Page 1 of 48 UNITED STATES ENVIRONMENTA L PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SA FETY AND POLLUTION PREVENTION MEMORANDUM Date: October 12 , 2010 SUBJECT: Fo mesafen Sodium : Human Health Risk Assessment for the Establishment of

Tolerances and Registration of New Use s of Fomesafen Sodium on Potatoes and Pep pers . PC Code: 123802 DP Barcode: D373600 Decision No.: 425353 and 426814 Re gistration No. : 100 - 993 Petition No . : 9F7563 (potato), 9F7667 (pepper) Regulatory Action: Section 3 Registration Risk A ss essment Type : Human Health Risk Assessment Case No.: NA T XR No.: NA CAS No.: 72178 - 02 - 0 MRID No . : NA 40 CFR: § 180.433 FROM: Alexandra LaMay , Risk Assessor

Christine Olinger , Chemist Kit Farwell , Toxicologist Risk Assessment Branch VII Health Effects Division (7509P) THROUGH: Michael Metzger , Branch Chief

Risk Assessment Branch VII Health Effects Division (7509P) TO: Michael Walsh, PM Team 23

Herbicide Branch , R egistration Division ( 7505 P) This document provides the Health Effects Division (HED) human health risk assessment for the proposed establishment of tolerances and registration of the new use s of the herbicide fomesafen sodium on potatoes and peppers .Page 2 of 48 Table of Contents 1.0 Executive Summary ................................ ................................ ................................ .......... 4 2.0 Ingredient Profile ................................ ................................ ................................ .............. 7 2.1 Summary of Registered and Proposed Uses ................................ ....................... 8 2.2 Structure and Nomenclature ................................ ................................ ............... 9 2.3 Physical and Chemical Properties ................................ ................................ ..... 10 3.0 Hazard Characterization/Assessment ................................ ................................ ........... 11 3.1 Hazard and Dose - Response Characterization ................................ .................. 11 3.1.1 Database Summary ................................ ................................ ................. 11 3.1.2 Toxicological Effects ................................ ................................ ............... 11 3.2 Absorption, Distribution, Metabolism and Excretion ................................ ..... 11 3.2 Safety factor for Infants and Children (FQPA Safety Factor) ....................... 12 3.3.1 Completeness of the Toxicology Database ................................ ............ 12 3.3.2 Evidence of Neurotoxicity ................................ ................................ ...... 12 3.3.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ................................ ................................ ................................ .................. 12 3.3.4 Residual Uncertainty in the Exposure Database ................................ .. 13 3.4 Hazard Identification and Toxicity Endpoint Selection ................................ .. 13 3.4.1 Level of Concern for Margin of Exposure ................................ ............ 13 3.4.2 Recommendation for Combining Routes of Exposures for Risk Assessment ................................ ................................ ................................ ........... 13 3.4.3 Classif

ication of Carcinogenic Potential ................................ ............... 13 3.4.4 Toxicological Doses and Endpoints ................................ ....................... 14 3.5 Endocrine Disruption ................................ ................................ ......................... 15 4.0 Public Health and Pesticide Epidemiology Data ................................ .......................... 15 5.0 Dietary Exposure/Risk Characterization ................................ ................................ ..... 15 5.1 Residues of Concern ................................ ................................ ........................... 15 5.2 Residue Profile ................................ ................................ ................................ .... 17 5.2.1 Drinking Water Residue Profile ................................ ............................ 17 5.2.2 Food Residue Profile ................................ ................................ ............... 18 5.3 Dietary Exposure and Risk ................................ ................................ ................ 19 5.3.1 Acute Dietary Expo sure/Risk ................................ ................................ . 19 5.3.2 Chronic (Non - Cancer and Cancer) Dietary Exposure/Risk ............... 19 5.4 Anticipated Residue and Percent Crop Treated (%C T) Information ........... 20 5.5 Tolerance Assessment ................................ ................................ ......................... 20 5.5.1 Enforcement Analytical Method ................................ ........................... 20 5.5.2 Tolerance Recommendation ................................ ................................ .. 20 5.5.3 International Harmonization ................................ ................................ . 21 6.0 Residential (Non - Occupational) E xposure ................................ ................................ ... 21 7.0 Aggregate Risk Assessments ................................ ................................ .......................... 22 8.0 Occupational Exposure and Risk ................................ ................................ .................. 22 8.1 Occupational Handler Exposure ................................ ................................ ....... 22 8.1.1 Occupational Handler Risk ................................ ................................ .... 23 8.2 Occupational Post - application Exp osure ................................ .......................... 25 9.0 Environmental Justice ................................ ................................ ................................ .... 26Page 3 of 48

10. 0 Data Needs ................................ ................................ ................................ ........... 27 11.0 References ................................ ................................ ................................ ............ 27 Appendix A: Toxicology Assessment ................................ ................................ ....................... 29 A.1 Toxicology Data Requirements ................................ ................................ .......... 29 A.2 Toxicity Profiles ................................ ................................ ................................ .. 30 Appendix B. Toxicity Summaries ................................ ................................ .............................. 33 Appendix C: Review of Human Research ................................ ................................ ............... 43 Appendix D: Rationale for Toxicology Data Requirements ................................ .................. 44 Appendix E. Confined Rotational Crop Summary Table ................................ ....................... 46Page 4 of 48

1.0 Executive Summary The Health Effects Division (HED) has conducted a human health risk assessment for the active ingredient f

omesafen 5 - [2 - chloro - 4 - (trifluoromethyl)phenox y] -N - (meth yl sulfonyl) - 2 - nitrobenz amide) for the purpose of establishing a tolerance and registering a new use on potatoes and peppers . Fomesafen sodium is an herbicide used for control of broadleaf weeds. Fomesafen products are formulated as the sodium salt and the concentration of the active ingredient in the formulation is expressed in terms of the acid equivalent (ae). Fomesafen sodium is in the diphenylether chemical class and it mode of action is via inhibition of protoporphy rinogen oxidase (PPO) in the plant. There are no resident ial uses for fomesafen . Reflex  Herbicide ( 22.8 % active ingredient sodium salt of fomesafen ) is applied at a maximum rate of 1 pt of product per acre (0.25 lb ae/A) on potatoes and at a maximum rate of 1.5 pt of product per acre (0.375 lb ae/A) on transpl anted peppers . The product is applied to potatoes as a broadcast pre emergence application after planting but before potato emergence with a 70 day pre - harvest interval (PHI) ; the product is applied to transplanted peppers as a pre - plant non - incorporated pre emergence broadcast applications up to seven days prior to transplanting peppers with a 60 day PHI . Hazard Characterization The toxicological database for fomesafen is considered complete and adequate for the purposes of this risk assessment. Fom esafen has a low order of acute toxicity by the oral route of exposure (Toxicity

Category I II), is severely

irritating to the eye and is moderatel y irritating to the skin. In the subchronic and chronic toxicity studies in rats and mice, food consumption o r food efficiency , body

weight/body

weight gain and histopathological changes in the liver were the parameters that were most often affected. In addition, dogs and mice also showed hematological changes (e.g., decreased ery throcy te count, hemoglobin, or h ematocrit). Carcinogenicity was not observed in the rat chronic toxicity /carcinogenicity study . Liver tumors were produced in the mouse carcinogenicity study; however, HED’s Cancer Assessment Review Committee (CARC) determined that fomesafen should be cl assified as “Not L ikel y to be Carcinogenic to Humans”. This decision was based on the weight - of - evidence which supports activation of peroxisome proliferator - activated receptor alpha (PPARα) as the mode of action for fomesafen - induced hepatocarcinogenesis in mice. Fomesafen was not considered to be mutagenic, nor did this chemical show signs of neurotoxicity . No quantitative or qualitative evidence of increased susceptibility was seen following in utero exposure to rats or rabbits in developmental studi es or in the reproduction study . Immunotoxicity, acute neurotoxicity , and subchronic neurotoxicity

studies are now required. An immunotoxicity study is expected to be completed b y Sy

ngenta in July

2011. There was no evidence of increased susceptibility of fetuses or offspring in developmental or reproductive toxicity

studies and the FQPA safety factor was reduced to 1X. There were no observed toxic effects which were attributable to a single dose of fomesafen; therefore, an endpoint for acute dietary risk was not selected , and quantitative aggregate dietary assessments were not conducted.Page 5 of 48

