Acute neurotoxicity screening battery 44769201 acceptable/ guideline 1999 NOAEL = 6 mg/ kg/ day
; 20 mg/ kg/ day  LOAEL = 20 mg/ kg/ day based on icreased grip strength and motor activity. 60 mg/ kg/ day based on tremors, convulsions, decreased motor activity and increased grip strngth. 870.6200b Subchronic neurotoxicity screening battery 44781101 acceptable/ guideline 1999 NOAEL = 7. 9 mg/ kg/ day
; 7. 1 mg/ kg/ day  LOAEL = 30. 2 mg/ kg/ day and 28. 1 mg/ kg/ day based on hypersensitivity to touch and hunched posture Lindane/ September 2000 RED Toxicology Chapter Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 39 870.6300 Developmental neurotoxicity 45073501 unacceptable/ guideline 1999 Maternal NOAEL = 5. 6 mg/ kg/ day LOAEL = 13. 7 mg/ kg/ day based on decreased body weight gains, decreased food consumption, and increased reactivity to handling. Offspring NOAEL = 1. 2 mg/ kg/ day LOAEL = 5. 6 mg/ kg/ day based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. 870.7600 Dermal penetration 40056107­ rat 40056108­ rabbit acceptable/ guideline 1987 18 % absorption at 10 hours Lindane/ September 2000 RED Toxicology Chapter 40 Table 2 Summary of Toxicological Dose and Endpoints for LINDANE for Use in Human Risk Assessment 1 Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary females 13­ 50 years of age not applicable; no relevant single exposure endpoint was identified Acute Dietary general population including infants and children NOAEL= 6 mg/ kg/ day UF = 100 Acute RfD = 0.06 mg/ kg/ day FQPA SF = 3 aPAD = acute RfD FQPA SF = 0. 02 mg/ kg/ day Acute Neurotoxicity in Rats/ MRID 44769201 LOAEL is 20 mg/ kg based on increased grip strength, increased Motor Activity Chronic Dietary all populations NOAEL= 0.47 mg/ kg/ day UF = 100 Chronic RfD = 0. 0047 mg/ kg/ day FQPA SF = 3 cPAD =chrRfD FQPA SF = 0. 0016 mg/ kg/ day Chronic Feeding and Carcinogenicity in Rats MRID 41094101, 41853701, 42891201 LOAEL is 4. 81 mg/ kg/ day based on periacinar hepatocyte hypertrophy, increased liver/ spleen weigt, increased platelets Short­ Term Dermal (1­ 7 days) (Occupational/ Residential) oral study NOAEL= 1. 2 mg/ kg/ day (dermal absorption rate = 10% ) LOC for MOE = 100 (Occupational) no residential exposure expected Developmental Neurotoxicity Study in Rats (MRID 45073501) LOAEL is 5. 6 mg/ kg/ day based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation Lindane/ September 2000 RED Toxicology Chapter Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects 41 Intermediate Term Dermal (1 week ­ several months) (Occupational) oral study NOAEL= 1. 2 mg/ kg/ day (dermal absorption rate = 10% ) LOC for MOE = 100 (Occupational) Developmental Neurotoxicity Study in Rats (MRID 45073501) LOAEL is 5. 6 mg/ kg/ day based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. Long­ Term Dermal (several months lifetime) (Occupational) oral study NOAEL= 0.47 mg/ kg/ day (dermal absorption rate = 10% ) LOC for MOE = 100 (Occupational) Chronic Feeding and Carcinogenicity in Rats MRID 41094101, 41853701, 42891201 LOAEL is 4. 81 mg/ kg/ day based on periacinar hepatocyte hypertrophy, increased liver/ spleen weigt, increased platelets Short­ Term Inhalation (1­ 7 days) (Occupational) inhalation study LOAEL= 0.13 mg/ kg/ day LOC for MOE = 100 (Occupational) 90­ Day Inhalation Toxicity MRID 00255003 based on clinical signs (diarrhea, piloerection) seen at day 14 and continuing for 20 days. Intermediate Term Inhalation (1 week several months) (Occupational) inhalation study NOAEL= 0.025 mg/ kg/ day LOC for MOE = 100 (Occupational) 90­ Day Inhalation Toxicity MRID 00255003 LOAEL is 0. 13 mg/ kg/ day based on micro lesions in kidney, increased kidney weight Cancer (oral) group B2/ C carcinogen Q1* = 1.1 (mg/ kg/ day) ­1 based on increased incidence of mouse liver tumors 1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, LOC = level of concern, MOE = margin of exposure Lindane/ September 2000 RED Toxicology Chapter 42 SignOff Date: 9/ 28/ 00 DP Barcode: D269338 HED DOC Number: 014351 Toxicology Branch: RRB4

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Supporting & Related Material

HED DOC. NO. 014272 August 2, 2000 MEMORANDUM SUBJECT: LINDANE ­ Report of the FQPA Safety Factor Committee FROM: Brenda Tarplee, Executive Secretary FQPA Safety Factor Committee Health Effects Division (7509C) THROUGH: Ed Zager, Chairman FQPA Safety Factor Committee Health Effects Division (7509C) TO: Sue Shallal, Risk Assessor Reregistration Branch 4 Health Effects Division (7509C) PC Code: 009001 The FQPA Safety Factor Committee met on July 24, 2000 to evaluate the hazard and exposure data bases for lindane and concluded that the FQPA Safety Factor (as required by Food Quality Protection Act of August 3, 1996) for use in human health risk assessment be reduced to 3x. 2 I. HAZARD ASSESSMENT (Memorandum: S. Shallal to M. T. Howard dated July 27, 2000) A. Adequacy of the Toxicology Database There are two developmental studies conducted in rats and rabbits in which Lindane is administered via the oral and subcutaneous (4 studies in all). Although the rabbit studies were classified as unacceptable, the HIARC concluded that a new developmental toxicity study in rabbits is not required (see Section I. B. below or refer to the HIARC document for details). An acceptable 2­ generation reproductive study is also available, as well as, acute, subchronic and developmental neurotoxicity studies. B. Determination of Susceptibility The data provided no indication of quantitative or qualitative increased susceptibility/ sensitivity in rats following in utero exposure to lindane. In the prenatal developmental toxicity studies in rats, developmental effects were observed only at or above doses causing maternal toxicity. The prenatal developmental study in rabbits is classified as Unacceptable (not upgradable) since maternal and developmental toxicity LOAELs were not identified and the highest dose did not approach the limit dose. Therefore, dose selection was considered inadequate. Doses were based on the results of a subcutaneous study in the rabbit (MRID 00062658) which is not a valid method for selecting doses for an oral study. Several other deficiencies were noted in the conduct of this study: percent purity of the test article was not given, dosing solutions were not analyzed for concentration, stability, or homogeneity, and much of the individual animal data were not included. Although the developmental toxicity study in rabbits was classified unacceptable, the HIARC concluded that a new study is not required because: 1) The developmental toxicity study in rabbits and rats using a subcutaneous route of administration shows no developmental effects at the maternally toxic dose; 2) The skeletal effects observed in the developmental toxicity study in rats, with gavage as the route of administration, are within historical controls; 3) More severe maternal effects are seen in the rabbit study with subcutaneous administration; 4) The rat appears to be the more sensitive species for developmental effects; 5) A developmental neurotoxicity study has already been submitted. There was, however, evidence of qualitative increased susceptibility in the rat multigeneration reproduction study: Both parental and offspring LOAELS are 13 mg/ kg; however there is a qualitative difference in effects. In the parental animals, toxicity was seen in the form of reduction in body weight gain during gestation while offspring toxicity was correlated with decreases in pup viability and pup body weight in the F1 and F2 generations as well as delayed 3 maturation in the F2 generation. Evidence for quantitative increase in susceptibility could not be ascertained due to the wide spread in the doses tested. There is also quantitative increased susceptibility demonstrated in the rat developmental neurotoxicity study: Maternal toxicity observed at 120 ppm (13.7 mg/ kg/ day, LOAEL) is based on decreased body weight gains, decreased food consumption, and increased reactivity to handling (maternal NOAEL is 50 ppm; 5. 6 mg/ kg/ day). Offspring toxicity was observed at 50 ppm (5. 6 mg/ kg/ day, LOAEL) and is based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation (NOAEL is 10 ppm; 1. 2 mg/ kg/ day). The offspring effects seen in the developmental neurotoxicity study were the same as those seen in the the two­ generation reproduction study ­ no additional functional or morphological hazards to the nervous system were noted. C. Studies from the Literature The open literature does contain citations which suggest an increase in susceptibility of fetuses and young animals exposed to lindane. The transfer of lindane via mother's milk also seems to be efficient, as well as, its metabolism into pentachlorobenzene (refer to the HIARC document for details). II. EXPOSURE ASSESSMENTS A. Dietary (Food) Exposure Considerations (Correspondence: T. Morton to B. Tarplee dated July 15, 2000) The registrant is supporting the use of lindane on barley, broccoli, brussels sprouts, cabbage, cauliflower, corn, lettuce, oats, radish, rye, sorghum, spinach, and wheat. Only seed treatment uses remain on the label. Seed treatment application rates range from 0. 33 to 3.57 oz. a. i./ cwt of seed. For comparison, the 3.57 oz. a. i./ cwt application rate is equivalent to 0.04 lb. a. i./ acre. Since the only supported use is seed treatment, application is made only once per season. Tolerances are currently established for residues of the insecticide lindane (gamma isomer of benzene hexachloride) in or on many raw agricultural commodities at levels ranging from 0.01ppm (pecans) to 7ppm (meat fat). Codex MRLs range from 0. 01 ppm in milk to 3 ppm in cranberry and strawberry. Codex MRLs for supported crops in the US are 0. 5 ppm for brussels sprouts, cabbage, cauliflower, and cereal grains; 0. 1 ppm for eggs; 2 ppm for head lettuce, meat of cattle, pigs, and sheep, and spinach; and 1 ppm for radish. The MARC has determined that until adequate seed treatment metabolism studies are submitted, the total radioactive residues will be used for risk assessment purposes. In a 4 confined rotational crop study, radioactive lindane was found in barley forage but not barley grain. It was also found in carrot tops and to a lesser extent in mature lettuce. No monitoring data is available which would definitively include lindane only from seed treatment uses. However, it may be possible to use available monitoring data for foliar uses on imported commodities. Field trials were conducted on wheat, feeding studies on ruminant and poultry, but will not be used since the MARC has concluded that the total radioactive residues must be used for risk assessment purposes. In 1998, BEAD provided percent crop treated data for small grains (7 % crop treated), field corn (6 % crop treated), and sorghum (10 % crop treated). HED has asked BEAD to supply current % crop treated data for the above crops and any other of the supported crops. The Dietary Exposure Evaluation Model (DEEM) is used to estimate the dietary risk resulting from the residues of lindane on foods. The DEEM analyses are refined using the available %CT data. B. Dietary (Drinking Water) Exposure Considerations (Correspondence: D. Young to B. Tarplee, dated July 10, 2000.) The environmental fate database for lindane is adequate to characterize the potential for contamination of drinking water sources. These data indicate that parent lindane is persistent and moderately mobile. It is transported through the environment by both hydrologic and atmospheric means. It is resistant to photolysis and hydrolysis (except at high pH), and degrades very slowly by microbial actions (980 day soil half life). Degradates are predominantly benzene hexachloride, pentachlorocyclohexane, 1,2,4,trichlorobenzene and 1, 2, 3­ trichlorobenzene. In submitted studies, degradates were observed at much less than 10% of applied. Currently, U. S. agricultural uses of lindane are restricted to seed treatments, and application rates are quite low. Even under these restriction, however, lindane may reach water resources at levels above the Maximum Concentration Level (MCL = 0. 2 µg/ L). Monitoring data are available which demonstrate the presence of lindane in the environment: In the U. S. EPA STORET data base, 720 detections (after culling of data to eliminate dubious data, e. g. K and U codes) in ground water were reported between the years 1968 and 1995, in nearly all regions of the country, with especially high numbers of detections in the South and West. For these 720 detections, the median and mean concentrations were 0.01 and 11 µg/ L, respectively. For surface waters, 8775 detections were reported with median and mean concentrations of 0. 005 and 0. 18 µg/ L. STORET Detections were reported in nearly all regions of the conterminous U. S. In the USGS NAWQA study, lindane was detected in 2. 58% of surface water samples 5 (0. 67% at levels greater than 0. 05 mg/ L, maximum concentration reported was 0. 13 mg/ L). For groundwater, USGS NAWQA reported a detection frequency of 0. 1 % (0. 07% at levels greater than 0. 01 mg/ L, maximum concentration reported was 0. 032 mg/ L). Since all monitoring data represent detections resulting from all previous uses of lindane (including foliar uses which are currently not supported by the registrant), models were used to calculate the estimated environmental concentrations (EECs): GENEEC model for surface water; and SCI­ GROWfor ground water. Due to the persistence of lindane, its past wide­ spread use, and its mobility by both atmospheric at hydrologic means, the extent of population exposed could be high in comparison to other chemicals. C. Residential Exposure Considerations (Telephone communication: D. Jaquith on July 19, 2000) Only seed treatment uses remain on the label for lindane. There are no registered residential uses and therefore, residential exposure to lindane is not expected. III. SAFETY FACTOR RECOMMENDATION, RATIONALE, AND APPLICATION A. Recommendation of the Factor The Committee recommended that the FQPA safety factor for protection of infants and children (as required by FQPA) should be reduced to 3x for lindane. B. Rationale for the Selection of the FQPA Safety Factor The FQPA SFC concluded that a safety factor is required for lindane since there is evidence of increased susceptibility of the young demonstrated in both the developmental neurotoxicity study (quantitative) and the 2­ generation reproduction study in rats (qualitative). The Committee recommended that the FQPA safety factor be reduced to 3x because: 1) the toxicology data base is complete; 2) the available data provide no indication of quantitative or qualitative increased susceptibility in rats from in utero exposure to lindane in the prenatal developmental study; 3) although the developmental toxicity study in rabbits was classified unacceptable, the HIARC concluded that a new study is not required (See Section I. B.); 4) the offspring effects seen in the developmental neurotoxicity study were the same as those seen in the the two­ generation reproduction study (no additional functional or morphological hazards to the nervous system were noted); and 5) adequate actual data, surrogate data, and/ or modeling outputs are available to satisfactorily assess food exposure and to provide a screening level drinking water exposure assessment; and 6 6) there are currently no residential uses. C. Application of the Safety Factor ­ Population Subgroups/ Risk Assessment Scenarios The FQPA safety factor for lindane is applicable to All Population Subgroups for Acute and Chronic Dietary Risk Assessments (there are currently no residential scenarios), since there is concern for increased susceptibility of the young demonstrated in the developmental neurotoxicity study and in the 2­ generation reproduction study.

