Docket Number: EPA-HQ-OPP-2007-1038 www.regulations.gov



## Isoxaben Summary Document Registration Review Docket
December 2007ii Isoxaben Summary Document 

## REGISTRATION REVIEW Preliminary Work Plan for
Isoxaben

CASE 7219

December 2007

Approved by: ____________________

__________ Steven Bradbury, PhD. Director Special Review and Reregistration Division

Date: ____________

__________________Table of Contents iii Isoxaben Summary Document 

### TABLE OF CONTENTS

Page #

I. Preliminary Work Plan (PWP) 1

II. Fact Sheet 6

III. Ecological Risk Assessment Problem Formulation 12

IV. Human Health Effects Scoping Document 38

V. Glossary of Terms and Abbreviations 45Preliminary Work Plan 1 Isoxaben Summary Document I. Preliminary Work Plan

Introduction:

The Food Quality Protection Act of 1996 mand ated a new program: registration review. All pesticides distributed or sold in the United St ates generally must be registered by EPA, based on scientific data showing that they will not cau se unreasonable risks to human health, workers, or the environment when used as directed on product labeling. The new registration review program is intended to make sure that, as the ab ility to assess risk evolves and as policies and practices change, all registered pesticides co ntinue to meet the st atutory standard of no unreasonable adverse effects. Changes in science, public policy, and pesticide use practices will occur over time. Through the new registrati on review program, the Agency periodically reevaluates pesticides to make sure that as ch ange occurs, products in the marketplace can be used safely. Information on this progra m is provided at the following website: http://www.epa.gov/oppsrr d1/registration_review/

.

The Agency has begun to implement the new registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungici de, and Rodenticide Act (FIFRA), and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration. The public phase of registration review begins when the initial docket is opened for each case. This docket is the Ag ency’s opportunity to state what it knows about the pesticide and what additional risk analyses an d data or information it believes are needed to make a registration review decision. After reviewing and responding to comments and data received in the docket during this initial comm ent period, the Agency will develop and commit to a final work plan and schedule for the registration review of isoxaben.

Isoxaben is a broad-spectrum benzamizole herbicide with pre-emergent activity for broadleaf weeds, grasses, and vines. EPA firs t registered isoxaben use in 1989. It works by disrupting an enzyme (found only in plants) necessa ry for protein synthesis. Isoxaben is used around non-bearing food crops, ornamental trees, and sh rubs. It is used in agriculture, nurseries, rights-of way, and urban settings.

Anticipated Risk Assessment and Data Needs:

The Agency anticipates conducting a comprehe nsive human health and ecological risk assessments for isoxaben. These risk assessments will include an endangered species assessment, and a complete dietary assessment to cover proposed new food uses. In addition, at this time, environmental fate and plant toxicity studies are required to complete the ecological risk assessment. Additional environmental fa te and effects studies may be needed, pending EPA’s review of submitted studies.

Ecological Risk and Data Needs:

• Although most environmental fate and ecological effects studies have been submitted, their review by EPA is not yet completed. If any of these studies are determined to be not scientifically valid, then replacement studies wi ll be included in a data call-in (DCI). NoPreliminary Work Plan 2 Isoxaben Summary Document matter the outcome of the preceding studies, EP A will issue a DCI for soil photolysis and terrestrial plant toxicity data that has not been submitted for this herbicide.

• Isoxaben has chemical characteristics similar to pesticides that have been shown to leach through soil to groundwater. The drinking water assessment for the registration of proposed new food uses of isoxaben under Pesticides Registration Improvement Act (PRIA) will include an estimate of potential groundwater con centrations. If the ri sk assessment indicates that concentrations of isoxaben in drinking water might pose a risk to human health, a prospective groundwater monitoring study may be required as a condition of registration for these new uses.

• No ecological risk assessment is available to draw from; however, in the Registration Review

– Problem Formulation for the Ecological Risk Assessment of Isoxaben , estimates of risk, based on provisional data, are provided to help guide the reader in understanding the potential for environmental risks of concern. A full ecological risk assessment, and an estimate of potential drinking water exposure, will be completed for registration review.

• The planned ecological risk assessment will allo w the Agency to determine whether isoxaben use has "no effect" or "may aff ect" federally listed threatened or endangered species (listed species) or their designated critical habitat. If the assessment indicates that isoxaben “may affect" a listed species or its designated critic al habitat, the assessment will be refined. The refined assessment will allow the Agency to determine whether use of isoxaben is “likely to adversely affect” the species or critical habitat or "not likely to advers ely affect" the species or critical habitat. When an assessment conclu des that a pesticide's use "may affect" a listed species or its designated critical habitat, th e Agency will consult with the U.S. Fish and Wildlife Service and National Marine Fisherie s Service (Services), as appropriate.

Human Health Risk and Data Needs:

• At this time, there are no esta blished tolerances on food or an imal commodities. Therefore, EPA does not consider isoxaben to have a food us e, and a dietary assessment is not required. However, with the proposed food uses in th e upcoming PRIA action, dietary assessments (acute, chronic, and cancer) will be required an d isoxaben will be subject to the Food Quality Protection Act (FQPA).

• The toxicological and exposur e database for isoxaben are adequate for the purpose of registration review and most likely for the propo sed food uses in the up coming PRIA action. EPA will need to select additional endpoints for dietary, incidental oral, dermal, and inhalation exposures for the new uses. These en dpoints will be used in registration review as well. Additionally, EPA will need to revisit th e cancer potency estimate based on the lack of a dose-response relationship.

• Drinking water risks have not been assessed fo r isoxaben. The current turf use requires screening-level groundwater and surface water exposure assessments. The proposed food uses in the upcoming PRIA action will also require screening-level groundwater and surface water exposure assessments.Preliminary Work Plan 3 Isoxaben Summary Document • Occupational and residential ha ndler and post-application asse ssments, with the exception of cancer risks for children on trea ted turf, have not been conduc ted for isoxaben and will be required during the registration re view process. Moreover, the children turf scenario cancer assessment will be updated depending on the outc ome of the cancer re-evaluation to reflect current Agency policies.

Timeline:

EPA has created the following estimated timeline for the completion of the isoxaben registration review.

Activities Estimated Year / Month
Phase 1: Opening the docket Open Isoxaben Public Docket 2007 – Dec
Close Public Comment Period 2008 - Mar Phase 2: Case Development Develop Final Work Plan (FWP) 2008 - May

Issue DCI 2009 - Jan - Mar
Data Submission 2011 - Jan - Mar Preliminary Risk Assessments 2012 – July - Sept Open Public Comment Period for Preliminary Risk Assessments 2012 – Oct – Dec Phase 3: Registration Review Decision Proposed Registration Review Decision 2013 – Jan - Mar Public Comment Period 2013 – Apr - Jun Final Reg Review Decision & Begin Post-Decision Follow-up 2013 Total (years) 6 years

Guidance for Commenters:

The public is invited to comment on EPA’s pr eliminary registration review work plan and rationale. The Agency will carefully consider all comments as well as any additional information or data provided prior to issuing a final work plan for the isoxaben case.

• Through the registration review process, the Ag ency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. Growers and other stakeholders are asked to comment on a ny trade irritant issues resulting from lack of Maximum Residue Limits (MRLs) or disparities between proposed U.S. tolerances and MRLs in key export markets, providing as much specificity as possibl e regarding the nature of the concern.

• Isoxaben is not identified as a cause of impairment for any wa ter bodies listed as impaired under section 303(d) of the Clean Water Act, based on information provided atPreliminary Work Plan 4 Isoxaben Summary Document http://oaspub.epa.gov/tmdl/water s_list.impairments?p_impid=3 . 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: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process” (see: http://www.epa.gov/oppfead1/cb/ppdc/2006/november06/session1-sop.pdf ), in order to ensure they can be used quant itatively or qualitatively in pesticide risk assessments.

• EPA seeks to achieve environmental justice, th e fair treatment and meaningful involvement of all people, regardless of race, color, nati onal origin, or income, in the development, implementation, and enforcement of environmenta l laws, regulations, 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 their location, cultu ral practices, or other factors, may have atypical, unusually high exposure to isoxaben, compared to the general population. Please comment if you are aware of any sub-populations that may have atypical or unusually high exposure compared to the general population.

Stakeholders are also specifically asked to pr ovide information and data that will assist the Agency in refining the human health a nd ecological risk asse ssments, including any species-specific effects determinations. The Agency is interested in 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, application intervals, a nd maximum number of applications per season f. geographic limitations on use
2. use or potential use distribution (e .g., acreage and geographical dist ribution of relevant crops)
3. use history

4. median and 90 th percentile reported use rates (lbs ai/acr e) from usage data – national, state, and county
5. application timing (date of first application and application intervals) by use site – national, state, and county
6. usage/use information for non-agricultural uses (e.g., forestry, residential)
7. directly acquired county-level usage data (not derived from state level data) a. maximum reported use rate (lbs ai/acre) from usage data – county
b. median and 90 th percentile number of applications – county c. total pounds per year – county d. the year the pesticide was last used in the county/sub-county area e. the years in which the pesticide wa s applied in the county/sub-county area
9. typical interval (days)
10. state or local use restrictionsPreliminary Work Plan 5 Isoxaben Summary Document 11. ecological incidents (non-target plant damage and avian, fish, reptilian, amphibian and mammalian mortalities) not alr eady reported to the Agency
12. monitoring data

Next Steps:

After the 90-day comment period closes in March of 2008, the Agency will review any comments received, and then issue a Final Work Plan for this pesticide.Fact Sheet 6 Isoxaben Summary Document II. FACT SHEET

Background Information:

• Isoxaben Registration Review case number: 7219

• Isoxaben PC Code: 125851 / CAS#: 82558-50-7

• Technical registrant: Dow Agrosciences

• First approved for use in a registered product in 1989.

• There are 15 FIFRA Section 3 act ive registrations for isoxaben.

• Not subject to reregistration because it wa s first registered af ter 1984; therefore, no Reregistration Eligibility Decision (RED) was prepared.

• Chemical Review Managers: Mark Howard ( howard.markt@epa.gov ) Jacqueline Guerry ( guerry.jacqueline@epa.gov )

• Product Managers: Joanne Miller ( miller.joanne@epa.gov ) Team Leader Eugene Wilson ( wilson.eugene@epa.gov )

Use and Related Information:

• Isoxaben is a preemergent herbicide mainly us ed to control broadleaf weed species by inhibiting cell wall growth in weed seedlings.

• Uses include: Christmas trees, conifer trees, or namentals (container grown, field grown, and landscape), ornamental bulbs, non-bearing fruit and nut trees , non-bearing vineyards, and non-commercially grown turf.

• Up to 150,000 lbs active ingredient (ai) /year is used (EPA estimates).

• Isoxaben is formulated as a granular, a water dispersible granule (also referred to as a dry flowable), and an impregnated material.

• Use information, such as application rates and number of applications, can be found in Appendix A in the docket.

Recent Regulatory Actions:

Dow AgroSciences has proposed to establis h tolerances in or on the following food commodities: grapes, grape juice; nut trees, pistachio and almond hulls, and has requested a waiver for the requirement of tolerances in or on the raw agricultural commodities: cattle, meat byproducts; meat and milk. (See 72 FR 42073 and Regulations.gov Docket no. EPA-HQ-OPP2007-0504.)

Two environmental fate studies (aerobic and anaerobic aqueous metabolism studies) were submitted in 2006, under section 6(a)(2) of FIFR A (adverse effects reporting requirement) for concerns about the poten tial for isoxaben residues in rotational crops. EPA has reviewed those studies and concluded, "given the limited pers istence of isoxaben in aerobic and anaerobic aquatic systems, exposure to subseque nt rotational crops is unlikely."Fact Sheet 7 Isoxaben Summary Document Environmental Risk Assessment Status :

To meet current standards, a complete ecological risk assessment (including a risk assessment for threatened and endangered plants and animals) is needed. However, EPA has conducted a preliminary review of the available environmental fa te and ecotoxicity data to determine the scope of work necessary to support the registration review process for isoxaben. Subject to the Agency’s decision on the propos ed addition of isoxaben use on food crops, an FQPA aggregate assessment is required, neces sitating the preparation of estimated drinking water concentrations. Please refer to Section III of this document, Registration Review – Preliminary Problem Formula tion for the Ecological Ri sk Assessment of Isoxaben , for a detailed discussion of the anticipated environmental risk assessment needs. A summary follows:

Environmental Fate

• Based on a preliminary assessment of the fate data, isoxaben is expected to be moderately persistent and may be mobile. There is some indication that the mobility of isoxaben decreases with increasing soil clay content and soil cation exchange capacity. It may represent a ground water concern when applied to certain soils and/or where high water tables are present (i.e., less than one foot belo w grade) and high rainfall/irrigation occurs.