The point of departure used to establish the chronic population adjusted dose ( cPAD ) was microscopic liver changes in the chronic toxicity study in rats. An endpoint for incidental oral exposure (short and intermediate term) for infants and children was microscopic liver changes, increased liver weights in males and females, and increases in liver enzy mes in a 90 - day

study in rats. The endpoint to assess short - and intermediate - term dermal risk was postimplantation loss and decreased maternal body weight gain in the developmental toxicity study in rats. A dermal absorption value of 20% (based on dermal absorption factors for similarly structured compounds) was appl ied. The endpoint to assess long - term dermal and inhalation risk was microscopic liver changes in the chronic toxicity study in rats. The endpoint to assess short and intermediate term inhalation exposure was microscopic liver changes, increased liver w eights in males and females, and increases in liver enzy mes in a 90 - day study in rats. Residue Data Sufficient residue data are available to support the proposed tolerance in/on potatoes and peppers . The residue of concern is onl y the parent, fomesafen. The residue data are supported by adequate storage stability data and an analy

tical method is available to support the proposed tolerance in/on potatoes and peppers . The residues in the magnitude of residue studies were below the level of detection . Di etary Exposure and Risk The environmental fate data indicated that fomesafen is likely to be persistent and mobile in aquatic and terrestrial environments. EFED has calculated estimated drinking water concentrations (EDWCs) in surface water using PRZM - EXAMS modeling and has recommended the use of a prospective groundwater water study to estimate concentrations in drinking water derived from groundwater sources. Since the only dietary assessment relevant to this action is a chronic dietary assessment, HED used the maximum annual average concentration value from PRZM - EXAMS of 10.5 ppb for surface water E DW Cs ; since the prospective groundwater moni toring concentration of 1.0 ppb is lower than the surface water value, dietary

assessment using the surface wate r residue will be protective for residues in groundwater. Chronic dietary

risk assessments were conducted for fomesafen sodium using the Dietary Exposure Evaluation Model (DEEM - FCIDTM), Version 2.03, which used food consumption data from the United States Department of Agriculture’s (USDA’s) Continuing Survey s of Food Intakes b y Individuals (CSFII) from 1994 - 1996 and 1998. A conservative chronic dietary exposure and risk assessment was conducted using tolerance level residues, 100% crop treated assumptions for most commodities, default processing factors in the absence of empirical data and modeled drinking water values. The dietary exposure analy ses in this assessment result in dietary risk estimates for food and water that are below the Agency ’s level of concern for chronic dietary exposure for all population groups. The subgroup with the highest exposure and risk estimates is infants. The exposure for food plus surface w ater was 0.000 813 mg/kg/day , which is 32% of the chronic population adjusted dose ( cPAD ) .Page 6 of 48

Aggregate Risk Assessment There are no residential uses for products formulated with fomesafen sodium, therefore an incidental oral exposure and risk assessment (short and intermediate term) was not required. Further, short - /intermediate - and long - term dermal and inhalation risk assessments were not required for residential exposures. Based on the lack of a relevant exposure scenario, short - and intermediate - term aggregate risk assessments are not required. Since no acute endpoint was selected, a quantitative acute assessment is not required. Since there are no residential uses for fomesafen, the chronic aggregate risk assessment would combine food and water onl y. As described above, the chronic dietary assessment is below the level of concern. Occupational Risk Assessment There is potential for occupational exposure to fomesafen during mixing, loading, and application activities; therefore, short - and intermediate - term work er exposure and risk assessments were conducted. The level of concern (LOC) for occupational populations is 100, which includes the standard safety factors of 10X for intraspecies variability and 10X for interspecies variability . The MOEs for occupational exposures were calculated for short/intermediate term dermal and inhalation exposures . These MOEs were calculated separately because the dermal and inhalation endpoints were different. Occupational exposure was evaluated b y following Exposure Science Advisory Council SOPs and data from the Pesticide Handlers Exposure Data base (PHED). Occupational Handler Risk : Occupational dermal and inhalation daily dose values were calculated and presented. For occupational handlers, dermal and inhalation MOEs above 100 are not of concern. All occupational exposure risk estimates f or Reflex  , for short - and intermediate - term exposures for handlers, are not of concern with single layer dermal Personal Protective Equipment (PPE) (includes long - sleeve shirt, long pants, gloves) or with engineering control enclosed cab (fixed wing airc raft). Dermal MOEs ranged from 9,9 00 to 1 1 0,000 and inhalation MOEs ranged from 220 to 5,900. Occupational Post - application Risk : As the herbicide is applied pre - emergence or pre - transplant for potato and pepper crops, no occupational post - application e xposures are expected. The label required restricted entry

interval (REI) of 24 hours is in compliance with the Worker Protection Standard (WPS). Human Studies : This risk assessment relies in part on data from studies in which adult human subjects were i ntentionally exposed to a pesticide or other chemical. These studies have received the appropriate ethical review. Environmental Justice : Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment. Regulatory RecommendationsPage 7 of 48

T here are no residue chemistry issues that would preclude granting a conditional registration for the use of sodium fomesafen on potatoes and peppers and establishing a tolerance for fomesafen in/on potatoes at 0.025 ppm and a tolerance in/on peppers at 0.025 ppm . There are now sufficient data to support rotation to other crops beyond those commodities that are currentl y registered and proposed as primary crops. All proposed PBIs for rotational crops on the draft label are acceptable, including a 4 month PBIfor small grains (wheat, rye, barley), a 10 month PBIfor corn, peanuts, peas, rice, and seed corn and an 18 month PBI for alfalfa, sunflowers, sugar beets and sorghum (based on phytotoxicity concerns), an d immediate replanting of so ybeans, cotton, dry beans, snap beans , potatoes and transplanted peppers and tomatoes only (ph yt otoxicity concerns permitting) . The registrant’s most recent Reflex® Herbicide label reflects regional use of fomesafen on potatoes and peppers . However, the residue chemistry data submitted in support of this action are of sufficient geographic representation to support full U.S. registration; therefore, HED recommends that these tolerances be listed in the general section of 40 CFR §180.433. According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expression for fomesafen should be revised to state: “Tolerances are established for residues of fomesafen, including its metabolites and degradat es, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only fomesafen [5 - [2 - chloro - 4 - (trifluorometh yl )phenox y] -N - (methylsulfonyl) - 2 - nitrobenzamide].” T he current tolerances l isted in 40 CFR § 180.433 for fomesafen in so ybeans, dry beans, and snap (succulent) beans are 0.05 ppm. HED continues to recommend for the reduction of the following tolerances, as described in a previous memo (D. Davis, DP No. D325801, 4/25/06): dry beans and snap (succulent) beans should be reduced to 0.025 ppm and the tolerance on so ybeans should be reduced to 0.02 ppm . Note that the lower tolerance values were used in the dietary risk assessment . Label Recommendations The label should be revised to remove the requirement of use of a respirator for mixer/loaders in support of aerial application handling more than 140 gallons of product per day . This requirement is not enforceable and should be removed from the label since there is no viable sy stem i n place for inspectors to validate dail y use patterns for applicators that would ensure this requirement is properl y implemented. According to the label, applications are not to be made through any type of irrigation equipment except center pivot s ys tems. The PM should note that there are other permanent sy stems outside of center pivot irrigation equipment which are essentially culturally

equivalent (e.g. drip irrigation sy stems for tomatoes and peppers in raised bed culture) . 2.0 Ingredient ProfilePage 8 of 48