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Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDE AND TOXIC SUBSTANCES HED DOC. NO. 014595 DATE: June 18, 2001 MEMORANDUM SUBJECT: Lindane (PC Code: 009001)­ A Second Report of the Hazard Identification Assessment Review Committee. FROM: Suhair Shallal, Toxicologist. Reregistration Branch 4 Health Effects Division (7509C) THROUGH: Elizabeth Doyle, Co­ Chairman and Jess Rowland, Co­ Chairman Hazard Identification Assessment Review Committee Health Effects Division (7509C) TO: Mark T. Howard Special Review and Registration Division On May 22, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) met to reconsider the endpoint for occupation risk assessment for the inhalation route of exposure. Previouslythe endpoint was based on kidneylesions and increased kidney weights resulting fromthe accumulation of alpha 2 globulin. These effects have been deemed not relevant for human risk assessment. The Committee's decision is presented in this report along with the previously conclusions of the June 13, 2000 HIARC meeting. In that meeting the Reference Dose (RfD) and the toxicological endpoints for acute and chronic dietary, as well as, occupational exposure risk assessments were selected. HIARC re­ assessed the Reference Dose (RfD) established in 1994, as well as the toxicological endpoints selected for acute dietary and occupational/ residential exposure risk assessments. The HIARC also addressed the potential enhanced sensitivity of infants and children from exposure to lindane as required by the Food Quality Protection Act (FQPA) of This Report has been revised to reflect a change in the endpoint selection for occupational risk assessment through the inhalation route of exposure. 2 1996. Committee Members in Attendance Members present were: Elizabeth Doyle David Nixon Jess Rowland Elizabeth Mendez William Burnam Pamela Hurley Yung Yang Brenda Tarplee Jonathan Chen Paula Deschamp Member( s) in absentia: Ayaad Assaad Data was presented by Suhair Shallal of the Reregistration Branch 4. Also in attendance were: Susan Henley, Whang Phang, Joseph Nevola Data Presentation: and Suhair Shallal, Report Presentation Toxicologist Report Concurrence: Brenda Tarplee Executive Secretary cc: RD Casewell file 3 I. INTRODUCTION On May 22, 2001, the Health Effects Division (HED) Hazard Identification Assessment Review Committee (HIARC) met to reconsider the endpoint for occupation risk assessment for the inhalation route of exposure. Previously the endpoint was based on kidney lesions and increased kidney weights resulting from the accumulation of alpha 2 globulin. These effects have been deemed not relevant for human risk assessment. The Committee's decision is presented in this report along with the previously conclusions of the June 13, 2000 HIARC meeting. In that meeting the Reference Dose (RfD) and the toxicological endpoints for acute and chronic dietary, as well as, occupational exposure risk assessments were selected. HIARC re­ assessed the Reference Dose (RfD) established in 1994, as well as the toxicological endpoints selected for acute dietary and occupational/ residential exposure risk assessments. The HIARC also addressed the potential enhanced sensitivity of infants and children from exposure to lindane as required by the Food Quality Protection Act (FQPA) of 1996. II. HAZARD IDENTIFICATION A. Acute Reference Dose (RfD)* General population Selected Study: Acute Neurotoxicity Study Guideline #: OPPTS 870.6200 [§ 81­ 8] MRID No.: 44769201 Executive Summary: In an acute oral neurotoxicity study, groups of 10 Crl: CD® BR rats/ sex/ dose were administered single dose of Lindane (Batch No. HLS96/ 1, Purity 99.78%) by gavage at concentrations of 0 (control), 6, 20, or 60 mg/ kg. Functional observational battery (FOB) and motor activity (MA) testing were performed prior to administration and within 3 hours (time of peak effect) of dosing (day 0), and on days 7 and 14 post­ dose. Body weights were recorded pre­ test, weeklyduring the study period and on FOBassessment days. Clinical signs were recorded at least once daily. At study termination all animals were sacrificed and fixed by whole body perfusion, designated tissues of the nervous system were processed for microscopic neuropathological evaluation. All animals survived to scheduled termination. One male in the 60 mg/ kg group was observed to convulse on the day of treatment within 2.75 hours after dosing. Clinical signs were also observed in females treated at 60 mg/ kg within 24 hours of dosing and included: staining of the fur, stained urogenital region, hunched posture, and piloerection. These effects in females persisted for four days. Significant treatment­ related decreases in body weight gains were observed for males in the 60 mg/ kg group compared to the control group for the first week of the study. Females administered this concentration also had slightly lower body weight gains throughout the study. Food consumption for males and females administered 60 mg/ kg was significantly decreased compared to controls for Week 1 of the study. Food conversion 4 Acute RfD = NOAEL (mg/ kg) =6= 0. 06mg/ kg UF 100 ratios in the treated groups were not changed compared to control groups. At the first FOB assessment on Day 0 (3 hours aft er dosing) males and females in the 60 mg/ kg group exhibited piloerection (1
,2  ), decreased rectal temperature (1
,1  ), increased hindlimb foot splay and hunched posture (4
,7  ). Among males dosed at 60 mg/ kg, increased respiration (3) and tremor/ twitching (1) were observed. Females administered 60 mg/ kg were observed to have increased incidences of walking on tip toes (10), licking behavior (3), decreased foot splay (3) and an absence of grooming (8) behavior. Females in the 20 mg/ kg also had decreased grooming (3) behavior and increased forelimb grip strength (2). Motor activity was significantly decreased for males and females treated with 60 mg/ kg as well as among females treated with 20 mg/ kg three hours post­ treatment. The 6 mg/ kg group remained comparable to controls in FOB assessment parameters and MA. No neuropathological changes were observed during the histological examinations of the peripheral or central nervous systems of these animals at any exposure concentration. The NOAEL for systemic toxicity is 20 mg/ kg for males and 6 mg/ kg for females. Based on the substance­ related effects on body weight, body weight gain, food consumption, and clinical signs of toxicity the LOAEL for systemic toxicity in males is 60 mg/ kg. The LOAEL for females is 20 mg/ kg based on a lower incidence of grooming behavior and decreased locomotor activity immediately after dosing, in addition to the parameters mentioned above. The NOAEL for neurotoxic effects is 6 mg/ kg for females and the LOAEL is 20 mg/ kg based on increased forelimb grip strength and decreased grooming behavior and motor activity (MA). The NOAEL for neurotoxicity in males is 20 mg/ kg and the LOAEL for males is 60 mg/ kg based on tremors, convulsions, decreased MA, and increased forelimb grip strength. This study is classified Acceptable/ guideline and satisfies the Subdivision F guideline requirement for an acute oral neurotoxicity study (§ 81­ 8) in rats. Dose and Endpoint for Establishing an Acute RfD: The NOAEL is 6 mg/ kg based on increased forelimb grip strength and decreased grooming behavior and motor activity in female rats Uncertainty Factor( s): 100 ; 10X intraspecies variations and 10X interspecies etrapolation Comments about Study/ Endpoint/ Uncertainty Factor( s): 5 Acute Reference Dose (RfD)* Females (13­ 50 years) An appropriate endpoint attributable to a single dose could not be ascertained fromeither the developmental toxicity study in rats and in rabbits or in the developmental neurotoxicity study. Although, there was evidence of increased susceptibility in the DNT, the offspring effects were not attributable to a single dose. A separate endpoint for this subpopulation was therefore not identified. 2.2 Chronic Reference Dose (RfD) Selected Study: Combined chronic toxicity/ oncogenicity feeding – Rat Guideline #: OPPTS 870.4300 [§ 83­ 5] MRID No.: 41094101, 41853701 and 42891201 Executive Summary: Results from interim sacrifice of 15 rats/ sex/ group at 30 days and 26 weeks, as well as, 15 rats/ sex/ group at 52 weeks and final results of an ongoing chronic/ oncogenicity study are presented in this report (MRID 41094101, 41853701 and 42891201). In this chronic toxicity/ oncogenicity study, Lindane (99.75% a. i., Lot no. DA433) was administered in the diet to groups of 115 male and 115 female Wistar rats at concentrations of 0, 1, 10, 100, or 400 ppm for 2 years. Corresponding delivered doses were 0, 0. 05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0. 06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. No clinical signs of toxicity were observed during the first 26 weeks; however by 52 weeks convulsions in 11 high­ dose females were observed. No other clinical signs were observed. Survival at the end of the study was 36, 36, 31, 20, and 16% for males and 49, 38, 44, 35, and 18% for females in the 0, 1, 10, 100, and 400 ppmgroups, respectively. Survival of highdose males was similar to the controls through week 93. For females, however, survival was significantly decreased in the high­ dose group with 50% survival reached at week 89 compared to week 104 for the control group. Body weights were slightly less than the controls for the high­ dose males (­ 6%) and females (­ 8%) during weeks 1­ 5 of the study, but gradually increased to within 2% of the control level by week 26 for males and week 9­ 10 for females. Because final body weights of the 100 ppm males were similar to the controls, the init ial reduction in weight gain was not considered biologically significant. Final body weights of the high­ dose males were significantly (­ 14%; p < 0. 05) less than the controls. Body weights and body weight gains for the treated females were similar to the controls throughout the study. Food consumption by t he high­ dose groups was decreased 15% in males and 19% in females during the first week of the study, however, total food consumption for the entire study was similar to the control levels. Platelet counts were significantly (p < 0.05 or 0.01) increased (20% or less) in the 100­ and 6 400­ ppm males at week 12 and in 100­ and 400­ ppm males and females at week 24, but not at later time points. High­ dose males and females had significant (p < 0.05 or 0.01) decreases in red blood cell parameters at week 104 as compared with the controls: hemoglobin was 15.6 and ­17.6%, respectively, erythrocyte counts were ­14.1% and ­21%, respectively, and PCV was ­15.9% and ­18.2%, respectively. Significant (p < 0.05 or 0.01) changes in clinical chemistry parameters were observed in highdose males and females during the first year of the study. Inorganic phosphorous was increased by 7.3­ 38.5% and calcium was increased by 3.4­ 10% in males and females; cholesterol was increased by 45­ 110% and urea was increased by 20­ 54% in females; and the albumin/ globulin ratio was decreased by 8. 3­ 18. 2% in females. All parameters were similar to the control levels by week 104. High­ dose males and females had increased absolute and relative liver weights at all interim sacrifices, although statistical significance was not always reached. At study termination, absolute and relative liver weights were significantly (p < 0.01) increased by 21. 2% and 38.5%, respectively, in high­ dose males and by 31.6% and 33.5%, respectively, in high­ dose females. At 100 ppm, absolute liver weights were increased by 8.6­ 11.2% (n. s.) and relative liver weights were increased by 14.4­ 17.6% (p < 0.05 or 0.01) for both sexes at week 104. Significant (p < 0.05 or 0.01) increases in absolute and relative spleen weights at week 52 and in relative spleen weights at week 104 were also noted, but the sex was not identified. The incidence rate of periacinar hepatocytic hypertrophy was significantly increased in the 100­ and 400­ ppmgroups with 25/ 50 males and 19/ 50 females affected at 100 ppmand 40/ 50 males and 43/ 50 females affected at 400 ppm. No treatment­ related histopathological lesions were observed in the spleen or bone marrow. Kidney lesions in males indicative of alpha 2 globulin accumulation were observed in animals treated with 10 ppm. Therefore, the systemic toxicity LOAEL for male and female rats is 100 ppm (4. 81 and 6.0 mg/ kg/ day, respectively) based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets. The systemic toxicity NOAEL is 10 ppm (0. 47 and 0.59 mg/ kg/ day for males and females, respectively). Eight additional males were identified as having adrenal pheochromocytomas. The revised percentages of animals with adrenal tumors in the 0, 1, 10, 100, and 400 ppm groups are 14, 16, 16, 6, and 24% for benign tumors, respectively, and 0, 0, 6, 8, and 2% for malignant tumors, respectively. Statistical significance was not reached by relevant tests. For comparison, historical control data fromCharles River and publications in the open literature were submitted. The 10 and 100 ppm groups had malignant tumor incidence rates greater than the historical control rate (0­ 2%). The high­ dose group also had a slight excess of benign and combined tumor rates as compared with the historical control rates (8­ 22% benign, combined could not be calculated), but this same net tumor incidence was the same as the control group of a published study. In the current study, pheochromocytomas were not considered the cause of death for any animal with the exception of a single animal in the 7 Chronic RfD = NOAEL (mg/ kg/ day) =0. 47= 0.0047 mg/ kg/ day UF 100 100 ppm group. Therefore, no evidence of dose­ related and statistically significant increase in adrenal tumors was observed in this study. The study was conducted at adequate dose levels. Dose and Endpoint for Establishing a Chronic RfD: The NOAEL is 0.47 mg/ kg/ day based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets in male rats Uncertainty Factor( s): 100; 10X intraspecies variations and 10X interspecies extrapolation Comments about Study/ Endpoint/ Uncertainty Factor( s): The HIARC concurred with the TES committee's decision (1994, DOC 013460) that the toxicological endpoint of concern was the periacinar hepatocyte hypertrophy and not kidney lesions associated with alpha 2 globulin which is thought to be inappropriate for human risk assessment. 2.3 Occupational/ Residential Exposure 2.3.1 Dermal Absorption Selected Study: Dermal absorption study Guideline #: OPPTS 870.7600 [§ 85­ 3] MRID No.: 40056107, 40056108 Executive Summary: In a dermal absorption study, 24 male Crl: CD ® (SD) BRrats per group received dermal applications of Lindane 20% emulsifiable concentrate ([ 14 C] Lindane and unlabeled Lindane) at doses of 0.1, 1.0, or 10 mg/ rat. Four animals/ group were bled and sacrificed at intervals of 0. 5, 1, 2, 4, 10, or 24 hours after application of the test article. Quantities absorbed increased with dose and duration of exposure while percent absorbed increased with time and decreased with dose. Percents of the low­, mid­, and high­ doses absorbed were 0. 6, 0. 96, and 0. 66% after 0. 5 hours; 18.07, 8.31, and 2.81% after 10 hours; and then, increased to 27.72, 20.86, and 5. 05% after 24 hours. The total amount of test article absorbed after 24 hours, as calculated from urine, feces, and carcass, was 0. 028, 0.21, and 0. 51 mg for the low­, mid­, and high­ dose groups, respectively. The process appears to be approaching saturation at the high dose. Recovered radioactivity (absorbed, skin, skin rinse, filter paper and spreader) was 74.19, 70.19 and 58.35% of the applied dose after 24 hours of exposure in the 8 low­, mid­, and high­ dose, respectively. This study is considered Acceptable/ guideline and satisfies the requirements for a dermal absorption study in rats [85­ 2]. Percent Dermal Absorption by Rats Based on Exposure and Duration Applied dose/ rat (mg/ kg) Exposure Duration 4 hr 10 hr 24 hours 0.1 mg (. 25 mg/ kg) 10.1 18.1 27.7% 1.0 mg (2.5 mg/ kg) 5.3 8. 3 20.9% 10.0 mg (25 mg/ kg) 2.0 2. 8 5.0% Executive Summary: In a dermal absorption study, 24 male Hra: (NZW) SPF rabbits per group received dermal applications of Lindane 20% emulsifiable concentrate ([ 14 C]­ Lindane and unlabeled Lindane) at doses of 0. 5, 5. 0, or 50 mg/ rabbit. Four animals/ group were bled and sacrificed at intervals of 0. 5, 1, 2, 4, 10, or 24 hours after application of the test article. Quantities absorbed increased with dose and duration of exposure while percent absorbed increased with time and decreased with dose. Percentages of the low­, mid­, and high­ doses absorbed were 5. 97, 6.68, and 1. 99% after 0. 5 hours; 51.68, 23.76 and 10.96% after 10 hours; and then increased to 55.68, 39.99, and 16.56% after 24 hours. The total amount of test article absorbed after 24 hours, as calculated from urine, feces, and carcass, was 0. 28, 2.00, and 8. 46 mg for the low mid­, and high­ dose groups, respectively. The original DER states that No evidence of saturation of the absorption process was observed; however upon further examination it appears that there is evidence of saturation at the highest dose (50 mg/ rabbit) tested. Recovered radioactivity (absorbed, skin, skin rinse, filter paper and spreader) was 82.01, 78.27 and 66.34% of the applied dose after 24 hours of exposure in the low­, mid­, and high­ dose, respectively. This study is considered Acceptable/ guideline and satisfies the requirements for a dermal absorption study in rabbits [85­ 2]. At 10 hours, 18% of the applied material is absorbed. IPCS (1991) sites even higher percentages at 24 hours, ranging from 28% for rat and 17 to 56% for rabbit. Percentage (%) Dermal Absorption: 9 The absorption has been determined to be 10%. Comments about Dermal Absorption: The HIARC concurred with the TES committee decision (HED Doc. # 013460) that the dermal absorption factor is 10% based on a published report by Feldman and Maibach (Toxicology and Applied Pharmacology 28, 126­ 132, 1974). The Maibach study tested 12 pesticides and herbicides, including Lindane, on human subjects (6 per chemical) to quantitate their dermal penetration. C 14 ­labeled chemicals were applied topically (4 g/ cm 2 ) to the forearm or via the intravenous route (1 Ci). Excretion of the chemicals was then monitored by collecting and analyzing urine samples during the 5 day testing period. All results were calculated as percent of the injected or applied dose. Data obtained after IV dosing was used to correct the skin penetration data for incomplete urinary recovery. Lindane was shown to have a penetration factor of 9.3% ± 3. 7 (SD). 2. 3. 2 Short­ term Dermal (1 ­ 7 days) Exposure Selected Study: Developmental Neurotoxicity Study Guideline #: OPPTS 870.6200 [§ 83­ 6] MRID No.: 45073501 Executive Summary: In a developmental neurotoxicity study (MRID 45073501), lindane (Batch No. HLS 96/ 1; 99.78% a. i.) was administered to presumed pregnant Hsd Brl Han: Wist (Han Wistar) rats in the diet at concentrations of 0, 10, 50, or 120 ppm from gestation day (GD) 6 through lactation day 10. These concentrations resulted in F0 maternal doses of 0. 8­ 0. 9, 4. 2­ 4. 6, and 8.0­ 10.5 mg/ kg/ day, respectively, during gestation and 1. 2­ 1. 7, 5. 6­ 8. 3, and 13.7­ 19.1 mg/ kg/ day, respectively, during lactation. The developmental neurotoxicity of lindane was evaluated in the F1 offspring. F1 animals (10/ sex) were evaluated for FOB, motor activity, auditory startle response, and learning and memory as well as developmental landmarks such as vaginal perforation and balanopreputial separation, and brain weights and histopathology on days 11 and 65, including morphometrics. Small differences in absolute maternal body weights (7­ 8%) were observed between the high dose and control groups during gestation and early lactation (through day 11). Body weight gains by the high­ dose dams from GD 6 through GD 20 were 64­ 79% (p
0.01) of the control level. Body weight changes during lactation were similar between the treated and control groups. During gestation, food consumption by the high­ dose group was significantly (p
0.01; 74­ 92% of controls) less than the control group for the intervals of GD 10­ 13, 14­ 17, and 18­ 10 19. Food consumption by the low­ and mid­ dose groups during gestation and by all treated groups during lactation was similar to the controls. Absolute body weights of the treated male and female pups in mid and high dose groups during lactation were 12­ 18% and 16­ 20% less than controls, respectively on days 4­ 11 of lactation with recovery to less than 10% by day 21. Body weight gains (p
0.05 or 0.01) on lactation days 1­ 4 and 1­ 11 were 76% and 84%, respectively, of the control levels for mid­ dose males, 79% and 79%, respectively, for mid­ dose females, 60% and 73%, respectively for high­ dose males, and 63 and 75%, respectively, for high­ dose females. Body weight gains by all treated groups were similar to the controls during lactation days 11­ 21. Except for mid and high dose females, postweaning, body weight gains were similar between the treated and control groups. Body weight differences for high dose dams were 10% less at the beginning of lactation and recovered to 6% less by the end of the study. The high­ dose group had a greater number of stillborn pups as indicated by a live birth index of 77% compared with 99% for the control group. In addition, nine highdose litters either died or were sacrificed moribund on lactation days 1­ 4. This resulted in a viability index for the high­ dose group of 71% compared with 89% for the controls. Pup mortality in the mid and high­ dose groups in litters surviving to weaning was greater before day 4 than in controls [ 3 pups in 2/ 20 controls; 18 pups in 8/ 22 litters, mid dose; 14 pups in 4/ 15 litters, high dose]. Survival was not affected at any time in the low dose group as compared with the control group. No dose­ or treatment­ related differences were observed between treated and control groups for duration of gestation, number of pups/ litter on day 1, or per cent male offspring. At necropsy, no treatment­ related gross abnormalities were observed in the dams or offspring. Absolute and relative liver and kidney weights of the offspring were not affected by treatment. A few clinical signs were observed in high dose dams and pups; increased reactivity to handling in dams on weeks 2 and 3 of dosing, and slower surface righting in pups on day 4. There were no effects on measures of physical or sexual development. There was an increase in motor activity at the mid and high dose during lactation in both sexes. Some decrease in habituation of motor activity in females on day 22 was also seen. While there was no effect on auditory startle reflex amplitudes, there was a clear reduction in auditory startle response habituation in both sexes at the high dose on day 28 and on day 60. Slight decreases in absolute, but not relative, brain weights in mid and high dose female pups were observed on postnatal day 11 (9­ 10%) but narrowed to 3­ 5% less by day 65. Brain lengths and widths were similar between the treated and control pups. Morphometric brain measurements did not show any significant differences in the sizes of the neocortex, hippocampus, corpus callosum, or cerebellum on days 11 or 65. There were no effects on histopathology of the nervous system. The maternal toxicity LOAEL is 120 ppm (13.7 mg/ kg/ day) based on decreased body weight gains, decreased food consumption, and increased reactivity to handling. The maternal toxicity NOAEL is 50 ppm (5. 6 mg/ kg/ day). 11 The developmental toxicity LOAEL is 50 ppm (5. 6 mg/ kg/ day) based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. The developmental toxicity NOAEL is 10 ppm (1. 2 mg/ kg/ day). This study is classified as Unacceptable/ Guideline [870.6300 (§ 83­ 6)] since laboratory validation studies of the neurobehavioral tests were not included, but it may be upgraded and found acceptable if this information is obtained. The number of animals tested at the highest dose is only 6 compared to the required number of 10 animals per dose. Dose and Endpoint for Risk Assessment: The NOAEL is 1.2 mg/ kg based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. Comments about Study/ Endpoint/ Uncertainty Factor( s): A 90­ day dermal toxicity study in rabbits was available; the NOAEL was 10 mg/ kg/ day and the LOAEL was 60 mg/ kg/ day based on hepatic toxicity. The HIARC did not consider this study to be appropriate for risk assessment and instead selected an oral endpoint due to: 1) the concern for developmental effects as seen in pups in the developmental neurotoxicity study 2) developmental effects are not evaluated in the dermal toxicity study 3) the dermal toxicity study was conducted in the rabbit, while the increased susceptibility was seen in rat pups via an oral route 4) this endpoint will be protective of dermally exposed workers Since an oral endpoint was selected, a 10% dermal absorption factor should be used for route to route extrapolation. Although this study is classified as unacceptable/ guideline, it is adequate for endpoint selection because the deficiencies are related to submission of additional data and not the quality of the study. 2.3.3 Intermediate­ term Dermal (1­ Week to Several Months) Selected Study: Developmental Neurotoxicity Study in rats Dose and Endpoint for Risk Assessment: The NOAEL is 1.2 mg/ kg based on reduced pup survival, decreased body weights and bodyweight gains during lactation, increased motor activity, and decreased motor activity habituation. Comments about Study/ Endpoint: See Short­ term Dermal Section 2. 3. 2 12 2.3.4 Long­ term Dermal (Several Months to Lifetime) Selected Study: Chronic toxicity and Oncogenicity Study in rats MRID No.: 41094101, 41853701 and 42891201 Dose and Endpoint: The NOAEL is 0.47 mg/ kg/ day based on periacinar hepatocyte hypertrophy, increased liver and spleen weights, and decreased platelets in male rats Comments about Study/ Endpoint: This dose and endpoint was used to derive the chronic RfD. Since an oral NOAEL was selected, a 10% dermal absorption factor should be used. 2. 4 Inhalation Exposure (All Durations) Short­ term (1­ 7 days): Selected Study: Subchronic Inhalation Toxicity Study Guideline #: OPPTS 870.3465 [§ 82­ 4] Accession No.: 255003 Executive Summary: In a subchronic inhalation toxicity study (Accession No. 255003), Lindane (99.9% a. i., Batch no. 79044/ 174) was administered by inhalation to groups of 12 male and 12 female Wistar rats at nominal concentrations of 0, 0.02, 0.10, 0.50, or 5.0 mg/ m 3 , 6 h/ day for 90 days. Additional control and high concentration groups, 12 rats/ sex, were treated for 90 days and allowed to recover for 6 weeks before sacrifice. Analytically measured atmospheric concentrations were 0, 0.02, 0.12, 0.60, and 4. 54 mg/ m 3 , respectively. The arithmetic mean particle size of the aerosol was 1. 11± 0.39 µm and the geometric mean was 1. 03± 1.45 µm. Lindane was detected in the brain, liver, fat, and serum of all exposed rats. The chemical accumulated in fat with levels reaching 127,120 µg/ g and 58,260 µg/ g in high­ dose females and males, respectively. After the recovery period, traces of lindane were still detectable in the tissues. All rats survived to scheduled sacrifice. "Slight" diarrhea and piloerection were observed in all males and females exposed to the highest concentration, beginning at 14 days after exposure and continuing for 20 days. No exposure­ related effects were noted for body weight gain, food consumption, water consumption, or urinalysis parameters. Although hematologyparameters did appear to be affected bytreatment, no individual animal data were included and the statistics could not be verified. Clinical chemistry results, especially for Na + , K + ,andCa ++ , were highly variable. Cytochrome p­ 450 in males and females exposed to 5 13 mg/ m 3 was 338% and 174%, respectively, of the control values after 90 days, but similar to the control levels after the recovery period. Bone marrow myelograms from animals exposed to 5 mg/ m 3 showed significantly (p
0.05) increased reticulocytes (+ 108%), stem cells (+ 31%), and myeloblasts (+ 33%) in males, and increased reticulocytes (+ 55) in females, and decreased (­ 45%) lymphocytes in females. However, these changes in bone marrow cannot be definitively attributed to treatment since bone marrow from the other exposed groups was not assayed. Males exposed to 5 mg/ m 3 had significantly (p
0.05 or 0.01) increased absolute (+ 7.8% to +11.7%) and relative (+ 19.1% to 19.2%) kidney weights as compared with the controls. Absolute and relative kidney weights in the males exposed to 0. 5 mg/ m 3 were increased by 8­ 9.8% and 6. 9­ 8. 2%, respectively. Although not statistically significant, the increases in kidney weights for these groups were considered biologically significant. After the recovery phase, kidney weights from the exposed males were similar to the controls. In females exposed to 5 mg/ m 3 absolute and relative kidney weights were increased (p
0.05) by 9.2­ 9.9% and 7. 9­ 8. 2%, respectively, as compared with the controls. In high­ dose males, absolute liver weights were not affected, but relative liver weights were slightly (6. 9%) higher than the controls. For females exposed to the highest dose, absolute and relative liver weights were 12.2% and 11.0% higher, respectively, than the controls. No differences in absolute and relative liver weights were noted between the exposed and control groups after the recovery period. Kidney lesions in males exposed to 0, 0. 02, 0.10, 0.50, or 5.0 mg/ m 3 , were observed in 17%, 0, 25%, 83% and 82%, respectively, of the animals. These lesions included cloudy swelling of the tubule epithelia, dilated renal tubules with protein containing contents, and proliferated tubules. After the recovery phase, only cloudy swelling of the tubule epithelia was observed in two control animals and one high­ concentration animal. These effects are consistent with the accumulation of alpha 2 globulin and is not relevant for human risk assessment. Therefore, the systemic toxicity LOAEL is 5.0 mg/ m 3 based on increased kidney weights of female rats and bone marrow effects. The systemic toxicity NOAEL is 0.5 mg/ m 3 . This study is considered Acceptable/ guideline and satisfies the requirement for a subchronic inhalation toxicity study in rats [82­ 4]. It should be noted that several translation errors were found and corrected by referring to the original text. Individual animal data were not available for statistical analysis of blood elements or clinical chemistry data. Dose and Endpoint for Risk Assessment: The NOAEL is 0.5 mg/ m 3 (0. 13 mg/ kg) based on clinical signs (diarrhea and piloerection) seen at day 14 after exposure and continuing for 20 days. 14 Comments about Study/ Endpoint: The HIARC established a NOAEL of 0.5 mg/ m 3 for this risk assessment based on clinical signs seen at the highest concentration tested (5 mg/ m 3 ). This NOAEL is applicable and appropriate only for short­ termexposure risk assessment because the effects were seen during this period of exposure. The Committee further noted that this dose would be protective against developmental effects. Intermediate term (7 days to several months): Selected Study: Subchronic Inhalation Toxicity Study Accession No.: 255003 Dose and Endpoint for Risk Assessment: The NOAEL is 0.5 mg/ m 3 (0. 13 mg/ kg) based on increased kidney weights in females and bone marrow effects (increased reticulocytes, increased myelocytes, decreased lymphocytes) at 5 mg/ m 3 . Comments about Study/ Endpoint: The NOAEL of 0.1 mg/ m 3 based on kidney lesions and increased kidney weights in male rats at 0.5 mg/ m 3 , selected previously on June 13 th , 2001 HIARC meeting, has been changed. The change in endpoint selection was necessary because the kidney effects are due to the accumulation of alpha 2 globulin, a low molecular weight protein in the male rat kidney, and this accumulation initiates a sequences of events that may lead to tumor formation. This phenomenon does not occur in female rats. The Agency has determined that in this special situation, the male rat is not a good model for assessing human risk (USEPA, 1991). The route and duration of exposure in this study is appropriate for this exposure scenario. Long Term Inhalation: Based on the use pattern (maximum of 60 days), no long­ term inhalation exposure is expected. If there is a change in the use pattern and a long­ term exposure becomes likely, then the inhalation NOAEL of 0. 5 mg/ m 3 (0. 13 mg/ kg) should be used for risk assessment. Recommendation for Aggregate Exposure Risk Assessments There are no registered residential uses at this present time; therefore, non­ occupational aggregate exposure risk assessment will be limited to food and water. For occupational risks, separate assessments should be conducted for dermal and inhalation exposures because the effects selected for assessment of dermal risk do not share a common toxicity with the effects selected for inhalation risk. 15 Margins of Exposures for Occupational/ Residential Exposure Risk Assessments An MOE of 100 is adequate for both dermal and inhalation occupational exposure at all time durations. III. CLASSIFICATION OF CARCINOGENIC POTENTIAL 3.1 Combined Chronic Toxicity/ Carcinogenicity Study in Rats MRID No.: 41094101, 41853701 and 42891201 Executive Summary: See Chronic RfD section Discussion of Tumor Data: No tumors were noted in this study. The findings included a significant increase in the incidence rate of periacinar hepatocytic hypertrophy in the 100­ and 400­ ppm groups with 25/ 50 males and 19/ 50 females affected at 100 ppm and 40/ 50 males and 43/ 50 females affected at 400 ppm. No treatment­ related histopathological lesions were observed in the spleen or bone marrow. For further details, please refer to the chronic RfD section­ 2.2. Adequacy of the Dose Levels Tested: The dose levels are adequate to assess the carcinogenic potential of Lindane. 3.2 Carcinogenicity Study in Mice NO ACCEPTABLE STUDY IS AVAILABLE Comments and Discussion: A new mouse carcinogenicity study is expected in December 2000 3.3 Classification of Carcinogenic Potential A new Cancer Assessment Review Committee (CARC) meeting will review the recently submitted mouse carcinogenicity study and establish a new classification for lindane, if applicable. According to the TES committee report (1994, Doc 013460), Lindane has not been classified by the HED Cancer Peer Review Committee. It was determined by the RfD/ Peer Review Committee (8/ 25/ 93) that: "The mouse carcinogenicity data were considered insufficient because of major deficiencies associated with all studies available." Lindane however had been previously classified by the Cancer Assessment Group of the Office of Research and Development (memorandum dated 7/ 23/ 85 from R. E. McGaughy to Anne Barton) as a group B2/ C carcinogen based on increased incidence of mouse liver tumors. The upper­ bound slope of the dose­ response was given in that memorandum as Q1* = 1.1 (mg/ kg/ day) ­1 . 16 IV. MUTAGENICITY Executive Summary: In a mammalian cell gene mutation assay (MRID 00144500) conducted in Chinese hamster V79 cells, lindane was tested in the absence of metabolic activation at dose levels of 2. 5, 5, 10, 25, 50, 70, 100, and 150 µg/ ml and in the presence of metabolic activation at dose levels of 5, 10, 25, 50, 100 250 and 500 µg/ ml. The S9 fraction used for metabolic activation was obtained from Aroclor 1254­ induced mouse liver. Tests with and without activation were conducted under aerobic and anaerobic conditions. Under anaerobic conditions, lindane without S9 was cytotoxic to the V79 cells at dose levels above 10 µg/ ml and with S9 at dose levels above 150 µ g/ ml. No mutagenic activity of lindane was observed in V79 cells under any combination of conditions up to cytotoxic doses. No statistical analysis was performed; solvent control values were somewhat variable; the positive control values were appropriate for the experiments under aerobic conditions, but the positive control employed for anaerobic conditions did not exhibit an increase in anaerobic mutation frequency compared to aerobic mutation frequency. Moreover, there was no experimental verification that anaerobic conditions were either established before exposure to lindane or maintained throughout the exposure period. Since the anaerobic positive control did not produce more mutations under anaerobic than under aerobic conditions, anaerobic metabolic pathways may not have been induced in the cells. This study is classified as Unacceptable/ Guideline and does not satisfy guideline requirements for a mammalian cell culture gene mutation assay in V79 cells (84­ 2) because of the deficiencies described above. This classification could not be upgraded without repeating the experiments. Executive Summary: In a mammalian in vivo sister chromatid exchange (SCE) assay (MRID 00024504), 50µg tablets of bromodeoxy­ uridine were implanted into male and female CF­ 1 mice. Two hours after implantation, lindane was administered ip in arachis oil at dose levels of 1.3, 6.4 and 32.1 mg/ kg. These doses were reported to be 1/ 75, 1/ 15 and 1/ 3 of the LD50 . The vehicle control group received arachis oil and the positive control group received 10 mg/ kg of cyclophosphamide in saline. Colcemid was administered 22 hours later to arrest cells in mitosis, and after another 2 hours the animals were sacrificed. For each dose level and control group, 30 bone marrow cells from each of 5 animals of each sex were examined for SCEs. No toxicity was reported in any treatment group. Slight but significant increases in SCEs over the vehicle controls were observed in female but not in male animals at all dose levels tested but were not dose­ related (1.29 [sic], 1.82, and 2. 12 SCE/ cell). Vehicle control 17 values for female animals were also found to be significantly lower than those for males (1. 56 ± 0.089 SCE/ cell compared to 1. 86 ± 0.207 SCE/ cell). When results for male and female animals were pooled, only the highest dose produced a significant increase in SCEs over the controls. Positive control values were appropriate. The study authors concluded that no chromosome damage was observed in this test. This study was classified as Acceptable/ Guideline and satisfies the guideline requirements for a sister chromatid exchange study in mice (in vivo SCE) (84­ 2). Executive Summary: In a mammalian dominant lethal assay (MRID 00062657), 10 male Sprague­ Dawley rats of unspecified age per group were exposed to lindane administered by subcutaneous injection in corn oil at doses of 0, 1, 3, and 10 mg/ kg five time per week for 10 weeks. Immediately following treatment, each male was housed with two virgin females. After one week, the females were replaced with two more virgin females. No positive control group was included in the study. Females were sacrificed 14 days after evidence of mating or, lacking evidence, 14 days after removal from males. Uteri were examined for live and dead implants and abnormalities. Males were also sacrificed and gross pathological analysis performed. Very slight but not statistically significant weight loss was observed in the male animals at the two higher doses. No mortality or treatment­ related clinical signs of toxicity were noted. No treatment related effect on pregnancy rate was observed, although pregnancy rates in all groups were low during the first week. The incidence of dead implants was significantly increased at the lowest dose but not at the two higher doses in the first week of mating but this increase was not observed during the second week. The authors conclude that lindane did not cause an increase in the incidence of dominant lethals in this study. This study is classified as Unacceptable/ Guideline and does not satisfy the guideline requirements for a dominant lethal test in the rodent (84­ 2) because no positive control was done, the criteria for toxicity were inadequate, animal age was not given, and insufficient numbers of pregnant dams were produced for meaningful evaluation. Moreover, no rationale was provided for the dose selection, unusual route of administration or dosing regime. This classification could not be upgraded without repeating the study. IPCS has also determined that Lindane does not appear to have mutagenic potential. 18 V. FQPA CONSIDERATIONS 5.1 Adequacy of the Data Base ­­ Acute delayed neurotoxicity study in hen (if applicable) ­X­ Acute and subchronic neurotoxicity studies (if applicable) ­X­ Developmental toxicity studies in Rat & Rabbits ­X­ Two­ Generation Reproduction Study ­X­ Developmental neurotoxicity study (if applicable) THESE STUDIES ARE AVAILABLE AND THE DATA BASE IS ADEQUATE FOR FQPA EVALUATION OF FQPA. 5. 2 Neurotoxicity Data 1­ Acute Neurotoxicity ­§ 81­ 7: See Acute RfD section 2­ Subchronic Neurotoxicity­ §82­ 5 MRID: 44781101 Executive Summary: In a subchronic oral neurotoxicity study (MRID 44781101), groups of 10 Crl: CD® BR rats/ sex/ group were administered Lindane (Batch No. HLS96/ 1, Purity 99.78%) in the diet for 13 weeks at concentrations of 0 (control), 20, 100, or 500 ppm. Due to severe toxic reactions to treatment at 500 ppm, the dose was reduced to 400 ppm on day 11 of treatment thereafter. These doses resulted in average daily intake values of 0, 1.4, 7.1, and 28.1 mg/ kg/ day for males and 0, 1.6, 7.9, and 30.2 mg/ kg/ day in females for 0, 20, 100, and 500/ 400 ppm, respectively. Functional observational battery (FOB) and motor activity (MA) tests were performed prior to administration and after 4, 8, and 13 weeks of treatment. Body weights were recorded pre­ test, weekly during the study period and on FOB assessment days. Clinical signs were recorded at least once daily. At study termination all animals were sacrificed and fixed by whole body perfusion and designated tissues of the nervous system were processed for microscopic neuropathological evaluation. Three females in the 500/ 400 group died prior to scheduled termination. These deaths were attributed to treatment with Lindane. One death was recorded on Day 11 of the study, one during week 10 and one during week 13. Clinical signs prior to death included weight loss, swollen muzzle with scabbing, hunched posture, piloerection, and staining of the anogenital region. Observations in surviving females treated at 500/ 400 ppm were hypersensitivity to touch, staining of the urogenital region, and scabbing of the toes. Significant treatment­ related decreases (p< 0.05 or p< 0.01) in body weight were observed 19 among males and females treated with 500/ 400 ppm of 14% and 23%, respectively. Decreases in body weight gains (70%
and 180%  , p< 0.01), food consumption (35%
and 50%  , p< 0.05 or p< 0.01, respectively), and food conversion ratios were observed for males and females in the 500 ppm groups compared to the control group for the first week of the study. Male rats tended to recover from these effects after the dose was lowered. Females, however, did not exhibit this same level of recovery as their food consumption remained slightly depressed throughout the remainder of the study. Females in the 100 ppm group had significantly decreased body weight gains (40%, p< 0.05) compared to the control group during the first week of the study and this effect continued, although not at a level of significance throughout the remainder of the study. Females in the 100 ppm group had significantly decreased food consumption (16%, p< 0.01) for the first week of the study and this trend continued throughout the study. Liver weights were also found to be increased at 500/ 400 ppm for both sexes; no additional information was given. During the FOB assessment (table A is attached at the end of this document), males and females treated at the highest dose (500/ 400 ppm) were perceived as difficult to handle. They also were observed to have piloerection and hunched posture. Females in the highest dose group had missing claws (3), tended to urinate more often than controls, had a higher incidence of grooming behavior, rearing, motor activity, and one female was observed to convulse. Females across the dose groups were observed walking on tiptoes (5­ 7) and these incidences were significantly increased compared to the control (1) for the highest dose group. Females (5) in the 100 ppm group also had increased incidences of grooming behavior at the Week 4 evaluation and one animal in this group was extremely difficult to handle. The assessments of forelimb and hindlimb grip strength as well as hindlimb splay revealed no differences for any of the treated groups compared to the control groups. Colburn motor activity was also similar among treated groups compared to the control groups. No neuropathological endpoints attributable to Lindane administration were observed during the histological examinations of the peripheral or central nervous systems of these animals at any exposure concentration. The NOAEL for systemic toxicity is 100 ppm for males (7. 1 mg/ kg) and 20 ppm for females (1.6 mg/ kg). Based on the substance­ related effects on body weight, body weight gain, food consumption, and clinical signs of toxicity the LOAEL levels for systemic toxicity in males is 500/ 400 ppm (28.1 mg/ kg) and 100 ppm for females (7. 9 mg/ kg). The NOAEL for neurotoxic effects is 100 ppm for males (7. 1 mg/ kg) and females (7. 9 mg/ kg). The neurotoxicity LOAEL is 500/ 400 ppm based on hypersensitivity to 20 touch and hunched posture. This study is classified Acceptable/ guideline and satisfies the Subdivision F guideline requirement for an acute oral neurotoxicity study (§ 81­ 8) in rats. 5.3 Developmental Toxicity Executive Summary: In a developmental toxicity study (MRID 42808001), 20 presumed pregnant CFY (derived from Charles River CD) rats per group were administered technical Lindane (purity not given; Batch No. 6801/ 403) by gavage in 0.5% carboxymethylcellulose at doses of 0, 5, 10, and 20 mg/ kg/ day on gestation days (GD) 6­ 15, inclusive. On GD 20, dams were sacrificed by CO2 , subjected to gross necropsy, and all fetuses examined externally. Approximately one­ third of each litter was processed for visceral examination and the remaining two­ thirds was processed for skeletal examination. Deaths of two high­ dose dams were attributed by the authors to treatment although the cause of death was not reported. No treatment­ related clinical signs of toxicity were observed in any animal. Body weight gains and food consumption by the mid­ and highdose groups were decreased during the treatment interval as compared with the controls. Body weight gains by the mid­ and high­ dose dams were 70% and 46%, respectively, of the control values during GD 6­ 14. Food consumption by the mid­ and high­ dose groups was 72% of the control level during GD 7­ 10 and 92% and 65%, respectively, during GD 11­ 14. It should be noted that data were not available for the entire dosing interval and that statistical analyses were not provided for these data. Maternal necropsy was unremarkable. Organ weights were similar between the treated and control groups. Therefore, the maternal toxicity LOAEL is 10 mg/ kg/ day based on reduced body weight gain and food consumption. The maternal toxicity NOAEL is 5 mg/ kg/ day. No significant differences were observed between the control group and the treated groups for number of corpora lutea, number of implantation sites, live fetuses/ dam, pre­ and postimplantation losses, fetal body weights, or fetal sex ratios. No treatment­ related effects were found at external or visceral examination of the fetuses. The percentage of litters in the control, low­, mid­, and high­ dose groups containing fetuses with extra (14th) ribs was 12.7, 21.0, 31.7, and 40.6% (p 0.05), respectively. The total incidences of litters containing fetuses with skeletal variants were 43.4, 52.7, 59.5, and 68.0% (p 0.01), respectively. Although the response rates in the high­ dose group for extra ribs and total variants are within the upper limit of historical control data, they were considered treatment­ related due to the dose­ related manner of increase. 21 Therefore, the developmental toxicity LOAEL is 20 mg/ kg/ day based on increases in extra ribs and total skeletal variants; a trend for increases in these endpoints at the lower doses is recognized. The developmental toxicity NOAEL is 10 mg/ kg/ day. This study is classified as Acceptable/ nonguideline and does satisfy the requirements for a developmental toxicity study (83­ 3a) in rats. Several deficiencies were noted in the conduct of this study: percent purity of the test article was not given, less than 20 litters/ group were available, dosing solutions were not analyzed for concentration, stability, or homogeneity, and much of the individual animal data were not included. This study was conducted prior to implementation of current guidelines. Executive Summary: In a developmental toxicity study (MRID 00062658), groups of presumed pregnant Sprague­ Dawley rats were administered Lindane (purity not given; Lot No. 36346) by subcutaneous injection in corn oil (1 ml/ kg) at doses of 0, 5, 15, or 30 mg/ kg/ day on gestation days (GD) 6­ 15, inclusive. On GD 19, dams were sacrificed and the fetuses removed. Approximately one­ third of the fetuses from each litter were sectioned and examined for visceral malformations/ variations. The remaining two­ thirds of each litter were "examined externally" and processed and examined for skeletal malformations/ variations. Two high­ dose animals died prematurely. Clinical signs of toxicity, including tremors, convulsions, urine stains, excitability, and anorexia, were reported for one high­ dose animal. However, it was not possible to correlate clinical signs with death since individual animal data were not included. No other clinical signs of toxicity were reported. Body weight gains by the mid­ and high­ dose dams were 76% and 23%, respectively, of the control levels during the treatment interval with both groups attaining statistical significance (p < 0.05). Overall body weight gain by the high­ dose group was 69% (p 0. 05) of the controls. Food consumption by the high­ dose group was 47% of the control level during GD 6­ 11. Body weight gains by the low­ dose group and food consumption for the low­ and mid­ dose groups were similar to the controls throughout the study. Gross necropsy data, other than uterine data, for the dams were not provided. Therefore, the maternal toxicity LOAEL is 15 mg/ kg/ day based on decreased body weight gain. The maternal toxicity NOAEL is 5 mg/ kg/ day. No treatment­ related effects were observed between the control group and the treated groups for number of corpora lutea, number of implantation sites, live fetuses/ dam, preand post­ implantation losses, fetal body weights, or fetal crown­ rump lengths. No treatment­ related visceral or skeletal malformations/ variations were observed in any of the fetuses. Results of external examination were not reported. 22 Therefore, the developmental toxicity NOAEL is >30 mg/ kg/ day and the developmental toxicity LOAEL was not identified. This study is classified as Unacceptable/ nonguideline and does not satisfy the requirements for a developmental toxicity study (83­ 3a) in rats. Several deficiencies were noted in the conduct of this study: the subcutaneous route is not the preferred method of administration, percent purity of the test article was not given, dosing solutions were not analyzed for concentration, stability, or homogeneity, less than 20 litters/ group were available for evaluation, and much of the individual maternal and fetal data were not included. However, this study may be used as supplemental information. This study was classified unacceptable; however, a new developmental toxicity study in rabbits is not required and thought to not be beneficial for the following reasons: 1) The developmental toxicity study in rabbits and rats using a subcutaneous route of administration shows no developmental effects at the maternally toxic dose. 2) The skeletal effects observed in the developmental toxicity study in rats, with gavage as the route of administration, are within historical controls. 3) More severe maternal effects are seen in the rabbit study with subcutaneous administration. 4) The rat appears to be the more sensitive species for developmental effects. 5) A developmental neurotoxicity study has already been submitted. Executive Summary: In a developmental toxicity study (MRID 42808002), 13 presumed pregnant New Zealand white rabbits per group were administered Lindane (purity not given; Batch No. 6801/ 403) by gavage in 0.5% carboxymethyl­ cellulose at doses of 0, 5, 10, or 20 mg/ kg/ day on gestation days (GD) 6­ 18, inclusive. On GD 29, dams were sacrificed, subjected to gross necropsy, and all fetuses examined for visceral and skeletal malformations/ variations. Data from external examination of the fetuses was not included. All does survived to scheduled sacrifice. No treatment­ related clinical signs of toxicity were observed. Maternal body weight and food consumption were similar between the treated and control groups. Gross necropsy was unremarkable. Organ weights were similar between the treated and control groups. Therefore, the maternal toxicity NOAEL is >20 mg/ kg/ day and the maternal toxicity LOAEL was not identified. No treatment­ related effects were observed in any dose group for number of corpora lutea, number of implantation sites, live fetuses/ dam, pre­ and post­ implantation losses, fetal body weights, or fetal sex ratios. No treatment­ related visceral or skeletal malformations/ variations were observed in any of the fetuses. 23 Therefore, the developmental toxicity NOAEL is >20 mg/ kg/ day and the developmental toxicity LOAEL was not identified. This study is classified as Unacceptable/ not upgradable and does not satisfy the requirements for a developmental toxicity study (83­ 3b) in rabbits. Maternal and developmental toxicity LOAELs were not identified and the highest dose did not approach the limit dose. Therefore, dose selection was considered inadequate. Doses were based on the results of a subcutaneous study in the rabbit (MRID 00062658) which is not a valid method for selecting doses for an oral study. Several other deficiencies were noted in the conduct of this study: percent purity of the test article was not given, dosing solutions were not analyzed for concentration, stability, or homogeneity, and much of the individual animal data were not included. Executive Summary: In a developmental toxicity study (MRID 00062658), 15 presumed pregnant New Zealand white rabbits per group following artificial insemination were administered Lindane (purity and Batch No. not given) by subcutaneous injection in corn oil (0.5 ml/ kg) at doses of 0, 5, 15, or 45 mg/ kg/ day on gestation days (GD) 6­ 18, inclusive. Due to excessive toxicity, the high dose was reduced to 30 mg/ kg/ day after GD 9. On GD 29, dams were sacrificed, subjected to gross necropsy, and all fetuses examined for visceral and skeletal malformations/ variations. Data from external examination of the fetuses was not included. One mid­ dose dam aborted and died on GD 21 and 14/ 15 high­ dose animals died between GD 10 and 26. The high­ dose group was then discontinued due to excessive mortality. Decreased activity and immobilized rear quarters were observed in the mid­ dose group (frequency and number affected not reported). No clinical signs of toxicity were observed in the low­ dose group. During GD 6­ 20, does in the mid­ dose group had a body weight loss of 126.7 g as compared with a body weight gain of 218.0 g by the controls. Body weight loss was accompanied by "markedly lower" food consumption by the mid­ dose animals. Body weight changes and food consumption for the low­ dose group were similar to the controls throughout the study. It appeared that does in the mid­ and high­ dose group had differences in the texture of the liver, however, data from gross necropsy were difficult to interpret due to poor copy quality of the original report. Therefore, the maternal toxicity LOAEL is 15 mg/ kg/ day based on clinical signs of toxicity, death, and reduction in body weight. The maternal toxicity NOAEL is 5 mg/ kg/ day. No treatment­ related effects were observed between the control group and the treated groups for number of corpora lutea, number of implantation sites, live fetuses/ dam, pre­ 24 and post­ implantation losses, fetal body weights, or fetal crown­ rump distances. No treatment­ related visceral or skeletal malformations/ variations were observed in any of the fetuses. Abortion by one mid­ dose doe was assumed to be due to excessive maternal toxicity and not to a direct effect on the embryos or fetuses. Therefore, the developmental toxicity NOAEL is >15 mg/ kg/ day and the developmental toxicity LOAEL was not identified. This study is classified as Unacceptable/ not upgradable and does not satisfy the requirements for a developmental toxicity study (83­ 3b) in rabbits. Several deficiencies were noted in the conduct of this study: the subcutaneous route is not the preferred method of administration, excessive toxicity occurred at the high­ dose, percent purity of the test article wast not given, dosing solutions were not analyzed for concentration, stability, or homogeneity, and much of the individual maternal and fetal data were not included. However, these study results may be used in conjunction with the oral developmental toxicity study in rabbits (MRID 42808002) as supplemental information. Study: Developmental Neurotoxicity Study Executive Summary: See Short­ Term Dermal (1­ 7 days); Section 2. 3. 2 5.4 Reproductive Toxicity Executive Summary: In a multigeneration reproductive toxicity study (MRID 42246101), Lindane (99.5% a. i.; Batch No. DA433) was administered to groups of 30 male and 30 female Charles River CD rats at dietary concentrations of 0, 1, 20, or 150 ppm (0. 087, 1.71, and 13.05 mg/ kg/ day, respectively) during the per mating period for two generations. One litter was produced in each generation. F1 pups chosen as parental animals were weaned onto the same diet as their parents. Test or control diets were administered to the F0 and F1 parental animals for 71 and 70 days, respectively, before the animals were mated within the same dose group. All animals were continuously exposed to test material either in the diet or during lactation until sacrifice. Premature sacrifices or intercurrent deaths of two F0 animals and five F1 animals were considered incidental to treatment; all other F0 and F1 males and females survived to terminal sacrifice. No treatment­ related clinical signs of toxicity were observed in males or females of either generation at any time during the study. No treatment­ related effects on body weights, body weight gains, food consumption, or food efficiency were observed for the F0 and F1 males and females during premating. Gross necropsy and hist opathology of females was unremarkable. During gestation days 10­ 13, mean body weight gain by the high­ dose F0 females was significantly reduced (11%). Mean body weight gains by the high­ dose F0 females were also 25 significantly lower on lactation day 1 (interval not specified) as compared to the controls, but recovery was apparent by weaning. No treatment­ related changes in body weights or body weight gains were observed in the F1 females during gestation or lactation. High­ dose male rats of both generations had a significantly (p < 0.01) increased incidence of pale kidneys (10/ 29 F0 males and 10/ 30 F1 males) as compared with the controls (0/ 30 and 0/ 28, respectively). Areas of change on the kidneys (not defined) were observed in 7/ 29 highdose F0 males compared with 2/ 30 controls and in 4/ 30 mid­ dose F1 males and 5/ 30 high­ dose F1 males compared with 1/ 28 controls. Significantly (p < 0. 01) increased incidence of hydronephrosis was observed in high dose F1 males (7/ 30) as compared to controls (0/ 28). Absolute and relative kidney weights of the mid­ and high­ dose F0 males and the high­ dose F1 males were significantly (p < 0.01) increased as compared with the controls. F0 and F1 males in the mid­ and high­ dose groups had significantly (p < 0.01) increased incidences of chronic interstitial nephritis, cortical tubular cell regeneration, hyaline droplets in proximal tubules, tubular necrosis with exfoliation and cellular casts, and cortical tubular casts (n. s.). These changes are characteristic of alpha 2 globulin accumulation, which is specific to male rats. Increased absolute and relative liver weights, accompanied by hepatocellular hypertrophy, in the mid­ and high­ dose males and females of both generations were considered adaptive and of no biological significance. Therefore, the LOAELfor systemic toxicity is 150 ppmbased on decreased body weight gains by the F0 females during gestation. The systemic toxicity NOAEL is 20 ppm. In addition, the LOAEL for male rats is 20 ppm based on increased kidney weights and histopathological lesions in the kidney characteristic of alpha 2u globulin accumulation; the NOAEL for males is 1 ppm. Mating, fert ility, gestation survival (postimplantation index), and liveborn indices, mean precoital interval, and mean gestation lengt h were similar between the treated and control groups of both generations. The sex distribution was not affected by the test material. Mean litter sizes of the treated groups were not different fromthe controls throughout lactation for both generations. Viability indices for t he high­ dose F1 and F2 pups were 81% and 85%, respectively, compared with 96% for the controls. This reduction in survival on lactation day 4 was due to the death or sacrifice (for humane reasons) of three F1 litters and two F2 litters. No treatment­ related clinical signs of toxicity were observed in the pups of either generation during lactation. Pup necropsy was unremarkable. Body weights of the low­ and mid­ dose F1 and F2 pups were similar to the controls throughout lactation. Body weights of the high­ dose pups of both generations were significantly (p < 0.01) less than the controls on lactation days 1 and 25. In high­ dose F2 pups, the onset and 26 completion of tooth eruption and completion of hair growth were significantly (p < 0.01) delayed 10.5%, 11.6%, and 24%, respectively, as compared with the controls. Therefore, the LOAELfor reproductive toxicity is 150 ppm based on reduced pup body weights and decreased viability in both generations and delayed maturation of the F2 pups. The reproductive toxicity NOAEL is 20 ppm. This study is classified as Acceptable/ guideline and satisfies the guideline requirements for a reproduction study (83­ 4) in rats. No major deficiencies were identified in the conduct of this study. 5.5 Additional Information from Literature Sources Karmaus, W. et al, Reduced Birthweight and Length in the Offspring of Females Exposed to PCDFs, PCP, and Lindane. Environmental Health Perspectives; 103( 12). 1995. 1120­ 1125. The objective of this study was to investigate a broad range of adverse health outcomes and their potential association to wood preservative used in daycare centers. This article focuses on reproductive effects. A sample of 221 exposed teachers was provided by the employer's liability insurers. A comparison group (n = 189) insured by the same two organizations was recruited from nonexposed daycare centers. In a face­ to­ face interview, job history and reproductive history of 398 female teachers were ascertained. Data on exposure were provided, including measurements on concentration of pentachlorophenol (PCP) and lindane in wood panels, and of PCP, lindane, polychlorinated dibenzo­ p­ dioxins and dibenzofurans in indoor air. An exposure matrix based on individual job history, independent exposure information from each center, and reproductive history was set up with regard to the vulnerable time windows for each pregnancy. Using this approach, 49 exposed and 507 nonexposed pregnancies were identified, including 32 exposed and 386 nonexposed live births. For subgroup analyses the observations were restricted to independent pregnancies, excluding multiple and consecutive births. The data were analyzed with linear regression techniques, taking confounders into account. The crude median difference between exposed and nonexposed was 175 g in birthweight and 2 cm in length. Controlling for confounders, the results showa significantly reduced but weight (p = 0.04) and length (p = 0.02) in exposed pregnancies, even after restricting the data to independent pregnancies and pregnancies for which data could be validated from the mother's health cards. These differences were not explained by differences in gestational age indicating that a toxic effect, which could cause small­ for date newborns, might have affected the fetus. Rivera, S. et al, Behavioral Changes Induced in Developing Rats by an Early Postnatal Exposure to Lindane. Neurotoxicity and Teratology, 12( 6). 1990. 591­ 595 The purpose of this studywas to determine whether the behavioral developmental pattern was altered by an early postnatal exposure to lindane. Male and female offspring of Wist ar rat s 27 were daily orally administered with a nonconvulsant dose of lindane (10 mg/ kg) during 7 days either the 1st or the 2nd postnatal week days. Effects on pups were evaluated with a reduced developmental neurotoxicological test battery. Body weight evolution, neuromotor reflexes (surface righting, cliff avoidance and tail hang reflex) and spontaneous motor activity were analyzed from day 1 after birth up to day 28. The body weight pattern was unaffected by treatment with lindane and no signs of overt toxicity were observed. Lindane­ treated pups showed an increased positive response of the neuromotor reflexes. Furthermore, lindane produced hyperactivity, especially manifested between days 12 and 16. Apeak of activity was reached at day 16 in lindane­ treated group, while control animals had a maximum between days 20 and 24. These results suggest that low nonconvulsant doses of lindane may induce behavioral changes in developing rats. Sircar, S. et al, Lindane (gamma­ HCH) Causes Reproductive Failure and Fetotoxicity in Mice. Toxicology 59( 2). 1989. 171­ 177. Lindane (gamma­ Hexachlorocyclohexane) was orally given to pregnant Swiss female mice at various stages of pregnancy. During early pregnancy (1­ 4 days of gestation), the insecticide caused total absence of any implantation site, while given during mid pregnancy (6­ 12 days of gestation), lindane caused total resorption of fetuses. Lindane administration during late pregnancy (14­ 19 days of gestation) resulted in death of all pups either within 12 h (high­ dosed group) or 5 days (low­ dosed group) of parturition. Body weight of such pups were also highly reduced. When estrogen was given together with lindane at early pregnancy, implantation was normal, although subsequent fetal development was adversely affected. Progesterone, unlike estrogen, could not correct lindane­ induced failure in implantation. On the other hand, when estrogen and progesterone were simultaneously given to lindane­ fed mice during early pregnancy, both implantation and subsequent fetal development became comparable to normal mice. The insecticide besides being fetotoxic, thus appears to cause steroid hormone deficiency resulting in reproductive and developmental failure. Pompa, G. et al, Transfer of Lindane and Pentachlorobenzene From Mother to Newborn Rabbits, Pharmacology and Toxicology; 74( 1). 1994. 28­ 34. After administration of gamma­ hexachlorocyclohexane (lindane) (30 mg/ kg) to sixteen pregnant rabbits, the transfer and distribution of this insecticide and its metabolite pentachlorobenzene, in foetuses and newborns at the 5th, 10th and 20th days after birth, were investigated. Over one lactation the mothers excreted via the milk about 30% of the lindane present in tissues at the 28 th day of pregnancy. The total amount of lindane transferred via milk to 5 day­ old newborns was higher than that transferred across the placenta during pregnancy. Lindane concentrations in newborns decreased in spite of the efficient transfer to off­ spring by lactating mothers. This cannot be explained by growth alone and indicates that newborns are able to actively metabolize the insecticide. The pentachlorobenzene metabolite produced after lindane administration to the mothers crossed the placental barrier with difficulty during pregnancy, but was readily transferred to off­ spring via milk. Pentachlorobenzene levels in 28 neonates increased during lactation by transfer and also as a consequence of endogenous production. At the 20th day of lactation the pentachlorobenzene concentration in maternal and foetal tissues was higher than that of lindane. 5.6 Determination of Susceptibility No quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses to in utero exposure in developmental toxicitystudies. Inthe two generation reproductive study, there was qualitative evidence of an increased susceptibility to exposure to lindane by pups. In the parental animals, toxicity was seen in the form of reduction in body weight gain during gestation while offspring toxicity was correlated with decreases in pup viability and pup body weight in the F1 and F2 generations as well as delayed maturation in the F2 generation. Evidence for quantitative increase in susceptibility could not be ascertained due to the wide spread in the doses tested. In the DNT study, there is supporting evidence of a qualitative and quantitative increase in susceptibility. At the high dose (13. 7 mg/ kg/ day) , animals in t he F0 generation have a reduced body weight and body weight gain while at the mid­ dose (5.6 mg/ kg/ day) F1 and F2 animals have a reduced survival rate, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation as compared to controls. The open literature also contains citations which suggest an increase in susceptibility of fetuses and young animals to exposure to lindane (see Section 5. 5). 6 HAZARD CHARACTERIZATION Lindane is a moderately toxic compound in EPA toxicity class II. It is neither an eye nor dermal sensitizer. Labels for products containing it must bear the Signal Word WARNING. Some formulations of lindane are classified as Restricted Use Pesticides (RUP), and as such may only be purchased and used by certified pesticide applicators. Lindane is no longer manufactured in the U. S., and most agricultural and dairy uses have been canceled by the EPA because of concerns about the compound's potential to cause cancer. The primary effect of Lindane is on the nervous system; in both acute, subchronic, and developmental neurotoxicity studies and chronic toxicity/ oncogenicity study, Lindane appears to cause neurotoxic effects including tremors, convulsions and hypersensitivity to touch. This is further corroborated by the published literature in which human exposure has been seen to produce neurologic effects. Lindane also causes renal and hepatic toxicity via the oral, dermal and inhalation routes of exposure as seen in subchronic, 2­ generation reproduction and chronic toxicity studies in the rat. In developmental toxicity studies, no developmental effects were seen at levels where maternal toxicity was evident. In the rat developmental study, the developmental effects (extra rib and total skeletal variations) were seen at dose levels (20 mg/ kg/ day) greater than maternal toxicity (10 29 mg/ kg/ day). In the reproductive toxicity study, both systemic and developmental LOAELs are 13 mg/ kg; however a qualitative difference in maternal and offspring effects (reduced body weight of maternal animals and reduced viability and delayed maturation in pups) indicates an increased susceptibility to exposure. This is further corroborated by a developmental neurotoxicity study in which a qualitative and quantitative increase in susceptibility is seen. At the high dose (13. 7 mg/ kg/ day) , animals in the F0 generation have a reduced body weight and body weight gain while at the mid­ dose (5.6 mg/ kg/ day) F1 and F2 animals have a reduced survival rate, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation as compared to controls. According to the TES committee report (1994, Doc 013460), Lindane has not been classified by the HED Cancer Peer Review Committee. It was determined by the RfD/ Peer Review Committee (8/ 25/ 93) that: "The mouse carcinogenicity data were considered insufficient because of major deficiencies associated with all studies available." Lindane however had been previously classified by the Cancer Assessment Group of the Office of Research and Development (memorandum dated 7/ 23/ 85 from R. E. McGaughy to Anne Barton) as a group B2/ C carcinogen based on increased incidence of mouse liver tumors. The upper­ bound slope of the dose­ response was given in that memorandumas Q1* = 1.1 (mg/ kg/ day) ­1 . Anew mouse oncogenicitystudyis expected in December 2000. Lindane does not appear to be mutagenic. The available mutagenicity studies are negative; they include a dominant lethal mutation assay, sister chromatid exchange assay and mammalian cell culture gene mutation in V79 cells. IPCS also states that Lindane does not appear to have mutagenic potential. 7 DATA GAPS none 30 8 ACUTE TOXICITY STUDY TYPE MRID CATEGORY RESULT 81­ 1 Acute oral 00049330 II LD50 88 mg/ kg ­ males 91 mg/ kg ­ females 81­ 2 Acute dermal 00109141 II LD50 1000 mg/ kg ­ males 900 mg/ kg ­ females 81­ 3 Acute inhalation Acc. 263946 III LC50 1.56 mg/ L both sexes 81­ 4 Eye irritation Acc. 263946 III PIS = 0.6 no corneal involvement irritation cleared after 24 hours 81­ 5 Dermal irritation Acc. 263946 IV PIS = 0 not an irritant 81­ 6 Dermal sensitization Acc. 263946 NA not a sensitizer 31 9 TOXICOLOGIC PROFILE EXPOSURE SCENARIO DOSE (mg/ kg/ day) ENDPOINT STUDY TYPE/ MRID Acute Dietary­ general population NOAEL= 6 mg/ kg UF = 100 LOAELis20 mg/ kgbased on increasedgrip strength, increased Motor Activity Acute Neurotoxicity in Rats/ 44769201 Acute Dietary­ females 13­ 50 NOAEL= N/ A UF = N/ A No relevant single exposure endpoint was identified. N/ A Acute RfD (Gen. Pop.) = 0. 06 mg/ kg/ day Acute RfD (Females 13­ 50) = N/ A Chronic Dietary NOAEL= 10 ppm (0. 47 mg/ kg/ day) UF = 100 LOAEL is 100 ppm (4. 81 mg/ kg/ day) periacinar hepatocyte hypertrophy, increased liver/ spleen weigt, increased platelets Chronic Feeding and Carcinogenicity in Rats 41094101 41853701 42891201 Chronic RfD = 0. 047 mg/ kg/ day Cancer Risk 3 Q1*= 1.1 (mg/ kg/ day) ­1 Short­ Term 1 (Dermal) NOAEL= 10 ppm (1. 2 mg/ kg/ day) LOAEL is 50 ppm based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. Developmental Neurotoxicity Study in Rats 45073501 Intermediate­ Term 1 (Dermal) NOAEL= 10 ppm (1. 2 mg/ kg/ day) LOAEL is 50 ppm based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation. Developmental Neurotoxicity Study in Rats 45073501 Long­ Term 1 (Dermal) NOAEL= 10 ppm (0. 47 mg/ kg/ day) LOAEL is 100 ppm (4. 81 mg/ kg/ day) periacinar hepatocyte hypertrophy, increased liver/ spleen weigt, increased platelets Chronic Feeding and Carcinogenicityin Rats 41094101 41853701 42891201 Dermal Absorption Factor = 10% Short Term 1 (Inhalation) 0.5 mg/ m 3 (0. 13 mg/ kg/ day) based on clinical signs (diarrhea, piloerection) seen at day 14 and continuing for 20 days 90­ Day Inhalation Toxicity 00255003 Intermediate Term 1 (Inhalation) 0.5 mg/ m 3 (0. 13 mg/ kg/ day) increased kidney weights in females and bone marrow effects (incr. reticul, incr myelo, decr. lympho.) 90­ Day Inhalation Toxicity 00255003 Long Term 2 (Inhalation) N/ A N/ A N/ A 1 An MOE of 100 was selected 2 Exposure thru this route for this duration is not expected 3 The Cancer Risk will be re­ evaluated upon review of the Mouse Carcinogenicity Study submitted in December 2000 32

