Docket Number EPA-HQ-OPP-2011-0153 www.regulations.gov



## Cyclanilide Summary Document Registration Review: Initial Docket

March 20113 TABLE OF CONTENTS

I. Preliminary Work Plan (PWP) 4

II. Fact Sheet 12

This Preliminary Work Plan and Fact Sheet su mmarize the Environmental Protection Agency’s current position based on the following documents:

1. EFED Registration Review Problem Formulation for Cyclanilide . March 3, 2011.

2. Cyclanilide. Human Health A ssessment Scoping Document in Support of Registration Review

. January 18, 2011.

3. Cyclanilide: Review of Human Incidents . November 30, 2010.

4. BEAD Chemical Profile for Registration Review: Cyclanilide . December 20, 2010.

5. Cyclanilide California Department of Pesticide Regulation Usage Data . May 26, 2010.

6. Cyclanilide Screening Level Usage Analysis (SLUA) . June 22, 2010.

7. PRD Appendix A: Food/Feed & Non-Food/Non- Feed Uses Consider ed in Registration Review Work Planning

. Cyclanilide (026201). March 26, 2010.

Supporting documents for the registration review of cyclanilide are located in docket EPA-HQOPP-2011-0153 at www.regulations.gov.4 I. PRELIMINARY WORK PLAN

Introduction

The Food Quality Protection Act (F QPA) of 1996 mandated a regist ration review program. All pesticides distributed or sold in the United Stat es (U.S.) generally must be registered by the Environmental Protection Agency (EPA or the Ag ency), based on scientific data showing that they will not cause unreasonable ri sks to human health or the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonabl e adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review prog ram, the Agency periodically r eevaluates pesticides to make sure that as change occurs, products in the mark etplace can be used safely. Information on this program is provided at: http://www.epa.gov/oppsrrd1/registration_review/

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The Agency is implementing the registration revi ew program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and will review each registered pesticide every 15 years to determine whether it continues to meet th e FIFRA standard for registration. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the Agency’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it belie ves are needed to make a registration review decision. After reviewing and responding to comments and data received in the docket during this initial comment period, the Agency will de velop and commit to a final work plan and schedule for the registration review of cyclanilide.

Cyclanilide is a plant growth regul ator and defoliant. It is cu rrently registered for use as a synergist or co-active ingredient on cotton as a harvest aid and fo r use to increase branching of trees, shrubs, and cut flowers in plant production f acilities and outdoor nu rseries; it is not registered for use in greenhouses. Cyclanilid e products registered for use on cotton contain cyclanilide mixed with one other active ingredie nt, either ethephon or mepiquat chloride. Nonagricultural ornamental use sites include shade trees, herbaceous plants, non-flowering plants, and woody shrubs. Outdoor nursery use sites include nursery stoc k of apple, cherry, pear, and plum. There are no residential uses. Cyclanilid e was first registered in the United States in 1997; therefore, it was not subject to th e reregistration requi rements of FIFRA.

Anticipated Risk Assessment and Data Needs

The Agency anticipates conducting a comprehe nsive human health and ecological risk assessment, including an endangered species risk assessment, for all uses of cyclanilide. The Agency anticipates needing data to conduct thes e assessments. The Agency also intends to require additional toxicol ogical data and to update and revise the human health risk assessment5 for cyclanilide. Below is a summary of the i ssues relevant to the registration review of cyclanilide and the anticipated data requirements.

Ecological Risk:

• The most recent ecological risk assessments for cyclanilide were conducted in 1996 in support of the first registration of this ch emical and in 2006 in support of the proposed new use of cyclanilide on ornamentals, cu t flower crops, and non- bearing fruit trees.

• The Agency anticipates conducting an updated environmental fate and ecological risk assessment for cyclanilide, including an endangered species assessment, during registration review.

• The Agency has not conducted a risk asse ssment that supports a complete endangered species determination for cyclanilide. Th e ecological risk asse ssment planned during registration review will allow the Agency to determine whether cyclanilide’s use has “no effect” or “may affect” federally listed threat ened or endangered sp ecies (listed species) or their designated critical ha bitats. When an assessment c oncludes that a pesticide’s use “may affect” a listed species or its designate d critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service (USFWS) and/or Nationa l Marine Fisheries Service (NMFS) (the Serv ices), as appropriate.