2.1 Summary of Registered and Proposed Uses Background on Currently Registered Use Pattern : Fomesafen (5 - [2 - chloro - 4 - (trifluorometh yl )phenox y] -N - (methylsulfonyl) - 2 - nitrobenzamide) is a selective herbicide which may be applied pre - plant, pre - emergence, and/or postemergence for control and suppression of broadleaf weeds, grasses, and sedges. Fomesafen sodium is a contact herbicide for control of broadleaf weeds. Fomesafen is currentl y registered for pre - plant, pre - emergence and early po stemergence use on cotton, dry beans and soy

beans. There are no residential uses of fomesafen. The existing labels allow ground and aerial application. Fomesafen products are formulated as the sodium salt and the concentration of the active ingredient i n the formulation is expressed in terms of the acid equivalent (ae). Fomesafen sodium is in the diphenylether chemical class and it mode of action is via inhibition of protoporphyrinogen oxidase (PPO) in the plant. Summary of Proposed New Use Pattern: R eflex  Herbicide (22.8% active ingredient sodium salt of fomesafen) will be applied at a maximum rate of 1 pt of product per acre (0.25 lb ae/A) on potatoes and at a maximum rate of 1.5 pt. of product per acre (0.375 lb ae/A) on transplanted peppers . The product is applied to potatoes as a broadcast pre - emergence application after planting but before potato emergence for control of weeds; the product is applied to transplanted peppers as a pre - plant non - incorporated pre - emergence broadcast applications up to seven day s prior to transplanting peppers for control of weeds . The current label for Reflex® Herbicide, the sole label proposed for amendment in this action, specifies a 24 - hr reentry interval for workers. The draft label specifies that use is re stricted to the eastern half of the U.S. Sy ngenta’s regional u se m ap for Reflex® is subdivided into five regions. Reflex® may be applied at a maximum of 0.3 75 lb ae/A per ye ar in Region 1, 0.375 lb ae/A in alternate years in Region 2, 0.313 lb ae/A in al ternate ye ars in Region 3, 0.25 lb ae/A in alternate years in Region 4, and 0.1875 lb ae/A in alternate ye ars in Region 5 . Spray additives : The draft label specifies that spray additives cleared for use on growing crops under 40 CFR §180.1001 may be used in the spray mixture. A nonionic surfactant (NI S), crop oil concentrates (COC), or other adjuvants may be used for postemergence applications only . Since the proposed uses on potatoes and peppers are either pre - emergence or pre - transplant, the use of surfactants is not needed when Reflex® is applied to these crops , as the label states adjuvants are not needed for preplant surface or preemergence applications unless Reflex® is being used in a burndown on emerged weeds . Application equipment : Ground ap plications are to be made in a minimum of 10 gal/A, and aerial applications are to be made in a minimum of 5 gal/A. Applications are not to be made through any typ e of irrigation equipment except center pivot sy stems. Reflex® alone or in tank mixture with other herbicides on the label, which are registered for center pivot application, may be applied in irrigation water pre - emergence (after planting but before weeds or crop emerge) at label - recommended rates. Tank mixtures with other products registered for use on potatoes and peppers : The draft label provides mixing procedures for tank mixes but does not specify specific tank mix partners forPage 9 of 48

potatoes and peppers . The use directions state that, for tank mix combinations, the recommendations, restrictio ns, and limitations for all products must be followed and that the most restrictive labeling is to apply . For pre - emergence application in potatoes, Reflex® may be tank mixed with other pesticide products registered for use in this way and timing in potat oes. For pre - plant non - incorporated pre - emergence applications prior to transplanting peppers , Reflex® may

also be tank mixed with other pesticide products registered for use in this way and timing in peppers . Table 2 .1 . U se Pa ttern Summary of Propose d New Use of Fo mesafen on Potatoes and Peppers Form ulations Liquid Pests B roadleaf weeds, grasses, and sedges Application Methods Groundboom ; chemigation (center pivot only) ; fixed - wing aircraft Application Rates and Intervals Potato : 1 pt /A (0.25 lb ae /A) ; Max 1 pt/A/season Pepper : 1.5 pt/A (0.375 lb ae/A) ; Max 1.5 pt /A/season Frequency No minimum rotation interval for potatoes and transplanted pepper Pre - Harvest Interval ( PHI ) Potatoes should not be harvested within 70 days after application. Peppers should not be harvested within 60 days after application. Personal Protective Equipment ( PPE ) Applicators and other handlers must wear: long sleeved shirt and long pants, chemical resistant gloves, shoes plus socks, and protective eyewear. Aerial applications mixers and loaders handling more than 140 gallons of Reflex ® Herbicide in a single workday must wear: dust/must filtering NIOSH - approved respirator with any N, R, P or HE filter. (Note: it is recommended that this requirement be removed from the label). Restricted Entry Interval ( REI ) 24 hours Use Directions and Limitations Potato: Broadcast pre - emergence application after planting but before potato emergence. Refer to Syngenta’s Regional Use Map for Reflex® * for determination of maximum use rate that may be applied in each geographic region. Do not apply to any field in Regions 2, 3, 4, or 5 more than once every two years. Do not apply to sweet potatoes or yams . Do not apply as a pre - plant incorporated application as crop injury may occur. Do not apply to emerged potato plants or severe crop injury will occur. Peppers : Broadcast pre - plant non - incorporated pre - emergence application up to 7 days prior to transplanting peppers . Refer to Syngenta’s Regional Use Map for Reflex® * for determination of maximum use rate that may be applied in each geographic region . Do not apply to any field in Regions 2, 3, 4, or 5 more than once every two years. *The draft label specifies five use regions with specific seasonal maximum application rates. The rates range with the label use Region 1 having the highest seasonal application rate reflects application at 0.375 lb ae/A each ye ar and label use Region 5 with the lowest seasonal application rate reflects application of up to 0.1875 lb ae/A in alternate years . 2.2 Structure and Nomenclature Tables 2.2a and 2.2b provide structures and nomenclature for fomesafen and sodium salt of fomesafen . Table 2.2a. Fom e safen Nomenclature.Page 10 of 48

Table 2.2a. Fom e safen Nomenclature. Compound Chemical Structure F 3 C

Cl O N O 2

O N H S C H 3 O O

Common name Fomesafen Company experimental name N/A Molecular Formula C 15 H 10 ClF 3 N 2 O 6 S Molecular Weight 438.77 PCcode N/A IUPAC name 5 - (2 - chloro - α,α,α - trifluoro -p - tolyloxy) -N - methylsulfonyl - 2 - nitrobenzamide CAS name 5 - [2 - chloro - 4 - trifluoromethyl)phenoxy] -N - (methylsulfonyl) - 2 - nitrobenzamide CAS # 72178 - 02 - 0 Table 2.2b. Sodium Salt of Fom esafen Nomenclature. Compound Chemical Structure F 3 C

Cl O N O 2

O N S C H 3 O O Na+

Common name Sodium Salt of Fomesafen Company experi mental name N/A Molecular Formula C 15 H 9 ClF 3 NaN 2 O 6 S Molecular Weight 460.75 PCcode 123802 IUPAC name 5 - (2 - chloro - α,α,α - trifluoro -p - tolyloxy) -N - methylsulfonyl - 2 - nitrobenzamide, sodium salt CAS name 5 - [2 - chloro - 4 - trifluoromethyl)phenoxy] -N - (methylsulfonyl) - 2 - nitro - benzamide, sodium salt CAS # 108731 - 70 - 0 End -use product/(EP) Reflex® Herbicide 2.3 Physical and Chemical Properties Table 2.3 . Physicochemical Properties of Fom esafen . Parameter Value Reference Melting point/range 220 - 221°C HED Memo, 9/3/82, W. Anthony pH 8.2 (94% TGAI) CSF (EPA Reg. No 100 - 1017; 10/13/00) Density 1.28 g/cm3 at 20 °C HED Memo, 9/10/86, C. Trichilo Water solubility at 25 ° C 600 g/L at pH 7 <10 ppm at pH 1 - 2 50 mg/L HED Memo, 9/3/82, W. Anthony HED Memo, 9/10/86, C. TrichiloPage 11 of 48

Table 2.3 . Physicochemical Properties of Fom esafen . Parameter Value Reference Solvent solubility g/L Acetone 300 Cyclohexanone 150 Methanol 25 Hexane 0.5 Xylene 1.9 HED Memo, 9/10/86, C. Trichilo