epa

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regulations

EPA-HQ-OPP-2002-0202-0011

Supporting & Related Material

CANCER ASSESSMENT DOCUMENT EVALUATION OF THE CARCINOGENIC POTENTIAL OF LINDANE PC. Code: 009001 Final Report November 29, 2001 CANCER ASSESSMENT REVIEW COMMITTEE HEALTH EFFECTS DIVISION OFFICE OF PESTICIDE PROGRAMS ii DATA PRESENTATION: Suhair Shallal, Toxicologist DOCUMENT PREPARATION: Sanjivani Diwan, Executive Secretary COMMITTEE MEMBERS IN ATTENDANCE: (Signature indicates concurrence with the assessment unless otherwise stated). Karl Baetcke William Burnam Marion Copley Kerry Dearfield Vicki Dellarco Virginia Dobozy Richard Hill Yiannakis Ioannou Tim McMahon Nancy McCarroll Esther Rinde Jess Rowland Joycelyn Stewart Clark Swentzel Linda Taylor Yin­ Tak­ Woo NON­ COMMITTEE MEMBERS IN ATTENDANCE (Signature indicates concurrence with the pathology report and statistical analysis of data, respectively) John M. Pletcher, Pathology Consultant Lori Brunsman, Statistical Analysis ii CONTENTS ExecutiveSummary............................................................. .iii I. Introduction............................................................... .. 1 II. BackgroundInformation ................................................... 1 III. Evaluation of Carcinogenicity ............................................... 2 1. CombinedChronicToxicity& CarcinogenicityStudyinCD­ 1Mice.............. 2 2. CarcinogenicityStudyinAgouti, PseudoAgoutiandBlackMice................ 7 3. NTPCarcinogenicityStudyinB6C3F1Mice ............................... 8 4. CarcinogenicityStudyinWistarRats .................................... 11 5. NTPChronicToxicity& CarcinogenicityStudyinOsborne­ MendelRats......... 13 IV. Toxicology............................................................ 14 1. Metabolism ....................................................... 14 2. Mutagenicity ...................................................... 15 3. StructureActivityRelationship......................................... 16 4. SubchronicandchronicToxicity ....................................... 16 5. ModeofActionStudies .............................................. 18 V. Committee'sAssessmentoftheWeight­ of­ theEvidence .......................... 19 VI. ClassificationofCarcinogenicPotential ....................................... 22 VII. QuantificationofCarcinogenicPotential....................................... 22 V. Bibliography........................................................... 23 LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT iii EXECUTIVE SUMMARY Lindane (gamma isomer of hexachlorocyclohexane, ­HCH) has been previously classified by the Cancer Assessment Group of the Office of Research and Development (CAG/ ORD, 1985) as a group "B2/ C" carcinogen based on an increased incidence of mouse liver tumors. In 1993, the RfD/ Peer Review Committee (1993) determined that the mouse carcinogenicity data were inadequate because of major deficiencies associated with the available studies. The Toxicology Endpoint Selection (TES) Committee concluded that a new carcinogenicity study in mice was needed to make a determination of the carcinogenic potential of lindane ( TES, 1994). On May30, 2001, the Cancer Assessment ReviewCommittee (CARC) of the Health Effects Division (HED) of the Office of Pesticide Programs met to evaluate the carcinogenic potential of lindane. At this meeting, the CARC could not make a determination of the carcinogenic potential of lindane because the NTP studies were limited in value and it was uncertain if the study on Agouti, Pseudoagouti and Black mice with limited data could be used for regulatory purposes. In addition, the CARC was informed that new histopathology data would be submitted. The Committee also requested additional information including results of a 90­ day subchronic range­ finding study in CD1 mice, an earlier RfD Committee report and analyses of the older studies on lindane. At the September 13, 2001 meeting, the Committee reevaluated all the available information/ data including the old and the newly gathered information that was previously not available for review. [A list of CARC members who attended one or both meetings on lindane is presented on page # i. These meetings were held jointly by teleconference with Pesticide Management Regulatory Agency (PMRA), HealthCanada, Canada]. The chronic toxicity/ carcinogenicitystudies were conducted using 5 different strains of mice and two strains of rats. The dietary doses administered in these studies were as follows: ·
CD­ 1 mice (50/ sex/ dose): 0, 10, 40, or 160 ppm. for 78 weeks (0, 1.3, 5.2, and 21 mg/ kg/ day for males and 0, 1. 8, 7. 1, and 26. 8 mg/ kg/ day for females, respectively).
Female Agouti, Pseudoagouti and Black mice (36­ 96 animals per strain): 0 or 160 ppm. for 24 months
B6C3F1 mice (50 /sex/ dose): 0, 80 or 160 ppm for 80 weeks
Wistar rats (50/ sex/ dose): 0, 1, 10, 100, or 400 ppm for 2 years ( 0, 0.05, 0.47, 4.81, and 19.66 mg/ kg/ day for males and 0, 0.06, 0.59, 6.00, and 24.34 mg/ kg/ day for females, respectively).
Osborne­ Mendel rats (50/ sex/ dose): For males: 320 or 640 ppm for 38 weeks and 160 or 320 ppm for the remaining 42 weeks. For females: 320 or 640 ppm for 2 weeks and 160 or 320 ppm for 49 weeks then for the remaining 29 weeks the dose was lowered to 80 or 160 ppm. Matched controls consisted of 10/ sex. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT iv The CARC concluded that lindane was carcinogenic only to female CD­ 1 mice based on the following: ! CD­ 1 female mice had significant increasing trends, and significant differences in the pair­ wise comparisons of the 160 ppm( 26.8 mg/ kg/ day) dose group with the controls, for lung alveolarbronchiolar adenomas and combined adenomas/ carcinomas, all at p < 0. 05. The incidence of lung adenomas was slightly outside the historical control range. However, the increased incidence of carcinomas was not dose­ dependent and the tumor response was variable. Lindane was not carcinogenic to male mice. The dosing at the highest level was adequate and not excessive based on increased incidences of centrilobular hepatocellular hypertrophy and eosinophilic foci of cellular alteration in males and a slight increase in bronchiolar­ alveolar adenomas in females. ! At 160 ppm, both the treated female Agouti and Pseudoagouti mice had an increase in benign lung adenomas; the treated Agouti mice also had an increased incidence of liver adenomas. No statistical analyses of tumor data were conducted. There was no increase in the incidence or decrease in latency period for liver tumors in Black and Pseudoagouti strains of mice. There was evidence of increased liver weights and an increased incidence of Clara cell hyperplasia in Agouti and Black strains of mice. However, the study was conducted on few animals, only a single dose and sex were tested, no statistical analyses of tumor data were presented and the results of the study were not adequately reported. The Committee concluded that although the liver effects appear to suggest that a dose of 160 ppm was adequate, additional dose groups could have provided confirmatory information. ! The CARC could not assess the carcinogenicity of lindane in B6C3F1 male and female mice because the data reporting was inadequate and there were no indications of toxicity in high dose females. Moreover, the use of only 10 mice per sex for the control group compromised the usefulness of the study. The Committee concluded that the increased incidence of lung tumors in female mice of three strains was treatment­ related because the statistically significant increase in lung adenomas in female CD­ 1 mice was corroborated with the increase in lung tumors in two genetically susceptible strains of mice. Although there is some evidence of liver tumor induction in these genetically susceptible strains of mice, no evidence of liver tumors was noted in CD­ 1 mice. Nevertheless, the evidence of hepatotoxicity (increased liver weight, hypertrophy and increased incidence of liver foci in both sexes) and promoting activity, indicates t hat t he liver, in addition to lung is a major target organ of toxicity. ! The CARC determined that lindane was not carcinogenic to male and female Wistar rats and the results of the study in Osborne Mendel rats were difficult to interpret and were not useful in determining the carcinogenic potential of lindane in that strain of rat. ! The results of a battery of acceptable mutagenicity assays indicate that lindane has a low LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT v concern for mutagenicity. These studies satisfy pre­ 1991 FIFRAguideline requirements. The Committee recommended that the dominant lethal assay be repeated to determine if there is a genetic component to the reproductive (germ cell) effects reported for lindane. ! The technical HCH and the alpha­ isomer are classified as category "B2" (probable human carcinogen). The beta­ isomer is classified as a group "C "( possible human carcinogen) while the delta and epsilon isomers are classified as group "D" (not classifiable as to human carcinogenicity) . ! No mechanistic studies were submitted to support the mode of action for lung tumor induction in mice. In accordance with the EPADraft Guidelines for Carcinogen Risk Assessment (July, 1999), the CARC classified lindane into the category "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" because lindane caused an increased incidence of benign lung tumors in female mice only. The Committee further recommended that quantification of human cancer risk is not required. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 1 Cl Cl Cl Cl Cl Cl I. INTRODUCTION Lindane (gamma isomer of hexachlorocyclohexane, ­HCH) was previously classified by the Cancer Assessment Group of the ORD (1985) as a group "B2/ C" carcinogen based on an increased incidence of mouse liver tumors; the calculated unit risk ( Q1*) was 1. 1 (mg/ kg/ day) ­1 human equivalents. The other isomers of hexachlorocyclohexane are classified in IRIS. Technical HCH and the alpha­ isomer are classified as "B2", probable human carcinogens. The beta­ isomer is classified as "C", possible human carcinogen. The delta and epsilon isomers are classified as D, not classifiable as to human carcinogenicity. In 1993, the RfD/ Peer Review Committee determined that the mouse carcinogenicity data were insufficient because of major deficiencies associated with all available studies. The TES committee concluded that a new carcinogenicity study in mice was needed to make a determination of the carcinogenic potential of lindane (TES, 1994). On May 30, 2001, the HED Cancer Assessment Review Committee (CARC) of the Health Effects Division (HED) of the Office of Pesticide Programs met to evaluate the carcinogenic potential of lindane. At this meeting, the CARC could not make a determination of the carcinogenic potential of lindane because the NTP studies were limited in value and the published study on Agouti, Pseudoagouti and Black mice could not be used for regulatory purposes. The Committee, therefore, requested additional information including results of a 90­ day subchronic range­ finding studyin CD­ 1 mice, an earlier RfD Committee report and analyses of the older studies on lindane. At the September 13, 2001 meeting, the Committee met to reevaluate the carcinogenic potential of lindane based on the available old and new information/ data. At this meeting, information/ data were presented by Dr. Suhair Shallal of Reregistration Branch 4. These data included a new mouse carcinogenicity study in CD­ 1 mice submitted by the registrant, a published study in Agouti, Pseudoagouti and Black mice, NCI studies in B6C3F1 mice and Osborne­ Mendel rats and a 2­ year chronic/ carcinogenicity study in Wistar rats. In addition, carcinogenicity and genetic toxicology data on structurally­ related compounds were presented. II. BACKGROUND INFORMATION Lindane (PC. Code is 009001 and CAS Number is 58­ 89­ 9) is a broad­ spectrum organochlorine compound used on a wide range of soil­ dwelling and plant­ eating (phytophagous) insects. Its chemical structure is provided below. Figure 1. Chemical Structure of ­HCH LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 2 The technical HCH consists of ­isomer: 65­ 67% , ­isomer: 11­ 13%,
­isomer: 13­ 15% , ­isomer: 3­ 5%, ­isomer: 4­ 6% and other isomers: <1%. Lindane is a
­ isomer (1 2 3 4 , 5 , 6 hexachlorocyclohexane). The other isomers are: ­isomer (1 2 3 4 , 5 , 6 hexachlorocyclohexane); ­isomer (1 2 3 4 , 5 , 6 hexachlorocyclohexane); ­isomer (1 2 3 4 , 5 , 6 hexachlorocyclohexane) and ­isomer: (1 2 3 4 , 5 , 6 hexachlorocyclohexane). Worldwide, lindane is commonly used on a wide variety of crops, in warehouses, in public health to control insect­ borne diseases, and (with fungicides) as a seed treatment. Lindane is also presently used in lotions, creams, and shampoos for the control of lice and mites (scabies) in humans; these pharmaceutical uses are regulated by FDA. In the U. S., the only registered food/ feed use is seed treatment for field and vegetable crops. Lindane may be found in formulations with a host of fungicides and insecticides. Labels for products containing the chemical must bear the Signal Word WARNING. Some formulations of lindane are classified as Restricted Use Pesticides (RUP), and as such may only be purchased and used by certified pesticide applicators. Lindane is no longer manufactured in the U. S., and most agricultural and dairy uses have been canceled because of concerns about its potential carcinogenicity. III. EVALUATION OF CARCINOGENICITY STUDIES 1. Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in CD­ 1 Mice Reference: Lindane, carcinogenicity study by dietary administration to CD­ 1 mice for 78 weeks (2000), final report (vols. 1­ 4). Huntingdon Life Sciences Ltd., Woolley Road, Alconbury, Huntingdon, Cambridgeshire, PE28 4HS, England, Report no. 00 3512, Huntingdon Life Sciences Project identity no. CIL/ 021, MRID 45291402. Experimental Design Lindane (99.78% a. i., batch no. HLS 96/ 1) was administered to groups of 50 Crl: CD­ 1 ® (ICR) BR mice/ sex/ dose in the diet at concentrations of 0, 10, 40, or 160 ppm. The test diets were given for 78 weeks. The concentrations of 10, 40, or 160 ppm resulted in mean daily compound intakes for males of 1. 3, 5. 2, and 21 mg/ kg/ day and for females of 1.8, 7.1, and 27 mg/ kg/ day, respectively. Discussion of Tumor Data Tumor Analyses As shown in Table 1. there was no statistically significant increase in tumors in male mice (Brunsman, 2001). The incidence of liver tumors was not statistically significant in either male or female CD­ 1 mice( Table 1). Table 1. CD­ 1 Mice­ Male and Female Liver Tumor Rates + and Exact Trend Test and Fisher's LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 3 Exact Test Results (p values)­ (Brunsman 2001) ppm 0 10 40 160 0 10 40 160 mg/ kg/ day 0 1. 3 5.2 20.5 0 1.8 7. 1 26.8 Males females Tumor Type Liver Tumor Adenoma % p = 10 a /48 (21) 0.1730 10/ 46 (22) 0.5570 9/ 43 (21) 0.5962 13/ 46 (28) 0.2752 0/ 47 (0) 0.2567 0/ 45 (0) 1.000 0/ 47 (0) 1.000 1 a /48 (2) 0.5053 Carcinoma % p = 4/ 48 (8) 0.4046 1/ 46 (2) 0.1943 1/ 43 (2) 0.2167 2 b /46 (4) 0.3592 No carcinomas were observed in females Combined % p = 13/ 48 (27) 0.1817 11/ 46 (24) 0.4543 10/ 43 (23) 0.4304 15/ 46 (33) 0.3594 + Number of tumor bearing animals/ Number of animals examined, excluding those that died before week 53. a First adenoma observed in males at week 67, dose 0 ppm; First adenoma observed in females at week 80, dose 160 ppm b First carcinoma observed in males at week 53, dose 10 ppm; no carcinomas were observed in females. Note: Significance of trend denoted at control. Significance of pair­ wise comparison with control denoted at dose level. If * , then p < 0.05. If ** , then p < 0.01. Treatment for up to 78 weeks with lindane resulted in a statistically significant increase in the incidence of bronchiolar­ alveolar adenomas and an increased incidence of carcinomas in female Crl: CD­ 1 mice; however, the increased incidence of carcinomas was not dosedependent and tumor response was variable. Female mice had significant increasing trends and significant differences in the pair­ wise comparisons of the 160 ppm dose group with the controls for lung alveolar­ bronchiolar adenomas and combined adenomas/ carcinomas, all at p < 0. 05 (Table 2a). The incidence of pulmonary adenomas in the control group was at the low end of the range in historical controls (6%) and the incidence in females administered the high dose (23%) was slightly outside of the high end of the range for the historical controls (6%­ 19%) (MRID 45291402). . Table 2a. Male and Female Lung Alveolar­ Bronchiolar Tumor Rates + and Exact Trend Test and Fisher's Exact Test Results (p values)­ Initial Diagnosis (Brunsman, 2001) LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 4 ppm 0 10 40 160 0 10 40 160 mg/ kg/ day 0 1. 3 5.2 20.5 0 1.8 7. 1 26.8 males females Tumor Type Lung Alveolar­ Bronchiolar Tumors Adenoma % p = 16 a /49 (33) 0.0270* n 15/ 48 (31) 0.5278 11/ 49 (22) 0.1830 8/ 48 (17) 0.0554 3 a /48 (6) 0.0274 * 7/ 46 (15) 0.1412 7/ 47 (15) 0.1497 11/ 48 (23) 0.0200 * Carcinoma % p = 0/ 49 (0) 0.3138 1/ 48 (2) 0.4948 3 b /49 (6) 0.1211 0/ 48 (0) 1.0000 1/ 48 (2) 0.4361 2 b /46 (4) 0.4839 2/ 47 (4) 0.4920 1/ 48 (2) 0.7526 Combined % p = 16/ 49 (33) 0.0186* n 16/ 48 (33) 0.5574 14/ 49 (29) 0.4134 8/ 48 (17) 0.0554 4/ 48 (8) 0.0389 * 8/ 46 (17) 0.1573 9/ 47 (19) 0.1080 12/ 48 (25) 0.0264 * a first adenoma observed in males at week 33, dose 0 ppm and in females at week 44, dose 0 ppm b first carcinoma observed males at week 65, dose 40 ppm and in females at week 53, dose 10 ppm n Negative trend Note: Significance of trend denoted at control. Significance of pair­ wise comparison with control denoted at dose level If * , then p < 0.05. If ** , then p < 0.01. A new report on the results of resectioning of lungs of female mice was later submitted by the Registrant (MRID 45470601). The results showed the presence of two additional pulmonary adenomas in the controls and two in the high dose group. The number of pulmonary adenomas and combined adenomas/ carcinomas in Group 4 remained still statistically significant (Table 2b), and was biologically significant, being well above the historical control range for this strain of mouse. The incidence in the controls and in the two intermediate dose groups was within the historical control range (6%­ 19%) for pulmonary adenomas in CD­ 1 females. It is, however, difficult to compare old tumor data versus the combined analyses based on the old and new findings without knowing the exact procedure involved in resectioning the lungs and why resectioning of the lung tissue was necessary. Therefore, without judging the validity of the new sectioning versus the original report, the end results appear to be the same. Table 2b. Lindane ­ CD­ 1 Mouse Study Female Lung Alveolar­ Bronchiolar Tumor Rates + [Additional Histopathology PLUS LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 5 Original Diagnoses] and Exact Trend Test and Fisher's Exact Test Results (p values)­ Results of Re­ sectioning (Brunsman, 2001) Dose (ppm) 0 10 40 160 Adenomas 5 a /48 7/ 46 7/ 47 13/ 48 (%) (10) (15) (15) (27) p = 0.0165* 0.3492 0.3644 0.0326* Carcinomas 1/ 48 2 b /46 2/ 47 1/ 48 (%) (2) (4) (4) (2) p = 0.4361 0.4839 0.4920 0.7526 Combined 6/ 48 8/ 46 9/ 47 14/ 48 (%) (12) (17) (19) (29) p = 0.0235* 0.3535 0.2723 0.0384* + Number of tumor bearing animals/ Number of animals examined, excluding those that died before week 44. a First adenoma observed at week 44, dose 0 ppm. b First carcinoma observed at week 53, dose 10 ppm. Note: Significance of trend denoted at control. Significance of pair­ wise comparison with control denoted at dose level. If * , then p < 0.05. If ** , then p < 0.01. Non­ Neoplastic Lesions At 78 weeks, there were increases in the incidences of centrilobular hepatocyte hypertrophy (control, 6%; 160 ppm, 30%; p< 0. 01) and eosinophilic focus/ foci of hepatocellular alteration (control, 4%; 160 ppm, 16%; p< 0.05) in high­ dose males compared to the control group (Table 3). No microscopic liver changes were seen in females Table 3. Non­ Neoplastic Lesions in CD­ 1 Mice Fed Lindane LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 6 Dose (ppm) 0 10 40 160 0 10 40 160 mg/ kg/ day 0 1. 3 5.2 20.5 0 1.8 7. 1 26.8 males females centrilobular hepatocyte hypertrophy 3/ 50 2/ 50 7/ 50 15/ 50 0/ 50 0/ 50 0/ 50 0/ 50 eosinophilic focus/ foci of hepatocyte. alterations 2/ 50 1/ 50 5/ 50 8/ 50 0/ 50 0/ 50 0/ 50 0/ 50 lung epithelial hyperplasia 1/ 50 1/ 50 1/ 50 2/ 50 1/ 50 0/ 50 0/ 50 2/ 50 lung congestion 16/ 50 12/ 50 16/ 50 11/ 50 6/ 50 13/ 50 8/ 50 13/ 50 Thyroid­ dilated follicles 9/ 49 4/ 16 3/ 16 14/ 50 2/ 50 1/ 19 0/ 17 3/ 50 LN Bronchial­ increased cellularity 1/ 16 0/ 17 1/ 15 0/ 11 0/ 12 1/ 15 2/ 15 3/ 14 Adequacy of the Dosing for Assessment of Carcinogenicity There was no significant change in body weight and the survival analyses indicated no statistically significant incremental changes with increasing doses of lindane in male or female mice (Brunsman, 2001). All dose groups and controls had
68% survival at study termination. Histopathologyrevealed an increased incidence of liver lesions in male mice. The LOAEL was 160 ppmfor males (20.5 mg/ kg/ day) and females (26.8 mg/ kg/ day) based on liver hypertrophy in males and a slight increase in bronchiolar­ alveolar adenomas in females. The doses selected for the above chronic/ carcinogenicity study were based on the results of a range­ finding subchronic toxicity study (MRID 45424301). In this study, lindane (99.78% a. i.) was administered to 10 CD­ 1 mice/ sex/ dose at dietary levels of 0, 40, 80, 160, 320 ppm (0, 5. 7, 12.2, 22.8 and 46.2 and 0, 8.9, 16.0, 32.9, and 62.6 mg/ kg/ day in males and females, respectively). Body weight gain was reduced by 27% in males and 9% in females at the highest dose. The four females in the highest dose (320 ppm) group that died during treatment period had hepatocellular hypertrophy and karyomegaly in the liver and Clara cell hypertrophy as well as congestion in the lungs. These findings were also seen in treated animals in the 160 and 320 ppm dose groups that were sacrificed at study termination; therefore, these deaths were considered to be treatment­ related. The early deaths in the 320 ppmdose group indicate that this dose was excessive. Based on the results of this study the majority of the CARC concluded that the dose levels of 0, 10, 40 160 ppm selected for the two­ year carcinogenicity study in mice appeared to be adequate. However, a few members felt that the animals could have tolerated a higher dose, based on the results of chronic study. 2. Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Agouti, Pseudoagouti and Black Mice LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 7 Reference: Wolff, G. L. et al. Tumorigenic responses to lindane in mice: potentiation by a dominant mutation, NCTR, Jefferson, AR ; Carcinogenesis 8( 12): 1889­ 97 (1987). Experimental Design In an NCI study, three strains of female mice, Agouti, Pseudoagouti, and Black, were administered lindane at dietary concentrations of 0 or 160 ppm. Groups of 36­ 96 animals per strain were continuously fed treated or control diets for up to 24 months. Additional groups of 48­ 96 Agouti and Black mice were fed treated or control diets for 6 months and then fed control diet for 6 or 18 months (recovery). Tumor Analysis: No evidence for an increased incidence or a decreased latency of liver tumors was observed for the black strain at any time during the 24 months of study or for the Pseudoagouti strain through the 18 month sacrifice. At 18 months, 0/ 34 control and 12/ 36 (33%) of the treated Agouti mice developed hepatocellular adenomas; one carcinoma each in the treated and control groups was noted. Both the treated Agouti and Pseudoagouti strains had clear increases in adenomas and slight increases in carcinomas at 24 months. The incidence rates for the control and treated Agouti groups were 9% and 35%, respectively, for adenomas and 13% and 17%, respectively, for carcinomas. The incidence rates for the control and treated Pseudoagouti groups were 5% and 12%, respectively, for adenomas and 2% and 5%, respectively, for carcinomas. Increases in Clara cell hyperplasia were noted in the lung at all sacrifice intervals for each strain and the incidence of lung tumors was increased in later months for the Agouti and Pseudoagouti strains. The percentage of mice with Clara cell hyperplasia in the control and treated groups was 6­ 31% and 72­ 92%, respectively, for the Agouti; 6­ 17% and 50­ 79%, respectively, for the Pseudoagouti; and 0­ 14% and 56­ 90%, respectively, for the Black strain. Lung tumors for the Agouti strain occurred in 0% of the control and 17% of the treated animals at 18 months and 4% of the control and 19% of the treat ed animals at 24 months. Lung tumors in the Pseudoagouti strain occurred in 6% of the controls and 14% of the treated animals at 24 months. After recovery, the incidences of Clara cell hyperplasia (Agouti and Black mice) and lung tumors (Agouti mice) remained slightly elevated as compared with the controls. Non­ neoplastic lesions: No clinical signs of toxicity and no survival information were reported. No apparent effects on body weights or food consumption were observed, but only limited data were presented. When compared with untreated controls at 6 and 12 months, benzo( a) pyrene monooxygenase activity in the liver was increased 1.61­ 1.84x in the Agouti, 2.71­ 2.78x in the Pseudoagouti, and 2. 07­ 2.09x in the Black strains. Liver weights were increased 14.7­ 31.2% in the Agouti, 13.5­ 22.0% in the Pseudoagouti, and 12.2­ 16.4% in the Black strains at sacrifice intervals up to 24 months. Following the recovery period, liver weights of the treated mice were similar to the controls. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 8 Adequacy of the dose: Only two dose groups were tested in this study, 0 and 160 ppm. The CARC concluded that although the liver effects appear to suggest that a dose of 160 ppm was adequate, additional dose groups may have provided confirmatory information. Amore thorough reporting of the clinical signs would have been useful in definitive determination of adequacy of dose. 3. NTP Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Mice Reference: NCI, Carcinogenesis Program, Bethesda, MD; DHEWPub # (NIH) 77­ 814, 1977. Experimental Design: Groups of 50 B6C3F1 mice/ sex were administered lindane at dietary concentrations of 80 or 160 ppm for 80 weeks then observed for an additional 10­ 11 weeks. Matched controls consisted of 10 mice/ sex. For statistical analysis, 40 untreated mice/ sex were pooled fromfour other bioassays of other test chemicals. Discussion of tumor data: The incidence of hepatocellular carcinoma in low­ dose males (19/ 49) was increased significantly (p= 0.001) when compared with pooled controls (5/ 49). The incidence of hepatocellular carcinoma in high­ dose male mice (9/ 46) was not significantly different than the matched (2/ 10) or pooled controls. Non­ neoplastic lesions The non­ neoplastic lesions are presented in Table 4 below. There were only slight increases in liver inflammation in males and spleen hyperplasia in females. Higher incidences of microscopic changes in the uterus and ovaries of treated mice were noted; however, no clear dose response was found. Table 4. Non­ neoplastic lesions in B6C3F1 male and female mice Dose 0 80 160 0 80 160 LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 9 males females liver, inflammation/ swelling 0/ 10 0/ 49 5/ 46 0/ 10 0/ 47 0/ 46 spleen, hyperplasia 0/ 10 1/ 50 0/ 47 0/ 8 2/ 49 4/ 48 uterus, hyperplasia N/ A 0/ 7 3/ 44 4/ 43 ovary , inflamation 3/ 7 14/ 42 10/ 46 Adequacy of Dosing for Assessment of Carcinogenicity Body weight was unaffected by the test material. No food or water consumption data was provided. The CARC concluded that the use of pooled controls compromised the usefulness of the study and the available data were inadequate to make an assessment of the carcinogenic potential of lindane. Table 5 provides a comparison of other available mouse studies and their deficiencies. Table 5. Mouse Carcinogenicity Studies, their Results and Deficiencies 1 Study design/ deficiencies/ classification Results 1. Carcinogenicity ­ CF­ 1 mouse Walker and Thorpe as published in Food Cosmetic Toxicology 11: 433­ 442,1973. Supplementary. Data in summary tables were not supported by individual animal data. Test material cannot be validated. Only one dose level which produced severe toxicity was used. Study was run concurrently with dieldrin, DDT, phenobarbitone Considered positive for liver tumors. Males Females Control( 45) BHC( 29) Control( 44) BHC( 29) Adenoma 20% 38% 23% 34% Carcinoma 4% 55% 0 34% Total 24% 93%** 23% 69%** [data are % of animals with tumor, the number in­( ) is the number of mice per sex examined.] ** P < 0.01 study author's statistics. CFl strain mouse, Dose levels tested: 0, 400 ppm and beta­ BHC for 105 to 109 weeks. 2. Carcinogenicit ­dd mouse Hamada, Yutani and Miya as published in GANN 64: 511­ 3( 1973). Supplementary. Data were available in summary form only. Very small number (only 3 or 4) of animals were dosed per group. The survival was poor and dosing period was only 32 weeks . Test material cannot be validated. Study was run concurrently with alpha, beta and gamma isomers of BHC. considered positive Three of f our males and one of three f emales receiving pure gamma isomer at 600 ppm were said to develop "hepatoma" or liver tumors. None of the controls or mice dosed with 100 or 300 ppm developed these tumors. dd strain mice, dose levels 0, 100, 300 or 600 ppm of gamma, alpha or beta hexachlorocyclohexane or crude "BHC" for 36 to 38 weeks. 3. Oncogenicity ­ B6C3F1 mouse NCI, No.: NCI­ CG­ TR­ 14, 1977 Supplementary: Use of only 10 mice per sex for the control group compromised the usef ulness of the study. Data were in summary tables only. There were no indications of toxicity at high dose. Test material cannot be validated. Considered positive at low dose only. Hepatocellular Carcinomas Dose Level Males Females Control 10 2( 20%) 10 0 80 ppm 49 19( 39%) 47 2( 4%) 160 ppm 46 9( 20%) 46 4( 7%) NCI study conclusion is that the chemical is not positive for liver tumors. Conclusion corroborated by Vesselinovich and Carlborg. The CAG of ORD considers low dose group positive. Dose levels tested were 0, 80 and 160 ppm for 80 weeks with 10 weeks recovery. B6C3CF 1 strain mice. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 10 4. Oncogenicity ­Chbb­ NMRI mouse Boehringer Sohn Ingelheim am Rhein, No Study No.: February 25. 1975 Supplementary: Insufficient raw data were used to support conclusions. There was no verif ication of identity of test material and no evidence of toxicity at high dose level. No evidence of liver neoplasms. Dose levels tested 0, 12.5, 25 and 50 ppm. Chbb­ NMRI strain mice. 5. Oncogenicity ­ mice (strain unspecified) Ito , Nagasaki, Arie, Sughara and Makiura, Nara Medical University No Study No.: as published in J. National Cancer Institute 51: 817­ 826, 1972 . Supplementary/ Invalid: No individual animal data were provided, test was conducted for only 24 weeks. There was no verif ication of the test material. gamma isomer was not shown to increase liver tumors. Alpha isomer was positive. Dose levels tested 0, 100, 250 or 500 ppm for 24 weeks. Strain was not specified. 6. oncogenicity ­ ICR­ JCL mouse Goto, Hattori, Miyagawa and Enomoto, Gakushin University, as published in Chemosphere 1( 6): 279­ 282 1972. No Study No., Supplementary: No individual animal data were available and there was no verif ication of the test material. Single dose level f or only 26 weeks. Other isomers were tested at the same time. No inf ormation on survival or reactions to treatment was available. Test material was not validated as lindane. considered positive Liver tumors developed in 5 of 10 mice dosed with gamma isomer after 26 weeks. Dose level tested: 0 and 600 ppm, other isomers of HCH also tested. ICR­ JCL strain mouse. 7. Carcinogenicit ­ dd mouse Nagasaki, Tonrii, Mega, Marugami and Ito, Nara Medical University, as published in Topics in Chemical Carcinogenesis, 1972 No Study No.: Supplementary: Technical ECCE (mixture of isomers) was used, not lindane. Data were available in summary tables only. Only males were tested. "Hepatoma" resulted in response to 660 ppm of the test material (mixture of isomers). Doselevelstested: 0, 6. 6, 66and660ppm. dd strain of mice, only males tested. 8. Carcinogenicity ­ mouse Wolff and colleagues. AS published in Carcinogenesis 8( 12): 1889­ 1892 , 1987 Supplementary: Data are in summary tables only. No verif ication of the test material. Only f emales tested. Only a single dose tested. No data on clinical observations, body weight or survival. This strain may metabolize lindane at a slower rate with resulting accumulation in tissue. Considered positive in two of three strains Liver and lung adenomas and liver carcinomas in "pseudoagouti" and "yellow" but not in black normal mice. Dose levels tested 0 and 160 ppm. Strains as indicated above. 1 This table developed by John Doherty (1993 RfD document) has been slightly modified. 5. Carcinogenicity Study in Rats Reference: Aymes, S. J. 1993. Lindane: Combined carcinogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks. Addendum to final report (Adrenal histopathology ­ additional investigations). Life Sciences Research, England. Study No. 90/ CIL002/ 0839. June 2, 1993. MRID 42891201. Unpublished. LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 11 Aymes, S. J. 1989. Combined carcinogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks. Life Sciences Research, England. Study No. 90/ CIL002/ 0839. November 7, 1989. MRID 41853701. Unpublished. Aymes, S. J. 1989. Lindane: Combined carcinogenicity and toxicity study by dietary administration to Wistar rats for 104 weeks ­ Interim report week 0­ 26. Life Sciences Research, England. Study No. 88/ CIL002/ 816. March 7, 1989. MRID 41094101. Unpublished. Experimental Design Lindane (99.75% a. i., Lot no. DA433) was administered in the diet to groups of 50 male and 50 female Wistar rats at concentrations of 0, 1, 10, 100, or 400 ppm for 2 years. Corresponding delivered doses were 0, 0. 05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0.06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. An additional 15 rats/ sex/ group were designated for interim sacrifices at 30 days and 26 weeks. Discussion of Tumor Data Male rats were identified as having adrenal pheochromocytomas (Table 6). The percentages of animals with adrenal tumors in the 0, 1, 10, 100, and 400 ppm groups were 14, 16, 16, 6, and 24% for benign tumors, respectively, and 0, 0, 6, 8, and 2% for malignant tumors, respectively. Statistical significance was not reached by relevant tests. When compared to historical controls, the incidence of adrenal pheochromocytomas in the current study slightly exceeded that of the historical control at the HDT (400 ppm). The range of adrenal pheochromocytomas observed in the historical control data was 4/ 50 to 11/ 50 (8% ­ 22%) for male rats examined in four studies conducted in 1990. Of the 18 studies in the historical control data, 6 were performed in 1990; the other 12 were performed between 1986 and 1988. Non­ Neoplastic Lesions The incidence rate of periacinar hepatocytic hypertrophy was significantly (p< 0.01) increased in the 100 and 400 ppm groups with 25/ 50 males and 19/ 50 females at 100 ppm and in 40/ 50 males and 43/ 50 females at 400 ppmcompared with the vehicle control. No treatment­ related histopathological lesions were observed in the spleen or bone marrow. Kidney lesions in males indicative of alpha 2µ globulin accumulation were observed in animals treated with