• On January 19, 2011, the Center for Biologi cal Diversity and the Pesticide Action

Network North America filed a lawsuit in th e United States District Court for the Northern District of California, against th e Environmental Protection Agency (EPA) for allegedly failing to undergo consultation w ith the USFWS and the NMFS regarding the effects of over 350 pesticides, includi ng cyclanilide, on over 200 endangered and threatened species throughout the United States (Center for Biologica l Diversity, et al. v. EPA, et al., No. C 11-00293 (N.D.Cal.).

• The Agency anticipates needing the followi ng data in order to conduct a complete ecological risk assessment, including an e ndangered species assessment, for cyclanilide:

Environmental Fate

o Guideline No. 835.4100 – Aerobic Soil Metabolism

o Guideline No. 835.6100 (footnote 7) – Terre strial Field Dissipation (the environmental chemistry method and associ ated independent la boratory validation (ILV) of the submitted analytical me thod are expected to be required)

o Guideline No. 835.6200 (footnote 7) – Aquatic Field Dissipation (the environmental chemistry method and an associated indepe ndent laboratory validation (ILV) of the submitted analytical method are expected to be required)6 Ecological Toxicity

o Guideline No. 850.1350 – Aquatic Invertebrate Life-cycle (saltwater)

o Guideline No. 850.1400 – Fish Early Life Stage (saltwater)

o Guideline No. 850.2100 – Avian Acute Oral Toxicity (passerine species)

o Guideline No. 850.4150 - Nontarget Area Phyt otoxicity Tier II, Vegetative Vigor 1

• Please refer to EFED Registration Review Problem Formulation for Cyclanilide , dated March 3, 2011, located in docket EPA-HQ-OPP-2011-0153 at www.regulations.gov, for a more detailed discussion of the anticipate d ecological risk asse ssment and data needs.

Human Health Risk:

• The most recent human health risk assessm ent was conducted in 2007 in support of the use of cyclanilide on ornamentals, cut flowers, and non-bearing fruit trees.

• During registration review, the endpoints, and safety factors used in the most recent human health risk assessment will be revisited based on current Agency policy, as well as any new data received.

• The cyclanilide tolerance expression will be reviewed during registration review to ensure that it appropriately covers the meta bolites and degradates of cyclanilide and that it specifies the residues to be measured for each commodity.

• The current 40 CFR §180.506 listing for sheep, meat is incorrectly given as 0.20 ppm.

This tolerance should be the same as that fo r the meat of cattle, goat, hog, and horse, at 0.02 ppm. The Agency anticipates correcting this list ed tolerance in ad vance of the draft

risk assessment.

• The Agency anticipates conducting updated dietary, aggregate, and occupational exposure risk assessments to include any ch anges in toxicological endpoints, doses, and procedures for dermal and i nhalation risk assessment.

1 A Tier II study is expected to be required. The DCI expected to be issued will provide that a Tier I plant study may be conducted in lieu of a Tier II study with the understanding that any adverse effects observed by the Tier I study would necessitate conduct and submission of a Tier II study as well. The purpose of a Tier II study is to

establish both a definitive No Observed Adverse Effect Con centration (NOAEC), or alternatively, a concentration at which there is a 5% observed inhibition effect (IC 05 ) to be used in a risk assessment and effects determination for endangered or threatened species (listed species), and a definitive IC 25 (concentration at wh ich there is a 25% observed inhibition effect) for assessing risk to non-listed nontarget plants. If any adverse effects are observed in a Tier I study and neither a definitive NOAEC nor a definitive IC 05 value is available, then the Agency may have to presume in its effects determination, that cyclanilide "may affect" and is “likely to adversely affect” listed plant species.7 • During registration review, the endpoints, doses, and safety factors used in the most recent human health risk assessment will be revisited based on current policy as well as to incorporate any new data received and determined to be adequate.

• During registration review, the Agency an ticipates conducting an updated dietary exposure risk assessment to reflect current methodologies.

• Based on current registered use patterns of cyclanilide and the current toxicological points of departure, the Agency does not an ticipate conducting an updated drinking water exposure risk assessment at this time. If, in the future, any new uses are requested or if there is any reason for re-evalu ation of the points of depart ure, a revised dietary (food + water) risk assessment may be needed.

• Currently, there are no registered uses for cy clanilide that would result in residential exposure. As such, risks from residential expos ures have not been considered in previous assessments nor would they be considered at this time. However, residential bystander inhalation exposures resulting from off-site tr ansport (e.g., spray drif t or volatilization) may occur as a result of applications of cycl anilide. The Agency is in the process of examining its policies and refining the methods used to complete residential exposure assessments. Therefore, the potential need fo r a bystander inhalation risk assessment for cyclanilide will be examined during registration review.