• Isoxaben does not appear to readily undergo ae robic and anaerobic degradation in soil. Primary routes of degradati on appear to be aqueous photol ysis, aerobic aqueous metabolism and anaerobic aqueous metabolism.

• A fish bioconcentration study submitted to th e Agency indicated that there was some concentration of isoxaben in fish tissues during the exposure period, but that isoxaben rapidly depurated when exposure ceased. EPA consid ered this information along with the low octanol-water partition coefficient (K ow ) of isoxaben to conclude that bioaccumulation of isoxaben is not likely in aquatic ecosystems. A different mode of exposure was considered in nine single dose rat metabolism studies. Ra diolabeled isoxaben was also accounted for as metabolites in the urine in most of these studie s. However, only 85% of the radioactivity was accounted for in male rats in one metabolism study, compared to 92.6% in female rats. The Agency’s review of this study in terpreted this as a sign of "p ossible bioaccumulation" which should be reevaluated at a future date. The pot ential for accumulation in meat and milk will be assessed as part of the risk assessments for the food us es proposed for registration under
PRIA.

• Two recent environmental fate studies were s ubmitted to EPA in 2006, under section 6(a)(2) of FIFRA (adverse effects repo rting requirement) for potentia l concerns about rotational crops. EPA has concluded, "given the limite d persistence of isoxaben in aerobic and anaerobic aquatic systems, exposure to subs equent rotational crops is unlikely."

• Several studies (leaching/adsorption/desorption, hydrolysis, aqueous phot olysis, and aerobic soil metabolism) are currently under review.Fact Sheet 8 Isoxaben Summary Document Ecotoxicity

• All ecological effects studies are currently under review.

• EPA has provisional environmental effects endpoi nts in its Pesticide Ecotoxicity Database; however, no formal, signed, data evaluation record s (DERs) are available to verify that these studies have been reviewed.

• Based on a preliminary review of the ecological effects database, isoxaben is expected to be practically non-toxic to birds, mammals, and inse cts; and moderately toxic to aquatic animals and plants. There is insufficient information to predict a level of toxicity to terrestrial plants.

Risk to the Environment

• EPA has not conducted a formal ecological risk assessment on isoxaben. However, in the Registration Review – Preliminary Problem Form ulation for the Ecological Risk Assessment of Isoxaben estimates of risk, based on provisional da ta, are provided to help guide the reader in understanding the potential for en vironmental risks of concern.

• Initial reviews suggest potentia l concern for acute effects to endangered aquatic animals and small birds, and for chronic effects to mammal s. The Agency cannot assess plant risks since no plant studies have been submitted.

• The addition of food uses for isoxaben will expand the scope of the environmental risk assessment due to increase acreage and need for a drinking water assessment.

Human Health Risk Assessment Status :

Please refer to Section IV of this documen t, Human Health Effects Scoping Document, for a detailed discussion of the anticipated risk assessment needs for human health. A summary follows:

Toxicology & Exposure Database

• The toxicological database for isoxaben is adeq uate for the purpose of registration review and is expected to be adequate for the pr oposed food uses in the upcoming PRIA action.

• EPA does not anticipate requesting any new toxicological or exposure data.

• The toxicological and exposure database fo r isoxaben are adequate for the purpose of registration review and most likely for the pr oposed food uses in th e upcoming (Pesticides Registration Improvement Act) PRIA action. EPA will need to select additional endpoints for dietary, incidental oral, dermal, and i nhalation exposures for the new uses. These endpoints will be used in registration review as well. Additionally, EPA will need to revisit the cancer potency estimate based on the lack of a dose-response relationship.Fact Sheet 9 Isoxaben Summary Document • A turf transferable residue study and a disl odgeable foliar residue study were submitted in 2000. These studies will be used in the occ upational and residential exposure assessments.

Dietary Risk

• No dietary risk assessments have been conduc ted for isoxaben, as th ere are currently no registered food uses. However, the new propos ed food uses will require an acute, chronic, and cancer dietary risk assessments.

• There are no drinking water risk assessments for isoxaben. The current turf use requires a screening level groundwater and surface water analysis. The proposed food uses in the upcoming PRIA action will also require scr eening-level groundwater and surface water analysis.

Occupational & Residential Risk

• Occupational and residential ha ndler and post application assessments, with the exception of cancer risks for children on trea ted turf, have not been c onducted for isoxaben. These assessments will be required during the regist ration review process. Also the cancer assessment needs to be reevaluated.

Aggregate Risk

• An aggregate assessment was not required previo usly, as there are (currently) no food uses for isoxaben. However, aggregate assessments (acute, chronic, and cancer) will be necessary in the isoxaben registration review based on the anticipated registration of food uses.

Cumulative

• EPA does not anticipate performing a cumulative ri sk assessment for isoxaben as part of its registration review, because the Agency has not yet determined if there are any other chemical substances that have a mechanism of toxicity common with that of isoxaben. For purposes of the Preliminary Work Plan, EPA has assumed that isoxaben does not have a common mechanism of toxicity with other substances.

Incident Reports:

• The Agency has received reports on five incidents (of phytotoxocity) in which use of isoxaben allegedly caused damage to tree seedli ngs and ornamental plants. These plants were treated directly with isoxaben. No reports have been received of damage to plants from movement of isoxaben off the site of treatment. Also, the agency has received no report of adverse field effects to animals attributed to use of isoxaben, and no report from pesticide registrants of isoxaben contamination of ground or surface water.Fact Sheet 10 Isoxaben Summary Document • Seventeen human incidents have been reported on isoxaben. Four were in an occupational setting with 3 symptomatic cases, two of wh ich visited a health care facility. The nonoccupational group had 8 exposures with two sy mptomatic cases. Four exposures were found in a group of children 5 and under with two symptomatic cases. One involved a 67 year old woman who reported respiratory proble ms after an applica tion near her home. There were no hospitalizations or ICU (Intensiv e Care Unit) treatments reported for these incidences. (For more details, see Review of Isoxaben Incident Reports ; M. Hawkins; Aug 30, 2007.)

Tolerances:

• There are no tolerances for food crops, nor for meat, milk, fat, and meat by-products, nor any (Section 18 Emergency Exemptions) time limited US tolerances.

• Maximum Residue Levels (MRLs) for isoxabe n have not been established by the Codex Commission or by Canada’s Pest Ma nagement Regulatory Agency.

• The registrant has submitted an application for fo od uses on fruit, tree nuts, and vineyards. This review is anticipated to be completed by March 2009.

Data Call-In Status:

• No Data Call-Ins (DCIs) have been issued for isoxaben.

• At present, EPA anticipates that the following studies, at a minimum, will be included in a DCI, pending review of submitted environmental fate and ecological effects studies: Seedling emergence 850.4100 (123-1a) and Vegetative vigor 850.4150 (123-1b), Lemna study 850.4400 (123-2), and soil photolysis (835.3410).

Labels :

Currently registered isoxaben products are listed below. Their labels can be obtained from the Pesticide Product Label System (PPLS) website: http://oaspub.epa.gov/pestlabl/ ppls.home

.

Registration # Registration Name Company Name % Active Ingredient

961-370 Lebanon Preen Pro 1.875g Lebanon Seaboard Corp .375

961-408 Preen Landscape Mulch Lebanon Seaboard Corp .0008

34704-917 Isoxaben 75DF Specialty Herbicide Loveland Products, Inc. 75

52287-13 Weed-Free One Eleven Harrell's Inc .05

62719-144 Gallery Technical Dow Agrosciences LLC 93.5

62719-145 Gallery 75 Dry Flowable Dow Agrosciences LLC 75

62719-175 Snapshot 2.5 Tg Dow Agrosciences LLC .5Fact Sheet 11 Isoxaben Summary Document Registration # Registration Name Company Name % Active Ingredient

62719-178 Gallery Turf Fertilizer Dow Agrosciences LLC .38

62719-192 Turf Fertilizer Contains Gallery Plus Team Dow Agrosciences LLC .29

62719-219 Gallery Milled Concentrate Dow Agrosciences LLC 50

62719-280 T&O Fertilizer-Contains Gallery Plus Team Dow Agrosciences LLC .38

62719-516 Showcase Dow Agrosciences LLC .25

62719-565 Turf Fertilizer - Contains Gallery Plus Team Pro Dow Agrosciences LLC .38

70506-53 Up-Shot DF Herbicide United Phosphorus, Inc 20

70506-55 Turf Fertilizer Contains Galley Plus Surflan United Phosphorus, Inc .29Problem Formulation 12 Isoxaben Summary Document III. ECOLOGICAL RISK ASSESS MENT PROBLEM FORMULATION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D.C., 20460

August 30, 2007

PC Code: 125851 DP Barcode: D341566

MEMORANDUM

Subject: Registration Review – Preliminary Prob lem Formulation for the Ecological Risk Assessment of Isoxaben

To: Kevin Costello, Team Leader Jacqueline Guerry, Chemical Review Manager Special Review Branch Special Review and Reregistration Division

From: Brian D. Kiernan, Biologist Amy A. McKinnon, Environmental Scientist Environmental Risk Branch IV Environmental Fate and Effects Division

Through: Elizabeth Behl, Chief Environmental Risk Branch IV Environmental Fate and Effects Division

Attached is the preliminary problem formulation for the environmental fate and ecological risk assessment to be conducted as part of the Regi stration Review of the herbicide isoxaben.Problem Formulation 13 Isoxaben Summary Document 

## REGISTRATION REVIEW

ECOLOGICAL RISK ASSESSMENT PROBLEM FORMULATION FOR:

ISOXABEN

N -[3-(1-ethyl-1-methylpropyl)-1,2-oxa zol-5-yl]-2,6-dimethoxybenzamide

CAS Registry Number: 82558-50-7

PC Code: 125851

Prepared by:

Brian D. Kiernan, Biologist Amy A. McKinnon, Environmental Scientist

Reviewed by:

Elizabeth Behl, Branch Chief U. S. Environmental Protection Agency Office of Pesticide Programs Environmental Fate and Effects Division Environmental Risk Branch IV 1200 Pennsylvania Ave., NW Mail Code 7507P Washington, DC 20460Problem Formulation 14 Isoxaben Summary Document Table of Contents

I. Background............................................................................................................... 15 II. Problem Formulation ................................................................................................ 15 A. Nature of Regulatory Action..................................................................... 15 B. Stressor Source and Distribution .............................................................. 16 1. Nature of the Chemical Stressor ....................................................................... 16 2. Overview of Pesticide Usage.............................................................................. 7 C. Receptors................................................................................................... 18 1. Aquatic and Terrestrial Effects ......................................................................... 18 2. Ecosystems Potentially at Risk ......................................................................... 19 D. Assessment Endpoints .............................................................................. 19 E. Conceptual Model..................................................................................... 19 1. Risk Hypothesis ................................................................................................ 20 2. Conceptual Diagram ......................................................................................... 20 F. Analysis Plan ............................................................................................ 21 1. Preliminary Identification of Data Gaps........................................................... 21 2. Measures of Effect ............................................................................................ 22 3. Incident Reports................................................................................................ 23 4. Measures of Exposure....................................................................................... 23 III. Risk Es timation..................................................................................................... 28 A. Preliminary Aquatic Risk.......................................................................... 30 B. Terrestrial Risk.......................................................................................... 31 IV. References............................................................................................................. 37Problem Formulation 15 Isoxaben Summary Document Background

The Environmental Fate and Effects Division (EFED) has conducted a preliminary review of the available environmental fate and ecotoxicity da ta to determine the scope of work necessary to support the registra tion review process for isoxaben. Isoxaben is a pre-emergent herbicide for various non-bearing food crops (e.g. apples, tree nuts), commercial turf, nursery/ornamentals, rights-of-way and other indust rial uses. No ecological risk assessment is available to draw from, although the environmen tal fate for isoxaben is summarized in the registration standard (Fat e Data Summary, 2/22/90).

The purpose of this scoping effort is to determ ine the extent of data available to support an environmental fate and ecological risk assessm ent for the reregistration review of isoxaben. This document is not an environmental fate a nd ecological risk assessment, although preliminary estimates of risk, based on provisional data, are provided to help guide the problem formulation.