10 ppm; but since this effect is species (rat) specific, it was not considered relevant to human health risk assessment. Table 6. Percentage (%) of animals with adrenal pheochromocytomas LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 12 Control (ppm) Benign Malignant Both (B & M) 0 14014 1 16016 10 16 6 18 100 6 8 14 400 24 2 26 Adjusted Rates 1 0 29029 1 39039 10 33.5 15.2 38.6 100 12.1 21.4 31.0 400 52.9 2. 9 54.2 Historical controls: Benign­ 8 to 22% and Malignant­ 0 to 2% 1 Kaplan­ Meier estimated tumor incidence at the end of the study after adjusting for inter­ current mortality. Adequacy of Dosing for Assessment of Carcinogenicity CARC concluded that the doses tested were considered to be adequate and not excessive in both sexes. This was based on decreased survival, decreased body weight gains, decreased food consumption, and increased spleen and liver weights correlated with periacinar hepatocyte hypertrophy in both sexes at the high­ dose, relative to the controls. Final body weights of the high­ dose males were significantly (­ 14%; p  0.05) less than the controls. Body weights and body weight gains for the treated females were similar to the controls throughout the study. Total food consumption for the entire study was similar to the control levels. Platelet counts were significantly increased in males at 100 and 400 ppm at week 12 and in males and females at week 24, but not at later time points. High­ dose males and females had significant decreases in red blood cell parameters at week 104 as compared with the controls. Significant changes in clinical chemistry parameters were observed in high­ dose males and females during the first year of the study. Inorganic phosphorous and calcium were increased in males and females; the cholesterol and urea were increased in females; and the albumin/ globulin ratio was decreased in females. All parameters were similar to the control LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 13 levels by week 104. High­ dose males and females had increased absolute and relative liver weights at all interim sacrifices, although statistical significance was not always reached. At study termination, absolute and relative liver weights were significantly increased in high­ dose males and females. At 100 ppm, absolute and relative liver weights were increased for both sexes. 6. NTP Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Rats Reference: NCI, Carcinogenesis Program, Bethesda, MD; DHEWPub # (NIH) 77­ 814, 1977. Experimental design: Lindane was administered in the diet of 50 Osborne­ Mendel rats/ sex/ dose for a total of 80 weeks. Males received 320 or 640 ppm for 38 weeks and 160 or 320 ppm for the remaining 42 weeks. Females received 320 or 640 ppm for 2 weeks and 160 or 320 ppm for 49 weeks; then for the remaining 29 weeks, the dose was lowered to 80 or 160 ppm. After the initial 80 week treatment period, all animals were observed for an additional 29­ 30 weeks. Matched controls consisted of 10 rats/ sex. For statistical analysis 45 untreated rats/ sex were pooled from four other bioassays of other test chemicals. Discussion of tumor data As shown in Table 7, there were three incidences of spleen hemangioma in the high­ dose male group only and none in the females. There were also increases in neoplastic lesions of the liver; however, these were within the historical control values in this tumor for this rat strain (0­ 12%, Goodman et al. 2000, personal communication). Other organs affected with primary tumors include: thyroid, pituitary, and mammary glands wit h only a few incidences and no clear dose­ response correlation. . Non­ neoplastic Lesions Microscopic changes were seen in the liver of both males and females, including cirrhosis, degeneration and necrosis in a dose dependent manner. Cysts, hyperplasia and atrophy were seen in the endocrine and reproductive organs of these animals. Table 7. Tumor data for Osborne­ Mendel rats fed lindane for 80 weeks Dose control low high control low high males females spleen hemangioma 0/ 8 0/ 44 3/ 44 ­­­­­­­­­­ ­­­­­­­­­ ­­­­­­­­­ LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 14 thyroid, adenoma carcinoma 1/ 6 5/ 37 0/ 37 0/ 8 1/ 44 1/ 42 0/ 6 1/ 37 4/ 37 0/ 8 1/ 44 0/ 42 liver, neoplastic nodule 0/ 10 3/ 45 2/ 45 0/ 10 4/ 48 2/ 45 pituitary, adenoma carcinoma 0/ 10 0/ 32 2/ 35 0/ 7 0/ 45 2/ 41 0/ 10 1/ 32 0/ 35 0/ 7 1/ 45 0/ 41 mammary, adenoma carcinoma 0/ 10 0/ 48 2/ 49 0/ 10 3/ 50 1/ 50 0/ 10 1/ 48 0/ 49 1/ 10 1/ 50 0/ 50 Adequacy of Dosing for Assessment of Carcinogenicity Mean body weight did not show consistent changes from the administration of lindane. The CARC concluded that the use of pooled controls compromised the usefulness of the study and the available data were inadequate to make an assessment of the carcinogenic potential of lindane. IV. TOXICOLOGY 1. Metabolism Lindane is distributed to all organs at measurable concentrations within a few hours after oral administration. The highest concentrations are found in adipose tissue. The metabolism of lindane is initiated through one of the following pathways: dehydrogenation leading to
HCH, dehydrochlorination leading to formation of
PCCH, dechlorination leading to formation of
­ tetrachlorohexene, or hydroxylation leading to formation of hexachlorocyclohexanol. Further metabolism leads to a large number of metabolites. Volatilizalion appears to be an important route of its dissipation under the high­ temperature conditions oftropicalregions. Lindane is converted byenzymatic reactions, mainlyin the liver. In mammals, including humans, lindane is excreted very rapidly in urine and feces after metabolic degradation; only small amounts are eliminated unchanged. The half­ life of lindane administered to rats is 2­ 4 days depending on the frequency of exposures, single or repeated. Other metabolites are also known to be associated with lindane exposure; these include 2,4,6­ trichlorophenol and 2, 4, 5­ trichlorophenol. Exposure to lindane in a residential setting is expected to be negligible except for use as a lice or scabies treatment. These uses are regulated by FDA and have not been evaluated in this document. 2. Mutagenicity As part of the Registration Standard prepared in 1985, the available literature and submitted mutagenicity studies were evaluated (HED Document No. 004704). Based on this evaluation, it was concluded that the weight­ of­ the­ evidence with conventional genotoxicity testing LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 15 indicated that lindane did not interact with DNA or interfere with genetic mechanisms. This position was reiterated in 1993 (memo by G. Ghali, 1993). Reviews prepared by IARC (1979/ 1987), IPCS (1990) and ATSDR( 1999) indicate that lindane and its associated isomers have mixed genotoxic potential. In addition, numerous mutagenicity studies have been evaluated by the European Commission (EU) in their draft monograph on lindane (2001). Representative studies were selected from the EU evaluation of lindane since they were performed according to OECD or EPA guidelines. These include: 1. A bacterial mutagenicity assay using Salmonella typhimurium with and without metabolic activation which was negative up to cytotoxic doses (5000 ug/ plate +S9) or insoluble doses (greater than or equal to 500 ug/ plate ­S9; greater than or equal to1500 ug/ plate +S9 ; Oesch, 1980). 2. An aerobic mammalian cell (V79) gene mutation assay was negative up to cytotoxic doses (greater than or equal to 50 ug/ mL ­S9; greater than or equal to 250 ug/ mL+ S9); the compound precipitated at greater than or equal to 250 ug/ mL (Glatt, 1984). EPA only received an anaerobic assay which had an acceptable aerobic portion (Glatt, 1985). 3. Mammalian cell cytogenetic assay was negative in CHO cells up to cytotoxic doses (greater than or equal to 33.2 ug/ mL ­S9; greater than 33.2 ug/ mL+ S9). (Murli, 1990). 4. UDS in primary rat hepatocytes was also found to be negative up to cytotoxic doses (15 ug/ mL) (Cifone, 1990). There are no acceptable in vivo studies but they are not necessary to satisfy pre­ 1991 FIFRA guideline requirements. Newer published data shows that lindane induces oxidative stress in the liver of treated rats (Carrion et al., 2001; Cornnejo et al., 2001; Videla et al., 2000). In agreement with these findings, the 1999 ATSDR review states that oxidative stress may be a possible mechanism of liver toxicity. The CARC has an additional concern related to possible genetic effects on germinal cells. Although an old submitted dominant lethal assay (MRID 00062657) was negative, it was considered unacceptable and not upgradable because of technical deficiencies. Recent information found in the open literature indicates that topical application of lindane led to rapid absorption and accumulation in rat testes (Suwalsky et al., 2000). The investigators reported widespread damage to a "great number" of Leydig cells after the application of 1% lindane once daily for 4 consecutive days. These findings are consistent with the work of Walsh and Stocco (2000) showing inhibition of steroidogenesis by reductions in steroidogenic acute regulatory (StAR) protein expression in mouse Leydig cells in vitro. Since there is some evidence that lindane reaches and damages germ cells, the Committee recommends that the dominant lethal assay be repeated to determine if there is a genetic component to the reproductive (germ cell) effects reported above for lindane. 3. Structure­ Activity Relationship LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 16 Technical­ grade hexachlorohexane (HCH) which consists of alpha, beta, gamma, delta and epsilon isomers of HCH is a carcinogen. In rodents studies, the pure alpha isomer of HCH has been found to induce liver tumors; this is also true for the pure beta isomer of HCH.. These studies are found in the NTP, IARC and IPCS reports on hexachlorohexanes. Lindane shares its structure with at least four other isomers. They differ only with respect to the position of the chlorine atoms in the alpha or beta positions, above or below the plane of the hexane ring structure. Structure of HCH (Lindane)::
­isomer: 1 2 3 4 , 5 , 6 hexachlorocyclohexane Other isomers: ­isomer: 1 2 3 4 , 5 , 6 hexachlorocyclohexane ­isomer: 1 2 3 4 , 5 , 6 hexachlorocyclohexane ­isomer: 1 2 3 4 , 5 , 6 hexachlorocyclohexane ­isomer: 1 2 3 4 , 5 , 6 hexachlorocyclohexane Isomers of hexachlorocyclohexane (HCH), other than lindane, have been classified as follows, according to IRIS: The technical HCH and the alpha­ isomer are classified as B2, probable human carcinogens. The beta­ isomer is classified as C, possible human carcinogen. The delta and epsilon isomers are classified as D, not classifiable as to human carcinogenicity. Appendix A contains a summary of various studies which examine the carcinogenicity of the gamma isomer (Lindane) alone or in comparison with the other isomers. 4. Subchronic, and Chronic Toxicity Subchronic Toxicity Mice A range­ finding subchronic toxicity study (MRID 45424301) was conducted to determine the doses to be used in a two­ year carcinogenicity study. In this study, Lindane (99. 78% a. i.) was administered to 10 CD­ 1 mice/ sex/ dose in the diet at dose levels of 0, 40, 80, 160, 320 ppm (0, 5. 7, 12.2, 22.8 and 46.2 and 0, 8.9, 16.0, 32.9, and 62.6 mg/ kg/ day in males and females, respectively). No treatment­ related clinical signs were observed. Five females died or were killed during the treatment period. Four were in the highest dose (320 ppm) group and one from the control group was a humane kill. These animals presented wit h no macroscopic changes. Histopathology revealed hepatocyte hypertrophy and karyomegaly in the liver and Clara cell hypertrophy and congestion in the lungs. These findings were also seen in treated animals in the 160 and 320 ppm dose groups that were sacrificed at study termination; therefore, these deaths were considered to be treatment­ related. Body weight was reduced by 6% in males and was unaffected in females in the highest dose tested (320 ppm). Body weight gain was reduced by 27% LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 17 in males and 9% in females. In a subchronic inhalation toxicity study, Lindane (99.6% a. i., Batch no. DA433) was administered by inhalation to groups of 45 male and 45 female CD­ 1 mice at nominal concentrations of 0, 0.3, 1.0, 5.0 to 10 mg/ m3 (0, 0. 1, 0. 4, 2. 0 or 4.0 mg/ kg/ 6 hrs), for 14 weeks. Exposures were 6 hours/ day, 5 day/ week as described in the pilot study. During the first five exposures, the high­ dose group was exposed to a mean concentration of 9. 72 mg/ m3 (4. 0 mg/ kg/ 6 hrs), but due to excessive deaths, the mean concentration was lowered to 4. 94 mg/ m3 (2. 0 mg/ kg/ 6 hrs). No exposure­ related effects were noted for body weight gain, food consumption, water consumption, or ophthalmoscopic, hematology, clinical chemist ry, or urinalysis parameters. Bone marrow analysis did not show any time­ or concentration­ related changes. Brain, kidney, lung, spleen, thymus, and adrenal, and testes weights were similar between the treated and control animals. Liver weights of females exposed to 5 mg/ m3 were increased 14% (p  0.05) at week 20. Rats In a subchronic oral neurotoxicity study (MRID 44781101), groups of 10 Crl: CD® BR rats/ sex/ group were administered lindane (Batch No. HLS96/ 1, Purity 99.78%) in the diet for 13 weeks at concentrations of 0 (control), 20, 100, or 500 ppm. Due to severe toxic reactions to treatment at 500 ppm, the dose was reduced to 400 ppm on day 11 of treatment thereafter. These doses resulted in average daily intake values of 0, 1.4, 7.1, and 28. 1 mg/ kg/ day for males and 0, 1.6, 7.9, and 30.2 mg/ kg/ day in females for 0, 20, 100, and 500/ 400 ppm, respectively. Significant treatment­ related decreases (p< 0.05 or p< 0.01) in body weight were observed among males and females treated with 500/ 400 ppm of 14% and 23%, respectively. Decreases in body weight gains (70%
and 180%  ,p< 0. 01), food consumption (35%
and 50%  , p< 0.05 or p< 0.01, respectively), and food conversion ratios were observed for males and females in the 500 ppm groups compared to the control group for the first week of the study. Male rats tended to recover from these effects after the dose was lowered. Females, however, did not exhibit this same level of recovery as their food consumption remained slightly depressed throughout the remainder of the study. Females in the 100 ppm group had significantly decreased body weight gains (40%, p< 0.05) compared to the control group during the first week of the study and this effect continued, although not at a level of significance throughout the remainder of the study. Females in the 100 ppm group had significantly decreased food consumption (16%, p< 0.01) for the first week of the study and this trend continued throughout the study. Liver weights were also found to be increased at 500/ 400 ppm for both sexes; no additional information was given. Chronic Toxicity In the chronic toxicity/ carcinogenicity study (MRID41853701), lindane (99.75% a. i., Lot no. DA433) was administered in the diet to groups of 50 male and 50 female Wistar rats at concentrations of 0, 1, 10, 100, or 400 ppm for 2 years. Corresponding LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 18 delivered doses were 0, 0. 05, 0.47, 4.81, and 19.66 mg/ kg/ day, respectively, for males and 0, 0. 06, 0.59, 6.00, and 24.34 mg/ kg/ day, respectively, for females. An additional 15 rats/ sex/ group were designated for interim sacrifices at 30 days and 26 weeks. Body weights were slightly less than the controls for the high­ dose males (­ 6%) and females (­ 8%) during weeks 1­ 5 of the study, but gradually increased to within 2% of the control level by week 26 for males and week 9­ 10 for females. High­ dose females hadsignificantlydecreased hemoglobin, decreased RBCcounts, and decreased PCV. These red cell parameters were "marginally lower" for high­ dose males (non statistically significant). Platelet counts increased in mid­ and high­ dose males and females. White cell counts significantly increased in mid­ dose and in highdose females due to increases in neutrophils. The liver appears to be the major target organ. Kidney lesions in male rats indicative of alpha 2µ globulin accumulation were observed in animals treated with
10 ppm, but are not considered relevant to human health risk assessment. Absolute kidney weights were significantly increased in high­ dose males. Absolute and relative kidney weights increased in mid­ dose males and high­ dose males and females. The incidence of periacinar hepatocytic hypertrophy was significantly increased in males at 100 and 400 ppm and in females at 400 ppm. This lesion was not seen in control animals of either sex. No treatment­ related histopathological lesions were observed in the spleen, adrenals, brain, or thymus. Bone marrow data presentation was inadequate for assessment. 5. Mode of Action Studies No mode of action studies have been submitted for lindane. There have been, however, several published studies which attempt to elucidate the initiator­ promoter activity of lindane. As discussed earlier lindane does not appear to have a clear mutagenic potential. Lindane may act as a promoter as evidenced by studies with Agouti, Pseudoagouti and Black mice. Only Agouti and Pseudoagouti mice, which have a transformed genotype linked to tumorigenicity, were found to have an increased incidence of liver and lung tumors. The Black mice had no tumors in the 24 month period of the study. The Pseudoagouti and Black mice had a low rate of spontaneous tumor incidence in the liver and lung, but of these two only the Pseudoagouti responded to lindane. Therefore, lindane appears to augment the propensity of these genetically altered mice to develop tumors. It has been suggested that lindane has a similar mode of action to phenobarbital, which also increases the incidence of benign tumors in these mice. As discussed earlier on page 13, oxidative stress may be a possible mechanism of liver toxicity. Suggestions have been made that the metabolites of lindane may contribute to its carcinogenic potential. One major urinary metabolite, 2,4,6­ TCP, is considered to be a carcinogen. However studies indicate that TCP may have only a minimal effect on LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 19 the overall carcinogenic potential of lindane. V. COMMITTEE'S ASSESSMENT OF THE WEIGHT­ OF­ THE­ EVIDENCE 1. Carcinogenicity The CARCconcluded that lindane is carcinogenic only to female mice and is not carcinogenic to male mice and male and female rats. ! CD­ 1 female mice had significant increasing trends and significant differences in pair­ wise comparisons of the 160 ppm( 26.8 mg/ kg/ day) dose group with the controls, for lung alveolar­ bronchiolar adenomas (23% vs 6% in controls) and combined adenomas/ carcinomas (25% vs 8% in controls), all at p < 0. 05; the incidence of lung adenomas (23%) was slightly outside the historical control range (6%­ 19%). The increased incidence of carcinomas was not dosedependent and tumor response was variable. Lindane was not carcinogenic to male mice. No non­ neoplastic liver changes were seen in females. The majority of the CARC considered the dosing to have been adequate and not excessive based on an increase in the incidence of centrilobular hepatocyte hypertrophy as well as eosinophilic foci of hepat ocellular alteration in high­ dose males compared to the control group; similar liver findings were also reported in a range­ finding subchronic toxicity study in which early deaths of four females were reported in the 320 ppm dose group indicating that this dose was excessive. However, based on the results of the chronic study a few members felt that the animals could have tolerated a higher dose. ! At 160 ppm, both the treated female Agouti and Pseudoagouti mice had an increased occurrence of benign lung tumors (19% vs 4% in controls and 14% vs 6% in controls, respectively). In addition, both the treated female Agouti and Pseudoagouti mice had increases in liver adenomas (35% vs 9% in controls and 17% vs 13% in controls, respectively) and slight increases in liver carcinomas (5% vs 2% in controls and 12% vs 5% in controls) at 24 months. No statistical analyses of tumor data were provided. There was no increase in incidence or decrease in latency period of liver tumors in Black and Pseudoagouti strains of mice. There was evidence of increased liver weights and increased incidence of Clara cell hyperplasia in Agouti and Black strains of mice. Increases in Clara cell hyperplasia were noted in the lung at all sacrifice intervals for each strain and the incidence of lung tumors was increased in later months for the female Agouti and Pseudoagouti mice. The percentage of mice with Clara cell hyperplasia in the treated and control groups was 72%­ 92% and 6%­ 31%, respectively, for the Agouti; 50%­ 79% and 6% 17 respectively, for the Pseudoagouti; and 56%­ 90% and 0%­ 14%, respectively, for the female Black mice. However, the study was conducted on few animals, only a single dose was tested, no statistical analyses of tumor data were presented; and the results of the studywere not adequately reported. The Committee concluded that although the liver effects appear to suggest that a LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 20 dose of 160 ppm was adequate, additional dose groups could have provided confirmatory information. ! The incidence of hepatocellular carcinoma in low­ dose B6C3F1 males (19/ 49) was significant (p= 0.001) when compared with that in pooled controls (5/ 49). The incidence of hepatocellular carcinoma in high­ dose male mice (9/ 46) was not significantly different than the matched (2/ 10) or pooled controls. The CARC could not assess the carcinogenicity of lindane in B6C3F1 male and female mice because the data reporting was inadequate, there were no indications of toxicity at the high dose and the test material could not be validated. Moreover, the use of only 10 mice per sex for the control group compromised the usefulness of the study. The Committee concluded that the increased incidence of benign lung tumors in female CD­ 1 mice was treatment­ related because the treatment­ related statistically significant increase in lung adenomas in female CD­ 1 mice was correlated with increases in lung tumors in two genetically susceptible strains of mice (Agouti and Pseudoagouti). Although there is some evidence of liver tumor induction in these genetically susceptible strains of mice, there was no evidence of liver tumors in CD­ 1 mice. Nevertheless, the evidence of hepatotoxicity (increased incidences of liver hypertrophy and liver foci in both sexes) and promoting activity suggests the liver as a major target organ of toxicity. ! The treated male Wistar rats developed adrenal pheochromocytomas. The percentages of animals with adrenal tumors in the 0, 1, 10, 100, and 400 ppm groups were 14%, 16%, 16%, 6%, and 24% for benign tumors, respectively, and 0%, 0%, 6%, 8%, and 2% for malignant tumors, respectively. Statistical significance was not reached by relevant tests and no dose­ response was evident. When compared to historical controls, the incidence of adrenal pheochromocytomas in the current studyslightlyexceeded that of the historical control at the HDT (400 ppm). The range of adrenal pheochromocytomas observed in the historical control data was 4/ 50 to 11/ 50 (8% ­ 22%) for male rats examined in four studies conducted in 1990. Of the 18 studies in the historical control data, 6 were performed in 1990; the other 12 were performed between 1986 and 1988. The Committee concluded that the adrenal tumors in male rats were not treatment­ related. The doses tested were considered to be adequate and not excessive in both sexes based on decreased survival, decreased body weight gains and decreased food consumption; the increased spleen and liver weights correlated with increased occurrence of periacinar hepatocyte hypertrophy in both sexes at the high­ dose. ! There were three spleen hemangiomas in 44 high­ dose male Osborne­ Mendel rats only (0/ 8 in controls) and none in the females. There were also non­ dose related increases in neoplastic lesions of the liver (3/ 45 and 2/ 45 in males and 4/ 48 and 2/ 45 in females in the low and high dose groups compared to 0/ 10/ sex in control groups) which were within the historical control values (0%­ 12%). Other organs with primary tumors include: thyroid, pituitary, and mammary LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 21 glands with only a few incidences but there was no clear dose­ response. Dosing at the highest level was considered to be adequate based on microscopic changes seen in the liver of both males and females, including cirrhosis, degeneration, necrosis in a dose dependent manner. Cysts, hyperplasia and atrophy were seen in the endocrine and reproductive organs of these animals. Survival of the animals was adequate for meaningful statistical analyses of the incidence of tumors. The CARC concluded that lindane was not carcinogenic to male and female Wistar rats and that the results of the study in Osborne Mendel rats were difficult to interpret and were not useful in determining the carcinogenic potential of lindane in that strain of rat. 2. Mutagenicity ! Lindane has been tested in a battery of pre­ 1991 mutagenicity assays which satisfies the guideline requirements. The review of both the guideline and literature studies suggests that lindane does not interact with DNAor interfere with genetic mechanisms. However, since there is some evidence that lindane reaches and damages germ cells, the Committee recommended that the dominant lethal assay be repeated to determine if there is a genetic component to the reproductive (germ cell) effects reported for lindane. 3. Structure Activity Relationship ! Isomers of hexachlorocyclohexane (HCH), other than lindane, have been classified for carcinogenic potential. The technical HCH and the alpha­ isomer are classified as B2, probable human carcinogens. The beta­ isomer is classified as C, possible human carcinogen. The delta and epsilon isomers are classified as D, not classifiable as to human carcinogenicity. 4. Mode of Action ! The tumor­ initiating activity reported in the literature has been discounted due to the lack of morphologic alterations in liver foci after treatment with lindane. Lindane appears to augment the propensity of genetically altered mice to develop tumors. However, no definitive studies have established the mode of action for liver tumor induction by lindane. There is a suggestion that oxidative stress may play a role in the liver toxicity of lindane. VI. CLASSIFICATION OF CARCINOGENIC POTENTIAL In accordance with the Agency's Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the Committee classified lindane into category: "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on the occurrence of benign lung tumors in one sex of one species (i. e., female CD­ 1 mice). LINDANE CANCER ASSESSMENT DOCUMENT FINAL REPORT 22 VII. QUANTIFICATION OF CARCINOGENIC POTENTIAL The Committee recommended that quantification of human cancer risk is not required. 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L. ; Lindane: Qualitative Risk Assessment Based On Crl: CD­ 1 (ICR) BR Mouse Dietary Study. Memorandum from Lori Brunsman, Science Information Management Branch, to Suhair Shallal, Reregistration Branch 4, Health Effects Division, Office of Pesticide Programs, Environmental Protection Agency, dated May 1, 2001. HED Doc.# 014556. ­­­­­­­­­­­­ Brunsman, L. L. ; ADDENDUMTo Lidane: Qualitative Risk Assessment Memo of 5/ 1/ 2001 Based OnAdditional HistopathologyInvestigations of Female Lung Tissues of Crl: CD­ 1( ICR) BR Mouse Dietary Study. MemorandumfromLori Brunsman, Science Information Management Branch, to Suhair Shallal, Reregistration Branch 4, Health Effects Division, Office of Pesticide Programs, Environmental ProtectionAgency, dated August 16, 2001. HEDDoc.# 014652. ­­­­­­­­­­­­ Fitzhugh, O. G.; Nelson, A. A.; and Frawley, J. P.; The chronic toxicities of technical benzene hexachloride and its alpha, beta and gamma isomers J. Pharmacol. Expt. Therapeutics. 100: 59 (1950).. ­­­­­­­­­­­­ Goto, M.; Hattori, M.; Miyagawa, T.; and Enomoto, M..; Contributions to ecological chemistry II. Hepatoma development in mice after administration of HCH isomers in high dosage Chemosphere 1( 6): 279­ 282 (1972). ­­­­­­­­­­­ Hanada, M.; Yutani, C.; and Miya, T.; Induction of hepatoma in mice with benzene hydrochloride GANN 64: 511­ 513 (1973). ­­­­­­­­­­ Ito, N.; Nagasaki, H.; Arai, M.; Sugihara, S.; and Makiura, S.; Pathologic and ultrastructural studies in the hepatocarcinogenicity of benzene hexachlooride in mice J. NCI 51: 817­ 826 (1973). ­­­­­­­­­ Ito, N.; Nagasaki, H.; et al.; Brief communication: development of hepatocellular carcinomas in rats treated with benzene hexachloride J. NCI 54: 801­ 805 (1975). ­­­­­­­­­­ Lindane, Environmental HealthCriteria 124, IPCS, WHO, Geneva, Switzerland (1991). ­­­­­­­­­­ Nagasaki, H.; Tonrii, S.; et al. ; Carcinogenicity of Benzene Hexachloride (BHC) Proc. of 2 nd Intern Symp of Princess Tokamatsu Cancer Center Res. Fund in Topics in Chem. Carcino. 1972 ­­­­­­­­­­­ NCI.; NTP Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Mice. National Cancer Institute, Carcinogenesis Program, Bethesda, MD; DHEW Pub # (NIH) 77­ 814 (1977). 25 ­­­­­­­­­­ NCI; NTP Combined Chronic Toxicity/ Carcinogenicity Study with Lindane in Rats. National Cancer Institute, Carcinogenesis Program, DHEWPub # (NIH) 77­ 814 (1977). ­­­­­­­­­­ Ortega, P.; Hayes, W. J.; and Durham, W. F.; Pathologic changes in the liver of rats after feeding low levels of various insecticides A. M. A. Archives of Pathology, 64: 614, (1957). ­­­­­­­­­­ Thorpe and Walker; The toxicology of dieldrin (HEOD). II. Comparitive longt erm oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, betaBHC and gamma­ BHC Fd. Cosmet. Toxicol, 11: 433­ 442 (1973). ­­­­­­­­­­ Wolff, G. L., Roberts, D. W., Morrissey, R. L., Greenman, D. L., Allen, R. R., Campbell, W. L., Bergman, H., Nesnow, S., and Firth, C. H. 1987. Tumorigenic responses to lindane in mice: potentiation by a dominant mutation. Carcinogenesis 8: 1889­ 1897 (1987). National Center for Toxicological Research, Jefferson, AK. APPENDIX A Carcinogenicity Studies comparing the toxicity of gamma­ HCH with other isomers Study # of animals doses results for lindane (gamma­ HCH) results for other isomers Carcinogenicityrat (The chronic toxicities of technical benzene hexachloride and its alpha, beta and gamma isomers) published: 1950 10
/10  Wistar rat 0, 5, 10, 50, 100, 400, 800 or 1600 ppm of
,  , or  HCH. At 100 ppm of  HCH , liver wt. incr no frank liver tumors induced by  HCH 26 CarcinogenicityRats (Pathologic changes in the liver of rats after feeding low levels of various insecticides) published: 1957 6
/ 6  0, 50, 100 ppm for 8 months. One 50 ppm
, and one each 100 ppm
and  developed centrilobular hypertrophy, peripheral migration of basophilic cytoplasmic granulations and cytoplasmic inclusion bodies. Carcinogenicity rats (Brief communication: development of hepatocellular carcinomas in rats treated with benzene hexachloride) published: 1975. 9 groups of
W rats (Japanese strain) 0, 500, 1000 or 1500 ppm of  ,
,  , or  BHC
BHC : cell hypertrophy  BHC: cell hypertrophy, nodular hyperplasia (27/ 41 dosed w/
1000 ppm for 48­ 72 wks), hepatocellular carcinoma (4/ 29 dosed w/
1000 ppm for 72 wks)  , , ,  :cell hypertrophy Carcinogenicity rats (Bioassay of lindane for possible carcinogenicity) NCI (NCI­ RG­ TR 14) 1977 10
/10  Osborne Mendel rats 50
50  0 ppm; 320 or 640 ppm for 38 wks, 160 or 320 ppm for 42 wks, then 0 ppm for 30 wks 320 or 640 for 2 wks, 160 or 320 ppm for 49 wks, 80 or 160 ppm for 29 wks, then 0 ppm for 30 wks. Incidence of liver neoplasia is within historical control levels Carcinogenicity mice (Bioassay of lindane for possible carcinogenicity) NCI (NCI­ RG­ TR 14) 1977 10
/10  BGC3F1 hybrid mice 50
/50  0 ppm 80 or 160 ppm for 80 wks then control diet for 10 wks hepatocellular carcinoma: 0 ppm (20%), 80 ppm (39%), 160 ppm (20%) 27 Carcinogenicitymouse (The toxicology of dieldrin (HEOD). II. Comparitive long­ term oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, beta­ BHC and gamma­ BHC) Thorpe and Walker (1973). CF1 mice 45
/45  30
/30  0 ppm (24/ 23%) 400 ppm (gamma­ BHC) 10 ppm (dieldrin) 100 ppm (DDT) 500 ppm (phenobarbitone) 200 ppm betaBHC
/  % of liver tumors (gamma­ BHC) 93/ 69%
/  % of liver tumors (dieldrin) 100/ 87% (DDT) 77/ 87 % (phenobarbitone) 80/ 75% (beta­ BHC) 73/ 43 % Carcinogenicitymouse (Testing of the substance Lindane for carcinogenic effects in mice using oral administrationduration 80 weeks) translated from German 1975 SPF mice ChbbNMRI 100
/ 100  50
/50  0 ppm 12.5, 25 or 50 ppm for 80 wks incidences (
/  ) liver cell adenomas: 4/ 1, 1/ 1, 0/ 0, 2/ 0 lung tumor: 13/ 8, 10/ 1, 5/ 3, 6/ 4 lymphosarcoma : 5/ 12, 0/ 7, 1/ 3, 2/ 5, respectively Carcinogenicitymouse (Pathologic and ultrastructural studies in the hepatocarcinogenic ity of benzene hexachlooride in mice) published (1973) 19 groups (20­ 40/ group)
,  ,  or  BHC at 100, 250, or 500 ppm and combos of 250 ppm ea. of
with  ,  , or  BHC. Only mice that were dosed w/
BHC in combo. or alone developed nodular hyperplasia and hepatocellular carcinoma Carcinogenicitymouse (Contributions to ecological chemistry II. Hepatoma development in mice after administration of HCH isomers in high dosage. Published: (1972). 8 groups of 20
ICR JCL mice 600 ppm of technical HCH (I),
HCH (II) ,  HCH (III), HCH (IV), a mix of  /  HCH (V), or 300 ppm of  HCH (IX) 5/ 10 in gp IX developed liver tumors and incr. Liver wgt. all of group I and II developed hepatomas 8/ 10 in gp V developed liver tumors and incr. Liver wgt. 28 Carcinogenicitymouse (Carcinogenicity of Benzene Hexachloride (BHC)) published: (1972) 4 groups of dd mice 0, 6.6, 66, 660 ppm of technical BHC
(67%),  (11%),  (15%) or  (6%) BHC and other isomers < 1% for 24 wks at all doses:  liver wgt, cellular hyperplasia, nodular hyperplasia, all 660 ppm mice developed hepatoma Carcinogenicitymouse (Induction of hepatoma in mice with benzene hydrochloride) published: (1973). 4 groups of dd mice 0, 100, 300 or 600 ppm with crude BHC, or pure
,  , or  isomer for 36­ 38 wks No control and 100 or 300 ppm  isomer mice developed hepatomas many mice in crude BHC, or pure
isomer developed hepatoma, Chronic feeding Dogs (Lindane toxicity study in beagle dogs) 1970 4 group of 4 beagles/ sex 0, 25, 50, or 100 ppm for 104 wks NOAEL: 50 ppm LOAEL: 100 ppm liver changes, slight inc liver wt.