• During registration review, the Agency anti cipates conducting upda ted occupational and postapplication assessments based on update d doses, endpoints, and procedures for dermal and inhalation risk assessment. The Agency anticipates including additional and

more detailed review of the handler and postapplication e xposure scenarios.

• The toxicity database for cyclanilide is complete except for the following studies, which the Agency anticipates requiring in order to conduct an updated human health risk

assessment:

o Guideline No. 870.3465 – 28-Day Inhalation Toxicity

o Guideline No. 870.7800 – Immunotoxicity

• Please refer to Cyclanilide. Human Health Assessm ent Scoping Document in Support of Registration Review , dated January 18, 2011, available in docket EPA-HQ-OPP-2011-0153 at www.regulations.gov, for a detailed discussion of th e anticipated human he alth risk assessment

and data needs.8 Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of its most recent cyclanilide registration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as re quired by FFDCA section 408(p), cyclanilide is subject to the endocrine screeni ng part of the Endocrine Disrup tor Screening Program (EDSP).

EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required

determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pest icide active ingredients and 9 iner t ingredients. Cyclanilide is not among the group of 58 pesticide active ingredient s on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issu e future EDSP orders/data callins, requiring the submission of EDSP screening assays for cyclan ilide. For further information on the status of the EDSP, the policies and procedur es, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screen ing battery, please visit our website: http://www.epa.gov/endo/

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Timeline

The projected timeline for the completion of the cy clanilide registration re view is presented in

Table 1.9 Table 1. Projected Cyclanilide Registration Review Timeline Activity Estimated Date Opening the Docket Open Docket and Open Public Comment Period 2011 – March

Close Public Comment Period 2011 – May Case Development Develop Final Work Plan (FWP) 2011 – August Issue Data Call-In (DCI) 2012 – April - June

Data Submission 2014 – April - June Develop Preliminary Risk Assessments and Open Public Comment 2015 – Oct. - Dec.

Close Public Comment Period 2016 – Jan. - March Registration Review Decision Develop Proposed Registration Revi ew Decision and Open Public

Comment Period 2016 – April - June

Close Public Comment Pe riod 2016 – July - Sept. Issue Registration Review Decision a nd Begin Post-Decision Follow-up 2017 Total (years) 6

Guidance for Commenters

The public is invited to comment on EPA’s preliminary work plan and rationales. The Agency will carefully consider all commen ts, as well as any additional information or data provided in a timely manner, prior to issuing a fina l work plan for the cyclanilide case.

Trade Irritants

Through the registration review process, the Ag ency intends to solicit information on trade irritants and, to the extent feas ible, take steps toward facilitating irritant resolution. Growers and other stakeholders are asked to comment on any tr ade irritant issues resulting from lack of Maximum Residue Limits (MRLs) or disparitie s between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the na ture of the concern.

Environmental Justice

EPA seeks to achieve environmenta l justice, the fair tr eatment and meaningful involvement of all people, regardless of race, color, national origi n, or income, in the deve lopment, implementation, and enforcement of environmental laws, regulati ons, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who, as a result of thei r location, cultural practices, or other factors, may have atypical, unusually high exposure to cyclanilid e compared to the general population. Please comment if you are aware of any sub-populatio ns that may have atypical, unusually high exposure, compared to the general population.10 Water Quality

Cyclanilide is not identified as a cause of impairment for an y water bodies listed as impaired under section 303(d) of the Clean Water Act 2 . In addition, no Tota l Maximum Daily Loads (TMDL) have been developed for cyclanilide 3 . More information on impaired water bodies and TMDLs can be found at the Agency’s website 4 . The Agency invites submission of water quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: In clusion of Impaired Water Body and

Other Water Quality Data in OPP’s Registratio n Review Risk Assessment and Management

Process 5 in order to ensure they can be used quant itatively or qualitativel y in pesticide risk

assessments.

Other Information

Stakeholders are also specifically asked to prov ide information and data that will assist the Agency in refining risk assessments, includ ing any species-specific ecological effects determinations, for cyclanilide. The Agency is interested in receiving the following information:

1. Confirmation on the following label information.

a. sites of application

b. formulations

c. application methods and equipment

d. maximum application rates

e. frequency of application, applicati on intervals, and maximum number of applications per season and per year

f. geographic limitations on use

2. Use or potential use distribution ( e.g . geographical distributio n of relevant uses).

3. Use history.

4. Median and 90 th percentile reported use rates (lbs ai/A, lbs ai/1000 sq. ft.) from usage data – national, state and county.