Problem Formulation

The purpose of problem formulation is to provide the foundation for the environmental fate and ecological risk assessment that will be conducted for the pre-emergent herbicide isoxaben.



### Nature of Regulatory Action

Isoxaben was registered for use as a pre-emer gent herbicide in 1989. There are currently twelve Section 3 registrations based on isoxaben as the active in gredient (ai). There are no current food-use registrations. Beginning in 2008, isoxaben is scheduled to undergo reregistration review. This document provides th e initial problem formulation for the ecological risk assessment in support of the re registration review of isoxaben.

A Section 3 new use (first food use) has been received by the Agency. The new use application is for the use of isoxa ben on tree nuts and grapes grown for harvest. Approval of this use would likely expand the total acreage of isoxaben usage for the affected crops. The PRIA decision date on the new use is March 2009 and ther efore will be included in the reregistration review risk assessment.

No ecological risk assessments have been conducted previously for isoxaben. Most environmental fate data are summarized belo w from the registration standard. Recently submitted aerobic and anaerobic aqueous metabo lism studies were reviewed by EFED in 2006 (MRIDs 46393201 and 46393202). The studies were submitted as 6 a)(2) data, and were reviewed because the Agency was concerned that there may be a rotational crop problem with soil residues. EFED concluded that "given the limited persistence of isoxaben in aerobic and anaerobic aquatic systems, exposure to subsequent rotational crops is unlikely". In addition, several hydrolysis, aqueous photolys is, aerobic soil metabolism and leaching/adsorption/desorption studies are currently under review (MRIDs132123 & 132124 under accession number 250449; 143786, 153107, 164645, 40532101).Problem Formulation 16 Isoxaben Summary Document Provisional environmental effects endpoint s are reported in the EFED Pesticide Ecotoxicity Database; however, no data evaluation records (DERs) are available to verify that these studies have been reviewed. All ecologi cal effects studies are currently under review.



### Stressor Source and Distribution

Nature of the Chemical Stressor

Isoxaben is a pre-emergent benzamide herb icide used for the control of broadleaf (dicotyledonous) weeds. The specific mode of action for isoxaben is not well understood, but isoxaben has been shown to inhib it the conversion of glucose to cel lulose in cell wall synthesis in sensitive species, with grasses (Family: Poaceae) tending to be mo re tolerant than other plant groups (Salihue et al. 1994). Isoxaben is not thought to be highly mobile in adult plants, apparently limiting its toxicity to older plants, but allowing efficacy in emerging seedlings.

Table 1. Nature of the Chemical Stressor Common name Isoxaben (EL-107) Chemical Name N- [3-(methylpent-3-yl)isoxazol -5-yl]-2,6- dimethoxy-benzamide Pesticide type, such as herbicide or insecticide, Herbicide

Chemical class benzamide
CAS number 82558-50-7 Empirical formula C 18 H 24 N 2 O 4 Molecular Mass (g/mol) 332.39 g

· mol -1 Vapor pressure <3.9 X 10 -7 Henrys Law Constant at 20 o C (dimensionless) 7.10E-06

Solubility in water 1 to 2 ppm Log Kow 2.64
PKa at 25 o C 9.78

Figure 1. Chemical structure of isoxaben.Problem Formulation 17 Isoxaben Summary Document Isoxaben is moderately persistent and may be mobile (MRIDs164646 and 41106303). There is some indication that the mobility of is oxaben decreases with increasing soil clay content and cation exchange capacity (CEC) (MRID 41106303). The compound may represent a ground water concern when applied to certain soils and/or where high water tables are present (i.e. less than one foot below grade) and high ra infall/ irrigation occurs (MRID 40059508).

Isoxaben does not appear to readily undergo aerobic and anaerobic degradation in soil (MRIDs 41106302, 143786, and 164646). Primary routes of degradation appear to be aqueous photolysis, aerobic aqueous metabolism and anaerobic aqueous metabolism (MRIDs 40059507, 46393201 and 46393202).

Major degradates detected during aerobic a nd anaerobic soil metabolism studies and aerobic and anaerobic aqueous metabolism studies include: N-[3-(2-hydr oxybut-2-yl)-isoxazol5-yl]-2,6-dimethoxybenzamide (201469); N-[3-( 1-hydroxyl-1-methylpropyl)-5-isoxazoyl]-2,6- dimethoxy-benzamide; dimethoxy benzamide; methoxyphenyl pyrimidinol and AEM hexenoyl isoxaben. Minor degradates id entified include: N-[3-(1-ace tyl-1-methylpropyl)-5-isoxazoyl]- 2,6-dimethoxybenzamide; N-[3-(1-hydroxyl-1-ethyl )-5-isoxazoyl]-2,6-dimethoxy-benzamide; N- [3-(1-ethyl-1-methylpropyl)-5-isoxazoyl ]-2-hydroxy-6-methoxyl-benzamide; hydroxyl methoxybenzamide; oxypropyl isoxaben, hydrox y isoxaben; desmethyl isoxaben and methoxyphenyl pyrimidinol (MRIDs 40059507, 46393201, 46393202, 41106302, 143786, and 164646). The major degradate (201469) may be mo re mobile than the parent compound (MRID 164646). To date, no degradates of concern have been identified by the He alth Effects Division (HED because no food uses have been previously proposed for registration. For that same reason, a drinking water assessment has not been conducted. A drinking water assessment will be conducted in support of the Sectio n 3 new use on tree nuts and grapes.



### Overview of Pesticide Usage

Isoxaben was registered in 1989 for various uses, including: ri ghts-of-ways, turf, landscaping, nurseries, other indus trial (noncrop) areas and non-b earing fruit and nut crops. The majority of uses have an applic ation rate of 1.0 lb ai/A/application, three applications per year with a 60-day reapplication interval , applied either as a dry flowab le product in a broadcast spray or as a granular product in a spreader. Some uses are only 0.5 lbs ai/A /application and there are hand-applied soil treatments at rates up to 2.0 lbs ai/A/application.

Based on label instructions for the 13 regi stered isoxaben product labels, most prohibit aerial application; it is not clear whether all of the current uses prohibi t aerial application ( e.g. usage on conifer seed orchards). There appe ars to be consistent label prohibitions on chemigation and direct applications to water. Warnings regarding the potential toxicity to aquatic organisms and avoidance of spray drift are on the labels.

In a memo from BEAD date d 08/01/2007, non-crop usage acc ounted for nearly 19,000 (94%) of the 20,372 lbs applied annually (on av erage) for the years 2003-2005, with rights-ofway alone accounting for an annual average of 11,619 lbs (57% of total applied).

Isoxaben is currently limite d to non-bearing food crops ( i.e. food crops not yet producing a marketable harvest); therefore only a small pe rcentage of total target crop area planted isProblem Formulation 18 Isoxaben Summary Document expected to be treated. For instance, accord ing the Screening Level Usage Analysis (SLUA, 2007) for isoxaben, the maximum area treated for almonds, apples grapes and walnuts is less than 2.5% of total area planted for each crop. Registered non-bearing crop uses include almond, apple, apricot, avocado, banana , blackberry (and other raspberry cr ops), blueberry, cherry, citrus fruits, elderberry, fig, grapes, nut trees, olive and pomegranate. Approval of the new food use on tree nuts and grapes would likely increase the amount of isoxaben used on these crops.



### Receptors

Aquatic and Terrestrial Effects

The receptor is the biological entity that is exposed to the stressor (US EPA, 1998). For isoxaben, biological entities pote ntially exposed include birds, mammals, terrestrial-phase amphibians, reptiles, freshwater fi sh and invertebrates, estuarine/ marine fish and invertebrates, aquatic-phase amphibians and terrestrial and aquatic plants.

Consistent with the process described in the Overview Document (US EPA, 2004), this risk assessment relies on surroga te species toxicity data to evaluate the potential ecological effects of isoxaben. Toxicity data generated from surrogate test species are intended to be representative of broad taxonomic groups and are used to extrapolate to potential effects on a variety of species (receptors) incl uded under these taxonomic groupings.

Acute and chronic toxicity data from studies submitted by pesticide registrants along with pertinent open literature are used to evaluate potential direct effects of isoxaben to the aquatic and terrestrial biological receptors. This incl udes toxicity data on th e technical grade active ingredient, degradates, and when available, formulated products. Open literature studies available through EPA’s ECOTOX database ( http://cfpub.epa.gov/ecotox/ ), provide EFED scientists the source for locating single chemical t oxicity data for aquatic life, terrestrial plants, and wildlife. The evaluation of both sources of da ta can also provide insight into the indirect effects of isoxaben on biotic communities due to lo ss of species that are sensitive to the chemical and changes in structure and functional characteristics of the affected communities.

Table 2 provides a summary of the taxonomic groups and the surrogate species tested to help understand potential acute eco logical effects of pe sticides to these no n-target taxonomic groups. In addition, the table provides a prelim inary overview of the poten tial acute toxicity of isoxaben by providing the acute t oxicity classifications. Based on this preliminary overview, isoxaben is characterized as practi cally nontoxic to terrestrial anim als and is moderately toxic to aquatic animals on an acute exposure basis. No data are available to assess the toxicity of isoxaben to terrestrial plants or aquatic vasc ular plants; however, the compound is moderately toxic to the one aquatic nonvascular for which data are reported.

Table 2. Test Species Evaluated for Assessin g Potential Ecological Effects of Isoxaben. Taxonomic Group Example(s) of Surrogate Species Acute Toxici ty Classification

Birds 1 Mallard duck ( Anas platyrhynchos ) Bobwhite quail ( Colinus virginianus ) Practically non-toxic

Mammals Laboratory rat ( Rattus norvegicus ) Practically non-toxic Insects Honey bee ( Apis mellifera L. ) Practically non-toxic
Freshwater fish 2 Bluegill sunfish ( Lepomis macrochirus ) Moderately toxicProblem Formulation 19 Isoxaben Summary Document Taxonomic Group Example(s) of Surrogate Species Acute Toxici ty Classification Japanese carp ( Cyprinus carpio ) Moderately toxic Freshwater invertebrates Water flea ( Daphnia magna ) Moderately toxic

Estuarine/marine fish Sheepshead minnow ( Cyprinodon variegatus ) Moderately toxic

Estuarine/marine invertebrates Grass shrimp ( Palaemonetes pugio ) Moderately toxic

Terrestrial plants 3 Monocots – Dicots – No data

Aquatic plants Green algae Moderately toxic

1 Birds are surrogates for terrestri al-phase amphibians and reptiles.

2 Freshwater fish are surrogate s for aquatic-phase amphibians.

3 Four species of two families of monocots, of which one is corn; six species of at least four dicot families, of which one is soybeans.



### Ecosystems Potentially at Risk

The ecosystems at risk are potentially extensiv e in scope, and as a result it may not be possible to identify specific ecosystems during the development of the baseline risk assessment. However, in general terms, terrestrial ecosystems potentially at risk could include the application sites and areas immediately adjacen t to the application sites that may receive drift or runoff. This could include the application site itself as well as other cultivated fields, fencerows and hedgerows, meadows, fallow fields or grassla nds, woodlands, riparian habitats and other uncultivated areas.

Aquatic ecosystems potentially at risk include water bodies adjacent to, or down stream from, the treated field and might include impounde d bodies such as ponds, lakes and reservoirs, or flowing waterways such as streams or rivers. For uses in coastal area s, aquatic habitat also includes marine ecosystems, including estuaries.

As an herbicide, isoxaben can potentially affect plant growth, survival and reproduction and thereby affect primary produc tivity in both aquatic and te rrestrial environments thereby impacting both aquatic and terrestrial ecosystems. The extent that aquatic and terrestrial communities are dependent of specific sources of primary productivity that may be impacted by isoxaben will dictate the extent to entire ecosystems may be at risk.



### Assessment Endpoints

Assessment endpoints represent the actual enviro nmental value that is to be protected, defined by an ecological entity (species, comm unity, or other entity) and its attribute or characteristics (US EPA, 1998). For isoxaben, the ecological enti ties may include the following: birds, mammals, freshwater fish and invertebra tes, estuarine/marine fish and invertebrates, terrestrial plants, insects, and a quatic plants and algae. The attr ibutes for each of these entities may include growth, reproduction, and survival.