epa

2024-06-07T20:31:43.129202

regulations

EPA-HQ-OPP-2002-0202-0012

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES July 31, 2002 MEMORANDUM SUBJECT: Revised EFED RED Chapter for Lindane PC Code No. 009001; Case No. 818566; DP Barcodes: D254764 TO: B. Shackleford, Branch Chief M. Howard, Team Leader Special Review and Reregistration Division (7508C) FROM: ERB V RED Team for Lindane: N. E. Federoff, Wildlife Biologist, Ecological Effects Reviewer, Team Leader F. A Khan, Ph. D., Environmental Scientist, Long­ range Transport Assessor J. Melendez, Chemist, Environmental Fate Reviewer Environmental Fate and Effects Division (7507C) THROUGH: Mah T. Shamim, Ph. D., Chief Environmental Risk Branch V­ EFED (7507C) The EFED Integrated Environmental Risk Assessment for Lindane is attached. The following is an overview of our findings: Major Conclusions Lindane is a persistent and moderately mobile organochlorine compound. Lindane is a potential endocrine disruptor in birds, mammals and possibly fish. There is a possibility of acute and chronic risk to avian and mammalian species consuming a majority of their body weight in treated seed per day. Based on a Tier I screening assessment (using GENEEC), the aquatic assessment resulted in risks to aquatic organisms. For estuarine/ marine invertebrates, possible high acute risk may occur even at the low application rates for seed­ treatment uses. Restricted use LOC's were exceeded for estuarine/ marine invertebrates and freshwater fish. Endangered species LOC's are exceeded for freshwater fish and invertebrates. Chronic risk to estuarine/ marine organisms could not be assessed due to a lack of data. Modeling studies showed that lindane concentrations in both surface and ground water may reach environmentally significant levels (> MCL), even when lindane is restricted to seed­ treatment uses only. However, the modeling assumption that 100% of the compound will disassociate from the seed surface may have produced highly conservative estimates and has thus overestimated the EEC's and resulting risks. Nevertheless, due to the compound's persistence, residues continue to last in various environmental media and probably is associated with longrange transport. Risk Factors
Produces significant reproductive effects in birds (including eggshell thinning) and small mammals.
Lindane is a lipophilic compound and has been found in milk from exposed lactating females.
Based on available literature, lindane has shown endocrine disrupting effects in birds, mammals and possibly in fish.
Very persistent and moderately mobile. In aerobic soil systems, lindane degrades very slowly. The registrant­ calculated half­ life was 980 days (MRID 406225­ 01).
Very highly toxic to a broad spectrum of aquatic species. Possible Mitigating Factors
Seeds that are incorporated in soil may reduce exposure rates to terrestrial wildlife.
Low use rates.
It appears that at least two bird species (quail and red­ winged blackbird) were averse to consuming lindane­ treated seeds in laboratory studies, which may decrease exposure, thus reducing risk.
Lindane is bio­ concentrated rapidly in microrganisms, invertebrates, fish, birds and mammals, however bio­ transformation and elimination are relatively rapid when exposure is discontinued
The modeling assumption that 100% of the compound will disassociate from the seed surface has likely produced highly conservative estimates and has thus overestimated the EEC's and resulting risks. EFED believes that a seed leaching study would greatly increase certainty regarding a more realistic estimate of the amount of available lindane on the seed surface and leaching from the seed surface. This in turn would allow a refinement of exposure estimates and environmental concentration values (EECs). Risks to Terrestrial Organisms
Seed treatment uses present acute and chronic risk to birds and mammals. Also, due to lindane's potential endocrine­ disrupting character, mammals and birds that ingest seeds may be at some additional risk. Also, in addition, there is a possibility of acute risk to small mammals with high metabolic rates that dig and cache seeds. Chronic risk to these species may be greater during breeding season due to high seed consumption over time and the persistence of the compound in soil.
There is a reduced acute risk to waterfowl and upland gamebirds from seed treatment. However, there is acute risk to songbirds (passerines) and other similar seed eating avian species.
Lindane is highly toxic (0. 2 to 0. 56 µ g/ bee) to honeybees. However, since this is a seed treatment application, low risk is assumed to flying insects, although beneficial soil dwelling insects may be at some risk. Risks to Aquatic Organisms
Restricted use and endangered species LOC's are exceeded (RQ= 0.40) for freshwater fish. No chronic LOC's are exceeded for freshwater fish.
The acute endangered species LOC is slightly exceeded (RQ= 0.07) for freshwater invertebrates. No chronic LOC's are exceeded for freshwater invertebrates.
No acute LOCs were exceeded for estuarine/ marine fish. Chronic risk to estuarine/ marine fish could not be assessed due to a lack of toxicity data.
Acute, restricted use and endangered species LOC's were exceeded (RQ= 8.7) for estuarine/ marine invertebrates. However, there are no estuarine/ marine invertebrates listed as endangered. Chronic risk to estuarine/ marine invertebrates could not be assessed due to a lack of toxicity data. Risks to Endangered Species
Endangered birds and especially small mammals that eat a large daily proportion of seeds may be at risk from the proposed seed treatment use pattern. Endangered freshwater fish and invertebrates may also be at acute risk. Also, exposed endangered birds, mammals and possibly fish may be at risk due to the potential endocrine disrupting properties of lindane combined with already limited population sizes and/ or losses in critical habitat. Incident reports Incident reports submitted to EPA involving lindane have been tracked by Incident Data System (IDS), microfiched, and then entered into a second database, the Ecological Incident Information System (EIIS). Since 1971, only four incidents which involve fish kills have been reported that are related to lindane use. The most recent incident occurred in 1995 in which hundreds of trout were killed on a tree farm in North Carolina after a spill close to a nearby stream. In 1993, an incident was reported that involved approximately 60 trout in California, and the other two incidents were reported 1971 and 1983. However, no aquatic incidents have been reported as having occurred under the normal use conditions of seed treatment under soil incorporated use patterns. Water Resource Assessment Fate studies show that lindane is both moderately mobile (mean Koc = 1368) and highly persistent (soil half life of 2. 6 years). Even considering lindane's very low use rate under the current use restriction to seed treatment (maximum of 0. 0512 lb a. i./ acre), lindane concentrations may be expected to reach water resources at environmentally significant levels. Modeling studies showed that lindane concentrations in both surface and ground water may reach environmentally significant levels (> MCL), even when lindane is restricted to seed­ treatment uses only. This conclusion is based solely on lindane's use as a seed treatment and does not consider past uses of lindane. However, note that lindane continues to persist in the environment from past uses. Endocrine Disruption Based on available scientific literature, lindane has the potential to be an endocrine disrupting compound in birds, mammals, and possibly in fish. Thus the following language is recommended: EPA's Interim Policy for Potential Endocrine Disruptors EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA), as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturallyoccurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific basis for including, as part of the program, the androgen­ and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). When the appropriate screening and or testing protocols being considered under the Agency's Endocrine Disruptor Screening Program have been developed, lindane may be subjected to additional screening and or testing to better characterize effects related to endocrine disruption. Other Concerns Formulations: Many formulated products containing lindane also contain other active ingredients (Pentachloronitrobenzene, Captan, Diazanon, Metalaxyl, Thiram, Carboxin, Maneb and Mancozeb) which can be as toxic or more toxic than lindane alone. It is not known if the combination of lindane and these other actives ingredients are more toxic than either is separately or if there may be toxic synergism. Thus, testing with certain formulated products may be required. The registrant is requested to submit any available information on the toxic synergism of these chemicals. Data Gaps Environmental Fate: The environmental fate database for lindane is largely complete and adequate for the present risk assessment. However, an anaerobic soil metabolism study is required for outdoor seed treatment uses (Memo from Denise Keehner re: EFED policy guidance for eco­ risk and drinking water assessments of seed treatment pesticides, 7/ 30/ 99). EFED also believes that a seed leaching study would greatly increase certainty regarding a more realistic estimate of groundwater leaching and runoff. This in turn would allow a refinement of exposure estimates and environmental concentration values (EECs). EFED has issued a guidance for this study (Memo from Denise Keehner re: Standard Method for Determining the Leachability of Pesticides from Treated Seeds, 7/ 6/ 2000). Ecotoxicity: The environmental toxicity database for lindane is largely complete and adequate for the present risk assessment. However, Tier I plant toxicity studies (850.4100­ Seedling emergence in 10 species and 850.5400­ Aquatic plant toxicity tests in 5 species) are required for outdoor seed treatment uses (Memo from Denise Keehner re: EFED policy guidance for eco­ risk and drinking water assessments of seed treatment pesticides, 7/ 30/ 99). In addition, the avian reproduction study (Mallard duck) needs to be repeated. Although the submitted study (MRID 448671­ 01) was classified as being supplemental due to guideline deviations as well as the low hatching success in the control group, the study should be repeated to determine if 15 ppm is a valid NOAEL value. The NOAEL value of 15 ppm will be used in risk assessments until further data is provided. Also, due to the acute toxicity of lindane (LC50s or EC50s < 1 mg/ l) to estuarine/ marine fish and invertebrates, and concentrations that may reach estuarine/ marine systems, chronic studies are required (72­ 4 a and b: Estuarine/ Marine Fish Early Life­ Stage and Estuarine/ Marine invertebrate life­ cycle). An estuarine/ marine fish early life­ stage and estuarine/ marine invertebrate life­ cycle toxicity test using the TGAI are required for lindane because the end­ use product may be expected to be transported to an aquatic environment from the intended use site, aquatic acute LC50/ EC50s were less than 1 mg/ l and studies of other organisms indicate the reproductive physiology of fish and/ or invertebrates may be affected. Also, the persistence of lindane is > 900 days. The preferred test species are sheepshead minnow and mysid shrimp. Aquatic testing will be held in reserve until a seed leaching study is submitted. Lastly, there is evidence that seed­ eating birds may not be exposed due to aversion to the compound. However, The Agency does NOT have any such data for seed­ eating mammals. Thus, it may be beneficial for submission of such data to better characterize risk to seed­ eating mammals. Labeling Recommendations EFED recommends that the labels for all lindane products carry the following statements: Environmental Hazards Manufacturing Use: This pesticide is toxic to fish, birds, and other wildlife. Do not discharge effluent containing this product into lakes, streams, ponds, estuaries, oceans, or other waters unless in accordance with the requirements of a National Pollutant Discharge Elimination System (NPDES) permit and the permitting authority has been notified in writing prior to discharge. Do not discharge effluent containing this product into sewer systems without previously notifying the sewage treatment plant authority. For guidance contact your State Water Board or Regional Office of the USEPA. End Use Products: Granular/ Seed Treatment This product is toxic to fish, birds, and other wildlife. Exposed treated seeds may be hazardous to birds and other wildlife. Dispose of all excess treated seeds by burial away from bodies of water. Do not apply directly to water. Do not contaminate water by disposing of equipment washwaters. Apply this product only as specified on the label. 1 LINDANE RED Chapter: Environmental Fate and Ecological Risk Assessment: Seed treatment Prepared by: N. E. Federoff, Wildlife Biologist, Team Leader F. A. Khan Environmental Scientist J. L. Melendez, Chemist United States Environmental Protection Agency Office of Pesticide Programs Environmental Fate and Effects Division Environmental Risk Branch V 401 M Street, SW Mail Code 7507C Washington, DC 20460 Reviewed and approved by: M. Shamim, Chief, ERB 5 2 EXECUTIVE SUMMARY Lindane is a persistent and moderately mobile organochlorine compound. At present, there is only one agricultural use (seed treatment) that might affect the environment. Lindane is a potential endocrine disruptr in birds, mammals and possibly fish. There is a possibility of acute and chronic risk to granivorous avian and mammalian species. However, at least two bird species (quail and red­ winged blackbird) were averse to consuming lindane­ treated seeds in a laboratory environment, which may drastically decrease exposure, thus reducing risk. In the field , Blus et al. (1985) found that when lindane was substituted for heptaclor (HE) for treatment of seed (Columbia Basin near the Umatilla NWR, in Oregon and Washington State, USA), lindane did not produce adverse effects in birds and residues were not detected in either their eggs or brains. Also, coincidental with the decrease in HE residues in Canada geese, mortality decreased, reproductive success improved, and the population increased rapidly (Blus et al. 1984). There was no evidence for either bio­ magnification of lindane residues from treated seeds to goose tissues or eggs, or for induction of adverse effects to avian species. This may be due to the fact that Canada geese, as well as other avian species, may have been repelled by lindane treated seed as a submitted study has suggested with quail and red­ winged blackbirds. A Tier I screening assessment (using GENEEC) indicated risks to aquatic organisms. For estuarine/ marine invertebrates, high acute risk may occur even at the low application rates for seed­ treatment uses. Restricted use LOC's were exceeded for estuarine/ marine invertebrates and freshwater fish. Endangered species LOC's are exceeded for freshwater fish and invertebrates and estuarine/ marine invertebrates. However, there are no estuarine/ marine invertebrates listed as endangered. Chronic risk to estuarine/ marine organisms could not be assessed due to a lack of data. Screening level Tier I modeling studies showed that lindane concentrations in both surface and ground water may reach environmentally significant levels (> MCL), even when lindane is restricted to seed­ treatment uses only. The modeling assumption that 100% of the compound will disassociate from the seed surface may have produced highly conservative estimates and may have overestimated the EEC's and resulting risks. A seed leaching study would greatly increase certainty regarding a more realistic estimate groundwater leaching and runoff. This in turn would allow a refinement of exposure estimates and environmental concentration values. Mode of Action Technical HCH consists of a number of isomers: alpha ( ), beta ( ), and gamma ( ) (known as lindane). The approximate composition of technical HCH is 55­ 70% ­ HCH, 5­ 14%, ­HCH, 10­ 18%, ­HCH and impurities. Lindane (99.5% ­HCH) is the most biologically active insecticidal isomer. In insects, lindane acts through the inhibition of the gamma­ aminobutyric acid (GABA) receptor of the CNS. GABA operates by increasing chloride ion permeability into neurons thereby inhibiting neurostimulation inducing overstimulation of the CNS causing rapid violent convulsions. The a isomer is much less active at inhibiting binding to the GABA receptor than lindane and the beta isomer seems not to exhibit inhibiting binding at all. 3 Cl Cl Cl Cl Cl Cl Alpha­ HCH Cl Cl Cl Cl Cl Cl Delta­ HCH Cl Cl Cl Cl Cl Cl Beta­ HCH Cl Cl Cl Cl Cl Cl Lindane (gamma­ HCH) Figure 1: Chemical Structure of Lindane and Isomers Use Characterization Although the only current agricultural use of lindane is for seed treatment, lindane has been extensively used in the past as an insecticide on a variety of crops, for home termite control, and as a wood preservative. Table 1 summarizes the current use rates for seed treatment that were used in this risk assessment. Table 1. Lindane seed­ treatment uses and application rates. Seed Type Label Rate [lb a. i./ 100 lb seed] Typical Seeding a [lbs seed/ acre] Estimated Application Rate, based on label rate and maximum seeding [lb. a. i./ acre] Barley 0.0375 60­ 96 0.036 Corn 0.125 10­ 14 0.018 Oats 0.03125 50­ 80 0.025 Rye 0. 0328 56­ 84 0.0276 Sorghum 0.0628 6.76 0.00425 Canola 1.075­ 1.456 4 0. 043­ 0.059 Wheat 0.0426 40­ 120 0.0512 a Based on information from BEAD. ENVIRONMENTAL FATE AND TRANSPORT ASSESSMENT Summary Laboratory studies indicate that lindane is persistent and moderately mobile. It is resistant to photolysis and hydrolysis (except at high pH), and degrades very slowly by microbial actions. Table 2 summarizes the physical­ chemical and environmental fate properties of lindane. Since most degradation pathways occur slowly, the presence of the degradates is generally at relatively low levels. There is possible evidence that lindane transforms to the alpha isomer of hexachlorocyclohexane by biological degradation although this issue remains to be conclusively resolved. Possible degradates could include isomers of pentachlorocyclohexene, 1,2,4,­ trichlorobenzene, and 1, 2, 3­ trichlorobenzene. Lindane is transported through the environment by both hydrologic and atmospheric means. Lindane has often been detected in surface and ground water, and in areas of non use (e. g., the arctic), indicating global 4 atmospheric transport (see long­ range transport section). Most of these detections have likely resulted from a combination of lindane's past widespread use and its extreme persistence. Currently, U. S. agricultural uses of lindane are restricted to seed treatments, and application rates are quite low. Based on a screening level assessment, lindane may reach water resources at levels above the MCL of 0. 2 µg/ L. Table 2. Physical­ chemical properties of lindane. Parameters Value Chemical name
­ 1, 2, 3, 4, 5, 6­ hexachlorocyclohexane CAS No.. 58­ 89­ 9 Molecular Weight 290.82 Solubility 7 mg/ l Vapor Pressure 9.4 x 10 ­6 torr Henry's Law Constant @ 2 5 C 10 ­2.49 pH 5 Hydrolysis half life stable pH 7 Hydrolysis half life stable pH 9 Hydrolysis half life 43­ 53 days Soil Photolysis half life stable Aquatic photolysis half life stable Aerobic soil dissipation half life 980 days Soil organic carbon partitioning (Koc ) 1368 mL/ g (mean of 4 soils) Octanol­ water partition coefficient (Kow )10 3.78 Hydrolysis Lindane is stable to hydrolysis at pH 5 and 7 and has a half life of from 43 ­53 days at pH of 9 (MRID 00161630). At pH 9, the degradates were pentachlorocyclohexane, 1,2,4,­ trichlorobenzene, and 1, 2, 3trichlorobenzene Quantitative data were not provided for the degradates in the submitted document. Aqueous Photolysis Lindane is stable to photolysis in aqueous systems. These studies (MRIDs 0016457; 001645545; 447931) showed no evidence of aqueous photodegradation during the 30­ day study period, even when acetone was used as a photosensitizer (MRID 001645545). Soil Photolysis Lindane in contact with soil does not photodegrade significantly. On a 1­ mm thick soil specimen exposed to artificial sunlight for 12 hour per day, lindane degraded only very slightly over the 30­ day test period. The extrapolated half­ life was greater than 150 days (MRID 444406­ 05). The dark control showed a 5% loss over the 30­ day study. The soil degradation half life with consideration for the dark control losses is 200 days. Because of the extreme extrapolation to obtain a half life, this study essentially gives no evidence of lindane photodegradation on soil. Aerobic Soil Metabolism In a 336­ day aerobic soil metabolism study, lindane degraded very slowly, with a registrant­ calculated half life of 980 days (MRID 406225­ 01). Minor degradation products were PCCH and BHC, which reached maximums of 3. 84% and 0. 77% of applied radioactivity, respectively. Total CO2 production was 4. 81% of the applied parent radioactivity at day 336. It was confirmed that both compounds were present at the beginning of the study; however, it was also observed that, even though there was some variability in the data, pentachlorocyclohexene (PCCH) showed a continuous increment in concentration from day 0 to day 336 (last test interval) of the study. In general, it appeared that there was metabolic transformation during 5 the study, where pentachlorocyclohexene was formed slowly. Although microbial transformation of lindane to
­HCH is technically possible, it does not occur to a significant extent. Lindane can isomerize to
­HCH by both photolysis and microbial degradation, although significant conversion under typical environmental conditions has not been demonstrated for either pathway. Anaerobic Soil Metabolism This study is at best considered only marginally useful, mainly because the material balances generally decreased throughout the study period and were unacceptably low, and because there was variability of in the data for the parent compound. Lindane degraded with a DT50 of 36.5 days in anaerobic (nitrogen) flooded sandy loam soil that was incubated in darkness up to 60 days following a 31­ day aerobic incubation period. During the aerobic phase, the parent compound was sampled only at the initial, 14 days, and 31 days (prior to flooding). During that time, the parent decreased from 97.6% of the applied radioactivity to 69.6% at 31 days post­ treatment. The registrant proposed to estimate the half­ life of the aerobic soil metabolism of lindane based on the extrapolation of the 31 day aerobic portion of the study. However, close inspection of the data indicates poor recovery of the radioactivity (from 103.0% at the initial to 85.74% at 31 days. Furthermore, only three data points are available for the calculation. EFED believes that to estimate a half­ life of aerobic soil metabolism under these conditions is inappropriate. After anaerobic conditions were induced by flooding and nitrogen gas, the parent compound in the total soil/ water system was initially 69. 6% (at day 0 prior to flooding), but it increased to 77.1% of the applied radioactivity by 3 days. Total volatiles (including CO2 ) were 39.2% at 60 days; 14 CO2 (NaOH trap only) was a maximum of 6. 0% by 60 days. At 60 days following initiation of anaerobic conditions, 12. 5% of the applied radioactivity was present as volatile parent compound. In the volatile phase, a major degradate to 11. 8% by 60 days following the initiation of anaerobic conditions. The registrant attempted to identify the degradate. It eluted on GC trials at 10.1 minutes. When the sample was spiked with
­HCH, it eluted with the unknown, suggesting the presence of
­HCH. However, this could not be confirmed by a second analytical technique, namely, HPLC. In addition, the registrant provided another study, MRID# 44867107, which is a non­ guideline study. Mobility The registrant­ calculated organic carbon partitioning coefficient (Koc ) ranged from 942 to 1798 mL/ g with a mean of 1368 mL/ g for the four soils tested (MRID 00164346). EFED considers compounds with this range of Koc values to be moderately mobile. Sorption of lindane was assessed in 24­ hour batch sorption studies. Soil characteristics and results are presented in Table 3. Table 3. Soil descriptions and results of 24­ hour batch adsorption studies of lindane. Texture Clay Loam Loam Loamy Sand Sand Sand 46 46 82 88 Silt 25 29 8 7 Clay 29 25 10 5 Organic Carbon (%) 0.99 1.58 1.58 0.39 CEC [meq/ 100 g] 19.4 22.2 18.2 8. 9 pH 7.84 7.22 6.9 7. 75 Kf [( ml/ g)( mg/ L) 1­ n ] a 16.8 14.9 28.4 3. 83 N a 0.96 0.92 0.93 0.89 Koc [mL/ g] b 1696 942 1798 1037 a Defined by the Freundlich isotherm: S= KF C N where S is sorbed concentration [mg/ kg], and C is aqueous concentration [mg/ L]. b Koc is taken as the organic carbon partitioning coefficient at an aqueous concentration of 1 mg/ L. 6 Laboratory Volatility The submitted study provides only supplemental information about the volatility of lindane. The study was initially designed and submitted to European agencies. The registrant submitted supplemental calculations along with the original submission. Lindane volatilized moderately after application. Immediately after application, a 1. 5 cm layer of soil was placed on top of the treated soil (according to the registrant this would simulate soil incorporation similar to the actual use as a seed protectant). During the first hour 2. 19% of the applied lindane was found in the volatile traps. The calculated mean volatilization rate of lindane was 0. 290 µg/ cm 2 /hr. The rate of volatilization decreased with time to an average of 0. 0347 µg/ cm 2 /hr in the 6­ 24 hour interval. After 24 hours, about 13% of the applied radioactivity was volatilized. Lindane represented >86% of the radioactivity extracted from the traps (MRID# 44445301). Terrestrial Dissipation Lindane, at 0.61 lbs a. i./ A, was applied at once to two test plots (loamy sand, pH 5.2) cropped with peaches and bareground, located in Georgia. Lindane dissipated slowly, with calculated half­ lives of 65 and 107 days for cropped and bareground soils, respectively, based on the average of 3 values of lindane in the 0­ 5 cm soil depth. Lindane was reported to be in the 5­ 10 cm soil depth between days 120 and 185, at levels between 0.04­ 0.05 ppm. (MRID 40622502) In another terrestrial field dissipation study (MRID 448671­ 03), lindane was applied uniformly to a field in California at a target rate that was 8 times higher than the label application rate for seed treatment. Results from day 0 measurements indicated that 58% of the target rate was actually applied. Lindane residues were not detected below 6 inches. However, the quantification limit was 0. 02 ppm, which is only about 5% of the original concentration; thus lindane in this study that leached below the 6 inches could have easily remain unquantified, and thus dissipation half lives may be underestimated. The registrant­ calculated dissipation half life was 25 days. Dissipation half­ lives are typically shorter in the field than data from laboratory studies due to volatilization, run­ off and other such variables. Degradates were not monitored. Bioconcentration Lindane bioconcentrates appreciably, but depurates rapidly. Bioconcentration studies were conducted with bluegill sunfish (Lepomis macrochirus) at nominal concentration of 0. 54 µg/ L of lindane for 28 days, followed by 14 days of depuration (MRID 400561­ 01). Bioconcentration factors were 780 for fillet, 2500 for viscera, and 1400 for whole fish tissues. After the 14 days of depuration, 14 C levels were reduced by 96% in fillet, 95% in viscera, and 85% in whole fish. Once released into the environment, lindane can partition into all environmental media. Lindane has been detected in air, surface water, groundwater, sediment, soil, ice, snowpack, fish, wildlife and humans. Lindane can bio­ accumulate easily in the food chain due to its high lipid solubility and can bio­ concentrate rapidly in microrganisms, invertebrates, fish, birds and mammals, however bio­ transformation and elimination are relatively rapid when exposure is discontinued (WHO 1991). Water Resource Assessment Lindane may reach surface and ground waters when used as a seed treatment, although concentrations are expected to be low. Fate studies show that lindane is both moderately mobile (mean Koc = 1368) and persistent (soil half life of 2. 6 years). Based on a screening level assessment, even at its very low use rate under the current use restriction to seed treatment (maximum of 0. 0512 lb a. i./ acre), lindane may reach water resources at environmentally significant concentrations. 7 Surface Water (Farm Pond) Surface water concentrations resulting from lindane use as a seed treatment were predicted with the Tier1 assessment model, GENEEC. Table 4 presents a summary of GENEEC inputs and results. The entire output file can be found in Appendix III. Table 4. GENEEC input parameters and results for lindane. Application Rate 1 x 0. 051 lb ai/ acre* Aerobic Soil Half Life 980 days (single value) Organic Carbon Partitioning Coefficient (Koc ) 942 mL/ g (lowest value) Peak 0.67 µg/ L 4­ day average 0.66 µg/ L 21­ day average 0.58 µg/ L 56­ day average 0.48 µg/ L *The highest effective application rate was for wheat at 0.0512 lb a. i. /acre (see Table 1). Ground Water Ground water concentrations were predicted with SCIGROW. Input parameters and output and the resulting EEC are summarized in Table 5. The entire SCIGROW output file is located in Appendix III. Table 5. SCIGROW input parameters and results for lindane. Application Rate 1 @ 0. 051 lb/ acre Aerobic Soil Half Life 980 days (mean Value) Organic Carbon Partitioning Coefficient (Koc ) 1367 mL/ g (median Value) EEC 0.011 µg/ L Drinking Water Recommendations to HED EFED recommends that the Health Effects Division (HED) use the concentrations presented in Table 6 for drinking water EECs. The drinking water EECs were based on the GENEEC (surface water) and SCIGROW (groundwater) simulations described above. Table 6. Drinking water EECs for lindane for use by HED. Acute Chronic Groundwater 0.011 µ g/ L 0. 011 µ g/ L Surface Water 0.67 µ g/ L 0. 48 µ g/ L Monitoring Data The presence of lindane in the environment, due to previous widespread agricultural use, is well documented in U. S. data bases. For example, In the U. S. EPA STORET data base, 720 detections (after culling of data to eliminate dubious data, e. g. K and U codes) in ground water were reported between the years 1968 and 1995, in nearly all regions of the country, with especially high numbers of detections in the South and West. For these 720 detections, the median and mean concentrations were 0.01 and 11 µg/ L, respectively. For surface waters, 8775 detections were reported with median and mean concentrations of 0.005 and 0. 18 µg/ L. STORET Dectections were reported in nearly all regions of the conterminous U. S. In the USGS NAWQA study, lindane was detected in 2.58% of surface water samples (0. 67% at levels greater than 0.05 µ g/ L, maximum concentration reported was 0.13 µ g/ L). For groundwater, USGS NAWQA reported a detection frequency of 0. 1 % (0.07% at levels greater than 0.01 µ g/ L, maximum concentration reported was 0.032 µ g/ L). 8 EFED would like to stress some basic general parameters when considering the possible use of these types of monitoring data for lindane:
EFED believes that utilizing "NAWQA" and/ or "STORET" data exclusively to establish exposures or to define aquatic risk is not appropriate in most cases. Both databases indicate that lindane has been found in surface and ground water. There is no indication that this has changed.
The models used by EFED (FIRST and GENEEC2) assume the chemical is applied in the area surrounding the water body from which exposures may occur. Random monitoring of agricultural areas does not automatically assure that lindane was used in the basin surrounding the body of water being sampled. Also, neither NAWQA nor STORET monitoring programs are designed or are intended to establish potential risk to aquatic organisms from agricultural chemicals.
The NAWQA and STORET monitoring programs are not designed, nor are they intended to establish potential risk to human health. NAWQA and STORET are status and trends program for general water quality. Monitoring is not "targeted" to specific pesticides and no validated link to a pesticides' use at the field level with an occurrence in either ground or surface water has been made.
The Agency acknowledges that lindane's use has decreased over time, and detections should decrease accordingly, but, once again, the purpose of the estimation of EEC's is to obtain potential concentrations of a pesticide when they are applied in the proximity of surface water intakes.
NAWQA and STORET data are limited by the extent of sampling conducted at any one site. Very few sites were sampled more than a few times in a year and still fewer for more than one year. Information such as, but not limited to, the timing of lindane application, proximity to the sampling site and proximity of sampling site to the nearest drinking water intake are necessary to better characterize the usefulness of the monitoring data. Long­ range Transport Potential of Lindane Hexachlorocyclohexane (HCH) is an organochlorine pesticide used throughout the world and is commonly available in two formulations: technical­ grade HCH, consists of mainly ­HCH (55­ 70%), ­HCH 1018 and trace amounts of ­ ­ and  ­HCH isomers (5­ 14%) and lindane (almost pure 99. 5% ­HCH). The United States and many other developed nations discontinued and banned ­HCH usage. Although the only current agricultural use of lindane in United States is for seed treatment, lindane has been extensively used in the past as an insecticide on a variety of crops, for home termite control, and as a wood preservative. Numerous studies of ambient air (Harner et al., 2001 and Waite et al., 1999), precipitation (Barrie et al., 1992 and Norstrom and Muir, 1994), and surface water (Harner, 1997 and Norstrom and Muir, 1994) have reported HCH residues, particularly and isomers, throughout North America. One concern is whether the current use of lindane in the United States has the potential of atmospheric burdens that arise from secondary emissions owing to agricultural practices like seed treatment and consequently their potential for long­ range transport and effects on the ecosystem. There are no specific studies that have been conducted in the United States to address this issue. Therefore, this section relied on available literature to address the relative influence of local and regional sources of lindane and their potential for long­ range transport. Lindane is a relatively volatile, persistence and lipophilic organochlorine pesticide and it can migrate over a long distance through various environmental media such as air, water, and sediment. Once lindane is applied to soil, it can either persist in soil as a sorbed phase or be removed through several physical, chemical, and biological processes. However, volatilization from soil and surface waters is the major 9 dissipation route for lindane. The Henry's law constant for lindane suggests that it will volatilize into the air, although microbial and chemical degradation and uptake by crops can also occur (Walker et al., 1999). Lindane can also enter the air as adsorbed phase onto suspended particulate matter, but this process does not appear to be a major contributor like volatilization (Walker et al., 1999 and Bidlemen, 1998). Lane et al. (1992) reported that 95% of the HCH isomers in ambient air were the gaseous phase. Brubaker and Hites (1998) measured the gas phase kinetics of the hydroxyl radical with ­HCH and ­HCH, and reported that these compounds have long atmospheric half­ lives in air and therefore can be transported long distance. Recently, soil and air samples were collected for organochlorine pesticides in northwest Alabama to estimate soil­ to­ air fluxes and their contribution to the atmospheric concentration (Harner et al., 2001). They attributed that the atmospheric concentration of lindane in northwest Alabama is possibly due to atmospheric advections or regional sources rather than the studied soils. A field study conducted by Waite et al. (2001) in Saskatchewan, Canada demonstrated volatilization of lindane from fields planted with lindane­ treated canola seed. They reported that significant quantities (12­ 30%) of applied lindane volatilize from treated canola seed to the atmosphere during the growing seasons and have direct implications on regional atmospheric concentrations of lindane. They have also estimated that a range of 66.4 to188.8 tons of atmospheric load of ­HCH occurred during 1997 and 1998 following the planting of canola in the region of the Canadian­ prairies. Poissant and Koprivnjak (1996) reported that 90% of elevated ­HCH concentration in the atmosphere at Villeroy, Quebec in 1992 was from secondary emissions of applied lindane­ treated corn, while the rest was from the volatilization of residual lindane from the previous year seed treatment. The production and usage of HCH isomers (especially ­HCH) have declined worldwide (except India) significantly in recent years (Li et al., 1998). However, many studies suggest that secondary emissions of residual lindane continue to recycle in the global system while they slowly migrated and redeposited in the northern Hemisphere. Harner et al. (1999) attributed the substantial increase of ­HCH compared to lindane in the Arctic to the differences in deposition and photochemical degradation of lindane to ­HCH. However, many other studies did not find substantial evidence of photoisomerization of lindane to ­HCH (Walker et al., 1999). They also suggested that the conversion of lindane to ­HCH in soil and sediment might occur and contribute a small fraction of ­HCH accumulation in atmosphere. Cleeman et al. (1995) measured the deposition of HCH isomers at four sites during 1990 to 1992 in Denmark. Elevated levels of ­and ­HCHs were detected in the spring and summer and were attributed to continuing use of HCH isomers and long­ range transport from European countries south and west of Denmark. Ockenden et al. (1998) observed a very similar trend in Norway. Iwata et al. (1993) compared surface water and air concentrations of HCH isomers. Results indicate that HCHs were primarily released from east Asia and India but were accumulating in the northern oceans. They suggested that HCH isomers were able to atmospherically transport to colder regions where it was deposited and became less volatile in colder sinks. Atmospheric concentrations of many organochlorine compounds have also been detected in the Arctic, but the highest concentrations are generally ­and ­HCHs (Harner, 1997). Even though, high concentrations of HCH isomers were detected in surface waters of the Arctic, bioaccumulation in the aquatic food chains was significantly less than the other organochlorine compounds (Norstrom and Muir, 1994). The behavior of HCH isomers in the environment is complex because they are multimedia chemicals, existing and exchanging among different compartments of the environment such as atmosphere, surface water, soil and sediment. Post­ application residual volatilization of lindane takes place over a much longer period. Once airborne, lindane may move into the upper troposphere for more widespread regional, and possibly transcontinental distribution as a result of large­ scale vertical perturbations that facilitate air mass movement out of the near surface. Also, it may reversibly deposit on terrestrial surfaces close to the source and still be transported over large distances, even global scales, through successive cycles of deposition and 10 re­ emission as result of ambient temperature and latitude differences known as "global distillation or fractionation" (Wania and Mackay, 1996). In order to understand the long­ range transport potential of a compound, a necessary step needs to consider if multimedia environmental partition and degradation processes can substantially remove the substance. In response, a number of multimedia models have emerged. Detailed information of multimedia model evolution and their significance can be found in a recent article by Wania and Mackay (1999). Recently, a workgroup was initiated by Wania and Mackey (2000) to compare the persistent and longrange transport potential estimated by models developed and used by various research groups. Even though there are some specific differences among the participants' models, all participants used essentially the basic multimedia Level III fugacity model developed by Mackey (1991). The Level III model is more complex and realistic than Level I and Level II fugacity models. A Level I model is a closed system mass balance of a defined quantity of chemical as it partitions at equilibrium between compartments. A Level II model is a steady­ state open system description of chemical fate at equilibrium with a constant chemical emission rate. The Level III model is a steady­ state of chemical fate between a number of well­ mixed compartments which are not at equilibrium. This model also assumes a simple, evaluative environment with user­ defined volumes and densities for the following homogeneous environmental media (or compartments): air, water, soil, suspended sediment, sediment, fish and aerosols. This model gives a more realistic description of a chemical's fate including the important degradation and advection losses and the intermedia transport processes. All participants of the workgroup evaluated the persistent and long­ range transport of lindane and 25 other chemicals using a set of physical, chemical, and environmental fate data by Mackey et al. (1992­ 1997). They calculated values termed "fugacity capacities" for selected environmental media (air, water, soil) in the model, based on the chemical and physical properties of the modeled substances. There are large differences in the absolute persistence value estimated by the various models ranging from 546 days to 1219 days for lindane and 368 days to 925 days for ­HCH. Similarly, the absolute atmospheric transport distances calculated by the participants are also large ranging from1000 km( 621 miles) to58396 km (36287 miles) for lindane and 1014 km (630 miles) to 72441 km (45014 miles) for ­HCH. Despite the large difference in the absolute values, the correlation between the overall persistence and long­ range transport values obtained by various models were high, with correlation coefficients averaging higher than 0. 