Vapor pressure <7.5 x 10 - 7 mmHg at 50 °C The Pesticide Manual 1 Dissociation constant (pKa) 2.7 at 20 °C Octanol/water partition coefficient log (Kow) Log KOW = 2.9 at pH 1 UV/visible absorption spectrum Not Provided 1 The Pesticide Manual; A World Compendium, The British Crop Protection Council (toxnet.nlm.nih.gov) 3.0 Hazard Characterization/Assessment 3.1 Hazard and Dose - Response Characterization 3.1.1 Database Summary The toxicological database for fomesafen is considered adequate f or hazard characterization. 3.1.2 Toxicological Effects Fomesafen has a low order of acute toxicity by the oral route of exposure (Toxicity Category III). Fomesafen is severely irritating to the eye and is moderate ly irritating to the skin. In the subchronic and chronic toxicity studies in rats and mice food consumption or food efficiency , body weight and body

weight gain and histopathological changes in the liver were parameters that were most often affected. In addition, dogs and mice also showed hematological changes (e.g., decreased ery

throcy te count, hemoglobin, or hematocrit). Carcinogenicity was not observed in the rat chronic toxicity /carcinogenicity study . Liver tumors were produced in the mouse carcinog enicity study ; however , HED’s Cancer Assessment Review Committee (CARC) determined that fomesafen should be classified as “Not L ikely to be Carcinogenic to Humans” (HED Doc No. 0053835). This decision was based on the weight - of - evidence which supports activation of peroxisome proliferator - activated receptor alpha (PPAR α) as the mode of action for fomesafen - induced hepatocarcinogenesis in mice. Fomesafen was not considered to be mutagenic. No quantitative or qualitative evidence of increased susceptibility was seen following in utero exposure to rats or rabbits in deve lopmental studies or in the reproduction study . 3.2 Absorption , Distribution, Metabolism and Excretion In a metabolism study

in rats, f omesafen wa s readily

absorbed in male and female rats after oral dosing. The major route of elimination in females wa s in the urine whereas in males, it wa s in the feces , with some enterohepatic recirculation evident . The sex difference wa s not evident atPage 12 of 48

higher doses where the urine wa s the main route of excretion for both sexes. At higher doses, the vast majority wa s excreted unchanged, but at lower doses a lesser amount (60%) wa s excreted unchanged. The major metabolite (10%) wa s 5 - (2 - chloro - α,α,α - trifluoro - tolyloxy) - anthranilic acid. Part, or all, of the metabolism may be due to action b y intestinal microorganism s. The rat has a very limited capacity

to metabolize fomesafen. In a metabolism study

in dogs, p eak blood levels occurred within 3 hours, then rapidl y declined. Excretion in both sexes was predominantl y in urine and to a lesser extent in the feces. Mos t of the fomesafen (96%) was excreted within 24 hours in both sexes. Fomesafen was not extensively

metabolized in the dog and was recovered to a large extent unchanged. 3.2 Safety factor for Infants and Children (FQPA Safety Factor) T he FQPA safety factor was reduced to 1X for the reasons described in sections 3.3.1 through 3.3.4 . The dietary

assessment is based on conservative assumptions, including 100% crop treated and tolerance - level residues, so the re are no residual uncertainties in the exposure database. 3.3.1 Completeness o f the Toxicology Database EPA began requiring functional immunotoxicity testing of all food and non - food use pesticides on December 26, 2007 . T hese data are not yet available for fomesafen, but an immunotoxicity study is expected to be completed by S yn genta in July

2011. In the absence of specific immunotoxicity

studies, the toxicity

database was e valuated to determine whether a database uncertainty factor is needed to account fo r potential immunotoxicity . No evidence of immunotoxicity

was found in the database. Due to the lack of evidence of immunotoxicity for fomesafen, it was concluded that a database uncertainty factor is not needed to account for potential immunotoxicity . EPA began requiring acute and subchronic neurotoxicity studies for all food and non - food use pesticides on December 26, 2007. T he toxicity database was evaluated for evidence of neurotoxicity

and no evidence for neurotoxicity was found in the database. It was therefore concluded that a database uncertainty factor is not needed to account for potential neurotoxicity . 3.3.2 Evidence of N eurotoxicity Although acute and subchronic neurotoxicity studies are not available for fomesafen, there were no signs of neurotoxicity

in the available toxicity

studies. 3.3.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal There is no evidence of increased susceptibility of rat fetuses to in utero exposure to fomesafen. The 2 - generation reproduction study in rats did not show evidence of increased susceptibility to fomesafen. Although the developmental toxicity study in rabbits was classified unacceptable due to mortality

from bacterial infections, there was adequate information to show that there wasPage 13 of 48

not any evidence of increased susceptibility of rabbit fetuses due to the treatment with fomesafen. Therefore, it is concluded that there is no evidence of increased susceptibility to fomesafen following pre - and/or post - natal exposure and there are no concerns for residual uncertainties for increased susceptibility . 3.3.4 Residual Uncertainty in the Exposure Datab ase There are no residential uses of fomesafen, so residential exposure was not assessed. The dietary assessment is based on conservative assumptions, including 100% crop treated and tolerance level residues, so there are no residual uncertainties in the exposure database. 3. 4 Hazard Identification and Toxicity Endpoint Selection 3. 4 .1 Level of Concern for Margin of Exposure A summary

of the levels of concern for risk assessment may be found in Table 3 . 4 . 1. The level of concern (MOEs ≥ 100) is based on 10x for interspecies extrapolation from animals to humans and 10x for variation in sensitivity between humans. Table 3. 4 .1 . Levels of Concern for Risk Assessment. Route Short - Term (1 - 30 Days) Inte rmediate - Term (1 - 6 Months) Occupational (Worker) Exposure Dermal 100 100 Inhalation 100 100 Residential Exposure Not applicable. There are no residential uses for fo mesafen . 3. 4 .2 Recommendation for Combining Routes of Exposures for Risk Assess ment Different endpoints were picked for dermal and inhalation exposure. No toxicity occurred in a 21 - day dermal toxicity

study at the high dose of 1000 mg/kg/day , however, this NOAE L would not be protective of post implantation loss in the developmental toxicity study in rats with a NOAEL of 100 mg/kg/day . Therefore, the oral endpoint from the developmental toxicity study was used for the dermal route of exposure. An inhalation toxicity study was not available and an oral endpoint of liver toxicity with a NOAEL of 0.5 mg/kg/day was used. The dermal and inhalation routes of exposure cannot be combined because the points of departure are based on different end points. 3. 4 .3 Classification of Carcinogenic PotentialPage 14 of 48

In accordance with the EPA Final Guidelines for Carcinogen Risk Assessment (March 29, 2005), the CARC classified Fomesafen as “Not Likel y t o be Carcinogenic to Humans”. This decision was based on the weight - of - evidence which supports activation of peroxisome proliferator activated receptor alpha (PPAR α) as the mode of action for fomesafen - induced hepatocarcinogenesis in mice. The data did not support either mutagenesis or cy totoxicity followed b y regenerative proliferation as alternative modes of action. While the proposed mode of action for liver tum ors in mice is theoreticall y plausible in humans, it is quantitatively implausible and unlikely

to take place in humans based on quantitative species differences in PPAR α activation and toxicokinetics. The quantification of risk is not required. 3. 4 .4 T oxicological Doses and Endpoints A summary

of the hazard endpoints selected may be found in Table 3. 4 .4. TABLE 3. 4 .4 Toxicological Doses and Endpoints for Fom esafen Human Health Risk Assessments. Exposure Scenario Dose Used in Risk

Assessment, UF Special FQPA

SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Ac ute Dietary (Females 13 - 49) No toxic effects attributable to a single dose of fomesafen were found in the database. Ac ute Dietary (General US Pop.) No toxic effects attributable to a single dose of fomesafen were found in the database. Chronic Dietary (all populations) NOAEL = 0.25

mg/kg/day UF = 100 Chronic RfD = 0.0025 mg/kg/day FQPA SF = 1X ( cPAD) = 0.0025 mg/kg/day Chronic toxicity

– rat

L OAEL = 5 mg/kg/day based on hyalinization of the liver in males Dermal Short - Term (1 - 30 days) Intermediate - Term (1 - 6 months) NOAEL = 100

mg/kg/day (Dermal absorption rate = 20%)* LOC for MOE = 100 (Occupational) LOC for MOE = 100 (Residential) Pre natal development

– rat

LOAEL = 200 mg/kg/day based on postimplantation loss

Inhalation Short - Term (1 - 30 days) Intermediate - Term (1 - 6 months) NOAEL = 0.5

mg/kg/day (Inhalation toxicity is assumed to be equivalent to oral toxicity) LOC for MOE = 100 (Occupational) LOC for MOE = 100 (Residential) 90 - Day

– rat

LOAEL = 10 mg/kg/day based on hyalinization of hepatocytes, increased eosinophilia, reduced granulation, increased liver weights in males and females, and increases in plasma alkaline phosphatase , alanine transminase and aspartate transaminase in males Long - Term (Dermal & Inhalation) NOAEL = 0.25

mg/kg/day (Dermal absorption rate = 20%)* (Inhalation toxicity is assumed to be equivalent to oral toxicity) LOC for MOE = 100 (Occupational) LOC for M OE = 100 (Residential) Chronic toxicity

– rat

LOAEL = 5 mg/kg/day based on hyalinization of the liver in males

Cancer (oral, dermal, inhalation) Classification: The CARC classified Fomesafen as “Not Likely to be Carcinogenic to Humans”Page 15 of 48