### Conceptual Model

For a pesticide to pose an ecological risk, it must reach ecological receptors in biologically significant c oncentrations. An exposure pathway is the means by which a pesticide moves in the environment from a source to an eco logical receptor. For an ecological pathway toProblem Formulation 20 Isoxaben Summary Document be complete, it must have a source, a release mechanism, an environmental transport medium, a point of exposure for ecological receptor s, and a feasible route of exposure.

A conceptual model provides a written desc ription and visual re presentation of the predicted relationships between isoxaben use pa tterns, potential routes of exposure, and the predicted effects on the assessment endpoint. Th e conceptual model consists of two major components: risk hypotheses and a conceptual diagram (US EPA, 1998).



### Risk Hypothesis

Risk hypotheses are specific statemen ts about potential adverse effects ( i.e ., changes in assessment endpoints) and are tested using theo ry and logic, empirical data, mathematical models, or probability models (USEPA 2004). For th is assessment, the risk is stressor-initiated, where the stressor is the release of isoxaben to the environment. The following risk hypothesis is presumed for this screening level assessment:

Based on the application methods, mode of action, persistence and mobility of isoxaben, direct deleterious effects to non-target terrestrial and aquatic plant communities and indirect effects to both a quatic and terrestrial species th rough habitat modification are likely. Direct acute toxic effects to animal s are expected to be limited, although chronic effects may occur.



### Conceptual Diagram

Ecological receptors that may be exposed to isoxaben include terrestrial wildlife ( i.e.

, mammals, birds, terrestrial-phase amphibians, te rrestrial invertebrates, reptiles, and plants) through ingestion or, in the case of plants, dire ct contact. Pathways not considered include inhalation and root uptake. Aquatic receptors (freshwater and estuarine/marine fish and invertebrates, aquatic-phase amphibians, and aquatic plants) may also be exposed as a result of potential migration of isoxaben via spray drift and/or runoff from the s ite of application to various aquatic environments. These potential ex posure pathways form the basis for identifying potential receptors and ecol ogical effects associated with isoxaben use (see Figure 2 ).

The assessment will not quantitatively acc ount for potential atmos pheric transport in estimating environmental concentrations, or potential exposure via groundwater, nor will it account for ingestion of isoxaben residues by anim als in contaminated grit, ingestion through preening activities, or uptake th rough inhalation or dermal abso rption by terrestrial animals. Exposure to terrestrial animals is based primarily on dietary consumption of foliar (and insect) residues. Aquatic assessments assume that all potential routes of dire ct exposure are accounted for.Problem Formulation 21 Isoxaben Summary Document Figure 2. Conceptual model of the transpor t and effects of isoxaben in the environment from ground spray application. *Dotted lines indicate that although this exposure route or pathway was considered, it was not thought to contribute significantly to the fate and transport of isoxaben.


### Analysis Plan

Preliminary Identification of Data Gaps

A total of thirty-six registrant-submitted studies are available for assessing the environmental fate of isoxaben. At this time no hydrolysis DERs were av ailable for review and isoxaben was presumed to be stable to hydrolysis. In addition, aqueous photolysis appears to be a route of dissipation for isoxaben in the aquatic environment. However, degradates were not completely characterized in th e available study. Several hyd rolysis and aqueous photolysis studies are currently under review (MRIDs 132123 & 132124 under accession number 250449 and 47140003). These studies may provide additional data that is needed to determine the degradation pathways for isoxaben and degradates. However, if any of the studies under review are found to be unacceptable, data gaps could be discovered. The only available soil photolysis half-life study indicated that is oxaben had a half life of 198 days on clay loam soil, however the study was deemed unacceptable because only the parent compound was analyzed for; the test

Stressor Isoxaben Application

Source/ Transport
Pathwa y s Direct Application Leaching (Infiltration /

Percolation

Source/ Exposure Media Terrestrial Food Items (foliage, fruit, insects, seeds) Upland Foliage/Soil Riparian/ Wetland Foliage/Soil Receiving Water Body/

Sediment Ground Water

Exposure
Route Ingestion Direct Contact/ Root Uptake Direct Contact/ Root Uptake Gill/Integument Uptake; Ingestion

Rece p tors

Attribute Changes Terrestrial Vertebrates: Birds, Mammals, Reptiles, Terrestrial Phase Amphibians Terrestrial Upland Plants

Individual Animals Reduced survival or reproduction Aquatic Invertebrates,
Vertebrates Wetland/ Riparian Plants

Individual Plants Reduced survival, growth, or reproduction Individual Vertebrates and Invertebrates Reduced survival or reproduction Plant Population Reduced population growth Aquatic
Plants Uptake/ Adsorption Spray DriftProblem Formulation 22 Isoxaben Summary Document substance was not technical grade or purer; and th e artificial light source was not comparable to natural sunlight. Therefore, this degradat ion pathway cannot be properly assessed.

Isoxaben has demonstrated the ability to le ach and may present a groundwater concern. Groundwater monitoring studies may need to be provided in the future for EFED to determine under what conditions isoxaben could pose a threat to groundwater. To date, no food uses have been assessed and a drinking water assessment ha s not been conducted, therefore degradates of concern have not been identified. Once the fi rst food uses are assess ed the Health Effects Division (HED) may be able to characterize degr adates of concern if appropriate data is available. If degradates of concern are id entified, a prospective groundwater study may be required to determine if they pose a threat to human health and the environment.

Provisional environmental effects endpoint s are available in the EFED Pesticide Ecotoxicity Database; however, no DERs are availa ble to verify that these studies have been reviewed. All ecological effects studies are cu rrently under review (expected completion early 2008). If the submitted studies are found to be acceptable, many of the ecological effects guideline data requirements could be considered to be met. However, if any of the studies under review are found to be unacceptable, data gaps c ould be discovered. Submitted terrestrial plant toxicity studies have been previously classi fied ‘unacceptable’ in draft DERs; should final review of these studies uphold the initial classifi cation, no data on terrestrial plant toxicity would be available for the risk assessm ent. Additionally, no aquatic vasc ular plant toxicity data are reported in the OPPIN bibliography; only one non-guideline aquatic nonva scular plant (green algae, species uncertain) is reported. Theref ore, effects to aquatic plant communities, and indirect effects to higher trophic pop ulations, would not be able to be assessed and direct risk to plants and indirect effects to both aquatic and terrestrial wildli fe would be presumed in the absence of data.



### Measures of Effect

Each assessment endpoint requires one or mo re measures of ecological effect, which are measurable changes in the attribute of an asse ssment endpoint in response to a stressor (e.g. avian acute oral LD 50 ). Table 3 summarizes the ecotoxicity data for isoxaben available in OPP’s Pesticide Ecotoxicity Database. However, all of the endpoints ar e provisional pending scientific review of the studies. Although two terrestrial plant studies ha ve been submitted, the draft review categorized both as ‘unacceptable’. There are no other data available through the Agency’s database of open literature, ECOTOX (www.epa.gov/ecotox).

Table 3 . Summary of Unreviewed Ecotoxicol ogical Endpoints Available for Isoxaben.
AI Species Duration Dose Toxicity Level Year Epaident Aquatic
Freshwater 92.4 Japanese carp 96 hr LC50 >1.1 mg ai/L 1982 00137844 92.4 Bluegill sunfish 96 hr LC50 >1.1 mg ai/L 1982 00132145

92.4 Water flea 48 hr EC50 >1.3 mg ai/L 1982 00132144

95.5 Water flea 21 D NOAEC 0.69 mg ai/L 1984 00137845

95.5 Fathead minnow 33 D NOAEC 0.4 mg ai/L 1983 00137848

95 Rainbow trout 28 D NOAEC 0.42 mg ai/L 1983 00137847 95.5 Grass shrimp 96 hr LC50 >1.0 mg ai/L 1987 40531303 Estuarine/ marine 95.5 Sheepshead 96 hr LC50 >0.87 mg ai/L 1987 40531304Problem Formulation 23 Isoxaben Summary Document AI Species Duration Dose Toxicity Level Year Epaident
minnow
95.5 Quahog clam 48 hr EC50 >0.96 mg ai/L 1987 40531302
Plants 92.4 Green algae 14 D EC50 >1.4 mg ai/L 1982 00132147
Terrestrial
92.4 Bobwhite quail 8 D LC50 >5000 mg ai/kg-diet 1982 00132142

92.4 Mallard duck 8 D LC50 >5000 mg ai/kg-diet 1982 00132143 92.4 Bobwhite quail 14 D LD50 >2000 mg ai/kg-bw 1982 00132141

95.5 Mallard duck 24WKS NOAEL 300 mg ai/kg-diet 1984 00153109 95.5 Bobwhite quail 24WKS NOAEL 1000 mg ai/kg-diet 1984 00153110 Tech Laboratory rat 14 D LD50 >10000 mg ai/kg-bw MJ031 Tech Laboratory rat NOAEL 500 mg ai/kg-diet MJ019

Tech Earthworm 14 D LC50 >100 mg ai/kg-soil 1982 ACC250793 95.5 Honey bee 96 hr LD50 >101.7 μg ai/bee 1984 0015311



### Incident Reports

The Agency has received reports on five in cidents in which use of isoxaben allegedly caused damaged to tree seedlings and ornamental plants treated directly with isoxaben. No reports have been received of damage to plan ts from movement of isoxaben off the site of treatment. Also, the agency has received no report of adverse field effects to animals attributed to use of isoxaben, and no report from pesticid e registrants of isoxaben contamination of ground or surface water.

A lack of reported incidents does not neces sarily mean that such incidents have not occurred. In addition, incide nt reports for non-target plants and animals typically provide information on mortality events only. Reports for other adverse effects, such as reduced growth or impaired reproduction, are rarely received.

EPA has looked at three databases to review any unintentional expos ure to isoxaben. A total of 16 people have reported exposures to isox aben. Four involved workers, two of which required treatment at a health care facility. Four occurred with children aged 5 and under. The other eight incidents involv ed non-occupational adults.

The Agency is not expecting to recommend any mitigation actions based on these incidents.



### Measures of Exposure

Fate Characteristics Isoxaben is moderately persistent an d may be mobile (MRIDs 164646 and 41106303). There is some indication that the mobility of is oxaben decreases with increasing soil clay content and cation exchange capacity (CEC) (MRID 41106303). The compound may present a ground water concern, especially when high water tables are present (i.e. less than one foot below grade) and high rainfall/ irrigation occurs (MRID 40059508).

Isoxaben does not appear to readily undergo aerobic and anaerobic degradation in soil (MRIDs 41106302, 143786, and 164646 and Microfiche 2653 70). Primary routes of degradation appear to be aqueous photolys is, aerobic aqueous metabolism and anaerobic aqueous metabolismProblem Formulation 24 Isoxaben Summary Document (MRIDs 40059507, 46393201 and 46393202). Major degradates (> 10% of total residues) detected during aerobic and anaerobic soil metabolism studies and aerobic and anaerobic aqueous metabolism studies include: N- [3-(2-hydroxybut-2-yl)-isoxazol-5-yl]-2,6- dimethoxybenzamide (201469); N-[3-(1-hydro xyl-1-methylpropyl)- 5-isoxazoyl]-2,6- dimethoxy-benzamide; dimethoxy benzamide; methoxyphenyl pyrimidinol and AEM hexenoyl isoxaben. Minor degradates id entified include: N-[3-(1-ace tyl-1-methylpropyl)-5-isoxazoyl]- 2,6-dimethoxybenzamide; N-[3-(1-hydroxyl-1-ethyl )-5-isoxazoyl]-2,6-dimethoxy-benzamide; N- [3-(1-ethyl-1-methylpropyl)-5-isoxazoyl ]-2-hydroxy-6-methoxyl-benzamide; hydroxyl methoxybenzamide; oxypropyl isoxaben, hydrox y isoxaben; desmethyl isoxaben and methoxyphenyl pyrimidinol (MRIDs 40059507, 46393201, 46393202, 41106302, 143786, and 164646). Benzamide, pyrazolone, an isoquinolone and benzopyrrolidone were identified as degradates during the aqueous photol ysis study. However, these degradates have not been fully characterized as to percentage of parent (MRID 40059507). The major degradate (201469) may be more mobile than the parent compound (MRID 164646).

Isoxaben residues accumulated in bluegi ll sunfish with maximum bioconcentration factors of 14X in edible tissue, 134X in non-edible tissue and 70X in whole fish during 28 days of exposure. Residues accumulated by exposure day 28 were depurated quickly; at day 14 of depuration, isoxaben residues were approximately 1.28 ppm in edible, nonedible, and whole fish tissues. This study is considered supplemental because isoxaben residues were incompletely characterized and residues in whole fish were not determined experimentally (MRID 40059509).