80. The differences between models can be attributed to the differences in the numbers and relative dimensions of the model compartments. In addition, environmental degradation rates, which can vary with temperature, humidity, and other environmental properties, may have significant influence on the variation among model results. Currently, the EPA is developing a PBT Profiler that estimates environmental persistence (P), bioconcentration potential (B), and aquatic toxicity (T). When a user accesses the PBT Profiler on the Internet, the program prompts the user to enter the Chemical Abstract Service (CAS) number of chemicals under consideration. The PBT Profiler is linked to a database containing CAS numbers and associated chemical structure for more than 100,000 discrete chemical substances. If the CAS number is in the database, the PBT Profiler will translate the CAS number into a chemical structure, predict the PBT characteristics, and provide a PBT Profile in an easy to understand format. The PBT profiler also uses the Level III fugacity model as described earlier to determine the percentage of a chemical in defined media. More information can be obtained from EPA's website (www. epa. gov/ opptintr/ p2framework/ docs/ profile. htm). A beta test of the PBT Profiler has been completed and the peer review phase is in progress. The PBT profiler was used to estimate PBT characteristics of lindane. The following italicized or underlined highlights in PBT outputs of lindane 11 indicate that the persistence and aquatic toxicity criteria have been exceeded and characteristics travel distance (CTD) or a half­ distance (analogous to half­ life) was 15000 km (9321miles). In summary, the presence of ­HCH and lindane in surface water, atmosphere and precipitation from sites remote from industrial and agricultural activities implies long­ range atmospheric migrations of these compounds. Concerns have been raised for their potential effects on human and ecosystem health of the northern hemisphere. It is conceivable that the elevated levels of lindane and ­HCH in the northern hemisphere, especially in the Arctic, resulted from long­ range transport. Persistence and long­ range transport of lindane was also reflected in monitoring data and various modeling efforts. Despite the progress made in recent years in estimating the persistence and long­ ranged transport using models for chemicals, a validated global model has not yet been published because of uncertainties involved in the source inventories, chemical fate data, degradative pathways and exposure analyses. Future work should be aimed at developing a comprehensive screening tool that can be used reliably in risk assessments for regulatory purposes. 12 ECOLOGICAL EFFECTS TOXICITY ASSESSMENT Toxicity testing reported in this section does not represent all species of bird, mammal, or aquatic organism. Only two surrogate species for both freshwater fish and birds are used to represent all freshwater fish (2000+) and bird (680+) species in the United States. For mammals, acute studies are usually limited to the Norway rat or the house mouse. Estuarine/ marine testing is usually limited to a crustacean, a mollusk, and a fish. Also, neither reptiles nor amphibians are tested. The assessment of risk or hazard makes the assumption that avian and reptilian toxicity are similar, and that fish and amphibians toxicity are similar. Generally, the most toxic endpoints for the technical grade active ingredient (TGAI) are used in the assessment to represent each group of organism. Based on ecological effects data, the toxicity endpoints + used in the assessment of lindane can be characterized as follows: * Avian acute oral ­ Moderately toxic (LD50= 56 mg/ Kg) * Avian acute dietary ­ Highly toxic (LC50= 425 ppm) * Avian chronic (reproduction)­ (NOAEC= 15 ppm) * Mammalian acute oral ­ Moderately toxic (LD50= 88 mg/ Kg) * Mammalian chronic (reproduction)­( NOAEL= 20 ppm) * Honey bee acute ­ Highly toxic (LD50= 0.2 ug/ bee) * Fish (freshwater) acute ­ Very highly toxic (LC50= 1.7 ppb) * Fish (freshwater) chronic ­ Reduced larval growth (NOAEC= 2. 9 ppb) * Fish (estuarine) acute ­ Very highly toxic (48 hr LC50= 23.0 ppb) * Fish (estuarine) chronic ­ No data * Invertebrate (freshwater) acute ­ Very highly toxic (96 hr LC50= 10. 0 ppb) * Invertebrate (freshwater) chronic­ Decreased reproduction (21­ day NOAEC= 54.0 ppb) * Invertebrate (estuarine) acute ­ Very highly toxic (96 hr LC50/ EC50= 0.077 ppb) * Invertebrate (estuarine) chronic ­ No data *Plants­ Nodata + For a complete listing of these and other toxicity studies for lindane, please see Appendix I. Toxicity to Terrestrial Organisms Bird and mammal overview Lindane is moderately toxic to birds and mammals on an acute exposure basis. Chronic reproductive effects include significant reductions in egg production, growth and survival parameters in birds, and decreased body weight gain in mammals. Avian Species (Acute Oral, Subacute Dietary and Reproduction) In acute oral toxicity studies conducted on bobwhite quail, starlings, red­ winged blackbirds and sparrows, the LD50s for lindane are 122, 100, 75 and 56 mg/ kg, respectively. The results suggest that lindane is moderately toxic to birds on an acute oral basis. Subacute dietary toxicity studies conducted on mallard duck, bobwhite quail, ring­ necked pheasant, and Japanese quail suggest that lindane is practically non­ toxic to highly toxic, with LC50s of >5000, 882, 561 and 425 ppm, respectively. An avian reproduction study on bobwhite quail indicated that significant reductions occurred in the number of eggs laid, eggs set, viable embryos, live 3­ week embryos, normal hatchlings and 14­ day old survivors, percentage of normal hatchlings/ eggs laid, normal hatchlings/ eggs set, normal hatchlings/ live 3 week embryos, 14­ day 13 survivors/ eggs set, 14­ day survivors/ normal hatchlings, eggshell thickness and hatchling weights. The No Observable Adverse Effect Concentration (NOAEC) and the Lowest Observable Adverse Effect Concentration (LOAEC) were determined to be 80 and 320 ppm, respectively. Also, an avian reproduction study using mallard ducks showed significant reductions in the number of viable embryos, live 3­ week embryos, and normal hatchlings at the two highest concentrations (45 and 135 ppm). The NOAEC and the LOAEC were determined to be 15 and 45 ppm, respectively. However, due to low hatching success in the control group, the study should be repeated to determine if 15 ppm is a valid NOAEL value. The NOAEL value of 15 ppm will be used in risk assessments until further data is provided. In addition, the registrant submitted two 14­ day free choice avian dietary toxicity studies (400561­ 03 and 400561­ 04). Results suggested that bobwhite quail and red­ winged blackbirds were repelled by treated sorghum seed. These studies clearly suggested that birds avoided lindane treated food when given a choice and even in a no­ choice situation, birds did not readily eat and were emaciated at study termination. Mammalian Species (Acute Oral and Reproduction) In toxicity studies conducted on laboratory rats for the Agency's Health Effects Division (HED), lindane is moderately toxic to small mammals on an acute oral basis (LD50 of 88 mg/ kg). Results from a chronic reproduction study indicate reproductive toxicity at a LOAEL of 150 ppm (NOAEL of 20 ppm) with decreased body weight gain, viability up to PP4 in both generation offspring and delayed onset and completion of tooth eruption and hair growth in F2 pups being the endpoints affected. Insects Lindane is highly toxic to bees on an acute contact basis (LD50s ranged from 0.20 to 0.56 µg/ bee). Toxicity to Non­ target Aquatic Animals Freshwater organism toxicity overview Lindane exhibits high to very high acute toxicity to freshwater fish (LC50 ranges of 1.7 to 131 ppb) and freshwater aquatic invertebrates (LC50 ranges of 10.0 to 520 ppb). Chronic effects include reduction in larval growth in freshwater fish (NOAEC= 2.9 µg/ L) and decreased reproduction in aquatic invertebrates (NOAEC= 54 µg/ L). Freshwater fish In acute toxicity studies conducted on coldwater and warmwater species, the 96­ hour LC50 values for the technical grade material ranged from 1. 7 to 131 ppb, suggesting that lindane will be highly to very highly toxic to freshwater fish on an acute basis. Early life­ stage toxicity tests conducted on rainbow trout show that lindane significantly affected larval growth at concentrations greater than or equal to 6. 0 µg/ L. Freshwater invertebrates Acute toxicity studies conducted on a variety of freshwater aquatic invertebrates suggest that the active ingredient of lindane is highly to very highly toxic on an acute basis. 48­ and 96­ hour LC50 or EC50 values ranged from 10.0 to 520 µg/ L in 6 studies. A life­ cycle toxicity test conducted with the active ingredient (99.5% ai) on waterflea (Daphnia magna) found a 21­ day NOAEC of 54.0 µg/ L and a LOAEC of 110.0 µg/ L. Decreased reproduction was the affected endpoint in the study. 14 Estuarine/ Marine organism toxicity overview Lindane exhibits high to very high acute toxicity to estuarine/ marine fish and ranges from moderately to very highly toxic to estuarine/ marine aquatic invertebrates. No data were submitted to assess chronic effects to either estuarine/ marine fish or estuarine/ marine aquatic invertebrates. Estuarine/ Marine fish Testing on a variety of species resulted in 48­ and 96­ hour LC50 range of 23.0 to 190.0 µg/ L, which is considered to be very highly to highly toxic on an acute basis. No data on the chronic effects of lindane estuarine/ marine fish have been submitted. Estuarine/ Marine invertebrates Acute toxicity testing on a variety of estuarine/ marine invertebrate species with the technical product resulted in 48­ and 96­ hour LC50 /EC50 values ranging from 0. 077 to 2800.0 µg/ L which fall into the highly to very highly toxic acute classes for estuarine/ marine invertebrates. No data on the chronic effects of lindane have been submitted. Toxicity to Plants Currently, plant testing is not required for pesticides other than herbicides and fungicides except on a caseby case basis (e. g., labeling bears phytotoxicity warnings, incident data or literature that demonstrates phytotoxicity). Because of the current low application rate, lack of incident data on plants and no available literature suggesting phytotoxicity, no plant data would normally be required. However, Tier I plant toxicity studies (850.4100­ Seedling emergence in 10 species and 850.5400­ Aquatic plant toxicity tests in 5 species) are required for outdoor seed treatment uses (Memo from Denise Keehner re: EFED policy guidance for eco­ risk and drinking water assessments of seed treatment pesticides, 7/ 30/ 99). Ecological Incident Data Incidents have been reported from the use of lindane and are on the USEPA incident database. These incidents are listed in a table in Appendix II. The incidents all involved fish and lindane was not the definite cause for most, however, one definite incident was an accidental spill that did kill trout. ENVIRONMENTAL RISK ASSESSMENT In order to evaluate the potential risk to aquatic and terrestrial organisms from the use of lindane, risk quotients (RQs) are calculated from the ratio of estimated environmental concentrations (EECs) to generally the most toxic ecotoxicity value (acute) or no­ effect level (chronic) for that group of organisms. These RQs are then compared to levels of concern (LOCs) used by OPP to indicate potential risk to nontarget organisms and the need to consider regulatory action. EECs are based on the maximum application rates (worst case) for selected modeled crop uses for lindane. Ecological effects data requirements and assessments for seed treatment pesticides are normally based on the granular risk assessment strategy. The seed treatment assessment process is designed to assess toxicological endpoints according to application rates, application method, and soil incorporation depth. Granules (seeds) are assumed to be consumed by terrestrial wildlife, and exposure may be limited by type of application method. Risk to Nontarget Terrestrial Organisms Ecological risks from seed treatments can be assessed by the same methods used for granular and bait products. The standard assessment is to calculate the number of LD50 per square foot of seeds exposed at the soil surface, accounting for incorporation of the seeds in the soil (Felthousen 1977). The number of 15 seeds that must be consumed by the non­ target organism to reach the LD50 can be calculated if the amount of active ingredient (AI) on each seed is known or can be estimated. If the concentration of active ingredient on the seed is known or can be estimated, then this concentration can be used as an EEC to assess risk to granivorous birds and mammals. For avian species, this EEC can be compared directly to the dietary LC50 value. For mammals, this EEC can be compared to the concentration of toxicant in food lethal to 50% of the population, which is calculated by dividing the LD50 value by the fraction of body weight consumed per day (McCann 1987). Birds and small mammals actively probe the soil while searching for food. While foraging, they are known to ingest soil, both intentionally and incidentally. Beyer, et al. (1994) estimated the soil content of the diet of a number of bird and mammal species to range from <2% to 30%. Nevertheless, soil incorporation will reduce overall species risk and/ or access to the compound. Terrestrial assessment The labels with the highest rates (lb lindane/ 100 lb seed) were used to evaluate potential maximum consumption of lindane by terrestrial animals. The current approach uses daily food intake calculated using the relationships described in Nagy (1987 as cited in USEPA, 1993). Acute risk quotients (RQ) were then calculated based on animals receiving their full diet from lindane­ treated seeds for a 1­ day time period B that is, mass of lindane consumed in 1 day from treated seeds RQ = species­ specific mass of lindane required to reach LD50 An RQ > 0.5 is defined as the level of possible acute risk. Details of the calculations are given in Appendix II. Results suggest that there may be potential acute and chronic risk to both endangered and nonendangered birds and mammals. Smaller birds and mammals (i. e., those with high food intake rates per body mass) are at greater risk than larger animals. The calculation pertains to consumption of food in dry weight. Seeds used for planting are expected to possess low water content, thus no adjustments were made for wet weight. Aquatic assessment The EFED model GENEEC was used to determine aquatic EECs. Wheat has the highest application rate in terms of lbs a. i per acre (see Table 1) and was used as the model crop scenario. Results of this assessment are listed in Appendix II and the GENEEC output file is in Appendix III. An analysis of the results suggest that for estuarine/ marine invertebrates, high acute risk (RQ = 8.7) may occur even at the low application rates for seed­ treatment uses. Restricted use LOCs were exceeded for estuarine/ marine invertebrates and freshwater fish. Endangered species LOCs are exceeded for freshwater fish and invertebrates and estuarine/ marine invertebrates. Chronic risk to estuarine/ marine organisms could not be assessed due to a lack of data. Exposure and Risk to Endangered Species In 1983, the Agency requested a "case­ by­ case" opinion for a Section 18 (emergency use exemption) for sugarcane use in Florida. Jeopardy to the snail kite, bald eagle and Florida panther was found from potential lindane use. The Agency agrees with the jeopardy to the snail kite due to reductions to its food source (apple snails) from the sugarcane use. However, even though lindane exhibits toxicity to birds and mammals, under the proposed seed treatment use patterns, low risk is assumed for most endangered species of these taxa based on their lifestyles, feeding habits and natural environments. 16 When the regulatory changes recommended in this IRED are implemented and the ecological effects and environmental fate data are submitted and accepted by the Agency, the Reasonable and Prudent Alternatives may need to be reassessed and modified based on the new information. The Agency is currently engaged in a Proactive Conservation Review with FWS and the National Marine Fisheries Service under section 7( a)( 1) of the Endangered Species Act. The objective of this review is to clarify and develop consistent processes for endangered species risk assessments and consultations. Subsequent to the completion of this process, the Agency will reassess the potential effects of lindane use to federally listed threatened and endangered species. At that time the Agency will also consider any regulatory changes recommended in the IRED that are being implemented. Until such time as this analysis is completed, the overall environmental effects mitigation strategy articulated in this document and any County Specific Pamphlets described in Section IV which address lindane, will serve as interim protection measures to reduce the likelihood that endangered and threatened species may be exposed to lindane at levels of concern. RISK CHARACTERIZATION Summary of Risk Lindane is a persistent, moderately mobile organochlorine and a potential endocrine disruptor in birds, mammals and possibly fish. There is a possiblity of acute and chronic reproductive risk from the use of lindane­ treated seed to endangered and non­ endangered avian and especially mammalian species consuming a majority of their body weight in seed per day. The assessment suggests acute risk to endangered and nonendangered freshwater fish may occur even at the low application rates for seed­ treatment uses. However, the aquatic assessment is based on the conservative assumption that 100% of the compound will disassociate from the seed surface. Thus, these risks may be overestimated somewhat. Based on a screening level assessment, both surface and ground water simulations show that lindane concentrations in water resulting from seed treatments may reach levels of environmental concern and may exceed the MCL for drinking water (0. 2ppb). Lindane in water bodies due to past uses will likely remain for long periods, due to lindane's extreme persistence. Avian and Mammalian Species Based on available scientific literature, lindane has shown adverse endocrine effects in mammals (Raizada et al. 1980; Uphouse 1987; Cooper et al. 1989) and has been reported to disturb male mammalian reproductive functioning (Chowdhury et al., 1987; Chowdhury and Gautam 1994; Dalsenter et al. 1997; Dalsenter et al. 1996). Lindane is also known to accumulate in fat tissues and to be slowly eliminated in milk during lactation (Pompa et al. 1994). Neurological and behavioral alterations are principal toxic effects of lindane in animals (Hulth et al. 1976; Joy 1982). Chakravarty et al. (1986) and Chakravarty and Lahiri (1986) found that when domestic ducks were force fed lindane (20 mg/ kg of body weight for 8 wks), significant egg­ shell thinning, reduced clutch size, and reduced laying frequencies were observed. They suggested that lindane induced estradiol insufficiency which causes inhibition of hepatic RNA and yolk protein synthesis, thereby preventing transformation of moderately differentiated oocytes to mature vitellogenic follicles, delaying ovulation and thus drastically reducing clutch size. Hoffman and Eastin (1982) found that lindane was teratogenic to mallard ducks only at doses that were greater than five times the field level of application, but did find that lindane was much more toxic on a lbs per acre basis when administered in oil. However, lindane in the diet of laying hens at 100 ppm caused reduced hatchability (Whitehead et al. 1972) and at 25 ppm the same effect was noted in Japanese quail (Dewitt and George 1957). In the field , Blus et al. (1985) found that when lindane was substituted for heptaclor (HE) for treatment of seed (Columbia Basin near the Umatilla NWR, in Oregon and Washington State, USA), lindane did not produce adverse effects in birds and residues were not detected in either their eggs or 17 brains. Also, coincidental with the decrease in HE residues in Canada geese, mortality decreased, reproductive success improved, and the population increased rapidly (Blus et al. 1984). There was no evidence for either bio­ magnification of lindane residues from treated seeds to goose tissues or eggs or for induction of adverse effects to avian species. This may be due to the fact that Canada geese, as well as other avian species, may have been repelled by lindane treated seed as a submitted study has suggested with quail and red­ winged blackbirds. The registrant submitted two 14­ day free choice avian dietary toxicity studies (400561­ 03 and 400561­ 04) using 40% lindane. Results suggested that bobwhite quail and red­ winged blackbirds were repelled by treated sorghum seed. These studies clearly suggested that birds avoided lindane treated food when given a choice and even in a no­ choice situation, birds did not readily eat and were emaciated at study termination. Other avian species may possibly also show aversion to lindane treated seed. However, birds of prey that consume small mammals that have accumulated lindane may be at risk from some level of secondary toxicity from chronic exposure over time. Also, lindane can be stored in the fat of birds; birds of prey in the Netherlands contained up to 89 ppm in their fat (Ulman 1972). Earthworms are known to accumulate lipophilic substances (such as lindane) through the epidermis and the intestine (Belfroid et al. 1994). In nature, worms constitute a link in the transport of environmental pollutants from soil to organisms higher up in the terrestrial food web. Avian and mammalian species may eat worms that have accumulated lindane, thus providing some level of risk to those species. Also, many young birds eat diets rich in animal foods (including worms), even though they may be strict vegetarians as adults. Many newly­ hatched young that feed themselves, instinctively select protein­ rich foods such as worms. Lindane­ treated seed will most likely be planted in the spring during, or just prior to, breeding season. Higher energy expenditures and higher caloric need in mammals during gestation and lactation imply a need for either more total food and/ or food with a higher caloric content. Conditions during breeding season present a need to keep in close proximity to the den and subsequent offspring. Because of this, mammals living near fields planted with lindane treated seed may not have the option of traveling to non­ treated areas and may in fact cache these readily available treated seeds. Most uses do not present high acute risk to larger seed eating mammals. However, due to the compound exhibiting endocrine­ disrupting effects and being lipophilic and eliminated in milk during lactation, mammals in general that may ingest seeds may be at some risk. Milk is known to be a major route of elimination for lipophilic persistent substances stored in adipose tissue. The milk: plasma concentration ratio for lindane indicates a much more efficient excretion of the compound in milk (Dalsenter et al. 1997). Milk possesses a great affinity on liposoluble substances due to its high fat content. The presence of lindane in mammalian milk exposes nursing offspring during critical periods of post­ natal development (Dalsenter et al. 1997). Small mammals with high metabolic rates that dig and cache seeds, may be at acute and especially chronic risk, due to consumption over time and the persistence of the compound in soil. Dalsenter et al. (1997) indicated that treatment of female rats on day 15 of pregnancy with only a single dose (30 mg lindane/ Kg of body weight) affects the sexual behavior of adult male offspring by altering libido and by reducing testosterone concentration without compromising fertility. Effects to offspring may be due to the indirect interference of lindane on hormonal regulation in males. Pertubation of the endocrine system during early stages of development can be influenced by small changes of hormonal imbalance. Aquatic Organisms Generally, from the results of the aquatic assessment, risks to aquatic organisms were low. The highest use rate (wheat) was modeled. Based on a Tier I screening assessment (using GENEEC) and assuming that 100% of the compound will disassociate from the seed surface, the aquatic assessment resulted in risks to 18 aquatic organisms. The greatest risk, due mainly to the toxicity of the compound, was to estuarine/ marine invertebrates from an acute exposure (RQ= 8. 7). There were no data available to assess chronic risk to these invertebrates. These data are especially important since the compound is persistent and can result in significant bio­ accumulation (bioconcentration factor is 1400 times the ambient water concentration). Acute risk to endangered and non­ endangered freshwater fish may also occur even at the low application rates for seed­ treatment uses. In addition, Petit et al. (1997) found that lindane exhibited estrogenic activity in two in vitro bioassays. Thus, lindane may also be an endocrine disrupting compound in aquatic species. EFED believes that a seed leaching study would greatly increase certainty regarding a more realistic estimate of the amount of available lindane on the seed surface. This in turn would allow a refinement of exposure estimates and environmental concentration values (EECs). However, the assumption that 100% of the compound will disassociate from the seed surface has likely produced highly conservative estimates and has thus overestimated the EEC's and resulting risks. Reproductive and population effects in other species of invertebrates have also been suggested. Blockwell et al. (1999) found that populations of H. azteca (a detritivorous crustacean) exposed to (LOAEL= 13.5 ug lindane/ L; NOAEC= 6.9 ug lindane/ L) lindane were significantly (ANOVA, p < 0. 001; Tukey­ Kramer, p <0.05) smaller than control populations in a 35 day chronic study. Reduction in population growth was observed and resulted from a combination of toxicant effects: disruption of the reproductive behavior patterns of adult H. azteca and a reduction in the growth of recruited individuals and consequently their delayed sexual development. This value is similar to the LOAECs produced from other chronic lindane toxicity studies conducted with freshwater crustaceans: 19 µg/ L for Daphnia magna in a 64­ d study and 8.6 µg/ L in a 17­ week study conducted with Gammarus fasciatus based on survivorship and reproductive success (Macek et al., 1976). Furthermore, an LOAEC of 9.9 ug lindane/ L was generated in a life cycle study conducted using Chironomous riparius (Insecta) (Taylor et al. 1993). Lindane has also previously been reported to reduce juvenile growth of the European amphipod Gammarus pulex (L.) at 6.1 µg/ L in a 14­ d study (Blockwell et al. 1996). However, data shows that concentrations of lindane above 2. 5 µg/ L (found in Lake Michigan tributary stream) were not reported as occurring in any aquatic system tested (ATSDR 1997). Incidents have been reported from the use of lindane and are in the EPA incident database. An incident classified as "highly probable" was reported as killing hundreds of trout on a tree farm in Watauga, North Carolina after a spill close to a nearby stream. However, no aquatic incidents have been reported as having occurred under normal use conditions of seed treatment under soil incorporated use patterns. Endocrine Disruption EPA is required under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act (FQPA), to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally­ occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disrupting Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific basis for including, as part of the program, the androgen­ and thyroid­ hormone systems, in addition to the estrogen­ hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticidal chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA has authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). 19 Based on available scientific literature, lindane has characteristics of an endocrine disrupting compound. The compound exhibits effects on birds, mammals and possibly fish. As stated previously, effects included disruption in male reproductive behavior and functioning in mammals (LD50= 88 mg/ kg with levels of only 30 mg/ kg resulting in effects), eggshell thinning possibly from estrogen deficiency in female birds, and estradiol insufficiency which may cause a delay in ovulation resulting in a drastic reduction in clutch size in birds (NOAEL/ LOAEC= 80/ 320 ppm with calculated EEC levels of 51.5 to 206.2 ppm resulting in a possibility of effects). In the submitted avian reproduction study using the mallard duck (MRID 448671­ 01), thyroid weights for males in the 135 ppm test concentration were significantly higher than those measured in the control. Histopathology revealed microscopic lesions in the thyroid glands consisting of thyroid follicular distension and coalescence, follicular hypertrophy and follicular hyperplasia. These lesions were more apparent at the 135 ppm than at 45 ppm. Analysis of the gonads of either sex were unremarkable with the exception of the possibility of reduced spermatogenesis in the group receiving 45 ppm. Exposure of mammalian neonates to lindane during lactation induces reproductive hazards to male offspring rats which are detectable at adulthood. Based on all these data, EFED recommends that when appropriate screening and or testing protocols being considered under the Agency's EDSP have been developed, lindane be subjected to more definitive testing to better characterize effects related to its endocrine disruptor activity under the current use pattern. Presence in the Environment Lindane, as well as other HCH isomers, do not naturally occur in the environment. Once released into the environment, lindane can partition into various environmental media. Because of long­ range transport, lindane has been detected in air, surface water, groundwater, sediment, soil, ice, snowpack, fish, wildlife and humans. HCH­ isomers (mainly and ) were the major organochlorine insecticide detected in arctic air, snow and seawater (Barrie et al. 1991). The Arctic is considered a "sink" for persistent organic pollutants. Once in the Arctic, lindane bio­ accumulates in the food chain due to its high lipid solubility. Lindane is bio­ concentrated rapidly in microrganisms, invertebrates, fish, birds and mammals, however biotransformation and elimination are relatively rapid when exposure is discontinued (WHO 1991). Lindane is strongly adsorbed on soils that contain large amounts of organic matter, however it can leach with water from rainfall or artificial irrigation. Lindane sorbed to soil can get into the atmosphere either by wind erosion of the soil particulates or by volatilization. Volatilization seems to be an important route of dissipation under higher temperature conditions such as those occurring in tropical regions (WHO 1991). Levels of lindane in the atmosphere seem to be seasonal and temperature dependent, with the highest air concentrations in the summer and lowest during winter, as would be expected from agricultural uses (Whitmore et al., 1994). Removal of foliar and broadcast type applications and uses in favor of low rate seed treatments will most likely limit the amount of available lindane for release into the environment. However, Waite et al. (1998) did find that release of lindane to the atmosphere begins within the first week the treated seed is sown. Most recently, Waite et al. (2001) found that between 30% (in 1997) and 12% (in 1998) of the lindane applied to canola fields (as treated seed) was lost through volatilization that began immediately after planting. Lindane is more soluble in water than most other OC compounds, therefore it has a greater possibility of remaining in the water column. Agricultural run­ off is likely the major contamination route of lindane to surface water. The three main transport pathways for atmospheric input to surface waters are wet deposition, dry deposition and gas exchange across the air­ water interface, although evaporative loss from surface water is not considered significant. Apart from atmospheric deposition and surface run­ off, point source discharges are also contributors of surface water contamination. In Canada, run­ off from canola fields was reported to contaminate surface water with maximum concentrations of 0.011 ppb and 0. 004 20 ppb for lindane and ­HCH, respectively (Donald et al., 1997). As stated previously, both surface and ground water simulations, based on a screening level assessment, show that lindane concentrations in water resulting from seed treatment may reach levels of environmental concern and may exceed the MCL for drinking water (0.2 ppb). Lindane in water bodies due to past uses will likely remain for long periods, due to lindane's extreme persistence. Persistence and long­ range transport of HCH­ isomers were also reflected in monitoring data and various modeling efforts. The most common hexachlorocyclohexane isomers found in the environment are lindane ( ­), ­, and ­HCHs, with ­HCH as the predominant isomer in air and ocean water and ­HCH the predominant isomer in soils, animal tissues and fluids (Willett et al., 1998). Recent data suggest that the declines of ­HCH isomer concentrations in the environment have resulted from reduced use of technical HCH, especially in Asian countries (Iwata et al., 1993). However, Oehme et al., (1995) have suggested that while there are some indications that total HCH in Arctic air has declined, mean levels of lindane have increased slightly, which likely reflects the increase in lindane use in northern hemisphere after the ban of technical HCH was imposed. Literature cited Agency for Toxic Substances and Disease Registry (ATSDR). 1997. Toxicological profile for Alpha­, Beta­, Gamma­, and Delta­ Hexachlorocyclohexane. U. S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. September 1997. Barrie L. A., D. Gregor, B. Hargrave, R. Lake, D. Muir, R. Shearer, B. Tracey and T. Bidleman. 1991. Arctic contaminants: sources, occurrence and pathways. The Science of the Total Environment 122: 1­ 74. Belfroid A., J. Meiling, D. Sijm, W. Hermens, K. van Gestel. 1994. Uptake of hydrophobic halogenated aromatic compounds from food by earthworms (Eisenia andrei). Archives of Environmental Contaminants and Toxicology 27: 260­ 265. Beyer, W. N., E. E. Conner and S. Gerould. 1994. Estimates of soil ingestion by wildlife. J. Wild. Management 58( 2): 375­ 382. Blockwell, S. J., D. Pascoe , and S. J. Maund. 1999. Effects of the organochlorine insecticide lindane on the population responses of the freshwater amphipod Hyalella azteca. Environmental Toxicology and Chemistry 18( 6): 1264­ 1269. Blockwell SJ, D. Pascoe, E. J. Taylor. 1996. Effects of lindane on the growth of the freshwater amphipod Gammarus pulex (L.). Chemosphere 32: 1795­ 1803. Blus, L. J., C. J. Henny, and A. J. Krynitsky. 1985. The effects of heptachlor and lindane on birds, Columbia Basin, Oregon and Washington, 1976­ 1981. Science of the Total Environment 46: 73­ 81. Blus, L. J., C. J. Henny, D. J. Lenhart, and T. E. Kaiser. 1984. Effects of heptachlor and lindane treated seed on Canada geese. Journal of Wildlife Management 48( 4): 1097­ 1111. Brubaker, W. W., and R. A. Hites Jr. 1998. OH reaction kinetics of gas­ phase a­ and ghexachlorocyclohexane and hexachlorobenzene. Environ Sci Technol. 32: 766­ 769. 21 Chakravarty, S. and P. Lahiri. 1986. Effect of lindane on eggshell characteristics and calcium level in the domestic duck. Toxicology 42: 245­ 258. Chakravarty, S., A. Mandal, and P. Lahiri. 1986. Effect of lindane on clutch size and level of egg yolk protein in domestic duck. Toxicology 39: 93­ 103. Chowdhury, A. R. and A. K. Gautam. 1994. Steroidogenic impairment after lindane treatment in male rats. Sangyo­ Ika­ Daigaku­ Zasshi 16: 145­ 152. Chowdhury, A. R., H. Venkatakrishna­ Bhatt, and A. K. Gautam. 1987. Testicular changes of rats under lindane treatment. Bulletin of Environmental Contamination and Toxicology 38: 154­ 156. Cleemann, M., Poulsen M. E., and G. Hilbert. 1995. Deposition of lindane in Danmark. Chemosphere 30: 2039­ 2049. Clench, M. H. and R. C. Leberman. 1978. Weights of 151 species of Pennsylvanian birds analyzed by month, age and sex. Bulletin of the Carnegie Museum of Natural History: 5; Tomlinson, R. E. 1975. Weights and wing lengths of wild Sonoran Masked bobwhites during fall and winter. Wilson Bulletin 87: 180­ 18 Cooper, R. L., R. W. Chadwick, G. L. Goldman, K. C. Booth, J. F. Hein, and W. K. McElroy. 1989. Effect of lindane on hormonal control of reproductive function in the female rat. Toxicology and Applied Pharmacology 99: 384­ 394. Dalsenter, P. R., A. S. Faqi, J. Webb, H­ J. Merker and I. Chahoud. 1997. Reproductive toxicity and toxicokenetics of lindane in the male offspring of rats exposed during lactation. Human and Experimental Toxicology 16: 146­ 153. Dalsenter, P. R., A. S. Faqi, J. Webb, H­ J. Merker and I. Chahoud. 1996. Reproductive toxicity and tissue concentrations of lindane in adult male rats. Human and Experimental Toxicology 15: 406­ 410. Dalsenter, P. R., A. S. Faqi, and I. Chahoud. 1997. Serum testosterone and sexual behavior in rats after prenatal exposure to lindane. Bulletin of Environmental Contamination and Toxicology 59: 360­ 366. Dewitt, J. B. and J. L. George. 1957. Pesticide wildlife review. U. S. Fish and Wildlife Service, USDI, Washington, D. C. Donald, D. B., H. Block and J. Wood. 1997. Role of groundwater on lindane detections in surface water in western Canada. Environmental Toxicology and Chemistry 16( 9): 1867­ 1872. Felthousen, R. W. 1977. Classification of granulated formulations. Internal EPA memo: Environmental Safety Section, 9/ 9/ 77, USEPA, pp. 1­ 20. Harner T. 1997. Organochlorine contamination of the Canadian Arctic, and speculation on further trends, Int. J. Environ. And Poll. 8: 51­ 73. Harner, T, T. F. Bidleman, L. M. M Jantunen, and D. Mackay. 2001. Soil­ air exchange model of pesticides in the United States cotton belt. Environ Toxi Chem 20: 1612­ 1621. 22 Harner, T., H. Kylin, T. F. Bidleman, and W. M. J. Strachan. 1999. Removal of (­ and hexachlorocyclohexane and enentiomers of (­ hexachlocyclohexane in the eastern Arctic ocean. Environ Sci Technol. 33: 1157­ 1164. Hoffman, D. J. and W. C. Eastin. 