5. Application timing (date of firs t application and application intervals) by use – national, state, and county.

6. Usage/use information for non-agricultural us es on ornamental use sites including shade trees, herbaceous plants, non-flowering plan ts, and woody shrubs, and on outdoor nursery use sites including nursery stock of apple, cherry, pear, and plum; and information on

effective alternatives.

7. Directly acquired county-level usage data (not derived from state level data).

a. maximum reported use rate from usage data – county

b. median and 90 th percentile number of applications – county

c. total pounds per year – county

2 http://iaspub.epa.gov/tmdl_waters10/attains _nation_cy.cause_detail_30 3d?p_cause_group_id=885

3 http://iaspub.epa.gov/tmdl_waters10/attain s_nation.tmdl_pollutant_detail ?p_pollutant_group_id=885&p_ pollutant_group_name=PESTIC IDES

4 http://www.epa.gov/owow/tmdl/

5 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm11 d. the year the pesticide was last us ed in the county/sub-county area

e. the years in which the pesticide was applied in the county/sub-county area

8. Typical application interval (days).

9. State or local use restrictions.

10. Ecological incidents (non-target plant dama ge and avian, fish, reptilian, amphibian, mammalian mortalities, and bee or beneficial insect mortalit ies) not already reported to the Agency.

11. Comparative efficacy information of cyclanilide to similar products registered for similar

uses in cotton.

12. Information on growers’ selecti on criteria for growth regulator at each crop stage where cyclanilide may be used.

13. For agricultural uses, worker activities that o ccur in treated fields at the typical time of cyclanilide applications.

14. Comparative costs of cyclanilide versus other growth regulators and defoliants in

identified use sites.

Next Steps

After the 60-day comment period closes, the Ag ency will review and respond to any comments received in a timely manner. The Agency expects to issue a Final Work Plan for cyclanilide in August 2011.12 II. FACT SHEET

Background Information

• Cyclanilide Registration Review Case Number: 7018.

• Cyclanilide Pesticide Ch emical (PC) Code: 026201.

• Cyclanilide Chemical Abstracts Service (CAS) Number: 113136-77-9.

• Cyclanilide was first registered in the U.S. in 1997.

• Currently, the technical registrant for cyclanilide is Bayer Crop Sciences LP.

• Cyclanilide was not subject to reregistration; therefore, there is no Reregistration Eligibility Decision (RED) for cyclanilide.

• U.S. tolerances for cyclanilide currently range from 0.02 ppm to 25.0 ppm [40 CFR 180.506]. There are established tolerances fo r residues of cyclanilide in cottonseed, cotton gin byproducts, milk, and the fat, meat, kidney, and meat byproducts (except kidney), of cattle, goats, horses, hogs, and sheep.

• Currently, there are seven Secti on 3 registrations for cyclanil ide, including one technical and six end-use products.

• Pesticide Re-evaluation Division (P RD) Contact: Katherine St. Clair ( stclair.katherine@epa.gov ).

• Registration Division (RD) Contacts: Shaja Joyner ( joyner.shaja@epa.gov ); CynthiaGiles Parker ( parker.cynthia@epa.gov ).

Use and Usage Information

For additional details, please refer to BEAD Chemical Profile for Registration Review: Cyclanilide , dated December 20, 2010; Cyclanilide California Department of Pesticide Regulation Usage Data , dated May 26, 2010; Cyclanilide Screening Level Usage Analysis (SLUA) , dated June 22, 2010; and PRD Appendix A: Food/Feed & Non-Food/Non-Feed Uses Considered in Registrati on Review Work Planning

. Cyclanilide (026201) , dated March 26, 2010; located in docket EPA-HQ-O PP-2011-0153 at www.regulations.gov.

• Cyclanilide is a plant growth regulator and defoliant. Cycl anilide’s mode of action is inhibition of auxin activity, especia lly in meristematic plant tissue.13 • Cyclanilide is currently registered for use as a synergist or co-ac tive ingredient on cotton

as a harvest aid and for use to increase branch ing of trees, shrubs, a nd cut flowers in plant production facilities and outdoor nurseries; it is not registered for use in greenhouses.

• Cyclanilide products registered for use on cotton contain cyclanilide mixed with one other active ingredient, either et hephon or mepiquat chloride.

• Non-agricultural ornamental use sites for cyclanilide include shade trees, herbaceous plants, non-flowering plants, and woody sh rubs. Outdoor nursery use sites for cyclanilide include nursery stock of apple, cherry, pear, and plum.