Table 4. General Chemical Properties and Enviro nmental Fate Parameters of Isoxaben
Chemical Fate / Parameter Value Source Chemical Name N- [3-(methylpent-3- yl)isoxazol -5-yl]-2,6- dimethoxy-benzamide Fate Data Summary, 2/22/90

Molecular Mass 332.39 g

· mol -1 Fate Data Summary, 2/22/90 Vapor Pressure (25°C) <3.9 X 10 -7 Fate Data Summary, 2/22/90 Solubility (20°C) 1 to 2 ppm Fate Data Summary, 2/22/90 Octanol-water partition coefficient (K ow ) 434 Fate Data Summary, 2/22/90

Mean adsorption coefficient (K d ); organic carbon partioning coefficient (K oc ) Kd = 0.81-6.6
Koc = 162-330 Fate Data Summary, 2/22/90

Hydrolysis half-life (pH 5, 25 °C) Presumed stable Data under review Hydrolysis half-life (pH 7, 25 °C) Presumed stable Data under review Hydrolysis half-life (pH 9, 25 °C) Presumed stable Data under review Aqueous photolysis half-life; Total residues of concern half-life (original data of study) % of parent curve of decline for parent – add in % of degradate 7-15 days; degradates not completely characterized MRID 40059507 Additional data under review

Soil photolysis half-life; Total residues of concern half-life Not available Data gap

Aerobic soil metabolism half-life; 4.3 months;n/a (clay loam soil) MRID 164646Problem Formulation 25 Isoxaben Summary Document Chemical Fate / Parameter Value Source
Total residues of concern half-life (soil texture) 5.6 months; n/a (loam soil) 10.6 months; n/a (sandy loam soil) Additional data under review

Anaerobic soil metabolism halflife; Total residues of concern half-life (soil texture) >120 days; n/a (loam soil) MRIDs 41106302, 00143786
& 00164646

Aerobic aqueous metabolism half-life; Total residues of concern half-life 13 days (linear)/13 days (nonlinear) MRID 46393202

Anaerobic aqueous metabolism half-life; Total residues of concern half-life (soil texture) 18 days (linear)/3 days (nonlinear) MRID 46393201

Terrestrial field dissipation halflife (soil texture) 30-40 days (spring treated sand soil – Florida and loam soil Indiana); 60-182 days (autumn treated sandy loam soil – Texas); 66-106 days (clay loam soil, Illinois) MRIDs 40059508,
40532102 & 40532103

Aquatic Exposure To assess the risk to aquatic life posed by a chemical, OPP estimates pesticide concentrations which would be expected in th e environment from labeled uses (exposure) and compares them to concentrations known to be to xic from laboratory tests (hazard). To initially screen exposure of isoxaben to aquatic life, the Tier I screening model GENEEC (GENeric Estimated Exposure Concentration; Parker, et. al ., 1995) was used. Initial aquatic exposure estimates are presented in Table 5

.

Table 5. Preliminary Aquatic EECs (GENEEC) for Isoxaben Applied as a Ground Spray at 1.0 lbs ai/A, three Applications 60 Days Apart (mg ai/L).
PEAK 4 DAY 21 DAY 60 DAY 90 DAY
0.141 0.141 0.140 0.138 0.137

Input parameter values are selected from th e environmental fate data submitted by the registrant and 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. In the absence of valid input data, conservative assumptions were made when r unning the GENEEC model. Isoxaben use was modeled at an application rate of 1.0 lb. ai/A, th ree applications per year at 60 day intervals. Conservative assumptions likely to increase estimated environmental concentrations (EEC) include the following:

• the lowest Koc value was used and aerobic soil metabolism was assumed stable ( i.e. half life of zero).

• Ground spray was assumed since aerial appl ications are prohib ited on all labels (except the conifer seed label).Problem Formulation 26 Isoxaben Summary Document • The EFED defaults of high boom sprayer, fine spray quality, a no spray zone of zero feet and a zero depth of inco rporation were also used.

• The upper limit of solubility (2 ppm) was chosen.

• Aerobic aquatic metabolism, hydrolysis, a nd photolysis were all assumed to be stable.

GENEEC is presumed to result in conservative EECs. Since the resulting RQs exceed some LOCs, a second tier of aquatic exposure mode ling could be performed to refine the aquatic EECs. The PRZM/EXAMS (Pesticide Root Zone Model (PRZM) (Carsel et al., 1984), and the EXposure Analysis Modeling System (EXAMS) (Bur ns et al., 1991) models would be used for scenario-specific refinement. PRZM simulates pesticide fate and transport as a result of leaching, direct spray drift, r unoff and erosion from an agricult ural field, and EXAMS estimates environmental fate and transport of pesticides in a surface water body for a 30-year period. The combined model is designed to estimate pesticide concentrations found in water at the edge of the treated field. As such, it provides high-end va lues of the pesticide concentrations that might be found in ecologically sensitiv e environments following pestic ide application. Standard scenarios simulate a 10-hectare field draining into a 1-hectare static pond th at is 2-meters deep and does not have an outlet. The pond serves as a surrogate for a variety of small water bodies that can be found at the top of a watershed. It is assumed that runoff is e qually likely to flow into the pond from all areas of the treate d field, and that the entire fiel d is cropped and treated. The location of the field is specific to the crop bei ng simulated using site-specific information on the soils, weather, cropping, and management factors associated with the scenario. The crop/location scenario is intended to represen t a high-end exposure site on whic h the crop is normally grown. Based on historical rainfall patte rns, the receiving water body receives multiple runoff events during the years simulated. Weat her and agricultural practices are simulated for 30 years so that the 10-year exceedance probability at the site can be estimated. The simulation was generated using 30 years of meteorological data, encomp assing the years from 1961 to 1990. Additional information on these models can be found at: http://www.epa.gov/oppefed1/ models/water/index.htm

.

Aquatic Exposure Monitoring

Isoxaben is not included as one of the analytes monitored in U.S. surface and groundwater under the USGS’s National Water Quality Assessment (NAWQA) program. OPP is not aware of other water monitoring data for isoxaben.

Terrestrial Exposure

Animals EECs are typically calculated for birds a nd mammals emphasizing a dietary uptake of pesticide through residues on vege tative and insect forage items. Avian terrestrial EECs are considered representative of potential exposure fo r terrestrial-phase amphi bians and reptiles as well. For exposure to terrestrial organisms, pe sticide residues on food items are estimated, based on the assumption that organisms are exposed to a single pesticide residue in a given exposure scenario and obtain 100% of their diet from treat ed areas. EECs are currently generated from a spreadsheet-based screening model (TREX v.1. 3.1) that calculates the exposure via food ingestion rates of various size /forage item categories for birds and mammals. The terrestrialProblem Formulation 27 Isoxaben Summary Document food item residue estimates are based on the methods of Hoerger and Kenaga (1972) as modified by Fletcher et al. (1994) and food ingestion rates are es timated using allometric equations (USEPA, 1993). When data on the foliar dissipation of a chemical are absent, as in this case, EFED assumes a 35-day foliar dissi pation half-life. Initial unad justed exposure estimates are presented in Table 6

.

Table 6. Unadjusted dietary-based estimated envir onmental concentrations (EECs) on terrestrial animal forage items following three applicati ons of isoxaben with a 60-day reapplication interval, based on TREX (version 1.3.2).

Application Rate Food Items Upper-bound EEC (ppm) a Mean EEC (ppm) a

Short grass 335 119

Tall grass 154 50

Broadleaf plants/small insects 189 63 1.0 lbs ai/A Three applications/60 day interval

Fruits, pods, seeds, and large insects 21 10

a Predicted residues based on Hoerger and Kenaga (1972) as modified by Fletcher et al. (1994).

Plants Currently, terrestrial plant e xposure is estimated using the TerrPlant (v1.2.2) screening model. TerrPlant estimates potential exposure from a singl e application using default assumptions for runoff and spray drift. For runoff plus drift, TerrPlant incorporates two similar conceptual models for depicting dry and semi-a quatic areas of terrestri al habitats. For both conceptual models, a non-target area is adjacent to the target area. Pesticide exposures to plants in the non-target area are estimated to receive runoff and drift from the target area. For a dry area adjacent to the treatment area, runoff exposure is estimated as sheet runoff. In the model, sheet runoff is defined as the amount of pesticide in water that runs off of the soil surface of atarget area of land which is equal in size to the non-target area (1:1 ratio of areas). For semiaquatic areas, runoff exposure is estimated as ch annelized runoff. In the model, channelized runoff is the amount of pesticide that runs off of a target area 10 times th e size of the non-target area (10:1 ratio of areas). The drift component is calculated as 1% of applied mass for ground spray and 5% for aerial application. There is no drift assumed for gr anular applications. Estimated exposures through runoff pl us drift and drift al one are then compared to measures of survival and growth (e.g. effects to seedling emergence and vegetative vigor) to develop RQ values. Initial exposure es timates are presented in Table 7

.

Table 7. Preliminary estimated environmental concentrations (EECs) for plant exposure following label-specified applications of isoxabe n determined using the TerrPlant model (lbs ai/A)

Rate Application
Method Adjacent Upland Loading a Adjacent Wetland Loading Drift Only

1.0 lbs ai/A Ground 0.02 0.11 0.01

a Loading is runoff plus drift (lbs ai/A)Problem Formulation 28 Isoxaben Summary Document Risk Estimation

The risk quotient (RQ) approach will be used in the isoxaben environmental risk assessment, comparing the ratio of exposure concentrations to effects endpoints with predetermined levels of concern (LOCs). Labor atory environmental fate, laboratory ecological effects, and use data that will provide the basi s for these risk quotients have been discussed previously in the assessment. Estimated envi ronmental concentrations (EECs) are divided by acute and chronic toxicity va lues to calculate RQs. Table 8 summarizes the measure of exposure and measure of effect the will be used to cal culate RQs. If the RQs exceed the LOCs, the Agency presumes potential for risk to the taxa. These LOCs ( Table 9 ) are the Agency’s interpretive policy and are used to determine the need to consider regulatory action by indicating whether a pesticide, used as dire cted on the label, has the poten tial to cause adverse effects on non-target organisms. Although risk is often de fined as the likelihood an d magnitude of adverse ecological effect, the risk quotient-based approach does not provide a quan titative estimate of likelihood and/or magnitude of an adverse effect.

Table 8. Measures of Effect and Exposure for Isoxaben. Assessment Endpoint Surrogate Species and Measures of Ecological Effect 1 Measures of Exposure

Survival Bobwhite acute oral LD 50 Bobwhite and mallard subacute dietary LC 50 Birds 2

Reproduction and growth Bobwhite and mallard chronic reproduction NOAEC and LOAEC

Survival Laboratory rat acute oral LD 50 Mammals

Reproduction and growth Laboratory rat oral reproduction chronic NOAEC and LOAEC Maximum residues on food items

Survival Japanese carp and bluegill sunfish
acute LC 50 Peak EEC 4 Freshwater fish 3

Reproduction and growth Fathead minnow chronic (early life-stage) NOAEC and LOAEC 60-day average EEC 4

Survival Water flea acute EC 50 Peak EEC 4 Freshwater invertebrates

Reproduction and growth Water flea chronic (life cycle) NOAEC and LOAEC 21-day average EEC 4

Survival Sheepshead minnow acute LC 50 Peak EEC 4 Estuarine/marine fish

Reproduction and growth No data 60-day average EEC 4

Survival Quahog clam acute EC 50 and Grass shrimp acute LC 50 Peak EEC 4 Estuarine/marine invertebrates

Reproduction and growth No data 21-day average EEC 4Problem Formulation 29 Isoxaben Summary Document Assessment Endpoint Surrogate Species and Measures of Ecological Effect 1 Measures of Exposure

Terrestrial plants5 Survival and growth Monocot and dicot seedling emergence and vegetative vigor
EC 25 , and NOAEC values (no data) Estimates of runoff and spray drift to non-target

areas

Insects Survival (not quantitatively assessed) Honeybee acute contact LD50 Maximum application rate

Aquatic plants and algae Survival and growth Algal and vascular plant (i.e., duckweed) EC 50 and NOAEC values for growth rate and biomass

measurements (limited data) Peak EEC

1 If species listed in this table represent most commonly encount ered species from registrant-sub mitted studies, risk assessment guidance indicates most sensitive species tested within taxonom ic group are to be used for baseline risk assessments. LD 50 = Lethal dose to 50% of the test population; NOAEC = No observed adverse effect concentration; LOAEC = Lowest observed adverse effect concentration; LC 50 = Lethal concentration to 50% of the test population; EC 50 /EC 25 = Effect concentration to 50%/25% of the test population.