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse - effect level, LOAEL = lowest observed adverse - effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable * The dermal absorption value of 20% wa s based on dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures. 3. 5 Endocrine D isruption As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to hav e the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any advers e endocrine related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application agricultural s cenarios. This list should not be construed as a list of known or likely endocrine disruptors. Fomesafen is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call - ins for all pesticide active ingredients . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. 4.0 Public Health and Pesticide Epidemiology Data At this time there is no information in the incident reports that affect this risk assessment. 5.0 Di etary Exposure/Risk Characterization 5.1 Residues of Concern Sy ngenta has previousl y submitted acceptable metabolism studies on tomatoes, soy beans, and cotton, but HED identified the lack of a root crop me tabolism study as a deficiency . InPage 16 of 48

conjunction with this petition, the registrant submitted a confined rotational crop study to support a residues of concern determination not only for rotational crops, but also root and tuber vegetables. The rotational crop study is adequate and supports the use on root crops. The residue of concern for the tolerance expression and dietary risk assessment is the parent, fomesafen. A summary

of the residues of concern that had been previously determined for water and li vestock may

be found in Table 5.1. Rotational Crops The registrant submitted a new confined rotational crop study to support this petition, as well as satisfy a condition of registration for existing uses of fomesafen. The new study is adequate; no additional confined rotational crop data are needed. The major residues identified were the parent compound, conjugates of 3 - chloro - 4 - hydroxy benzoic acid (R052850), conjugates of trifluoroacetic acid, and 2 - amino - 3 - (3

–methanesulfonylamino - carbonyl - 4 - nitro - phenyl sulfany 1) - propionic acid (R290493). HED has used a qualitative structure activity relationship (SAR) tool, DEREK (v. 11), to screen for any potential health effects that may be different from the parent. R052850 residues are not of concern. No structural alerts were identified using DEREK. These residues were found onl y in two animal feed items, and at levels less than 0.06 ppm. Benzoic acid conjugates are polar and therefore likel y to be quickly eliminated through the urinary or fecal routes prior t o adversely effecting health. Therefore, HED has no concerns for R052850 residues on rotational crops for tolerance enforcement and dietary risk assessment. Although R290493 residues were >10% of the total radioactive residues (TRR), levels were less than 0.016 ppm. DEREK produced structural alerts similar to the parent compound because of the aromatic ring structure with a nitro group. However, R290493 is likely to be more polar than the parent due to the presence of the sulfonyland carboxylic acid groups, and therefore, is not likely to be readil y absorbed by humans. Accordingl y, at the current application rates for the primary crops, HED does not have concern for R290493 residues on rotational crops. Trifluoroacetic acid (TFAA) conjugate residues w ere significant in several rotational crop commodities on a relative basis (92% of the TRR in mature spinach, 224 - day PBI, 0.023 ppm) and absolute basis (0.136 ppm, soy bean hay , 27% TRR). The registrant submitted a discussion on the toxicological relevanc e of TFFA conjugate residues (MRID 47937601). Below is a summary of the major discussion points:

 TFAA is not mutagenic.  TFAA is a weak peroxisome proliferator, indicating low probability of liver tumor formation following chronic exposures in rodents and less likelihood in humans.  TFAA itself is not likely to elicit a cell - mediated immunological reaction based on absence of DNA formation in cultured ly mphocy tes and lack of correlation between delayed h ypersensitivity

and observed hepatic necrosis followin g halothane exposure.  TFAA does not cause reproductive or developmental toxicity effects at dose levels well above human exposure levels. Additionally , following oral or inhalation exposure, the primary target organ of TFAA is liver. High exposures (>114 mg/kg) result in increased liver weight and altered enzy me activity.Page 17 of 48

TFAA does not accumulate in vivo following multiple exposures due to rapid clearance from the body (half - life of 25 - 32 hours in human plasma) and saturable oral absorption. Since the highest residues found were in livestock feed items, and residues are unlikel y to transfer to livestock tissues, there is not likely to be significant human exposure to TFAA. Therefore, HED is not concerned about TFFA conjugates in rotational crops for fo mesafen at currentl y identifiable residues of 0.2 ppm identified in rotational crop commodities. Additional data on TFAA residues in/on rotational crops may be of concern if the registrant proposes significantl y higher application rates in the future. T able 5.1. Summary of Metabolites and Degradates to be included in th e Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Fomesafen Fomesafen Plants Rotation al Crop Fomesafen Fomesafen Livestock Fomesafen , 5 - ( 2 - chloro - α,α,α trifluoro - p - tolyloxy) anthranilic acid , 5 - (2 - chloro α,α,α - trifluoro - p - tolyloxy) -N methylsulfonylanthranilamide. Not required at this time. Drinking Water Fomesafen NA 5.2 Residue Profile 5.2 . 1 Drinking Water Residue Profile Environmental Fate and Effects Division’s (EFED) assessment s of potential drinking water impacts from the proposed uses of fomesafen are detailed in the memorandum s entitled Tier II Drinking Water Assessment for Fomesafen use on cotton, soy beans, dry

beans and snap beans (J. Hetrick, 9/27/20 05, D314014) , Drinking Water Assessment for Fomesafen use on cotton, soy beans, dry

beans, snap beans, potato and tomato (J. L in, 12/10/20 09, D365204) , and Drinking Water Assessment for Fomesafen use on Pepper (J. L in, 3/2/2010, D373599 and 373601) . Environmental fate data indicate that fomesafen should be very mobile and highl y persistent in terrestrial and aquatic environments. The major routes of dissipation from the application site are expected to be runoff and leaching. The surface water assessment was conducted using environmental fate data in the PRZM EXAMS model. There is a complete environmental fate data base except for the sediment halflife value. The surface water mo deling was conducted on standard EFED scenarios for cotton in TX, NC, MS ; soy

beans in MS ; dry

beans and snap beans in IL, MI; potato in ME, FL ; tomato in Fl, PA ; and nursery

crop in FL, TN . These scenarios were selected because they are expected to be rep resentative of use sites prone to high runoff as well as representative of the highest regional use rates for fomesafen. Application rates were selected to reflect maximum applicationPage 18 of 48

rate s of 0.375 lbs ae/A for soy bean, dry and snap bean, cotton, peppers and tomato; 0.25 lbs ae/A for potato; and 0.5 lb ae/ A for nursery crop . F omesafen aerial applications were simulated to account for spray

drift of fomesafen to surface waters. The half life of fomesafen in sediment was assumed to be stable. No surface water monitor data were available for fomesafen. The scenario leading to the highest EDWC in surface water for chronic exposure (1 in 10 ye ar annual mean concentration) using PRZM - EXAMS was MD cotton, aerial application, with a concentration of 10.535 μg/L (ppb ) , adjusted for Percent Crop Area (PCA) of 0.87 (D314014) . This value was used directly in the dietary

exposure assessment. EFED conducted a ground water assessment using the available environmental fate data and the SCI - GROW model. EFED notes th at although the Koc model is inappropriate for estimation of fomesafen soil - water partitioning, the lowest reported Koc was used in the assessment. The SCI GROW modeling indicated that peak and long - term average concentrations of fomesafen in shallow groun d water were not expected to exceed 11.2 μg/L (ppb ) . No USGS groundwater monitoring data were located for fomesafen, however, the registrant submitted a prospective monitoring study

for fomesafen use on soy beans in North Carolina which clearl y showed that fomesafen has a potential to leach to ground water. Fomesafen was detected at concentrations of 1 μg/L (ppb) , which is the detection limit for the compound. The detections were confirmed using an alternate anal yt ical technique. EFED recommends using the ground water monitoring concentration of 1 μg/L (ppb) as the benchmark concentration for fomesafen in ground water source drinking water because it represents actual use conditions of fomesafen on so ybeans on a vulnerable soil. Since this value was lower than the surface water EDWC, only the surface water value was incorporated into the dietary assessment. Surface and ground w ater estimated drinking water concentrations ( EDWCs ) for fomesafen are described below:  The scenario leading to the highest EDWC in surface water for chronic exposure (1 - in 10 year annual mean concentration) using PRZM - EXAMS was MS cotton, aerial application , with a concentration of 10.535 ppb, adjusted for a Percent Crop Area (PCA) of 0.87. This value was used directl y in the diet ary exposure assessment.