1982. Effects of lindane, paraquat, toxaphene, and 2,4,5­ trichlorophenoxyacetic acid on mallard embryo development. Archives of Environmental Contamination and Toxicology 11( 2): 79­ 86. Hulth, L., R. Larsson, R. Carlsson, and J. E. Kihlstron. 1976. Convulsive action of small single oral doses of the insecticide lindane. Bulletin of Environmental Contamination and Toxicology 16: 133­ 137. Iwata, H., S. Tanabe, N. Sakai and R. Tatsukawa. 1993. Distribution of persistent organochlorines in the oceanic air and surface seawater and the role of ocean on their global transport and fate. Environmental Science and Technology 27: 1080­ 1098. Joy, R. M. 1982. Mode of action of lindane, dieldrin and related insecticides in the central nervous system. Neurobehavioral Toxicology and Teratology 4: 813­ 823. Lane, D. A., N. D. Johnson, M. J. Hanley, Schroeder W. H., and D. T. Ord . 1992. Gas­ and particle ­phase concentrations ­hexachlorocyclohexane and ­hexachlorocyclohexane and hexachlorobenzene in Ontario air. Environ Sci Technol. 26: 126­ 133. Li, Y. F., T. F. Bidleman, L. A. Barrie, and L. L. McConnell. 1998. Global hexachlorocyclohexane use trends and their impact on the arctic atmospheric environment. Geophys Res Lett. 25: 39­ 41. Macek K. J., K. S. Buxton, S. K. Derr, J. W. Dean, and S. Sauter. 1976. Chronic toxicity of lindane to selected aquatic invertebrates and fishes. EPA­ 60013­ 76­ 047. U. S. Environmental Protection Agency, Washington, DC. Mackey, D. 1991. Multimedia environmental models. The fugacity approach. Lewis Publication, Boca Raton, FL. Mackey, D., W. Y. Shiu, K. C. Ma. 1992­ 1997. Illustrated handbook of physical­ chemical properties and environmental fate for organic chemicals. Vol. I to V. Lewis Publication, Chelsea, MI McCann, J. A., W. Teeters, D. J. Urban, and N. Cook. 1981. A short­ term dietary toxicity test on small mammals. In Avian and Mammalian Wildlife Toxicology: Second Conference, ASTM STP, pp. 132­ 142. Nagy, K. A. 1987. Field metabolic rate and food requirement scaling in mammals and birds. Ecology Monographs 57: 111­ 128. Norstrom, R. J., and D. C. G. Muir. 1994. Chlorinated hydrocarbon contaminants in arctic marine mammals. Sci Total Environ. 154: 107­ 128. Ockenden, W. A., E. Steinnes, C. Parker, and K. C. Jones. 1998. Observations on persistent organic pollutants in plants: implications of their use as passive air samplers and POP cycling. Environ Sci Technol. 33: 3482­ 3488. 23 Oehme, M., J.­ E. Haugen and M. Schlabach. 1995. Ambient levels of POPs in spring 1992 at Spitzbergan and the Norwegian mainland: comparison with 1984 results and quality control measures. Sci Total Environment 160/ 161: 139­ 152. Petit, F., P. Le Goff, J. P. Cravedi, Y. Valotaire, and F. Pakdel. 1997. Two complementary bioassays for screening the estrogenic potency of xenobiotics: recombinant yeast for trout estrogen receptor and trout hepatocyte cultures. Journal of Molecular Endocrinology 19( 3): 321­ 335. Poissant, L. and J. F. Koprivnjak. 1996. Fate and atmospheric concentrations of a­ and ghexachlorocyclohexane in Quebec, Canada. Environ Sci Technol. 30: 845­ 851. Pompa, G., L. Fadini, F. Di­ Lauro, and F. Caloni. 1994. Transfer of lindane and pentachlorobenzene from mother to newborn rabbits. Pharmacology and Toxicology 74: 28­ 34. Raizada, R. B., P. Misra, I. Saxena, K. K. Datta, and T. S. Dikshitt. 1980. Weak estrogenic activity of lindane in rats. Journal of Toxicology and Environmental Health 6: 483­ 492. Taylor E. J., S. J. Blockwell, S. J. Maund, and D. Pascoe. 1993. Effects of lindane on the life­ cycle of a freshwater macroinvertebrate Chironomous riparius Meigen (Insecta: Diptera). Archives of Environmental Contaminants and Toxicology 24: 145– 150. Ulman, E. 1972. Monograph of an insecticide. Schillinger Verlag, Federal Republic of Germany. Uphouse, L. 1987. Decreased rodent sexual receptivity after lindane. Toxicology Letters 39: 4­ 14. USEPA. 1993. Wildlife exposure factors handbook (Volume I). EPA/ 600/ R­ 93/ 187a. Waite, D., N. P. Gurprasad and T. Thompson. 1998. Atmospheric studies of Hexachlorobenzene (HCB) and y­ Hexachlorocyclohexane (lindane or y­ HCH) in the prairies. EAD Seminar 10/ 22/ 98. Waite, D., N. P. Gurprasad, J. F. Sproull, D. V. Quiring and M. W. Kotylak. (2001). Atmospheric movements of lindane from canola fields planted with treated seed. Journal of Environmental Quality 30: 768­ 775. Walker, K., D. A. Vallero and R. G. Lewis. 1999. Factors influencing the distribution of lindane and other hexachlorocyclohexanes in the environment. Environ Sci Technol 33, pp. 4373­ 4378. Wania, F. and Mackay, D. 2000. A comparison of overall persistence values and atmospheric travel distances calculated by various multimedia fate models. WECC Report2/ 2000. WECC Wania Environmental Chemists Corp. Toronto, Canada. Wania, F. and Mackay, D. 1999. The evolution of mass balance models of persistent organic pollutant fate in the environment. Environ Poll. 100: 223­ 240. Wania, F. and Mackay, D. 1996. Tracking the distribution of persistent organic pollutants. Environ Sci Technol. 30: 390A­ 396A. Whitehead, C. C., A. G. Downing, and R. J. Pettigrew. 1972. The effects of lindane on laying hens. Br. Poultry Science 13: 293 24 Willet, K., E. M. Ulrich and R. A. Hites. 1998. Differential toxicity and environmental fates of hexachlorocyclohexane isomers. Environmental Science and Technology 32 (15): 2197­ 2207. Whitmore, R. W., F. W. Immerman, D. E. Camann, A. E. Bond, R. G. Lewis and J. L. Schaum. 1994. Nonoccupational exposures to pesticides for residents of two US cities. Archives of Environmental Contaminants and Toxicology 26: 47­ 59. World Health Organization (WHO). 1991. Lindane (Environmental Health Criteria 124). 208 pp. 25 Appendix I: Ecological Effects Data Ecological toxicity studies required by the Agency for the registration/ re­ registration of a pesticide, and the rational behind these requirements, are listed in 40 CFR 158. The following studies submitted by the registrant were used to develop an ecological toxicity assessment for lindane. Toxicity to Terrestrial Animals Birds, Acute and Subacute Avian Acute Oral Toxicity Species %ai LD50 (mg/ kg) Toxicity Category Acc No. Author/ Year Study Classification 1 Bobwhite quail (Colinus virginianus) 95.5 122 Moderately toxic 00263944 Bio­ life, 1986 Core Red­ winged BB (Agelaius phoeniceus) Tech 75 Moderately toxic 00020560, Schafer, 1972 Supplemental Starling (Sturnus vulgaris) Tech 100 Moderately toxic 00020560, Schafer, 1972 Supplemental House Sparrow (Passer domesticus) Tech 56 Moderately toxic 00020560, Schafer, 1972 Supplemental Common Grackle (Quiscalus quisula) Tech >100 Moderately toxic 00020560, Schafer, 1972 Supplemental Mallard Duck (Anas platyrhynchos) 25 2000 practically non toxic 00160000 Hudson et al, 1984 Supplemental 1 Core (study satisfies guideline). Since the LD50s using the technical grade range from 56 to 122 mg/ kg, lindane is considered to be moderately toxic to avian species on an acute oral basis. The guideline (71­ 1) is fulfilled (ACC# 00263944). Avian Subacute Dietary Toxicity Species %ai 5­ Day LC50 (ppm) 1 Toxicity Category Acc No. Author/ Year Study Classification Mallard duck (Anas platyrhynchos) >95 >5000 prac. non­ toxic 00022923 Hill et al, 1975 core Northern bobwhite quail (Colinus virginianus) >95 882 moderately toxic 00022923 Hill et al, 1975 core Ring­ necked pheasant (Phasianus colchicus) >95 561 moderately toxic 00022923 Hill et al, 1975 core Japanese quail (Coturnix japonica) >95 425 highly toxic 00022923 Hill et al, 1975 supplemental 1 Test organisms observed an additional three days while on untreated feed. Since the LC50 falls in the range of 425 to >5000 ppm, lindane is considered to be highly to practically non­ toxic to avian species on a subacute dietary basis. The guideline (71­ 2) is fulfilled. (ACC# 00022923). 26 In addition, the registrant submitted two 14­ day free choice avian dietary toxicity studies (MRIDs 400561­ 03 and 400561­ 04). Results suggested that bobwhite quail and red­ winged blackbirds in a laboratory environment were repelled by treated sorghum seed. When given a choice and even in a no­ choice situation, these birds did not readily eat and were emaciated at study termination. Birds, Chronic Avian Reproduction Species/ Study Duration %ai NOAEC/ LOAE C 1 (ppm) LOAEC Endpoints MRID No. Author/ Year Study Classification Northern bobwhite quail (Colinus virginianus) 99.8 80/ 320 egg production, survival, eggshell thickness and hatchling wt. 448122­ 01 Dreumel and Heijink, 1999 Core Mallard duck (Anas platyrhynchos) 99.8 15/ 45 viable embryos, live 3wk embryos and normal hatchlings 448671­ 01 Dreumel and Heijink, 1999 Supplemental 1 NOAEC = No Observed Effect Concentration; LOAEC = Lowest Observed Effect Concentration, ND = Not Determined The guideline (71­ 4) is not fulfilled (MRID 448122­ 01 and 448671­ 01). The avian reproduction study (Mallard duck) needs to be repeated. Although the submitted study (MRID 448671­ 01) was classified as being supplemental due to guideline deviations as well as the low hatching success in the control group, the study should be repeated to determine if 15 ppm is a valid NOAEL value. The NOAEL value of 15 ppm will be used in risk assessments until further data is provided. Mammals, Acute and Chronic In most cases, rat or mouse toxicity values obtained from the Agency's Health Effects Division (HED) substitute for wild mammal testing. These toxicity values are reported below. Mammalian Toxicity: Acute and Chronic Species %ai Test Type Toxicity Value Year MRID/ Acc No. Laboratory rat (Rattus norvegicus) technical LD50 88 (males); 91 (females); moderately toxic Gaines 1969. Tox. & Appl. Pharm. 14: 515­ 534 00049330 Laboratory rat (Rattus norvegicus) 99.5 2 Generation reproduction NOAEL= 20 ppm LOAEL= 150 ppm 1991 422461­ 01 27 Insects Nontarget Insect Acute Contact Toxicity Species %ai LD50 (
g/ bee) Toxicity Category ACC No. Author/ Year Study Classification Honey bee (Apis mellifera) Honey bee (Apis mellifera) technical technical 0.56 0.20 Highly toxic Highly toxic 00036935,1975 05001991,1978 core core The results indicate that lindane is highly toxic to bees on an acute contact basis. The guideline (141­ 1) is fulfilled. (ACC# 00036935 and 05001991). Terrestrial invertebrates Nontarget Terrestrial Invertebrate Acute Toxicity Species %ai LC50 (ppb) Toxicity Category ACC No. Author/ Year Study Classification Sowbug (Asellus brevicaudus) 99 10.0 Moderately toxic 400946­ 02 Supplemental The results indicate that lindane is moderately toxic to terrestrial invertebrates on an acute dietary basis. There are no guideline requirements for terrestrial invertebrates (MRID# 400946­ 02). Toxicity to Aquatic Organisms Freshwater Fish, Acute Freshwater Fish Acute Toxicity Species %ai 96­ hour LC50 (ppb) Toxicity Category MRID/ Acc No. Study Classification Goldfish (Carassius auratus) 99 131.0 Highly toxic 400946­ 02 Supplemental Rainbow trout (Oncorhynchus mykiss) 99 18.0 Very highly toxic 400980­ 01 Core Brown trout (Salmo trutta) 99 1.7 Very highly toxic 400946­ 02 Core Bluegill sunfish (Lepomis macrochirus) 99 25.0 Very highly toxic 400980­ 01 Core Black bullhead (Ictalurus melas) 99 64.0 Very highly toxic 400946­ 02 Core Brown trout (Salmo trutta) 99 22.0 Very highly toxic 400980­ 01 Core Freshwater Fish Acute Toxicity Species %ai 96­ hour LC50 (ppb) Toxicity Category MRID/ Acc No. Study Classification 28 Channel catfish (Ictalurus punctatus) 99 44.0 Very highly toxic 400946­ 02 Core Yellow perch (Perca flavescens) 99 68.0 Very highly toxic 400946­ 02 Core Fathead minnow (Pimephales promelas) 99 77.0 Very highly toxic 400980­ 01 Core Fathead minnow (Pimephales promelas) 99 67.0 Very highly toxic 400980­ 01 Core Lake trout (Salvelinus namaycush) 99 32.0 Very highly toxic 400946­ 02 Core Lake trout (Salvelinus namaycush) 99 24.0 Very highly toxic 400980­ 01 Supplemental Carp (Cyprinus carpio) 99 90.0 Very highly toxic 400946­ 02 Supplemental Coho salmon (Oncorhynchus kisutch) 99 23.0 Very highly toxic 400946­ 02 Core Green sunfish (Lepomis cyanellus) 99 70.0 Very highly toxic 400980­ 01 Core Largemouth bass (Micropterus salmoides) 99 32.0 Very highly toxic 400946­ 02 Core MRID 400946­ 02= Macek and McAllister. 1970. Insecticide susceptibility of some common fish family representatives. Trans. Amer. Fish Soc. 99: 20­ 27. Because the 96­ hour LC50 for the technical grade material falls in the range of 1.7 to 131 ppb, lindane is considered to be highly to very highly toxic to freshwater fish on an acute basis. The guideline (72­ 1) is fulfilled (MRID/ Acc# 400946­ 02 and 400980­ 01). Freshwater Fish, Chronic Freshwater Fish Early Life­ Stage Toxicity Under Flow­ through Conditions Species %ai NOAEC/ LOAEC (ppb) MATC 1 (ppb) Endpoints Affected MRID No. Study Classification Rainbow trout (Oncorhynchus mykiss) 99.5 2. 9/ 6. 0 4.2 Larval wet wt. 444054­ 01 and 400561­ 05 Supplemental 1 MATC = Maximum Allowed Toxic Concentration, defined as the geometric mean of the NOAEC and LOAEC. 29 This study was scientifically sound but did not fulfill guideline requirements. The study contained enough information that if repeated, would not add further information. The guideline (72­ 4) is fulfilled (MRID# 444054­ 01 and 400561­ 05). The data indicate that lindane significantly affected larval growth at concentrations equal to or greater than 6.0 ppb. In a memo dated 8/ 27/ 98, after review by the EFED Aquatic Biology Technical Team, it was concluded that the study produced a valid NOAEC and LOAEC even with the problems encountered during the course of this study, thus, even though the study was classified as being supplemental, the study does not need to be repeated. Freshwater Invertebrates, Acute Freshwater Invertebrate Acute Toxicity Species % ai 48­ hour LC50/ EC50 (ppb) Toxicity Category MRID/ Acc No. Study Classification Waterflea (Daphnia pulex) 99 460.0 Highly toxic 400946­ 02 Core Scud (Gammarus fasciatus) 99 10.0 (96 hr) Very highly toxic 400946­ 02 Supplemental Scud (Gammarus fasciatus) 100 88.0 (96 hr) Very highly toxic 400946­ 02 Supplemental Stonefly (Pteronarcys californica) 99 1.0 (96 hr) Very highly toxic 400980­ 01 Core Stonefly (Pteronarcys californica) 99 4.5 (96 hr) Very highly toxic 400980­ 01 Core Waterflea (Simocephalus serrulatus) 99 520.0 Highly toxic 400946­ 02 Supplemental Because the LC50/ EC50 of the TGAI ranges from 1. 0 to 520 ppb, lindane is considered to be very highly to highly toxic to aquatic invertebrates on an acute basis. The guideline (72­ 2) is fulfilled (MRID# 400946­ 02). Freshwater Invertebrate, Chronic Freshwater Aquatic Invertebrate Life­ Cycle Toxicity Species % ai 21­ day NOAEC/ LOAEC (ppb) MATC 1 (ppb) Endpoints Affected MRID No. Study Classification Waterflea (Daphnia magna) 99.5 54/ 110 77 Reproduction 444054­ 02/ 400561­ 06 Supplemental 1 Maximum Allowed Toxic Concentration, defined as the geometric mean of the NOAEC and LOAEC. The data indicate that lindane significantly reduced reproduction at concentrations equal to or greater than 110 ppb. This study was scientifically sound but did not fulfill guideline (72­ 4) requirements (MRID# 444054­ 02/ 400561­ 06). The study contained enough information that if repeated, would not add further information. 30 Estuarine and Marine Fish, Acute Estuarine/ Marine Fish Acute Toxicity Species %ai 96­ hour LC50 (ppb) Toxicity Category MRID No. Study Classification Pinfish (Lagodon rhomboides) 100 31.0 Very highly toxic 402284­ 01 Supplemental Sheepshead minnow (Cyprinodon variegatus) 100 100.0 Very highly toxic 402284­ 01 Supplemental Longnose killfish (Fundulus similis) 100 190.0 (48 hr) Highly toxic 402284­ 01 Supplemental Spot (Leiostomus xanthurus) 100 23.0 (48 hr) Very highly toxic 402284­ 01 Supplemental Striped mullet (Mugil cephalus) 100 23.0 (48 hr) Very highly toxic 402284­ 01 Supplemental Since the 48 and 96 hr LC50s range from 23.0 to 190.0 ppb, lindane is considered to be very highly toxic to highly toxic to estuarine/ marine fish on an acute basis. The data above, taken together, fulfill the guideline (72­ 3a) requirements (MRID 402284­ 01). Estuarine and Marine Fish, Chronic No data were submitted. Estuarine and Marine Invertebrates, Acute Estuarine/ Marine Invertebrate Acute Toxicity Species %ai. 96­ hour LC50/ EC50 (ppb) Toxicity Category MRID/ Acc No. Study Classification Eastern oyster (spat) (Crassostrea virginica) 100 240 Highly toxic 402284­ 01 Core Eastern oyster (Emb/ Larval) (Crassostrea virginica) 99.5 2820 (48hr EC50) Moderately toxic 00264036/ 443555­ 01 Supplemental Brown shrimp (Penaeus aztecus) 100 0.22 (48 hr EC50) Very highly toxic 402284­ 01 Supplemental Mysid (Mysidopsis bahia) 100 6.3 Very highly toxic 402284­ 01 Supplemental Grass shrimp (Palaemonetes vulgaris) 100 4.4 Very highly toxic 402284­ 01 Supplemental Seed Shrimp (Cypridopsis vidua) 99 3.2 (48 hr LC50) Very highly toxic 400946­ 02 Supplemental Pink Shrimp (Penaeus duorarum) 100 0.077 Very highly toxic 402284­ 01 Supplemental 31 Because the LC50s range from 0. 077 to 2820 ppb, the TGAI of lindane is considered very highly to moderately toxic to estuarine/ marine invertebrates on an acute basis. The guideline (72­ 3b and 72­ 3c) is fulfilled (MRID/ Acc# s 264036, 400946­ 02, and 402284­ 01). Estuarine and Marine Invertebrate, Chronic No data were submitted. Toxicity to Plants Currently, plant testing is not required for pesticides other than herbicides and fungicides except on a caseby case basis (e. g., labeling bears phytotoxicity warnings, incident data or literature that demonstrates phytotoxicity). Because of the current use pattern (incorporated seed treatment), low application rate, lack of incident data on plants and no available literature suggesting phytotoxicity, no plant data are required. 32 Appendix II: Risk Assessment A means of integrating the results of exposure and ecotoxicity data is called the quotient method. For this method, risk quotients (RQs) are calculated by dividing exposure estimates by ecotoxicity values, both acute and chronic. RQ = EXPOSURE/ TOXICITY RQs are then compared to OPP's levels of concern (LOCs). These LOCs are criteria used by OPP to indicate potential risk to nontarget organisms and the need to consider regulatory action. The criteria indicate that a pesticide used as directed has the potential to cause adverse effects on nontarget organisms. LOCs currently address the following risk presumption categories: (1) acute high ­ potential for acute risk is high, regulatory action may be warranted in addition to restricted use classification (2) acute restricted use ­ the potential for acute risk is high, but this may be mitigated through restricted use classification (3) acute endangered species ­ the potential for acute risk to endangered species is high, regulatory action may be warranted, and (4) chronic risk ­ the potential for chronic risk is high, regulatory action may be warranted. Currently, EFED does not perform assessments for chronic risk to plants, acute or chronic risks to nontarget insects, or chronic risk from granular/ bait formulations to mammalian or avian species. The ecotoxicity test values (i. e., measurement endpoints) used in the acute and chronic risk quotients are derived from the results of required studies. Examples of ecotoxicity values derived from the results of short­ term laboratory studies that assess acute effects are: (1) LC50 (fish and birds) (2) LD50 (birds and mammals) (3) EC50 (aquatic plants and aquatic invertebrates) and (4) EC25 (terrestrial plants). An example of a toxicity test effect level derived from the results of long­ term laboratory studies that assess chronic effects is: (1) NOAEC (birds, fish and aquatic organisms). Risk presumptions, along with the corresponding RQs and LOCs are tabulated below: Risk Presumptions for Terrestrial Animals Risk Presumption RQ LOC Birds Acute High Risk EEC 1 /LC50 or LD50/ sq ft or LD50/ day 3 0.5 Acute Restricted Use EEC/ LC50 or LD50/ sq ft or LD50/ day (or LD50 < 50 mg/ kg) 0. 2 Acute Endangered Species EEC/ LC50 or LD50/ sq ft or LD50/ day 0. 1 Chronic Risk EEC/ NOAEC 1 Wild Mammals Acute High Risk EEC/ LC50 or LD50/ sq ft or LD50/ day 0. 5 Acute Restricted Use EEC/ LC50 or LD50/ sq ft or LD50/ day (or LD50 < 50 mg/ kg) 0. 2 Acute Endangered Species EEC/ LC50 or LD50/ sq ft or LD50/ day 0. 1 Chronic Risk EEC/ NOAEC 1 1 abbreviation for Estimated Environmental Concentration (ppm) on avian/ mammalian food items 2 mg/ ft 2 3 mg of toxicant consumed/ day LD50 * wt. of bird LD50 * wt. of bird 33 Risk Presumptions for Aquatic Animals Risk Presumption RQ LOC Acute High Risk EEC 1 /LC50 or EC50 0. 5 Acute Restricted Use EEC/ LC50 or EC50 0. 1 Acute Endangered Species EEC/ LC50 or EC50 0. 05 Chronic Risk EEC/ MATC or NOAEC 1 1 EEC = (ppm or ppb) in water Risk Presumptions for Plants Risk Presumption RQ LOC Terrestrial and Semi­ Aquatic Plants Acute High Risk EEC 1 /EC25 1 Acute Endangered Species EEC/ EC05 or NOAEC 1 Aquatic Plants Acute High Risk EEC 2 /EC50 1 Acute Endangered Species EEC/ EC05 or NOAEC 1 1 EEC = lbs ai/ A 2 EEC = (ppm/ ppb) in water Terrestrial Exposure Assessment The terrestrial exposure assessment for lindane seed treatment use is based on the calculation of the amount of seeds that a bird must ingest to receive a lethal LD50 dose compared to the amount of seeds a bird could ingests (if the diet consisted of only lindane­ treated seeds). Other Factors Affecting Risk Only two bird species are usually required to be tested B one waterfowl species and one upland gamebird species B under the Fish and Wildlife Data Requirements listed in CFR 158. There is a great deal of uncertainty associated with extrapolating from the acute oral and subacute dietary data from two species to the large numbers of bird species associated with agricultural areas. Field surveys indicate that a large variety of birds are associated with these areas, including a multitude of songbirds and many others. Waterfowl are also likely to be present in these regions. As the EFED ecological database indicates that songbirds tend to be more sensitive than the two required test species, using the maximum estimated environmental concentration to calculate risk helps to compensate for this uncertainty in the toxicity data. However, in this case, actual acute data are available for songbirds (Sparrow LD50= 56 mg/ kg and Redwinged blackbird LD50= 75 mg/ kg). The lack or small number of reported incidents involving birds or mammals does not prove that animals are not dying from pesticide exposure. Finding dead animals in the field is difficult, even when experienced field biologists are searching treated fields. Reporting of incident data is still rather accidental, and only carefully designed field studies can confidently indicate the likelihood of field kill incidents occurring. 34 ECOLOGICAL INCIDENTS SUMMARY The number of documented kills in the Ecological Incident Information System is believed to be but a very small fraction of total mortality caused by pesticides. Mortality incidents must be seen, reported, investigated, and have investigation reports submitted to EPA to have the potential for entry into the database. Incidents often are not seen, due to scavenger removal of carcasses, decay in the field, or simply because carcasses may be hard to see on many sites and/ or few people are systematically looking. Poisoned birds may also move off­ site to less conspicuous areas before dying. Incidents seen may not get reported to appropriate authorities capable of investigating the incident because the finder may not know of the importance of reporting incidents, may not know who to call, may not feel they have the time or desire to call, may hesitate to call because of their own involvement in the kill, or the call may be long­ distance and discourage callers, for example. Incidents reported may not get investigated if resources are limited or may not get investigated thoroughly, with residue and ChE analyses, for example. Also, if kills are not reported and investigated promptly, there will be little chance of documenting the cause, since tissues and residues may deteriorate quickly. Reports of investigated incidents often do not get submitted to EPA, since reporting by states is voluntary and some investigators may believe that they don't have the resources to submit incident reports to EPA. Incident reports submitted to EPA since approximately 1994 have been tracked by assignment of I­# s in an Incident Data System (IDS), microfiched, and then entered to a second database, the Ecological Incident Information System (EIIS). This second database has some 85 fields for potential data entry. An effort has also been made to enter information to EIIS on incident reports received prior to establishment of current databases. Although many of these have been added, the system is not yet a complete listing of all incident reports received by EPA. Incident reports are not received in a consistent format (e. g., states and various labs usually have their own formats), may involve multiple incidents involving multiple chemicals in one report, and may report on only part of a given incident investigation (e. g., residues). While some progress has been made in recent years, both in getting incident reports submitted and entered, there has never been the level of resources assigned to incidents that there has been to the tracking and review of laboratory toxicity studies, for example. This adds to the reasons cited above for why EPA believes the documented kills are but a fraction of total mortality caused by lindane and other highly toxic pesticides. Incidents entered into EIIS are categorized into one of several certainty levels: highly probable, probable, possible, unlikely, or unrelated. In brief, "highly probable" incidents usually require carcass residues, substantial ChE inhibition in avian and/ or mammalian species, and/ or clear circumstances regarding the exposure. "Probable" incidents include those where residues were not available and/ or circumstances were less clear than for "highly probable." "Possible" incidents include those where multiple chemicals may have been involved and it is not clear what the contribution was of a given chemical. The "unlikely" category is used, for example, where a given chemical is practically nontoxic to the category of organism killed and/ or the chemical was tested for but not detected in samples. "Unrelated" incidents are those that have been confirmed to be not pesticide­ related. Incidents entered into the EIIS are also categorized as to use/ misuse. Unless specifically confirmed by a state or federal agency to be misuse, or there was very clear misuse such as intentional baiting to kill wildlife, incidents would not typically be considered misuse. Data entry personnel often do not have a copy of the specific label used in a given application, and would not usually be able to detect a variety of labelspecific violations, for example. 35 Incidents have been reported from the use of lindane and are on the EPA incident database. These incidents are listed in the table below: Incident # Date State Organism Tissue analysis Tissue/ soil Concentration Use Site Certainty index I002166­ 001 4/ 28/ 95 NC Trout (100s) Yes+ 0.43­ 10.74 ppm in tissue 0.12­ 1.6 ppm in soil Tree farm Highly Probable (Accident) B0000­ 204 5/ 1/ 83 SC Mullet (100) No N/ A Ag area Possible I004632­ 033 4/ 29/ 93 CA Trout (60) No N/ A N/ R Probable B0000­ 244­ 01 8/ 7/ 71 MA Fish (15,000) No N/ A Cranberries Probable += positive Exposure and Risk to Nontarget Terrestrial Organisms Birds: Acute Granular products/ Seed Treatment: Birds may be exposed to granular pesticides and seed treatments by ingesting granules or seeds when foraging for food or grit. They also may be exposed by other routes, such as by walking on exposed granules or drinking water contaminated by granules or treated seeds. The assessment below bases acute exposure on the quantity of seeds that a bird could ingest in one day and that the bird eats only lindanetreated seeds. This approach defines a risk quotient (RQ) as RQ= Dose/ LD50 where Dose = the amount of lindane that a bird could receive by ingesting treated­ seeds in a 24­ hour period per bird mass (dose units in mg/ Kg). Risk is assumed to occur for any RQ value greater than0.5. The dose that a bird could receive by eating treated seeds can be approximated from the estimated amount of food that a bird can eat in a day. The dose can be described as Dose = (FI)( C)( T)/ Mbird where FI = the food ingestion rate [kg/ day] C = active ingredient concentration on seed (mg/ kg) T = relevant duration time for food consumption (assumed to be 1 day in this assessment) [day]. Mbird = mass (wet) of bird [kg]. The rate of food consumption (FI) of a bird can be estimated by the method of Nagy (1987; also see EPA, 1993). For passerines, the Nagy relationship is FI = 0. 141 (Mbird) 0.850 and for non­ passerines the relationship is FI = 0. 054 (Mbird) 0.751 36 RQ results for this analysis are summarized in the table below. The results suggest that acute risk is highest for for birds eating seeds for broccoli, brussel sprouts, cabbage, and cauliflower. Small birds, which consume proportionally larger quantities of food with respect to their body weight, are at greater risk than larger birds. RQs exceeded 0.5 for the sparrow and the red­ winged black bird under for all seed treatments. For the quail, RQ indicated risk only for the seeds with the highest application rate (broccoli, brussel sprouts, cabbage, and cauliflower). Table Summary of RQ evaluation. RQs in bold indicate potential risk.. Lindane Seed Conc (per label) Dose (mg ai consumed per day /kg bird) RQ =Dose/ LD50 crop example label # lb ai/ 100 lb seed mg ai/ kg seed sparrow (FI = 0.00613 kg/ day) a RWBB (FI = 0.0114 kg/ day) a quail (FI = 0.0148 kg/ day) a sparrow (LD50=56 mg/ kg) RWBB (LD50=75 mg/ kg) quail (LD50=122 mg/ kg) barley 34704­ 658 0.0375 375 92.0 82.4 31.1 1.64 1.10 0.25 corn 71096­ 2 0. 125 1250 307 275. 103. 5.48 3.67 0.85 oats 2935­ 0492 0.0313 313 76.6 68.7 25.9 1.37 0.92 0.21 rye 2935­ 0492 0.0328 328 80.4 72.1 27.2 1.44 0.96 0.22 sorghum 8660­ 53 0.0628 628 154. 138. 52.1 2.75 1.84 0.43 wheat 555­ 144 0.0426 426 104. 93.5 35.3 1.87 1.25 0.29 a Dose = seed concentration x food intake rate, where food intake rate (FI) is based on Nagy equation (see text), assuming the following typical bird weights: Sparrow wt = 25 g; Red winged BB wt = 52 g, Bobwhite quail wt = 178 g (Clench and Leberman. 1978). Birds: Chronic To determine chronic risk to birds, the concentration on the food item (seeds) was determined from the the label. Chronic RQ was calculated using the following equation: RQ = Concentration on seeds / NOAEC. Results are given in the table below and suggest a potential for chronic reproductive risk to avian species from the use of lindane­ treated seed. Table summary of chronic RQ evaluation. RQs in bold indicate potential risk.. Lindane Seed Conc (per label) RQ =Seed Conc./ NOAEC crop example label # lb ai/ 100 lb seed mg ai/ kg seed mallard (NOAEC= 15 mg/ kg) Quail (NOAEC = 80 mg/ kg) barley 34704­ 658 0.0375 375 25 4.7 corn 71096­ 2 0. 125 1250 83.3 15.6 oats 2935­ 0492 0.0313 313 20.8 3. 9 rye 2935­ 0492 0.0328 328 21.9 4. 1 sorghum 8660­ 53 0.0628 628 41.9 7. 9 wheat 555­ 144 0.0426 426 28.4 5. 3 Mammals: Acute Granular products/ Seed Treatment: Mammals may be exposed to granular pesticides ingesting granules or seeds when foraging for food or grit. They also may be exposed by other routes, such as by walking on exposed granules or drinking water contaminated by granules or treated seeds. The assessment was performed in a similar manner as for birds as given above. The Nagy relationship for the general case of all mammals is FI = 0. 0687 (Mmammals) 0.822 where Mmammals is the mammal mass in kg. Results are summarized below. Since RQs above 0. 5 indicate potential risk, the results indicate the possibility of acute risk to seed­ eating mammals for all seed treatments, with smaller mammals being more vulnerable than larger mammals.. 37 Table summary of RQ evaluation. RQs in bold indicate potential risk.. Lindane Seed Conc (per label) Dose (mg ai consumed per day /kg mammal) RQ =Dose/ LD50 crop example label # lb ai/ 100 lb seed mg ai/ kg seed 0.015 kg mammal (FI = 0.00218 kg/ day) a 0.035 kg mammal (FI = 0.00437 kg/ day) a 1 kg mammal (FI = 0.0687 kg/ day) a 0.015 kg mammal LD50=88 mg/ kg) b 0.035 kg mammal (LD50=88 mg/ kg) b 1 kg mammal (LD50=88 mg/ kg) b barley 34704­ 658 0.0375 375 54 47 26 0.62 0.53 0.29 corn 71096­ 2 0. 125 1250 181 156 86 2.1 1. 8 0.98 oats 2935­ 0492 0.0313 313 45 39 21 0.51 0.44 0.. 24 rye 2935­ 0492 0.0328 328 47 41 23 0.54 0.46 0.26 sorghum 8660­ 53 0.0628 628 91 78 43 1.0 0. 89 0.49 wheat 555­ 144 0.0426 426 62 53 29 0.70 0.60 0.33 a Dose = seed concentration x food intake rate, where food intake rate (FI) is based on Nagy equation (see text). Weights were chosen to represent typical small mammals. b AllLD50s were based on the rat. Mammals: Chronic To determine chronic risk to mammals, the concentration on the food item (seeds) was determined from the the label. Chronic RQ was calculated using the following equation: RQ = Concentration on seeds / NOAEC. The NOAEC for the rat (20 mg/ L) was used as an approximation for all mammals. Results are given in the table below and indicate a potential for chronic reproductive risk to mammalian species from the use of lindane­ treated seed. Table summary of chronic RQ evaluation. RQs in bold indicate potential risk.. Lindane Seed Conc (per label) RQ =Seed Conc./ NOAEC crop example label # lb ai/ 100 lb seed mg ai/ kg seed rat (NOAEC= 20 mg/ kg) barley 34704­ 658 0.0375 375 19 corn 71096­ 2 0. 125 1250 63 oats 2935­ 0492 0.0313 313 16 rye 2935­ 0492 0.0328 328 16 sorghum 8660­ 53 0.0628 628 31 wheat 555­ 144 0.0426 426 21 Insects Currently, EFED does not assess risk to nontarget insects. Results of acceptable studies are used for recommending appropriate label precautions. As lindane is highly toxic (0.2 to 0. 56 ug/ bee) to honeybees, precautions in respect to spray drift to flowering plants should be followed. Since this is a seed treatment application, low risk is assumed to flying insects, however beneficial soil dwelling insects may be at risk. Plants No data was available for lindane to assess risk to terrestrial or aquatic plants. Exposure and Risk to Nontarget Freshwater Aquatic Animals 38 EFED uses GENEEC to calculate Tier I EECs and assumed that 100% of the compound will disassociate from the seed surface. EECs are tabulated in Appendix III. I. Freshwater Fish Acute and chronic risk quotients are tabulated below. Risk Quotients for Freshwater Fish Based On a bluegill LC50 of 1.7 ppb and a fathead minnow NOAEC of 2.9 ppb. Site LC50 (ppb) NOAEC (ppb) EEC Initial/ Peak (ppb) EEC 56­ Day Ave. (ppb) Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) wheat 1. 7 2. 9 0. 67 0. 48 0. 40 0. 17 An analysis of the results indicate that restricted use and endangered species LOC's are exceeded for freshwater fish. No chronic LOC's are exceeded for freshwater fish. ii. Freshwater Invertebrates The acute and chronic risk quotients are tabulated below. Risk Quotients for Freshwater Invertebrates Based On a daphnia EC50/ LC50 of 10.0 ppb and a daphnia NOAEC of 54 ppb. Site LC50 (ppb) 21 day NOAEC (ppb) EEC Initial/ Peak (ppb) EEC 21­ Day Average Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) wheat 10 54 0. 67 0. 48 0.07 0.01 An analysis of the results indicate that the acute endangered species LOC is exceeded for freshwater invertebrates. No chronic LOC's are exceeded for freshwater invertebrates. iii. Estuarine and Marine Fish The acute and chronic risk quotients are tabulated below. Risk Quotients for estuarine/ marine fish based on a striped mullet LC50 of 23 ppb. No data was submitted to assess chronic risk to estuarine/ marine fish. Site LC50 (ppb) NOAEC (ppb) EEC Initial/ Peak (ppb) EEC 56­ Day Average Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) wheat 23 N/ A 0.67 0.48 0.03 N/ A An analysis of the results indicate that no acute LOCs were exceeded for estuarine/ marine fish. iv. Estuarine and Marine Invertebrates 39 Risk Quotients for Estuarine/ Marine Aquatic Invertebrates Based on a pink shrimp LC50/ EC50 of 0.077 ppb. No data was submitted to assess chronic risk to estuarine/ marine invertebrates. Site/ Application Method LC50 (ppb) NOAEC/ (ppb) EEC Initial/ Peak EEC 21­ Day Average Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) wheat 0. 077 N/ A 0. 67 0. 48 8. 70 N/ A An analysis of the results indicate that high acute, restricted use and endangered species LOC's were exceeded for estuarine/ marine invertebrates. Chronic risk to estuarine/ marine invertebrates could not be assessed due to a lack of toxicity data. 40 Appendix III: GENEEC OUTPUT (FOR SURFACE WATER ASSESSMENT) RUN No. 1 FOR lindane INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RATE (#/ AC) APPLICATIONS SOIL SOLUBILITY % SPRAY INCORP ONE( MULT) NO.­ INTERVAL KOC (PPM) DRIFT DEPTH( IN) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .051( .051) 1 1 942.0 7.0 .0 1.0 FIELD AND STANDARD POND HALFLIFE VALUES (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED (FIELD) RAIN/ RUNOFF (POND) (POND­ EFF) (POND) (POND) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 980.00 2 N/ A .00­ .00 .00 ******* GENERIC EECs (IN PPT) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ PEAK AVERAGE 4 AVERAGE 21 AVERAGE 56 GEEC DAY GEEC DAY GEEC DAY GEEC ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 671.90 655.43 579.19 483.61 SCIGROW OUTPUT (FOR GROUND WATER ASSESSMENT RUN No. 1 FOR lindane INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APPL (#/ AC) APPL. URATE SOIL SOIL AEROBIC RATE NO. (#/ AC/ YR) KOC METABOLISM (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .051 1 .051 1367.0 980.0 GROUND­ WATER SCREENING CONCENTRATIONS IN PPB ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .010993 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ A= 975.000 B= 1372.000 C= 2.989 D= 3.137 RILP= 2.578 F= ­. 668 G= .215 URATE= .051 GWSC= .010993 41 Ecological Effects Data Requirements for: LINDANE Guideline # Data Requirement Is Data Requirement Satisfied? MRID #'s Study Classification 71­ 1 Avian Oral LD50 Yes 00263944 Core 71­ 2 2 Avian Dietary LC50's Yes 00022923 Core 71­ 4 Avian Reproduction Yes No 448122­ 01 448671­ 01 Core Supplemental 72­ 1 2 Freshwater Fish LC50 Yes Yes 400946­ 02 400980­ 01 Core Core 72­ 2 Freshwater Invertebrate Acute LC50 Yes 400946­ 02 Core 72­ 3( a) Estuarine/ Marine Fish LC50 Yes in combination 402284­ 01 (5 studies) Supplemental 72­ 3( b) Estuarine/ Marine Mollusk EC50 Yes 402284­ 01 Core 72­ 3( c) Estuarine/ Marine Shrimp EC50 Yes in combination 402284­ 01 400946­ 02 (5 studies) Supplemental Supplemental 72­ 4( a) Freshwater Fish Early Life­ Stage Yes 444054­ 01 400561­ 05 Supplemental 72­ 4( b) Estuarine Fish Early Life­ Stage Required 72­ 4( c) Estuarine Invertebrate Life­ Cycle Required 72­ 4( d) Freshwater Invertebrate Life­ Cycle Yes 444054­ 02 400561­ 06 Supplemental 72­ 5 Freshwater Fish Full Life­ Cycle Reserved 81­ 1 Acute Mammalian LD50 Yes 00049330 Core 83­ 5 2­ generation mammalian reproduction Yes 422461­ 01 Core 122­ 1( a) Seed Germ./ Seedling Emergence Required 122­ 1( b) Vegetative Vigor Required 122­ 2 Aquatic Plant Growth Required 123­ 1( a) Seed Germ./ Seedling Emergence Reserved 123­ 1( b) Vegetative Vigor Reserved 123­ 2 Aquatic Plant Growth Reserved 144­ 1 Honey Bee Acute Contact LD50 Yes Yes 00036935 05001991 Core Core Non­ guideline 14­ day free choice avian dietary toxicity test (aversion) Not required 400561­ 03; 400561­ 04 Supplemental 42 Environmental Fate Data Requirements for: LINDANE Guideline # Data Requirement Is Data Requirement Satisfied? MRID #'s Study Classification 161­ 1 Hydrolysis Yes 00161630 Accepted 161­ 2 Photodegradation in Water Yes 00164547 00164545 44793101 Supplemental Supplemental Acceptable 161­ 3 Photodegradation on Soil Yes 44440605 Acceptable 161­ 4 Photodegradation in Air N/ A N/ A N/ A 162­ 1 Aerobic Soil Metabolism Yes 40622501 Accepted 162­ 2 Anaerobic Soil Metabolism No 44867102 Unacceptable 162­ 3 Anaerobic Aquatic Metabolism N/ A N/ A N/ A 162­ 4 Aerobic Aquatic Metabolism N/ A N/ A N/ A 163­ 1 Leaching­ Adsorption/ Desorption yes 00164346 00164538 40067301 Accepted 163­ 2 Laboratory Volatility No 44445301 Unacceptable 1 163­ 3 Field Volatility N/ A N/ A N/ A 164­ 1 Terrestrial Field Dissipation Yes 44867103 Supplemental 165­ 4 Accumulation in Fish/ Bioconcentration Yes 40056101 40056102 Accepted 1. Sorption properties of lindane and the soil were not reported. Additional volatility study submissions are not needed to assess this chemicals fate, since lindane's volatility is well documented in open literature.