2 Birds represent surrogates for amphibians (terrestrial phase) and reptiles.

3 Freshwater fish may be surrogate s for amphibians (aquatic phase).

4 One in 10-year return frequency.

5 Four species of two families of monocots (i ncluding corn), six species of at least four dicot families (includi ng soybeans.)

Table 9. Levels of concern (LOCs) for various taxa.

Risk Presumption RQ LOC

Birds

Acute Risk EEC/LC 50 or LD 50 /sqft or LD 50 /day 0.5

Acute Restricted Use EEC/LC 50 or LD 50 /sqft or LD 50 /day (or LD 50 < 50 mg/kg) 0.2

Acute Endangered Species EEC/LC 50 or LD 50 /sqft or LD 50 /day 0.1

Chronic Risk EEC/NOAEC 1

Wild Mammals

Acute Risk EEC/LC 50 or LD 50 /sqft or LD 50 /day 0.5

Acute Restricted Use EEC/LC 50 or LD 50 /sqft or LD 50 /day (or LD 50 < 50 mg/kg) 0.2

Acute Endangered Species EEC/LC 50 or LD 50 /sqft or LD 50 /day 0.1

Chronic Risk EEC/NOAEC 1

Aquatic Animals

Acute Risk EEC/LC 50 or EC 50 0.5

Acute Restricted Use EEC/LC 50 or EC 50 0.1

Acute Endangered Species EEC/LC 50 or EC 50 0.05

Chronic Risk EEC/NOAEC 1Problem Formulation 30 Isoxaben Summary Document Risk Presumption RQ LOC

Terrestrial and Semi-Aquatic Plants

Acute Risk EEC/EC 25 1

Acute Endangered Species EEC/NOAEC or EC 05 1

Aquatic Plants

Acute Risk EEC/EC 50 1

Acute Endangered Species EEC/NOAEC or EC 05 1



### Preliminary Aquatic Risk

Based on preliminary results from GEN EEC and the provisional ecotoxicological endpoints, RQs do not exceed the acute risk LOCs , but do exceed the endangered species LOCs for fish, aquatic invertebrates and aquatic-phase amphibians ( Table 10 ). Chronic RQs are below the LOC, as is the RQ for aquatic nonvascular pl ants. Due to lack of data, risk to aquatic vascular plants is presumed.

Table 10. RQs for Aquatic Species Based on Preliminary EECs and Provisional Ecotoxicological Endpoints.
Species Endpoint EEC RQ

Freshwater Acute Carp LC50 >1.1 PPM 0.141 <0.13 Bluegill sunfish LC50 >1.1 PPM 0.141 <0.13

Water flea EC50 >1.3 PPM 0.141 <0.11

Chronic Fathead minnow NOEC 0.4 PPM 0.138 0.35

Rainbow trout NOEC 0.42 PPM 0.138 0.33

Water flea NOEC 0.69 PPM 0.140 0.20 Estuarine/marine Acute Grass shrimp LC50 >1 PPM 0.141 <0.14 Sheepshead minnow LC50 >0.87 PPM 0.141 <0.14 Quahog clam EC50 >0.96 PPM 0.141 <0.15 Plants Acute Aquatic vascular EC50 No data 0.141 -- Green algae EC50 >1.4 PPM 0.141 <0.10
*Bold indicates exceedance of LOC

Because the many of the studies do not resu lt in definitive endpoints, the exceedances noted above are uncertain. Typically acute aqua tic limit tests are conducte d to at least 100 ppm, but the solubility of isoxaben may have been a limitation in the submitted studies. While the actual acute RQs are less than the calculated RQ presented, it is not known how much lower the actual RQ would be. Review of the studies ma y provide insight into the degree of actual exceedance, if any, but that is uncertain at th is time. As noted in guideline 850.1000, in cases where solubility of a chemical limits the ability to determine toxicity ( i.e. testing limited to below 100 ppm), the use of formulated product in toxicity tests could provide a reasonable upper-bound estimate of possible exposure. Howeve r, given that isoxaben is a dry flowableProblem Formulation 31 Isoxaben Summary Document formulation, the use of appropriate levels of solvent in the submitted studies must be confirmed to assure toxic effects are above reasonable solubility limits.

While GENEEC is generally considered a Tier 1 model, there are PRZM/EXAMS scenarios (such as turf) that, in some instances, could result in higher EECs. Given that the vast majority of isoxaben is used in rights-of-way, turf, landscaping and othe r non-crop sites, specific scenarios may need to be developed to character ize the extent to which isoxaben may be present in aquatic ecosystems, given the potentia l risk to listed aquatic resources.



### Terrestrial Risk

Avian

Dietary-based and dose-based avian RQ values are calculated using the sub-acute dietary
LC 50 and the acute oral LD 50 , respectively. The dose-based ca lculation takes into account that different-sized animals have to consume diff erent amounts of food and the differing nutritional value of feed items. The LD 50 may give a better indication of inherent toxicity than the LC 50 in cases where food avoidance may be an issue in th e test animals. The greater energy demands in wild birds could make similar avoidance in natural settings unlikely. The subacute dietary LC 50 for isoxaben exceeded the highest dietary test co ncentration (2000 ppm; practically non-toxic); therefore, a definitive dietary-based RQs cannot be calculated. Using the highest dose tested to calculate RQs ( Table 11 ), the acute risk listed species LOC would be exceeded for birds foraging on short grass. However, it is not known how much higher than the highest dose tested the actually LC 50 would be, and based on the scientific re view of the study, acute avian dietary risk might not be of concern.

Table 11. Upper-bound Kenega Subacute Avian Dietary-based Risk Quotients EECs and RQs

Short Grass Tall Grass Broadleaf Plants/ Small Insects Fruits/Pods/ Seeds/ Large Insects

LC50 EEC RQ EEC RQ EEC RQ EEC RQ

>2000 335 <0.18 154 <0.08 189 <0.09 21.0 <0.01 Size class not used for dietary risk quotients

A definitive dose-based LD 50 for isoxaben was not defined, and the LD 50 exceeded the highest test dose (5000 ppm; practically non-t oxic), definitive dose-based RQs cannot be calculated. Using the highest dose tested to calculate RQs ( Table 12 ), the acute risk listed species LOC would be exceeded for the short gra ss forage category. However, it is not known how much higher than the highest dose tested the actually LD 50 would be, and based on the review of the study, acute avian diet ary risk might not be of concern.Problem Formulation 32 Isoxaben Summary Document Table 12. Upper-bound Kenega Acute Avian Dose-based Risk Quotients EECs and RQs

Short Grass Tall Grass Broadleaf Plants/ Small Insects Fruits/Pods/ Seeds/ Large Insects Size Class (grams) Adjusted LD50

EEC RQ EEC RQ EEC RQ EEC RQ

20 >3602 382 <0.11 175 <0.05 215 <0.06 24 <0.01

100 >4586 218 <0.05 100 <0.02 122 <0.03 14 <0.01

1000 >6477 98 <0.02 45 <0.01 55 <0.01 6.1 <0.01

Based on provisional data regarding avian re production, the chronic LOC is exceeded for birds foraging on short grass at the upper-bound of the Kenega nomogram ( Table 13 ). There are no chronic avian exceedances at the mean Kenega EEC, but the mean is expected to be exceeded about half the time. Terrestria l animal RQs are calculated usi ng a default foliar dissipation half life of 35 days. If data were generated that de monstrated, hypothetically, three-day half life was appropriate, the maximum RQ would be 0.8.

Table 13. Upper-bound Kenega Chronic Avian Dietary Based Risk Quotients

EECs and RQs

Short Grass Tall Grass Broadleaf Plants/ Small Insects Fruits/Pods/ Seeds/ Large
Insects NOAEC (ppm) EEC RQ EEC RQ EEC RQ EEC RQ

300 335 1.1 154 0.51 189 0.63 21 0.07
Size class not used for dietary risk quotients

Mammalian

With an LD50 >10,000 mg/kg-bw is classified as practically non-toxi c to mammals on an acute exposure basis. RQs calculated for illustrative purposes fall well below the acute risk LOC ( Table 14 ).

Table 14. Upper-bound Kenaga Acute Mammalian Dose-Based Risk Quotients

EECs and RQs

Short Grass Tall Grass Broadleaf Plants/ Small Insects Fruits/Pods/ Seeds/ Large Insects Granivore Size Class (grams) Adjusted
LD50

EEC RQ EEC RQ EEC RQ EEC RQ EEC RQ
15 21978 320 <0.01 147 <0.01 180 <0.01 20 <0.01 4.0 <0.01

35 17783 221 <0.01 101 <0.01 124 <0.01 14 <0.01 3.0 <0.01

1000 7692 51 <0.01 23 <0.01 29 <0.01 3.2 <0.01 0.71 <0.01Problem Formulation 33 Isoxaben Summary Document Two methods (dietary-based and dose-based) are used to estimate chronic risk to mammals and can result in considerably differe nt RQ estimates. The dose-based calculation takes into account that differe nt-sized animals have to consume different amounts of food and that the food itself has differing nutritional valu e. The dose-based RQ may give a better indication of inherent toxicity than the dietary-based RQ in cas es where food avoidance may be an issue in the test animals. If the dietary- based RQ values are adjusted to account for these factors, it is possible that these RQs would be roughly similar to the dose-based RQ values. Dose-based chronic RQs using the upper-bound residue s exceed the chronic risk LOC for all size classes foraging on short grass, ta ll grass and broadleaf plant/sma ll insect by factors of up to 6- fold (Table 15). Dietary-based chronic ri sk quotients do not exceed the LOC using upper-bound residue estimates for mammals ( Table 16 ). Using the mean residues, dose-based RQs exceed the LOC only for small and medium size classe s foraging on short grass and small mammals foraging on broadleaf plants/small insects. Howe ver, the mean residues are expected to be exceeded about half of the time.

Table 15. Upper-bound Chronic Mammalian Dose-Based Risk Quotients

Table 16. Upper-bound Chronic Mammalian Dietary-Based Risk Quotients EECs and RQs

Short Grass Tall Grass Broadleaf Plants/ Small Insects Fruits/Pods/ Seeds/ Large
Insects NOAEC (ppm)

EEC RQ EEC RQ EEC RQ EEC RQ

500 335 0.67 154 0.31 189 0.38 21 0.04 Size class not used for dietary risk quotients

There are both broadcast spra y and granular applications for isoxaben. While not presented here, the acute RQs from granular uses (EEC/LD 50 per ft 2 ) are similar to the broadcast acute RQs presented for both birds and mammals. Currently, chronic exposure from granular uses is not typically assessed, but because of the chronic LOC exceedances, potential chronic exposure from granular uses will need to be evaluated in the risk assessment.

Plants

Given that isoxaben is used as an herbicid e, effects on plants are to be expected. However, there are no data with which to evaluate the extent of effect isoxaben might have on non-target terrestrial plan ts. Given the role of plants in any given ecosystem (e.g. primary productivity, habitat), negative effects on plan t species, populations, and community composition EECs and RQs

Short Grass Tall Grass Broadleaf Plants/ Small Insects Fruits/Pods/ Seeds/ Large
Insects Granivore Size Class

(grams) Adjusted NOAEL

EEC RQ EEC RQ EEC RQ EEC RQ EEC RQ

15 54.95 320 5.8 147 2.7 180 3.3 20 0.36 4.4 0.08

35 44.46 221 5.0 101 2.3 124 2.8 14 0.31 3.1 0.07

1000 19.23 51 2.7 23.5 1.2 29 1.5 3.2 0.17 0.71 0.04Problem Formulation 34 Isoxaben Summary Document could have appreciable indirect effects on higher trophic-level or ganisms, including endangered species.

Preliminary Identification of Data Gaps

Until the submitted studies are fully reviewed, the extent of environmental fate data needed to conduct an ecological ri sk assessment is uncertain. If the provisional data can be used, need for new data may be limited.