 Sy ngenta submitted a prospective ground water monitoring study for fomesafen use on soy beans. EFED recommended using the ground water monitoring concentration of 1 ppb, since it represents actual use conditions of fomesafen on so yb eans on a vulnerable soil. Since this value was lower than the surface water EDWC, only the surface water value was incorporated into the assessment.

 The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/ . 5. 2 . 2 Food Residue Profile In support of the proposed tolerance in/on peppers and potatoes, thirteen crop field trials were submitted for each crop . Residues in all trials were non - detectable at a limit of quantitation of 0.025 ppm for both peppers and potatoes . This is consistent with trials on other crops.Page 19 of 48

Processing factors could not be calculated for potatoes as residues were non - detectable in/on the raw and processed commodities. The metabolism, crop field trial, and processing studies are supported by

adequate storage stability studies. The multi - residue methods are not suitable for the anal ys is of fomesafen. The LC /MS/MS method (GRM045.01A) is an adequate anal yt ical meth od for the enforcement of tolerances , which has been adequatel y validated for anal ys is of fomesafen residues in various crop commodities. Confined rotational crop data have been submitted and are acceptable . Limited rotational crop field trials reflecting analy sis of onl y the parent compound are available. Rotational crop tolerances are not needed based on the proposed plant - back interval. There are no livestock feed items associated with the use on peppers . The livestock feedstuffs associated with the proposed uses on potato are potato culls and processed waste . The existing uses of fomesafen and the proposed use of fomesafen on potato and pepper result in a 180.6 (a)(3) situation, that there is no reasonable expectation of finite residues and no to lerances in/on livestock commodities are needed. 5. 3 Dietary Exposure and Risk Please see DP Barcode: D382064 , Fomesafen Sodium: Chronic Dietary Exposure Assessment to Support Proposed New Use on Potatoes and Peppe rs , October 12, 20 10 by Alexandra LaMay for the complete fomesafen sodium dietary assessment. 5. 3 .1 Acute Dietary Exposure/Risk No toxic affects attributable to a single dose of fomesafen were found in any stu dy ; therefore no acute dietary

exposures risks assessment was required . 5. 3 .2 Chronic (Non - Cancer and Cancer) Dietary Exposure/Risk Chronic dietary

risk assessments were conducted using the Dietary Exposure Evaluation Model (DEEM - FCIDTM), Version 2.03, which used food consumption data from the United States Department of Agriculture’s (USDA’s) Continuing Survey s of Food Intakes by Individuals (CSFII) from 1994 - 1996 and 1998. The analy ses were performed to sup port the proposed uses of fomesafen on peppers and potatoes. See Table 5.3.2 below for a summary of fomesafen chronic dietary

exposure risk estimates for food and drinking water. The assessments resulted in dietary risk estimates for food alone and food and drinking water that are below the HED’s level of concern for chronic dietary exposure. T he highest exposure and risk estimates were for all infants (<1 ye ar old), where the aggregate food and water exposure is at 32% of the cPAD . Table 5. 3.2 . Sum mary of Dietary (Food and Drinking Water) Exposure and Risk for Fomesafen . Population Subgroup Ac ute Dietary 1 Chronic Dietary Cancer2 Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) RiskPage 20 of 48

General U.S. Population NA NA 0.000308 12 NA NA All Infants (< 1 year old) 0.000813 32 Children 1 - 2 years old 0.000536 22 Children 3 - 5 years old 0.000492 20 Children 6 - 12 years old 0.000336 14 Youth 13 - 19 years old 0.000247 9.9 Adults 20 - 49 years old 0.000280 11 Adults 50+ years old 0.000281 11 Females 13 - 49 years old 0.000275 11 1 No toxic affects attributable to a single dose of fomesafen were found in any study . 2 Fomesafen classified as “not likely to be carcinogenic”. aPAD = acute population adjusted dose; cPAD = chronic population adjusted dose 5. 4 Anticipated Residue and Percent Crop Treated (%CT) Information Neither anticipated residues nor perc ent crop treated were used in the dietary assessment. 5. 5 Tolerance Assessment 5. 5 .1 Enforcement Analytical Method Sy ngenta Crop Protection has submitted descriptions and validation data for enforcement method, Method GRM045.01A, which is entitled “Fome safen Anal yt ical Method for the Determination of Residues of Fomesafen in Crop Commodities by L C - MS/MS.” This high performance liquid chromatography with tandem mass spectrometry detection (L C/MS/MS) method is based on previously submitted gas chromatogra phy with nitrogen phosphorus detection (GC/NPD) methods (refer to DP# 325801, D. Davis, 4/25/06) developed by Z eneca AG. Method GRM045.01A uses extraction procedures modified from the previous GC/NPD methods. In the revised method, fomesafen residues are extracted with 1% h ydrochloric acid in acetonitrile . An aliquot is subjected to an SPE cleanup and analyzed using LC/MS/MS. A second ion transition may be monitored for confirmation. The LOQ is 0.02 ppm for fomesafen in each matrix. Representative spe ctra and linearity data were submitted demonstrating adequate sensitivity . Adequate multi - residue method testing data are available, which indicate that the FDA multi residue methods are not suitable for determining residues of fomesafen. 5. 5 .2 Tolerance Recommend ationPage 21 of 48

Sufficient residue data are available to support a tolerance of 0.025 ppm in/on potatoes and a tolerance of 0.025 in/on peppers . Processed commodity tolerances are not needed since detectable residues were not found in either raw or proce ssed potato commodities. According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expression for fomesafen should be revised to state: “Tolerances are established for residues of fomesafen, including its metabol ites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only fomesafen [5 - [2 - chloro - 4 - (trifluorometh yl )phenox y] -N - (methylsulfonyl) - 2 - nitrobenzamide].” 5. 5 .3 I nternational Harmonization No Codex, Canadian, or Mexican MRL s have been established for residues of fomesafen in/on pepper or potato . 6.0 Residential (Non - Occupational) Exposure There are no residential uses for fomesafen sodium; therefore, an evaluation of exposures resulting from residential uses was not required. Spray Drift Exposure Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground a pplication method employed for fomesafen sodium . The Agency

has been working with the Spray Drift Task Fo rce, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical b y chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to re duce off - target drift with specific products with significant risks associated with drift. Inhalation Exposure Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for fomesafen sodium at this time. However, volatilization of pesticides may

be a potential source of postapplication inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticide s from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, developing policies and procedures, to identifying the need for and, subsequentl y, the way to incorporatePage 22 of 48

postapplication inhalation exposure into the Agency's risk assessments. If new p olicies or procedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for fomesafen sodium. 7.0 Aggregate Risk Assessments A ty pical aggregate risk assessment may include residential, food, and drinking water exposure. Because there are no residential uses for fomesafen, the aggregate assessment includes food and drinking water onl y, as discussed in Section 5.2. 8 .0 Occupational Exposure and Risk This section presents a summary of the occupational exposure and risk estimates for fomesafen . Please see DP Barcode : D 373961 , Fomesafen Sodium: Occupational Exposure Assessment for a Proposal to Add New Uses on Potatoes and Tomatoes , Alexan dra LaMay , February 19 , 2010 , and DP Barcode: D382063 , Fomesafen Sodium: Occupational Exposure Assessment for a Proposal to Add New Uses on Peppers, Alexandra L aMay , October 12 , 2010, for the complete fomesafen occupational exposure and risk assessment s . This section describes the occupational exposure and risk assessments conducted to support applications of fomesafen on potatoes and peppers . HED determined that the potential for occupational exposure to Reflex  Herbicide exists in a variety of scenarios . The anticipated use patterns indicate several occupational exposure scenarios based on the types of equipment and techniques that can potentially be used for Reflex  Herbicide applications . 8.1 Occupational Handler Exposure Occupational handler scenari os include handling of Reflex  during mixing, loading, and applying processes . The proposed label states loaders, applicators, and other handlers must wear a long - sleeved shirt, long pants, shoes plus socks and chemical - resistant gloves as personal protec tive equipment (PPE) . Therefore , these scenarios were assessed. Also, for aerial applications, mixers/loaders handling more that 140 gallons of product per day must wear a dust/ mist filtering NIOSH respirator (80% protection factor, PF5) according to th e proposed label. For the uses on potatoes and peppers , it is assumed that a mixer/loader would not handle more than 140 gallons of product per day ; therefore this scenario was not assessed with use of a respirator. However, it is recommended that this requirement be removed from the label as it is not an enforceable requirement. Short - term and intermediate - term exposures may occur; long term exposures are not expected. Exposure and risk were evaluated using the Pesticide Handlers Exposure Database (PHE D). In this exposure assessment, the use parameters were based on the label instructions and default exposure assumptions for quantity handled per day (ExpoSAC SOPs). The potential absorbed dose and MOEs were calculated using standard EPA exposure algorithms and generic unit exposure values from the PHED Version 1.1 (US EPA, 1998). The following exposure scenarios were assessed for agricultural workers:Page 23 of 48