epa

2024-06-07T20:31:43.146436

regulations

EPA-HQ-OPP-2002-0202-0013

Supporting & Related Material

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES WASHINGTON, D. C. 20460 PC Code: 009001 DP Barcodes: D283667 MEMORANDUM SUBJECT: Addition of corn and canola seed treatment use to revised Lindane RED TO: B. Shackleford, Branch Chief M. Howard, Team Leader Special Review and Reregistration Division (7508C) FROM: N. E. Federoff, Wildlife Biologist F. A. Khan, Ph. D., Environmental Scientist Environmental Risk Branch V Environmental Fate and Effects Division REVIEWED and APPROVED by: Mah Shamim, Ph. D., Branch Chief Environmental Risk Branch V Environmental Fate and Effects Division (7507C) CANOLA AND CORN SEED ASSESSMENT EFED was asked to add canola and corn to its list of lindane treated seeds for ecological risk assessment. This document supersedes the Revised EFED RED chapter for lindane (D254764) and provides updated and revised risk information regarding canola and corn. Both a terrestrial (avian and mammalian acute and chronic) and an aquatic assessment (freshwater and marine fish and invertebrates) were performed as well as calculation of surface and groundwater EECs. The rates used were the proposed maximum 1. 456 lb ai/ 100lbs seed x 8 lbs seed/ acre = 0. 116 lbs ai/ acre for canola and a new lower rate of 0.0558 lb ai/ 100lbs seed x 14 lbs seed/ acre= 0.0078 lbs ai/ acre for corn. There are approximately 113,000­ 227,000 seeds per pound of canola seed and 1200­ 1600 seeds per pound of corn seed. Summary Risk to birds and mammals have increased in magnitude (over 10X) for the new proposed canola use and were reduced (about 2X) for corn under the new rate scenario. However, uncertainty exists regarding actual risk to seed eating avian species due to factors associated with exposure. Seed incorporation may reduce availability of treated seed to some species and aversion and field studies (Blus et al. 1984 and 1985) suggest birds may not be consuming treated seed. These exposure factors are not applicable to small seed eating mammals that eat a large proportion of their bodyweight in seed per day. Therefore, the potential for risk to these mammals is not as uncertain. Risks to aquatic organisms did increased from the new higher rate for canola. However, the assumption for GENEEC 2 (Tier I water exposure model) that 100% of the compound will disassociate from the seed surface has likely produced highly conservative estimates and has thus may have overestimated risks. Drinking Water Assessment EFED recommends that the Health Effects Division (HED) use the groundwater (acute and chronic = 0.05 ppb) and surface water concentrations (acute = 4. 16 ppb and chronic = 1. 95 ppb) for canola presented in the table below for drinking water EECs ONLY IF the proposed canola use will be supported. IF canola will not be supported for registration, then the concentrations for wheat should be used. The drinking water EECs were based on the Tier I FIRST (surface water) and SCIGROW (groundwater) simulation models. The GENEEC model is no longer used to estimate EECs for drinking water. Therefore, surface water EECs for wheat have been revised using the Tier I FIRST model. The results are provided in the following table: Drinking water EEC comparison for lindane wheat and canola seed treatments. WHEAT Application Rate (lbs ai/ A) Acute Chronic Groundwater 0.051 0.011 µ g/ L 0. 011 µ g/ L Surface Water 0.051 0. 98 µ g/ L 0. 46 µ g/ L CANOLA Application Rate (lbs ai/ A) Acute Chronic Groundwater 0. 116 0.025 µ g/ L 0. 025 µ g/ L Surface Water 0.116 4.16 µ g/ L 1. 95 µ g/ L Ground Water Ground water concentrations were predicted with SCIGROW. Input parameters are summarized in the table below. The entire SCIGROW output file is located in Appendix I at the end of this memo. SCIGROW input parameters and results for lindane. Application Rate: Wheat Canola 1 @ 0. 051 lb/ acre 1 @ 0. 116 lb/ acre Aerobic Soil Half Life 980 days (mean Value) Organic Carbon Partitioning Coefficient (Koc) 1367 mL/ g (median Value) EEC: Wheat Canola 0.011 µg/ L 0.013 µg/ L Surface Water The following inputs were used for the FIRST modeling. The FIRST output file is located in Appendix I at the end of this memo. Input Parameters for FIRST Parameter Value Application Rate and Number 0. 051 lb ai/ A x 1 application (Wheat) 0. 116 lb ai/ A x 1 application (Canola) Organic Carbon Partitioning Coefficient 942 ml/ g lowest of 4 values (MRID 00164346) Solubility 7 ppm Application Type Granular/ incorporated to 1. 2 inches Percent Cropped Area 56% for Wheat and 87% for Canola Aerobic Soil Half­ life 980 days single value (MRID 406225­ 01)* Aerobic Aquatic Half­ life 1960 days (aerobic soil halflife x 2) Photolysis stable (MRIDs 0016457; 001645545; 447931) Hydrolysis stable (MRID 00161630) *In a 336­ day aerobic soil metabolism study, lindane degraded very slowly, with a registrant­ calculated half life of 980 days, thus the "3x" rule was not applied. Terrestrial and Aquatic Assessments Risk to birds and mammals have increased in magnitude (over 10X) for the proposed canola use. However, uncertainty exists regarding actual risk to seed eating avian species due to factors associated with exposure. Seed incorporation may reduce availability of treated seed to some species. Aversion and field studies (Blus et al. 1984 and 1985) suggest birds may not be consuming treated seed. These exposure factors are not applicable to small seed eating mammals that eat a large proportion of their bodyweight in seed per day. Therefore, the potential for risk to these mammals is not as uncertain. Risks to aquatic organisms increased only slightly. The assumption for GENEEC 2 (Tier I water exposure model) that 100% of the compound will disassociate from the seed surface has likely produced highly conservative estimates and has thus likely overestimated the EEC's and resulting risks. EFED also believes that a seed leaching study would greatly increase certainty regarding a more realistic estimate of compound for groundwater leaching and runoff. This in turn would allow a refinement of exposure estimates and environmental concentration values (EECs). EFED has issued a guidance for this study (Memo from Denise Keehner re: Standard Method for Determining the Leachability of Pesticides from Treated Seeds, 7/ 6/ 2000). The results of the risk assessment are as follows: Avian The labels with the highest rates (lb lindane/ 100 lb seed) were used to evaluate potential maximum consumption of lindane by terrestrial animals. The current approach uses daily food intake calculated using the relationships described in Nagy (1987 as cited in USEPA, 1993). Acute risk quotients (RQ) were then calculated based on animals receiving their full diet from lindane­ treated seeds for a 1­ day time period. In addition, RQs were calculated using the mg ai/ kg/ seed and the dietary LC50 endpoint. Birds may be exposed to granular pesticides and seed treatments by ingesting granules or seeds when foraging for food or grit. They also may be exposed by other routes, such as by walking on exposed granules or drinking water contaminated by granules or treated seeds. The assessment below bases acute exposure on the quantity of seeds that a bird could ingest in one day and that the bird eats only lindane­ treated seeds. This approach defines a risk quotient (RQ) as: RQ= Dose/ LD50 where Dose = the amount of lindane that a bird could receive by ingesting treated­ seeds in a 24­ hour period per bird mass (dose units in mg/ Kg). Risk is assumed to occur for any RQ value greater than 0.5. The dose that a bird could receive by eating treated seeds can be approximated from the estimated amount of food that a bird can eat in a day. The dose can be described as: Dose = (FI)( C)( T)/ Mbird where FI = the food ingestion rate [kg/ day] C = active ingredient concentration on seed (mg/ kg) T = relevant duration time for food consumption (assumed to be 1 day in this assessment) [day]. Mbird = mass (wet) of bird [kg]. The rate of food consumption (FI) of a bird can be estimated by the method of Nagy (1987; also see EPA, 1993). For passerines, the Nagy relationship is: FI = 0. 141 (Mbird) 0.850 and for non­ passerines the relationship is: FI = 0. 054 (Mbird) 0.751 Acute RQ results for this analysis are summarized in the table below. Small birds, which consume proportionally larger quantities of food with respect to their body weight, are at greater risk than larger birds. RQs exceeded 0.5 for the sparrow and the red­ winged black bird for all seed treatments. For the quail, RQ indicated risk only for the seeds with the highest application rates. However, even when RQs were calculated using the dietary LC50 for quail, risk was exceeded for all seed types. Thus it can be implied that seed eating birds with smaller body­ weights than the quail may be at increased risk since lindane toxicity seems to be inversely related to bodyweight. Table Summary of RQ evaluation. RQs in bold indicate potential risk.. Lindane Seed Conc (per label) Dose (mg ai consumed per day /kg bird) RQ =Dose/ LD50 RQ= Seed concentration/ LC50 crop example label # lb ai/ 100 lb seed mg ai/ kg seed sparrow (FI = 0.00613 kg/ day) a RWBB (FI = 0.0114 kg/ day) a quail (FI = 0.0148 kg/ day) a sparrow (LD50=56 mg/ kg) RWBB (LD50=75 mg/ kg) quail (LD50=122 mg/ kg) Quail LC50=425 ppm barley 34704­ 658 0.0375 375 92.0 82.4 31.1 1.64 1.10 0.25 0.88 corn 71096­ 2 0. 125 1250 307 275 103 5.48 3.67 0.85 2.94 LOW rate corn proposed 0. 0558 558 137 122 46 2.45 1.64 0.38 1.31 oats 2935­ 0492 0.0313 313 76.6 68.7 25.9 1.37 0.92 0.21 0.74 rye 2935­ 0492 0.0328 328 80.4 72.1 27.2 1.44 0.96 0.22 0.77 sorghum 8660­ 53 0.0628 628 154 138 52.1 2.75 1.84 0.43 1.48 wheat 555­ 144 0.0426 426 104 93.5 35.3 1.86 1.25 0.29 1.00 Canola (proposed maximum rate) proposed 1. 456 14560 3570 3192 1211 63.75 42.56 9.93 34.26 Canola ½ rate proposed 0. 72 7200 1765 1578 599 31.51 21.04 4.91 16.94 a Dose = seed concentration x food intake rate, where food intake rate (FI) is based on Nagy equation (see text), assuming the following typical bird weights: Sparrow wt = 25 g; Red winged BB wt = 52 g, Bobwhite quail wt = 178 g (Clench and Leberman. 1978). Chronic To determine chronic risk to birds, the concentration on the food item (seeds) was determined from the label. Chronic RQ was calculated using the following equation: RQ = Concentration on seeds / NOAEC. Results are given in the table below and suggest a potential for chronic reproductive risk to avian species from the use of lindane­ treated seed. RQs in bold indicate potential risk. Lindane Seed Conc (per label) RQ =Seed Concentration/ NOAEC crop example label # lb ai/ 100 lb seed mg ai/ kg seed mallard (NOAEC= 15 mg/ kg) Quail (NOAEC = 80 mg/ kg) barley 34704­ 658 0.0375 375 25.0 4.7 corn 71096­ 2 0. 125 1250 83.3 15.6 LOW rate corn proposed 0. 0558 558 37.2 6.9 oats 2935­ 0492 0.0313 313 20.8 3.9 rye 2935­ 0492 0.0328 328 21.9 4.1 sorghum 8660­ 53 0.0628 628 41.9 7.9 wheat 555­ 144 0.0426 426 28.4 5.3 Canola (proposed maximum rate) proposed 1. 456 14560 970.7 182.0 Canola ½ rate proposed 0. 72 7200 480.0 90.0 Mammalian Mammals may be exposed to granular pesticides ingesting granules or seeds when foraging for food or grit. They also may be exposed by other routes, such as by walking on exposed granules or drinking water contaminated by granules or treated seeds. The mammalian assessment was performed in a similar manner as for birds as given above. In addition, RQs were calculated using the mg ai/ kg/ seed and the dietary LC50 endpoint. The Nagy relationship for the general case of all mammals is: FI = 0. 0687 (Mmammals) 0.822 where Mmammals is the mammal mass in kg. Results are summarized below. Since RQs above 0. 5 indicate potential risk, the results indicate the possibility of acute risk to seed­ eating mammals for all seed treatments, including canola, with smaller mammals being more vulnerable than larger mammals. Table summary of RQ evaluation. RQs in bold indicate potential risk.. Lindane Seed Conc (per label) Dose (mg ai consumed per day /kg mammal) RQ =Dose/ LD50 RQ= Seed concentration/ LC5 Calculated dietary effect concentration crop example label # lb ai/ 100 lb seed mg ai/ kg seed 0.015 kg mammal (FI = 0.00218 kg/ day) a 0.035 kg mammal (FI = 0.00437 kg/ day) a 1 kg mammal (FI = 0.0687 kg/ day) a 0.015 kg mammal LD50=88 mg/ kg) 0.035 kg mammal (LD50=88 mg/ kg) 1 kg mammal (LD50=88 mg/ kg) 419 ppm 587 ppm 1760 ppm barley 34704­ 658 0.0375 375 54 47 26 0.62 0.53 0.29 0.90 0.64 0.21 corn 71096­ 2 0. 125 1250 181 156 86 2.1 1. 8 0.98 3.00 2.13 0.71 LOW rate corn proposed 0. 0558 558 81 70 38 0.92 0.79 0.44 1.33 0.95 0.32 oats 2935­ 0492 0.0313 313 45 39 21 0.51 0.44 0.24 0.75 0.53 0.18 radish 7501­ 16 0.0323 323 47 40 22 0.53 0.45 0.25 0.77 0.55 0.18 rye 2935­ 0492 0.0328 328 47 41 23 0.54 0.46 0.26 0.78 0.56 0.19 sorghum 8660­ 53 0.0628 628 91 78 43 1.0 0. 89 0.49 1.50 1.07 0.36 wheat 555­ 144 0.0426 426 62 53 29 0.70 0.60 0.33 1.02 0.73 0.24 Canola (proposed maximum rate) proposed 1. 456 14560 2116 1818 1000 24 21 11 34.75 24.80 8.27 Canola ½ rate proposed 0. 72 7200 1046 899 495 12 10 6 17.18 12.27 4.09 a Dose = seed concentration x food intake rate, where food intake rate (FI) is based on Nagy equation (see text). Weights were chosen to represent typical small mammals. All calculated LD50s andLC50s were based on the LD50 (88 mg/ kg) data for the rat. RQ = EEC (mg/ kg) LD50 (mg/ kg)/ % Body Weight Consumed where the % body weight consumed varies with body size: Granivores: 21% for 15 g wt; 15% for 35 g wt; 5% for 1000 g wt. Chronic To determine chronic risk to mammals, the concentration on the food item (seeds) was determined from the the label. Chronic RQ was calculated using the following equation: RQ = Concentration on seeds / NOAEC. The NOAEC for the rat (20 mg/ kg) was used as an approximation for all mammals. Results are given in the table below and indicate a potential for chronic reproductive risk to mammalian species from the use of lindane­ treated seed. Table summary of chronic RQ evaluation. RQs in bold indicate potential risk.. Lindane Seed Conc (per label) RQ =Seed Concentration/ NOAEC crop example label # lb ai/ 100 lb seed mg ai/ kg seed rat (NOAEC= 20 mg/ kg) barley 34704­ 658 0.0375 375 19 corn 71096­ 2 0. 125 1250 63 LOW rate corn proposed 0. 0558 558 28 oats 2935­ 0492 0.0313 313 16 radish 7501­ 16 0.0323 323 16 rye 2935­ 0492 0.0328 328 16 sorghum 8660­ 53 0.0628 628 31 wheat 555­ 144 0.0426 426 21 Canola (proposed maximum rate) proposed 1. 456 14560 728 Canola ½ rate proposed 0. 72 7200 360 Aquatic Assessment EFED uses GENEEC 2 to calculate Tier I aquatic EECs and assumed that 100% of the compound will disassociate from the seed surface. A 1. 2 inch incorporation depth was used for wheat and 1 inch for canola. Input parameters and the resulting EECs for wheat and canola are tabulated below: GENEEC 2 input parameters and results for wheat and canola. Application Rate: wheat canola 1 x 0. 051 lb ai/ A 1 x 0. 116 lb ai/ A Aerobic Soil Half Life 980 days (single value) Aerobic Aquatic Half Life 1960 days (aerobic soil T1/ 2 x 2) Incorporation depth 1.2 inches for wheat and 1 inch for canola Hydrolysis stable Photolysis stable Spray Drift incorporated seed treatment = 0 Organic Carbon Partitioning Coefficient (Koc) 942 mL/ g (lowest value) Solubility 7 mg/ L Expected EEC's Wheat Canola Peak 1.09 µg/ L 2.57 µg/ L 4­ day average 1.08 µg/ L 2.56 µg/ L 21­ day average 1.06 µg/ L 2.49 µg/ L 60­ day average 1.00 µg/ L 2.36 µg/ L I. Freshwater Fish Acute and chronic risk quotients are tabulated below. Risk Quotients for Freshwater Fish Based On a brown trout LC50 of 1.7 ppb and a rainbow trout NOAEC of 2.9 ppb. Site LC50 (ppb) NOAEC (ppb) EEC Initial/ Peak (ppb) EEC 56 or 60­ Day Ave. (ppb) Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) wheat 0. 05 1. 7 2. 9 0. 94 0. 86 0.55 0.30 Canola 0.116 1.7 2. 9 2.57 2.36 1.51 0.81 An analysis of the results indicate that acute, restricted use and endangered species LOC's are exceeded for freshwater fish. No chronic LOC's are exceeded for freshwater fish. II. Freshwater Invertebrates The acute and chronic risk quotients are tabulated below. Risk Quotients for Freshwater Invertebrates Based On a stonefly EC50/ LC50 of 1.0 ppb and a daphnia NOAEC of 54 ppb. Site LC50 (ppb) 21 day NOAEC (ppb) EEC Initial/ Peak (ppb) EEC 21­ Day Average Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Wheat 0. 05 1. 0 54 0.94 0.91 0.94 0.02 Canola 0.116 1.0 54 2. 57 2. 49 2.57 0.05 An analysis of the results indicate that the acute, restricted use and endangered species LOCs are exceeded for freshwater invertebrates at maximum use rates. No chronic LOC's are exceeded for freshwater invertebrates. III. Estuarine and Marine Fish The acute and chronic risk quotients are tabulated below. Risk Quotients for estuarine/ marine fish based on a striped mullet LC50 of 23 ppb. No data was submitted to assess chronic risk to estuarine/ marine fish. Site LC50 (ppb) NOAEC (ppb) EEC Initial/ Peak (ppb) EEC 56­ Day Average Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Wheat 0. 05 23 N/ A 0.94 0.86 0.04 N/ A Canola 0.116 23 N/ A 2. 57 2. 36 0. 11 N/ A An analysis of the results indicate that acute restricted and endangered species LOCs were exceeded for canola for estuarine/ marine fish. IV. Estuarine and Marine Invertebrates Risk Quotients for Estuarine/ Marine Aquatic Invertebrates Based on a pink shrimp LC50/ EC50 of 0. 077 ppb. No data was submitted to assess chronic risk to estuarine/ marine invertebrates. Site/ Application LC50 (ppb) NOAEC/ (ppb) EEC Initial/ EEC 21­ Day Acute RQ (EEC/ LC50) Chronic RQ (EEC/ NOAEC) Wheat 0. 05 0. 077 N/ A 0. 94 0. 91 12.20 N/ A Canola 0.116 0.077 N/ A 2. 57 2. 49 33.40 N/ A An analysis of the results indicate that acute, restricted use and endangered species LOC's were exceeded for estuarine/ marine invertebrates. Chronic risk to estuarine/ marine invertebrates could not be assessed due to a lack of toxicity data. APPENDIX I: Water Resource Model Results GENEEC 2 for Canola RUN No. 1 FOR Lindane ON Canola * INPUT VALUES * ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RATE (#/ AC) No. APPS & SOIL SOLUBIL APPL TYPE NO­ SPRAY INCORP ONE( MULT) INTERVAL Koc (PPM ) (% DRIFT) (FT) (IN) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .116( .116) 1 1 942.0 7.0 GRANUL( .0) .0 1.2 FIELD AND STANDARD POND HALFLIFE VALUES (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED (FIELD) RAIN/ RUNOFF (POND) (POND­ EFF) (POND) (POND) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 980.00 2 N/ A .00­ .00 ****** 1960.00 GENERIC EECs (IN MICROGRAMS/ LITER (PPB)) Version 2.0 Aug 1, 2001 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ PEAK MAX 4 DAY MAX 21 DAY MAX 60 DAY MAX 90 DAY GEEC AVG GEEC AVG GEEC AVG GEEC AVG GEEC ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 2.57 2.56 2.49 2.36 GENEEC 2 for Wheat RUN No. 3 FOR Lindane ON Wheat * INPUT VALUES * ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RATE (#/ AC) No. APPS & SOIL SOLUBIL APPL TYPE NO­ SPRAY INCORP ONE( MULT) INTERVAL Koc (PPM ) (% DRIFT) (FT) (IN) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .051( .051) 1 1 942.0 7.0 GRANUL( .0) .0 1.2 FIELD AND STANDARD POND HALFLIFE VALUES (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED (FIELD) RAIN/ RUNOFF (POND) (POND­ EFF) (POND) (POND) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 980.00 2 N/ A .00­ .00 ****** 1960.00 GENERIC EECs (IN NANOGRAMS/ LITER (PPB) Version 2.0 Aug 1, 2001 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ PEAK MAX 4 DAY MAX 21 DAY MAX 60 DAY MAX 90 DAY GEEC AVG GEEC AVG GEEC AVG GEEC AVG GEEC ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 0.941 0.937 0.914 0.864 0.829 SCI­ GROW for Canola (Ground Water Assessment) RUN No. 1 FOR Lindane INPUT VALUES ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ APPL (#/ AC) APPL. URATE SOIL SOIL AEROBIC RATE NO. (#/ AC/ YR) KOC METABOLISM (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 0.116 1 0.116 1367.0 980.0 GROUND­ WATER SCREENING CONCENTRATIONS IN PPB ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .024907 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ A= 975.000 B= 1372.000 C= 2.989 D= 3.137 RILP= 2.578 F= ­. 668 G= .215 URATE= .116 GWSC= .024907 First Output (Surface Water Assessment) for Wheat RUN No. 1 FOR Lindane ON Wheat * INPUT VALUES * ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RATE (#/ AC) No. APPS & SOIL SOLUBIL APPL TYPE %CROPPED INCORP ONE( MULT) INTERVAL Koc (PPM ) (% DRIFT) AREA (IN) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .051( 0.051) 1 1 942.0 7.0 GRANUL( .0) 56.0 1.2 FIELD AND RESERVOIR HALFLIFE VALUES (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED (FIELD) RAIN/ RUNOFF (RESERVOIR) (RES.­ EFF) (RESER.) (RESER.) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 980.00 2 N/ A .00­ .00 ****** 1960.00 UNTREATED WATER CONC (MICROGRAMS/ LITER (PPB)) Ver 1.0 AUG 1, 2001 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ PEAK DAY (ACUTE) ANNUAL AVERAGE (CHRONIC) CONCENTRATION CONCENTRATION ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 0.98 0.46 First Output for Canola (Surface Water Assessment) RUN No. 1 FOR Lindane ON Canola * INPUT VALUES * ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ RATE (#/ AC) No. APPS & SOIL SOLUBIL APPL TYPE %CROPPED INCORP ONE( MULT) INTERVAL Koc (PPM ) (% DRIFT) AREA (IN) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ .116( 0.116) 1 1 942.0 7.0 GRANUL( .0) 87.0 1.0 FIELD AND RESERVOIR HALFLIFE VALUES (DAYS) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED (FIELD) RAIN/ RUNOFF (RESERVOIR) (RES.­ EFF) (RESER.) (RESER.) ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 980.00 2 N/ A .00­ .00 ****** 1960.00 UNTREATED WATER CONC (MICROGRAMS/ LITER (PPB)) Ver 1.0 AUG 1, 2001 ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ PEAK DAY (ACUTE) ANNUAL AVERAGE (CHRONIC) CONCENTRATION CONCENTRATION ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 4.16 1.95

epa

2024-06-07T20:31:43.165187

regulations

EPA-HQ-OPP-2002-0202-0014

Supporting & Related Material

PC Code: 009001 DP Code: D283648 MEMORANDUM DATE: June 17, 2002 SUBJECT: Qualitative Assessment of Long­ range Transport and Atmospheric Deposition of Lindane to Great Lakes TO: Betty Shackleford, Branch Chief M. Howard, Team Leader Reregistration Branch III Special Review and Reregistration Division (7508C) FROM: Faruque A. Khan, Ph. D., Environmental Scientist Environmental Fate and Effects Division (7507C) THROUGH: Mah T. Shamim, Ph. D., Chief Environmental Risk Branch V Environmental Fate and Effects Division (7507C) This memo presents the qualitative assessment of long­ range transport and atmospheric deposition of lindane to the Great Lakes. The following qualitative assessment is based on current literature available at the present time. ASSESSMENT: LINDANE IN THE GREAT LAKES The ubiquitous presence of lindane in atmosphere, natural water bodies, soils, and sediments of the Great Lakes regions implies redeposition of lindane from secondary emissions and long­ range transport of lindane from agricultural and industrial sites. There is very limited information available to link lindane loading from global, regional, or local sources to Great Lakes. Strachan (1985) estimated 290 kg/ yr of lindane and 860 kg/ yr of ­HCH loading from precipitation to Lake Superior. Since 1983, Environment Canada is measuring the deposit of toxic contaminants from the atmosphere to the Canadian side of the Great Lakes basin. Williams et al. (1998) reported that the deposition of lindane from precipitation has not changed since 1990. They also observed a seasonal pattern of increased lindane concentrations during spring and summer, which suggests that agricultural activities during that time may have been causing 2 temporal increases of lindane concentration. Reported concentrations of water samples from the channels of Great Lakes are very similar throughout the Great Lakes suggest that the atmosphere is the predominant source of lindane. Elevated concentrations in Lake Erie suggest that regional source may have been contributing as well. There are increasing national and international efforts to assess the atmospheric transport and deposition of toxic substances to the Great Lakes. The Integrated Atmospheric Deposition Network (IADN) was established in 1990 by the United States and Canada for conducting air and precipitation monitoring in the Great Lakes Basin to determine the magnitude and trends of atmospheric loadings of toxic contaminants. IADN maintains monitoring stations on each of the Great Lakes to monitor atmospheric deposition of selected pollutants. IADN incorporates wet deposition, dry deposition, and net gas exchange atmospheric deposition processes into its loading estimates. The temporal regional flows for both ­HCH and lindane ( ­HCH) are presented in Figure 1, which shows that ­HCH significantly decreased across the Great Lakes basin and has a net volatilization for the first time in 1998. In contrast, the flows for lindane remain relatively stable since their decrease in 1995 due to restricted use of lindane and the ban of ­HCH, which also contain 10 18% of ­HCH isomer (USEPA, 1998). Figure 1. Total flows of ­HCH and ­HCH over all Great Lakes (Sources: www. epa. gov/ glnpo/ iadn/ resources­ 1998) Considerable progress has been made in monitoring and assessing the loading of lindane and many other toxic contaminants for the Great Lakes regions. The importance of long­ range transport and atmospheric deposition of toxic contaminants into the Great Lakes and their effects on the chronic exposer of human, terrestrial, and aquatic organisms are only the beginning to be understood. Therefore, continuing long­ term monitoring programs and the evaluation of pertinent 3 data will help the scientists and regulatory authorities to develop preventive measures in reducing or eliminating the toxic contaminants to Great Lakes. References: Strachan, W. M. J. 1985. Organic substances in the rainfall of Lake Superior: 1983. J. Environ. Toxicol. Chem. 4: 677­ 683. U. S. EPA, 1998. Atmospheric deposion of toxic substances to the Great Lakes: IADN Results through 1998. Environment Canada and the United States Environmental Protection Agency www. epa. gov/ glnpo/ iadn/). Williams, D. J., K. W. Kuntz, S. L'ltalien, and V. Recardson. 1998. Lake Ontario surveillance program: spatial and temporal trends of selected parameters with emphasis on 1992­ 93 results. Environment Canada, Ecosystem Health Division Report 98­ 01/ I.

epa

2024-06-07T20:31:43.169161

regulations

EPA-HQ-OPP-2002-0202-0015

Supporting & Related Material

PC Code: 009001 DP Code: D283648 MEMORANDUM DATE: July 31, 2002 SUBJECT: Correction in Qualitative Assessment of Long­ range Transport and Atmospheric Deposition of Lindane to Great Lakes TO: Betty Shackleford, Branch Chief M. Howard, Team Leader Reregistration Branch III Special Review and Reregistration Division (7508C) FROM: Faruque A. Khan, Ph. D., Environmental Scientist Environmental Fate and Effects Division (7507C) THROUGH: Mah T. Shamim, Ph. D., Chief Environmental Risk Branch V Environmental Fate and Effects Division (7507C) This memo presents a correction to the memorandum titled "Qualitative Assessment of Long­ range Transport and Atmospheric Deposition of Lindane to the Great Lakes" dated June 22, 2002. In the 1 st paragraph of page 2, the last sentence "In contrast, the flows for lindane remain relatively stable since their decrease in 1995 due to restricted use of lindane and the ban of ­HCH, which also contain 10 18% of ­HCH isomer (USEPA, 1998)" should read as follows: In contrast, the flows for lindane remain relatively stable since their decrease in 1995 due to restricted use of lindane and the ban of technical­ grade HCH, consists of mainly ­HCH 5570 ­HCH (10­ 18%) and trace amounts of ­ ­ and
­HCH isomers (5­ 14%) (USEPA, 1998).

epa

2024-06-07T20:31:43.171862

regulations