• There are no registered uses of cyclanilide that would result in residential exposure; a residential exposure assessment was not conducted.

• Cyclanilide formulation types includ e liquid and emulsifiable liquid.

• Cyclanilide application methods include groundboom and aerial equipment, and backpack and low-pressure handwand sprayers.

• Cyclanilide usage is mainly on cotton and it fl uctuates from year to year. According to June 2010 screening level estimates of the agri cultural uses of cyclanilide in the U.S., approximately 150,000 pounds of active ingredient are used annually. The largest and only agricultural use is on cotton, with an aver age of 10 percent of the crop treated and a maximum of 20 percent of the crop treated. Ac cording to private market research data from 1998-2008, the average agricultural us age of cyclanilide in the U.S. is approximately 156,000 pounds of active ingredient on approximately 1.5 million acres

per year.

Recent and Pending Actions

• There are no recent or pending actions for cyclanilide.

Ecological Risk Assessment Status

The following are key findings from the most rece nt ecological risk assessments regarding the environmental fate, ecological effects and risks of cyclanilide. Please refer to EFED Registration Review Problem Formulation for Cyclanilide , dated March 3, 2010 located in docket EPA-HQ-OPP-2011-0153 at www.regula tions.gov, for a detailed discussion.

• The most recent ecological risk assessments for cyclanilide were conducted in 1996 in support of the first registration of this ch emical and in 2006 in support of the proposed new use of cyclanilide on ornamentals, cu t flower crops, and non- bearing fruit trees.14 Ecological Effects:

• Previous ecological risk assessments concl uded that the use of cyclanilide exceeded acute Levels of Concern (LOCs) for listed bi rds that feed on insects and for small-tointermediate-sized mammals that feed on short grass.

• Previous ecological risk assessments concl uded that the use of cyclanilide exceeded

chronic LOCs for listed and non-listed mammals.

• Previous ecological risk assessments concl uded that the use of cyclanilide exceeded LOCs for listed and non-listed species of terrestrial plants (dicots). Pote ntial risk to listed and non-listed terrestrial plants was not quantitatively assess ed in the most recent 2006 risk assessment because the previously-submitted vegetative vigor study was classified as

invalid.

Human Health Risk Assessment Status

The following are key findings from the human h ealth risk assessments conducted for cyclanilide registered uses. Please refer to Cyclanilide. Human Health Assessment Scoping Document in Support of Registration Review , dated January 18, 2011, located in docket EPA-HQ-OPP-2011- 0153 at www.regulations.gov, for a detailed discussi on of the human health risk assessment

status.

• The most recent human health risk assessm ent was conducted in 2007, in support of the use of cyclanilide on ornamentals, cut flowers, and non-bearing fruit trees.

Hazard Characterization – Cyclanilide:

• The acute toxicity of technical grade cyclan ilide is severe by the oral route (toxicity category II), but has moderate to mild dermal and inhalation acute toxicity (categories III and IV, respectively). It is a severe eye irritant (toxicity category II), but not a skin irritant (toxicity category IV). It is not a skin sensitizer.

• Cyclanilide has been classified as “not likely to be carcinogenic in humans.” There is no mutagenicity concern for cyclanilid e based on the available data.

• A 3X uncertainty factor was retained for the chronic dietary risk assessment to account for the extrapolation of the lowest observed adverse effect level (LOAEL) to the no

observed adverse effect level (NOAEL) in the rat reproductiv e study selected for chronic dietary risk assessment.

Summary of Risks – Cyclanilide:15 Dietary (Food and Drinking Water)

• Acute and chronic dietary risk estimates for cyclanilide were below the Agency’s level of concern for the general U.S. population a nd all sub-populations. Cyclanilide was classified as “not likely to be carcinogenic to humans.” Th erefore, a cancer dietary risk assessment was not conducted for cyclanilide.

• In the acute dietary risk assessment, the Ag ency found that cyclanilide exposure for the general U.S. population resulted in an estimated risk equivalent to less than 1% of the acute population adjusted dose (aPAD). Infa nts less than one year old was the most highly exposed population subgroup, wh ich used 1% of the aPAD.

• In the chronic dietary risk assessment, the Agency found that cyclanilide exposure for the general U.S. population resulted in an estimat ed risk equivalent to 6.3% of the chronic population adjusted dose (cPAD). Children one to two years old was the most highly exposed subpopulation, which used 25% of the cPAD.

Residential

• Cyclanilide is not registered for use in reside ntial settings and there is currently no risk concern for residential exposure.