Table 17. Evaluation of the need fo r additional fate data on isoxaben Assessment endpoint with data gap Projected status of data gap Basis for decision

Photodegradation in soil (161-3) Required A soil photolysis study is required under 40 CFR Part 158, Data Requirements for Registration. In addition, no route of dissipation for isoxaben in the terrestrial environment has been established. Therefore, the soil photolysis study is required to determine if this is a route of dissipation for isoxaben in the terrestrial environment. Prospective groundwater study (166-1) Proposed to hold study ‘In Reserve’ Isoxaben has demonstrated the ability to leach and may present a groundwater concern. However, no food uses have been assessed to date, therefore degradates of concern and potential negative effects to human health have not been evaluated. Therefore, a prospective groundwater study should be held ‘In Reserve’ at this time. Hydrolysis (161-1) Required (pending review of submitted studies MRIDs 132123 & 132124) At this time no hydrolysis DERs were available for review and isoxaben was presumed to be stable to hydrolysis. If the hydrolysis studies submitted for review are found to be acceptable, th e data gap may be filled. However, if these studies are not acceptable, the data gap may remain and present additional uncertainty when assessing the fate of isoxaben. Aqueous photolysis (161-2) Required (pending review of submitted study MRID 47140003) Aqueous photolysis appears to be a route of dissipation for isoxaben in the aquatic environment. However, degradates were not comple tely characterized in the available study. An additional aqueous photolysis was submitted for review and if this study is found to be acceptable, the data gap may be filled. However, if this study is not acceptable, the data gap may remain and present additional uncertainty when assessing the fate of isoxaben.

Based on the information presented in this pr oblem formulation, a soil photolysis study will be needed to conduct an environmental risk assessment. A soil photolysis study is required under 40 CFR Part 158, Data Requirements for Regist ration. In addition, no route of dissipation for isoxaben in the terrestrial environment has been established. Therefore, the soil photolysis study is required to determine if this is a route of dissipation for isoxaben in the terrestrial environment. At this time no hydrolysis DERs were available for review and isoxaben was presumed to be stable to hydrolysis. In additi on, aqueous photolysis appe ars to be a route of dissipation for isoxaben in the aquatic environment. However, degradates were not completely characterized in the available st udy. Additional hydrolysis and aqueous photolysis studies wereProblem Formulation 35 Isoxaben Summary Document submitted for review and if these studies are found to be acceptable, the data gaps may be filled. However, if these studies are not acceptable, th e data gaps may remain and present additional uncertainty when assessing the fate of isoxaben. Finally, isoxaben has demonstrated the ability to leach and may present a groundwater concern. However, no food uses have been assessed to date, therefore degradates of concern and poten tial negative effects to human health have not been evaluated. Therefore, a pros pective groundwater study should be held ‘In Reserve’ at this time.

Table 18. Evaluation of the need for addi tional effects data on isoxaben

Assessment endpoint with data gap Projected status of data gap Basis for decision

Toxicity to non-target terrestrial plants, crops and non-crop species (850.4100, 850.4150, seedling emergence and vegetative vigor) Required Scientifically justifiable alterna tive conservative assumptions will be made concerning potential risk to terrestrial plants in the absence of terrestrial plant toxicity data for an herbicide. These data are considered critical for herbicides. An action area for endangered speci es is dependent on toxicity to terrestrial plants. Also, potential mitigation measures cannot be evaluated without valid terrestrial plant studies.

Toxicity to non-target aquatic vascular plants (850.4500) Required Scientifically justifiable alterna tive conservative assumptions will be made concerning potential risk to aquatic vascular plants in the absence of toxicity data for an herbicide. Indirect effects to endangered species through forage reduction and habitat alteration cannot be evaluated in the absence of toxicity data

Toxicity to Aquatic Nonvascular plants
(850.4400) Required (pending review of submitted study MRID 00132147) This study is non-guideline, but may be sufficient for an ecological risk assessment pending review. However, four aquatic non-vascular plants should be tested.

Avian Single Dose Oral Toxicity
(71-1) Required (pending review of submitted study MRID 00132141) These data are required to assess the potential risk the use of isoxaben may pose to birds, reptiles and terrestrial-phase amphibians.

Avian Dietary Toxicity
(71-4) Required (pending review of submitted studies
MRIDs 00132142 & 00132143) These data are required to assess the potential risk the use of isoxaben may pose to birds, reptiles and terrestrial-phase amphibians.

Avian Reproduction
(71-4) Required (pending review of submitted studies MRIDs 00153109; & 00153110) These data are required to assess the potential risk the use of isoxaben may pose to birds, reptiles and terrestrial-phase amphibians.

Acute Toxicity to Freshwater Fish
(72-1) Required (pending review of submitted studies MRIDs 00132145, 00132146 & 00137844) These data are required to assess the potential risk the use of isoxaben may pose to fish and aquatic-phase amphibians.

Acute Toxicity to Freshwater Invertebrates
(72-2) Required (pending review of submitted study MRID 00132144) These data are required to assess the potential risk the use of isoxaben may pose to freshwater invertebrates.Problem Formulation 36 Isoxaben Summary Document Assessment endpoint with data gap Projected status of data gap Basis for decision

Acute Toxicity to Estuarine/Marine Organisms (72-3) Required (pending review of submitted studies MRIDs 40531302, 40531303 & 40531304) These data are required to assess the potential risk the use of isoxaben may pose to estuarine/marine organisms.

Fish Early Life-stage/Aquatic Invertebrate Life Cycle
(72-4 ) Required (pending review of submitted studies MRIDs 00137845, 00137847, & 00137848) These data are required to assess the potential risk the use of isoxaben may pose to fish and aquatic-phase amphibians.

The full extent of ecotoxicological data need ed to conduct an ecological risk assessment will not be known until the submitted data is fully reviewed. If the provisional data can be used, the need for new data may be limited. Based on the information presented in this problem formulation, terrestrial plant vegetative vigor an d seedling emergence studies will be needed to conduct an environmental risk assessment. Without these studies, risk to all plants will need to be presumed, and it will not be possible to evalua te potential risk mitigation measures nor will it be possible to define the action area for direct an d indirect effects to Fe derally-listed threatened and endangered species. Similarly, there are no data assessing the potential effect of isoxaben to aquatic vascular plants, and theref ore risk will need to be presumed, and the same limitations on the risk assessment listed above fo r terrestrial plants will apply.Problem Formulation 37 Isoxaben Summary Document References

Fletcher, J.S., J.E. 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. Toxicol. Chem. 13: 1383-1391.

Hoerger, F. and E.E. Kenaga. 1972. Pesticide re sidues on plants: correlati on of representative data as a basis for estimation of their magnitude in the environment. Environmental Quality and Safety. 1: 9-28.

Salihu S., K. K. Hatzios and J. F. Derr. 1998. Comparative Uptake, Translocation, and Metabolism of Root-Applie d Isoxaben in Ajuga ( Ajuga reptans ) and Two Ornamental Euonymus Species. Pesticide Biochemistry and Physiology , 60:2 pp 119-131

Urban D.J. and N.J. Cook. 1986. Hazard Evalua tion Division Standard Evaluation Procedure Ecological Risk Assessment. EP A 540/9-85-001. U.S. Environmen tal Protection Agency, Office of Pesticide Programs, Washington, DC.

USEPA. 1998. Guidelines for Ecological Risk Assessment. Risk Assessment Forum, Office of Research and Development, Washington, D.C. EPA/630/R-95/002F. April 1998.

USEPA. 2000. Risk Characterization Handbook. Science Policy Council, U.S. Environmental Protection Agency, Washington, D.C. 20460. EPA 100-B-00-002. December 2000.

USEPA. 2002. Guidance for Selecting Input Parame ters in Modeling the E nvironmental Fate and Transport of Pesticides. U.S. Environmenta l Protection Agency, Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, Environmental Fate and Effects Division. Feb. 28, 2002. Online at: http://www.epa.gov/oppefed1/models /water/input_guidance2_28_02.htm/.

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs, U.S. Environmental Protection Agency. Endangered and Threatened Species Effects Determinations. Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, Washington, D.C. January 23, 2004.

USEPA. 2005. Generic Format and Guidance for the Level I Screening Ecological Risk Assessments Conducted in the Environmental Fate and Effects Division. Office of Pesticide Programs, Washington, D.C. January 24, 2005.

USEPA. 2006. Water Models. U.S. Environmenta l Protection Agency, Pesticides: Science and Policy. Last updated May 2, 2006. Online a t: ttp://www.epa.gov/oppefed1/models/water/.

Willis, Guye H., and Leslie.L. McDowell. 1987. Pesticide Persistence on Foliage. in Reviews of Environmental Contamination and Toxicology . 100:23-73.Scoping Document 38 Isoxaben Summary Document UNITED STATES ENVIRONMEN TAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE: August 16, 2007

SUBJECT: Isoxaben: Registration Review Scoping Document for Human Health Assessments; PC Code: 125851; DP Number: D341567; Registration Review Case Number: 7219.

REVIEWER: Charles Smith, Risk Assessor/Environmental Scientist Deborah C. Smegal, M.P.H, Toxicologist Donald Wilbur, Chemist Reregistration Branch 2 Health Effects Division (7509P)

THROUGH: Jack Housenger, Associate Division Director Health Effects Division (7509P)

TO: Jaqueline Guerry, Chemical Review Manager Reregistration Branch III Special Review and Re registration Division (7508C)

Attached is the human health scoping documen t to support the regist ration review of the herbicide isoxaben.Scoping Document 39 Isoxaben Summary Document HED Preliminary Work Plan for th e Registration Review of Isoxaben (PC Code 125851)

Introduction

The Health Effects Division (HED) Isoxaben Regist ration Review Team has evaluated the status of the human health assessments for the herbic ide isoxaben to determine the scope of work necessary to support registration review. The team looked at th e hazard and exposure databases for isoxaben to determine whether changes in scien ce policy, newly available data or deficiencies in the databases materially affected the overall risk picture. The primary sources for the status update were HED and OPPIN databases and a se arch of the open literature using Google Scholar. The HED Risk Assessment team includes Charles Smith, Deborah Smegal, and Donald Wilbur.

Isoxaben is a preemergent herbicide mainly used to control broadleaf weed species. The primary effect of isoxaben is on seedling growth; germin ation is not prevented, but once germination occurs, growth is inhibited. It was first re gistered by the Environmental Protection Agency on December 4, 1989. Both residential and occupati onal exposures can be expected to occur from the registered uses of isoxaben which in cludes uses on Christmas trees, conifer trees, ornamentals (container grown, field grown, a nd landscape), ornamental bulbs, non-bearing fruit and nut trees, non-bearing vineyards, and turf (n ot for use on commercially grown turf). The Agency has also recently received a request to re gister isoxaben for food uses under the Pesticide Registration Improvement Act (PRIA).

HED does not believe that any new toxicological or exposure data are needed for isoxaben. The toxicological database for isoxaben is adequate for the purpose of regist ration review and most likely also for the proposed food uses in the upco ming PRIA action. HED will need to revisit the cancer potency estimate based on the lack of a dose-response relationshi p as well as select additional endpoints for acute dietar y, incidental oral, dermal a nd inhalation exposures during the registration review process.

Isoxaben currently has no estab lished tolerances on food or an imal commodities. Therefore isoxaben is currently considered to be a non-food use and a dietary assessment is not required. The proposed food uses in the upcoming PRIA ac tion will require dietary assessments (acute, chronic, and cancer) and will be subject to FQPA.

Drinking water risks have not been assessed fo r isoxaben. The current turf use requires screening level groundwater and surface water anal yses. The HED isoxaben team believes that drinking water risks should be evaluated to ensure the turf use is acceptable at current use rates. The proposed food uses in the upcoming PRIA action will also require screening level groundwater and surface water analyses.

Occupational and residential handler and postapp lication assessments, with the exception of cancer risks for children on treate d turf (USEPA 1989); have not b een conducted for isoxaben. These assessments will be required during the registration review process.Scoping Document 40 Isoxaben Summary Document Section 1. Chemical Identity

Table 1.1 Chemical Identity
Common Name Isoxaben
IUPAC name N -[3-(1-ethyl-1-methylpropyl)-1,2-ox azol-5-yl]-2,6-dimethoxybenzamide
CAS name N -[3-(1-ethyl-1-methylpropyl)-5-iso xazolyl]-2,6-dimethoxybenzamide
PC Code 125851 CAS registry number 82558-50-7 Registration Review
Case No. 7219

Chemical Structure

Section 2. Toxicology

Isoxaben is a pre-emergent herbic ide for control of broadleaf weeds. The technical chemical consists of three isomers, which differ in the isox azolyl side chain. Pesticidal uses of isoxaben do not currently involve use on f ood and therefore, are not subject to the Food Quality Protection Act (FQPA) (1996). However, the Agency has r ecently received a request to register isoxaben for food uses under the Pesticide Registration Im provement Act (PRIA). This new action would be subject to FQPA.