Mixer/Loaders (M/L) : (1) M/L liquids for Aerial Application/ Chemigation ; (2) M/L liquids for Ground boom Applications ; Applicators: (3) Appl yi ng by Enclosed Fixed Wing Aircraft ; (4) Appl yi ng by

Groundboom [ open cab]; Flagging ( 5 ) Flagging in Support of Aerial Application ; Based on handler’s activity use pattern, the duration of exposure is expected to be short - term (1 to 30 day s) and intermediate term (1 to 6 months) for occupational handlers. Occupational workers may

be exposed to fomesafen sodium during the mixing/loading and/or application process. Based on the product labels, fomesafen sodium can be applied at a maximum rate of 0.25 lbs ae/A on potatoes and 0.375 lbs ae/A on peppers . Maximum application rates have been assessed in this document to more inform risk managers about the specific conditions of the proposed label amendments . The advers e affects for short - and intermediate - term dermal risk assessment are female - specific; therefore the body weight of an average female (60 kg) was used to estimate dermal exposure. Since the adverse effects for the short - and intermediate - term inhalation e ndpoints are not gender specific, the body weight of an average adult (70 kg) was used to estimate inhalation exposure. Assumptions for the area treated per day were based on the EPA default values listed in ExpoSAC SOP #9.1. The work day was assumed to b e 8 hours for all agricultural workers. For all use scenarios, the product application rates and amount handled per day are listed in Table 8.1. Table 8 .1 . Application Rates Assessed and Quantity Handled per Day Use Scenario Crop Group Application Rates Assessed (lb ae/A) Area Treated per Day Liquid: Aerial/ Chemigation Mixer/ Loader Potato 0.25 350 Pepper 0.375 Liquid: Aerial Applicator Potato 0.25 350 Pepper 0.375 Liquid: Groundboom Mixer/Loader; Applicator Potato 0.25 80 Pepper 0.375 Flagging Potato 0.25 350 Pepper 0.375 Risks were calculated as a MOE, which is a ratio of the toxicological Point of Departure (POD) to the daily

dose. Daily

dose values were calculated by first calculating exposures by considering application parameters (i.e., rate and area treated) along with unit exposures. Exposures were then normalized by body weight. 8.1.1 Occupational Handler RiskPage 24 of 48

The proposed label indicates that applications are made pre - emergence to potatoes and peppers . The proposed la

bel allows for liquid application with a groundboom or an enclosed fixed wing aircraft. See Table 8.1.1 below. For mixer/loaders at single layer dermal PPE ( chemical - resistant gloves, no respirator) :  For mixer/loader exposure scenarios, dermal and inhalation risks do not exceed HED’s level of concern (i.e., the MOEs are greater than 100) at the proposed maximum application rate of 0.25 lbs a e /A for potatoes and 0.375 lb ae/A for peppers : o F or mixer/loaders for aerial application/ chemigation on potatoes , the dermal MOE is 15,0 00 and the inhalation MOE is 330 . o For mixer/loaders for aerial application/chemigation on peppers , the dermal MOE is 9,9 00 and the inhalation MOE is 22 0. o For mixer/loader for groundboom application on potatoes , the dermal MOE is 65 ,00 0 and the inhalation MOE is 1,500 . o For mixer/loader for groundboom application on peppers , the dermal MOE is 43 ,000 and the inhalation MOE is 970 . For applicators at single layer dermal PPE ( chemical - resistant gloves, no respirator) for groundboom applic ators or engineering control of enclosed cab for aerial applicators :  For applicator scenarios, dermal and inhalation risks do not exceed HED’s level of concern (i.e., the MOEs are greater than 100) at the maximum proposed application rate of 0.25 lbs ae /A for potatoes and 0.375 lb ae/A for peppers : o For applicators using engineering control of enclosed fixed wing aircraft application on potatoes , the dermal MOE is 62 ,000 and the inhalation MOE is 5,900 . o For applicators using engineering control of enclosed fixed wing aircraft application on peppers , the d ermal MOE is 4 2 ,000 and the inhalation MOE is 3,900 . o For applicators using groundboom open cab on potatoes , the dermal MOE is 11 0,000 and the inhalation MOE is 2,400 . o For applicators using groundboom open ca b on peppers , the dermal MOE is 71 ,000 and the inhalation MOE is 1,600 . For flagging at single layer dermal PPE ( chemical - resistant gloves, no respirator) :  For flagging scenarios , dermal and inhalation risks do not exceed HED’s level of concern (i.e., the MOEs are greater than 100) at the maximum proposed application rate of 0.25 lbs ae /A for potatoes and 0.375 lb ae/A for peppers : o For flaggers op e n cab for potatoes , the dermal MOE is 29 ,000 and the inhalation MOE is 1,100 . o For flaggers op e n cab for peppers , the dermal MOE is 19 ,000 and the inhalation MOE is 760 . The proposed label require s single layer clothing and chemical - resistant gl oves for all loaders, applicators, and other handlers. HED notes that the risk estimates on the proposed label PPE would have MOEs that do not exceed the LOC . Refer to Table 8.1.1 for detailed information.Page 25 of 48

Table 8 .1 .1 . Short - and Intermediate - Term Fomesafen Sodium Occupational Handler Risk Estimates Exposure Scenario Crop Application Rate 1 (lb a e/ acre) Min PPE

Dermal Unit Exposure 2 (mg/lb ae ) Baseline

Inhalation Unit Exposure 3 (μg/lb ae ) Ar ea

Treated Daily 4 (acres) Single Layer +

Gloves Dermal Daily Dose (mg/kg/ day) 5 Inhalation

Daily Dose (mg/kg/ day) 6 Single

Layer + Gloves Dermal MOE 7 Baseline

Inhalation MOE 8 Mixe r/L oader Scenarios Mix/Load Liquids for Aerial Application / Chemigation Potato 0.25 With Gloves: 0.023 1.2 350 0.0067 0.0015 15,000 330 Pepper 0.375 0.01 0.00225 9,900 220 Mix/Load Liquids for Groundboom Application Potato 0.25 80 0.0015 0.00034 65,000 1,500

Pepper 0.375 0.0023 0.00051 4 43,000 970

Applicator Scenarios Applying Sprays by Enclosed Fixed Wing Aircraft 9 Potato 0.25 Eng . Control: 0.0055 Eng.

Control: 0.068 350 0.0016 0.000085 62,000 5,900 Pepper 0.375 0.0024 0.00013 42,00 0 3,900 Applying Sprays by Open Cab Groundboom Potato 0.25 With Gloves: 0.014 0.74 80 0.00093 0.00021 110,000 2,400 Pepper 0.375 0.0014 0.00032 71,000 1,600 Flagger Scenario Flagging for Liquid Aerial Application Potato 0.25 With Gloves: 0.012 0.35 350 0.0035 0.00044 29,000 1,100 Pepper 0.375 0.00525 0.00066 19,000 760 1 Application rates are based on maximum values found on the label . 2 Minimum PPE dermal unit exposure represent long pants, long sleeved shirts, shoes, socks and chemical - resistant gloves. Engineering control unit exposures represent use of enclosed cab. Values are reported in the PHED Surrogate Exposure Guide dated August 1998. 3 Baseline Inh alation unit exposures represent no respirator protection (baseline) . Engineering control unit exposures represent use of enclosed cab. Values are reported in the PHED Surrogate Exposure Guide dated August 1998. 4 Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern. 5 Daily Dermal Dose = (Dermal Unit Exposure (mg a e /lb ae ) * A pplication Rate (lb ai /A) * Area Treated (A /day)) / Body Weight ( 6 0 kg) * 20% Dermal Absorption (0.20) 6 Daily Inhalation Dose = (Inhalation Unit Exposur e (μg a e / lb ae ) * Conversion Factor (1 mg /100 0 μg) * Applicati on Rate (lb ae/A) * Area Treated (A/day)) / Body Weight (70 kg) 7 Dermal MOE = PoD (NOAEL of 100 mg/kg/day)/ Daily dermal dose (mg/kg/day) 8 Inhalation MOE = PoD (NOAEL of 0.5 mg/kg/day) / Daily inhalation dose (mg/kg/day) 9 App lication by fixed - wing aircraft has engineering control of enclosed cab. 8.2 Occupational Post - application Exposure As the proposed label states that the product is applied to potatoes as a broadcast pre - emergence application after planting but before potato emergence, post - application exposures are not anticipated for this use. Also, as the product is applied as a pre - plant non - incorporated pre emergence broadcast application prior to transplanting peppers ; post - application exposures are not anticipated for this use ; therefore a quantitative post - application exposure assessment was not conducted. Dermal ExposurePage 26 of 48