Aggregate

• Since a residential risk assessment was not conducted for cyclanilide, acute and chronic aggregate risks were equivalent to acute a nd chronic dietary risk s and were below the Agency’s level of concern.

Occupational

• Occupational handler and postappl ication dermal and inhalation exposures were assessed qualitatively in 1997 for use of cyclanilide as a harvest aid on cotton. In 2007, a quantitative handler (dermal and inhalation) and postapplication (dermal) exposure assessment was performed for use of cyclanilide as a plant growth regulator for ornamentals, non-bearing fru it trees, and cut flowers.

• In those assessments, occupational handler scenarios resulted in dermal and inhalation exposure risk estimates below the Agency’s level of concern based on use of the personal protective equipment (PPE) require d by the product label. Occupational postapplication scenarios also resulted in exposure risk estimates below the Agency’s

level of concern.

Cumulative16 • The Agency has not determined whether cyclanilide shares a common mechanism of toxicity with other chemical substances. If, in the future, EPA obtains new data suggesting that cyclanilide sh ares a common mechanism of to xicity with other chemical substances, the Agency will revisit the need for a cumulative risk assessment.

Human Studies

• Past cyclanilide risk assessments rely in pa rt on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, invo lving exposure to many different pesticides, comprise generic pesticide exposure database s such as the Pestic ide Handlers Exposure Database (PHED) and the Agricultural Reen try Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relativ e to the ethical standards prevailing at the time the research was conducte d. All applicable re quirements of EPA’s

Rule for the Protection of Hu man Subjects (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to c ontinued reliance on these studies.

Incidents

Ecological Incidents:

• In September 2010, the Agency reviewed the Ecological Incident Information System (EIIS), which is maintained by the EPA Office of Pesticide Programs, and the Avian Monitoring System (AIMS), which is maintain ed by the American Bird Conservancy, for ecological incident reports associated with the use of cyclanilide in the U.S. There were no reported ecological incidents as sociated with the use of cycl anilide. A review of the EFED Aggregate Incident Repor t database also yielded no ec ological incident reports for cyclanilide.

• Although no incidents have been reported to the Agency, the absence of reported

incidents should not be construed as the absence of incidents.

Human Health Incidents:

• In November 2010, the Agency reviewed the O PP Incident Data System (IDS) for human health pesticide incident data associated with the use of cyclanilide in the U.S. to identify potential patterns on the freque ncy of health effects attribut ed to cyclanilide exposure. The IDS aggregate summaries from January 1, 2002 to May 27, 2010 include four cases reported for cyclanilide. This aggregate report does not provide details about the incidents, and single chemical incidents are not distinguished from multiple chemical17 incidents. A review of the main IDS fr om January 1, 2002 to October 7, 2010 found no cases reported in the database for th e single chemical cyclanilide only.

• Based on the low frequency of incident cases reported in the OPP IDS, there does not appear to be a concern at this time that w ould warrant further invest igation of cyclanilide human health incidents in the preliminary ri sk assessment phase of registration review. However, the Agency anticipates continuing to monitor the incident information and including additional analysis in the registration review risk assessment if a concern is triggered.

Tolerances and International Harmonization

• A table listing the differences between U. S. tolerances and Canadian, Mexican, and CODEX Maximum Residue Limits (MRL) for cyclanilide is included in the Cyclanilide. Human Health Assessment Scoping Docu ment in Support of Registration Review , dated January 18, 2011, available in docket EPA- HQ-OPP-2011-0153 at www.regulations.gov. Currently, there are no harmonization issues with Canada, CODEX, or Mexico. During registration review, if any C odex MRLs have been establis hed, the Agency anticipates harmonizing the U.S. tolerances with the Codex MRLs when the data warrant

harmonization.

• U.S. tolerances for cyclanilide are established for residues of cyclanilide in or on the crop

and livestock commodities listed in 40 CF R §180.506. Tolerances are established in terms of the parent compound [1-(2,4-di chlorophenylaminocarbonyl)-cyclopropane carboxylic acid] only. Currently, residues ar e determined as 2,4-dicloroaniline and calculated as cyclanilide.

• During registration review, the Agency antici pates revising the tole rance expression so that it addresses both coverage and measurement.

Existing Data Call-Ins

• There are currently no outstanding da ta requirements for cyclanilide.

Labels

• Active Section 3 labels for cyclanilide can be obtained from the Pesticide Product Label System (PPLS) website: http://oaspub.epa.gov/pestlabl/ppls.home

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