Isoxaben has low acute toxicity vi a the oral and dermal routes (category III and IV), and is slightly more toxic via the inhalation route (categor y II and III). It is not an acute eye or skin irritant and is not a dermal sensitizer. The major target organ for isoxaben is the liver in rats, dogs and mice. In rats, liver effects include increased enzymes, and organ weight with concurrent liver hypertrophy. In dogs, increased liv er weight and enzyme induction were noted. In the chronic mouse study, liver adenom as, hyperplasia, increased liver weight, hepatocytomegaly and hepatocelluar vacuolatio n were observed at high doses following chronic

exposure.

The evidence from the considerable body of me tabolism data indicates a possible concern for bioaccumulation. However, there are currently adequate metabolism data to support evaluation of the existing uses.

In the rat developmental study, fetal toxicity manifested as increased preimplantation loss, increased resorptions, smaller litter size and increas ed numbers of runt fetuses and occurred in the presence of maternal toxi city (decreased body weight) at the limit dose of 1000 mg/kg. There was no significant maternal or fetal toxicity in rabbits at the limit dose of 1000 mg/kg. In a three generation rat reproductive study, deve lopmental toxicity (d ecreases in viableScoping Document 41 Isoxaben Summary Document fetuses/litter, increased hydr oureter, and microphthalmia) occu rred only in the presence of maternal toxicity (decreased body weight/body wei ght gain, increased liver /body weight ratios).

The toxicological database for isoxaben is adequa te for the purpose of registration review and most likely also for the proposed food uses in the upcoming PRIA action. A short-term inhalation study is not available to assess occupati onal and residential risk. As such an oral guideline toxicity study and endpoint will likely be used to estimate risk from inhalation exposure. The toxicity endpoints shown in Tabl e 2.1, below were selected by HED in 1987 and
1989.

In 1987, HED evaluated the existing toxicology data and selected an RfD (Acceptable daily intake) that was verified by the Agency-wide RfD Committee and is currently available on the Integrated Risk Information System (IRIS). In addition, HED classified isoxaben as a group C (possible human carcinogen), wit hout a quantitative risk assess ment based on a statistically significant increase in benign tumors in one spec ies only (mouse). The tumors in the mouse (liver adenomas) were present in both sexes howev er, tumor incidence was statistically increased at the high dose only, the tumors were of a co mmon type, were predominantly benign, and there was no decrease in latency. The incidence was above historical controls, but a dose-response relationship was not found. The weight-of-eviden ce suggests there is not an overt mutagenicity concern for isoxaben. Subsequently, HED estim ated an oral cancer potency value (Q1*) and dermal absorption factor to assess the hypothetical can cer risks for a child playing on treated turf.

The risk assessment team has reevaluated the exis ting RfD and found this value to be consistent with current science policy. Since Agency cancer policies have changed since the 1987 isoxaben cancer review, HED recommends that the cancer pot ency estimate be re-evaluated based on the lack of a dose-response relationship. This re -evaluation will be performed by the HED Cancer Assessment Review Committee (CARC) and based on the recent EPA Guidelines for Carcinogen Risk Assessment (March 2005). HED will also need to select additional endpoints for incidental oral, dermal and inhalation exposures to assess the residential and occupational uses of isoxaben. The HED team believes that there are reliable da ta to select these endpoints and determine the appropriate uncertainty factors for the process of registration review. In addition, the HED team believes there are reliable toxicol ogical data to select an acute dietary endpoint to assess potential drinking water and future food exposures.Scoping Document 42 Isoxaben Summary Document Table 2.1 Summary of Toxicological Doses and Endpoints for Isoxaben for Use in Human Risk Assessments

Exposure Scenario Point of Departure Uncertainty
Factor RfD, Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (females 13-49) and General population Value not previously selected, but database is sufficient to identify an endpoint.

Chronic Dietary (all populations) NOAEL =
5 mg/kg/day UF A = 10x
UF H = 10x RfD = 0.05 mg/kg/day Combined chronic toxi city/ carcinogenicity study in rats. LOAEL=50.7 mg/kg/day based on increased blood urea nitrogen (BUN), decreased alkaline phosphatase and aspartate aminotransferase (AST), decreased food efficiency and increased heart/body weight in males.
Incidental Oral (all durations) Value not previously selected, but database is sufficient to identify an endpoint.

Dermal (all durations) Value not previously selected. No systemic toxicity was found in the dermal 21-day study at the limit dose of 1055 mg/kg/day.
Inhalation (All durations) Value not previously selected, but database is sufficient to identify an endpoint.

Cancer Classification Group “C”, without quantitative risk assessment. Previous Screening Level Q1*= 2.3x10 -3 (mg/kg/day) -1 and dermal absorption factor of 11%.

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of human population (intraspecies). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. RA = risk assessment.

HED does not anticipate that any new toxicology data would be required for the registration review process.

Section 3. Current Dietary Assessments

Isoxaben currently has no estab lished tolerances on food or an imal commodities. Therefore isoxaben is currently considered to be a non-food use pesticide and a dietary assessment is not required. However, the Agency has recently receiv ed a request to register isoxaben for food uses under the PRIA. These new food uses will require dietary assessments (acute, chronic, and cancer) and will be subject to FQPA.

Drinking water risks have not been assessed fo r isoxaben. The current turf use requires a screening level groundwater and surface water anal ysis. The HED isoxaben team believes that drinking water risks should be evaluated to ensure the turf use is acceptable at current use rates. The proposed food uses in the upcoming PRIA action will also require screening level groundwater and surface water analysis.

Section 4. Aggregate and Cumulative ExposureScoping Document 43 Isoxaben Summary Document An aggregate assessment is not required since there are currently no food uses for isoxaben. However, aggregate assessments (acute, chronic, and cancer) will be necessary in the future based on the recent request to register food uses for isoxaben.

Section 5. Occupational and Residential Exposure

Occupational handler and postapplic ation assessments have not been conducted for isoxaben. Occupational handler assessments will be require d in registration review for ornamentals, conifers, bulbs, and turf. Occupational postapplication assessments will be required in registration review for or namentals and conifers.

Residential handler and postapplication assessmen ts have not been conducted for isoxaben with the exception of a 1989 cancer risk assessment for children on trea ted turf (USEPA 1989). The children turf scenario cancer assessment will need to be updated depending on the outcome of the cancer re-evaluation (discussed in Section 2) and to reflect current Agency policies. Residential handler and postapplication assessments will be required in registration review for ornamentals and turf.

The isoxaben registrants have previously subm itted a Turf Transferable Residue (TTR) study (MRID 45040701) and a Dislodgeable Foliar Re sidue (DFR) study (MRID 45249801) in 2000. Both of these studies will be used by HED in the occupational and residential exposure assessments produced for isoxaben during the registration review process.

Section 6. Anticipated Data Needs

HED does not believe additional data are needed for registration review.

Section 7. Tolerances

Isoxaben currently has no tole rances established under 40 CFR.

Section 8. Overall Conclusions

HED does not believe that any new toxicological or exposure data are needed for isoxaben. The toxicological database for isoxaben is adequate for the purpose of regist ration review and most likely also for the proposed food uses in the upcoming PRIA action. During the registration review process, HED will need to revisit the ca ncer potency estimate based on the lack of a doseresponse relationship as well as select additiona l endpoints for acute diet ary, incidental oral, dermal and inhalation exposures.

Isoxaben currently has no estab lished tolerances on food or an imal commodities. Therefore isoxaben is currently considered to be a non-food use and a dietary assessment is not required. The proposed food uses in the upcoming PRIA ac tion will require dietary assessments (acute, chronic, and cancer) and will be subject to FQPA.Scoping Document 44 Isoxaben Summary Document Drinking water risks have not been assessed fo r isoxaben. The current turf use requires a screening level groundwater and surface water anal ysis. The HED isoxaben team believes that drinking water risks should be evaluated to ensure the turf use is acceptable at current use rates. The proposed food uses in the upcoming PRIA action will also require screening level groundwater and surface water analysis.

Occupational and residential handler and postapp lication assessments have not been conducted for isoxaben. These assessments will be re quired during the registra tion review process.

Section 9. Reference Memoranda

The memoranda and studies listed in Table 9.1 were considered in the development of this document.

Table 9.1. HED Memoranda Relevant to Registration Review

Author Barcode Date Title Becky Daiss D263674, D235658,
D235659 2/05/03 Review of “Dissipation of Transferable Residues of Isoxaben and Oryzalin on Turf Treated with Formulations of the Pesticides”
Michael Firestone N/A 3/14/89 Isoxaben Exposure Estimate for Children Playing on Treated Lawns Margaret L.
Jones TXR 006559 12/15/87 EL-107 (Isoxaben) Toxicology Chapter of the New Chemical Registration Standard C.J. Nelson R055411 5/1/87 Isoxaben, Rat and Mouse study—Qualitative Risk Assessment of Combined Toxicity and Oncogenicity Study
Esther Rinde TXR 0052703 10/3/87 Peer Review of Isoxaben
K. Clark Swentzel TXR 004012 5/4/89 Isoxaben 9Gallery): Risk Assessment for Children Playing on Treated Lawns K. Deerfield 037073.pdf 6/17/88 Overview of Submitted Mutagenicity Studies on IsoxabenGlossary 45 Isoxaben Summary Document V. Glossary of Terms and Abbreviations

ai Active Ingredient AR Anticipated Residue CFR Code of Federal Regulations cPAD Chronic Population Adjusted Dose CSF Confidential Statement of Formula CSFII USDA Continuing Surveys for Food Intake by Individuals DCI Data Call-In DEEM Dietary Exposure Evaluation Model DFR Dislodgeable Foliar Residue DNT Developmental Neurotoxicity DWLOC Drinking Water Level of Comparison EC Emulsifiable Concentrate Formulation EDWC Estimated Drinking Water Concentration EEC Estimated Environmental Concentration EPA Environmental Protection Agency EUP End-Use Product FDA Food and Drug Administration FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FFDCA Federal Food, Drug, and Cosmetic Act FQPA Food Quality Protection Act FOB Functional Observation Battery GENEEC Tier I Surface Water Computer Model IR Index Reservoir
LC 50 Median Lethal Concentration. A statistica lly derived concentration of a substance that can be expected to cause death in 50% of test animals. It is usually expressed as the weight of substance per weight or volume of water, air or feed, e.g., mg/l, mg/kg or ppm.
LD 50 Median Lethal Dose. A statistically derive d single dose that can be expected to cause death in 50% of the test animals when admini stered by the route i ndicated (oral, dermal, inhalation). It is expressed as a weight of substance per unit weight of animal, e.g., mg/kg. LOC Level of Concern LOAEL Lowest Observed Adverse Effect Level μg/g Micrograms Per Gram μg/L Micrograms Per Liter mg/kg/day Milligram Per Kilogram Per Day mg/L Milligrams Per Liter MOE Margin of Exposure MRID Master Record Identifi cation (number). EPA's system of recording and tracking submitted studies. MUP Manufacturing-Use Product NA Not Applicable NAWQA USGS National Ambient Water Quality Assessment NPDES National Pollutant Discharge Elimination System NR Not Required NOAEL No Observed Adverse Effect Level OPP EPA Office of Pesticide Programs OPPTS EPA Office of Prevention, Pesticides and Toxic Substances PAD Population Adjusted Dose PCA Percent Crop Area PDP USDA Pesticide Data Program PHED Pesticide Handler's Exposure DataGlossary 46 Isoxaben Summary Document PHI Preharvest Interval ppb Parts Per Billion PPE Personal Protective Equipment ppm Parts Per Million PRZM/EXAMS Tier II Surface Water Computer Model Q 1 * The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer Risk Model RAC Raw Agriculture Commodity RED Reregistration Eligibility Decision REI Restricted Entry Interval RfD Reference Dose RQ Risk Quotient SCI-GROW Tier I Ground Water Computer Model SAP Science Advisory Panel SF Safety Factor SLN Special Local Need (Registra tions Under Section 24©) of FIFRA) SOP Standard Operating Procedure TGAI Technical Grade Active Ingredient USDA United States Department of Agriculture UF Uncertainty Factor WPS Worker Protection Standard WQ Water Quality