This risk assessment for fomesafen sodium evaluates the potential risks associated with its pre plant/pre - emergent uses on peppers and potatoes. There is a low potential for occupational post application exposure associated with the use of pre - plant/pre - emergent herbicides because there are no hand labor activities ty pically associated with the production of crops that would require significant co ntact with treated soil and no foliage is present that could also lead to exposure via contact including potatoes and peppers . There is a possible concern that some level of soil contact could occur during mechanically assisted pepper transplanting activi ties, but this is likely to result in negligible exposures. This is because transplanting activities involve moving starter plants onto a rotating wheel while riding upon an implement being moved across a field. In such cases there would be minimal conta ct with machinery that has small amounts of field soil on it because of the possibility of mechanical injury . Also, commercial pepper cultivation is ty picall y in tarped , raised beds with small planting holes punched in the tops of the raised beds , which also minimizes the potential for contact with treated soil because of the phys ical barrier. These conclusions are appropriate even though fomesafen sodium has a long half - life in soil (i.e., mean soil half life of ~390 days). Inhalation Exposure Based o n the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment was not performed for fomesafen sodium at this time. However, there are multiple potential sources of postapplication inhalation exposure to indiv iduals performing postapplication activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency

sought expert advice and input on is sues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meeting s/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available postapplication inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational postapplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative oc cupational postapplication inhalation exposure assessment for fomesafen sodium . Restricted Entry

Interval The label - required restricted entry interval (REI) of 24 hours is in compliance with the Worker Protection Standard (WPS) . 9 .0 Environmental Justic e Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Lo w - Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) ty pically considers the hi ghest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to,Page 27 of 48

people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and p eople who may be exposed when harvesting crops. Should these high exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information. 10. 0 Data Needs Toxicology The following toxicology data gaps exist: 869.1200 Acute Dermal Toxicity Study 870.1300 Acute Inhalation Toxicity Study 869.2600 Skin Sensitization Study 870.7200 Acute Neurotoxicity Study 870 .7200 Subchronic Neurotoxicity Study 870.7800 Immunotoxicity Study Residue Chemistry None. Occupational and Residential Exposure None. 11.0 References Occupational/Residential Exposure : Fomesafen Sodium: Occupational Exposure Assessment for a Proposal to Add New Uses on Potatoes and Tomatoes , D 373961 , A. LaMay , 2/ 19 /20 10. Fomesafen Sodium: Occupational Exposure Assessment for a Proposal to Add New Uses on Peppers , D382063 , A. LaMay , 10/12 /2010. Residue Chemistry: Fomesafen Sodium. Petition for the Establishment of Tolerances and Registration of New Uses on Potato and Tomato; and Response to Data Gaps for Conditional Registration on Cotton, Dry Bean, and Snap Be an. Summary of Anal yt ical Chemistry

and Residue Data, D365199, C. Olinger, 1/21 /2010. Fomesafen Sodium. Petition for the Establishment of Tolerances and Registration of New Uses on Pepper and Potato, and Response to Data Gaps for Conditional Registratio n based on Submission of Confined Rotational Crop Metabolism Study . Summary of Analy tical Chemistry and Residue Data. D373544 and D382067, A. LaMay , 10/12 /2010 .Page 28 of 48

Dietary : Fomesafen Sodium: Chronic Dietary Exposure Assessment to Support Proposed New Use on Potatoes and Peppers, D382064 , A. LaMay , 10/12 /2010. Water : Tier II Drinking Water Assessment for Fomesafen use on cotton, soy beans, dry

beans, and snap beans, D314014, J. Hetrick, 9/27/2005. Drinking Water Assessment for Fomesafen use on cotton, s oy beans, dry

beans, snap beans, potato and tomato , D365204 , J. L in, 12/10/20 09 . Drinking Water Assessment for Fomesafen use on Pepper. D 373599 and 373601, J. L in, 3/2/2010. Endpoint Selection : Fomesafen: Second Report of the Cancer Assessment Review C ommittee, TXR No. 0053835, J. Kidwell, 11/3/2005 . Fomesafen Sodium: Response to a request by S yngenta Crop Protection, Inc. for revision of the toxicity endpoints and unit exposures for the occupational exposure assessment, D337945, W. Phang and M. Llo yd, 4/29/08.Page 29 of 48

Appendix A: Toxicology Assessment A.1 Toxicology Data Requirements The requirements (40 CFR 158.500) for food use for fo mesafen are presente d below . Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Test Technical Required Satisfied 870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 P rimary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

no no yes yes no 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... yes yes yes no no yes

yes yes

-

- 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

no yes 870.4100a Chronic Toxicity (r odent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5300 Muta genicity

—Gene Mutation

– mammalian ............... 870.5xxx Mutagenicity

— Structural Chr omosomal Aberrations ... 870.5 xxx Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox. (hen) ................................ ..... 870.6100b 90 - Day

Neurotoxicity (h en) ................................ ........... 870.6200a Acute Neurotox. Screening Battery (rat) ....................... 870.6200b 90 - Day

Neuro. Screening Battery (rat) .......................... 870.6300 Develop. Neuro ................................ .............................. no no yes yes no -

- no no

- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

no noPage 30 of 48

A.2 Toxicity Profiles Table A.2.1 Acute Toxicity Profile - Fo mesafen Guideline Study Type (Date) MRID Results Tox. Cat. 870.1100 (§ 81 - 1) Ac ute Oral 00247589 LD 50 = 1250 - 2 000 mg/kg III 870.1200 (§ 81 - 2) Ac ute Dermal - - - 870.1300 (§ 81 - 3) Ac ute Inhalation - - - 870.2400 (§ 81 - 4) Primary Eye Irritation 00247589 Severe Irri t ation II 870.2500 (§ 81 - 5) Primary Dermal Irritation 00247589 Moderate Irri t ation III 870.2 600 (§ 81 - 6) Dermal Sensitization - -

- Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile Guideline No./Study Type MRID No. (year)/

Classification/Doses Results 870.3050 28 - day mice - diet 40786709 (1980)

Acceptable/Non - Guideline 0, 5, 1 5, 50, 150, 500, 1500 or 1500 ppm (0/0, 0.71/0.94, 2.13/2.87, 7.20/8.30, 20.7/27.1, 68.9/83.4, 209.1/246.8, or 917.2/1247.6 mg/kg/day) [M/F] NOAEL = 1500 ppm (209/247 mg/kg/day) LOAEL = 5000 ppm (917/1247 mg/kg/day in M/F) based on decreased body weights and body weight gains, decreased food efficiency, hematology (decreased erythrocyte count, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), bile duct hyperplasia, decreased uterine size in females, and decreased size of the seminal ves icles in males 870.3100 90 - day rats - diet 00103013 (1981)

Acceptable/ Guideline 0, 1, 5, 100 or 1000 ppm (0, 0.1, 0.5, 10 and 100 mg/kg/day) NOAEL = 5 ppm (0.5 mg/kg/day) LOAEL = 100 ppm (10 mg/kg/day) based on hyalinization of hepatocytes, increased eosinophilia, reduced granulation, increased liver weights in males and females, and increases in plasma alkaline phosphatase, alanine transaminase and aspartate transminase in males 870.3150 26 - Week dogs - diet 0.00103014 (1981)

Acceptable/Guideline 0, 0.1, 1 .0 or 25 mg/kg/day NOAEL = 1.0 mg/kg/day LOAEL = 25 mg/kg/day based on hematology (decreased hemoglobin and hematocrit concentrations and erythrocyte count and increased platelet count and prothrombin time)Page 31 of 48

Guideline No./Study Type MRID No. (year)/

Classification/Doses Results 870.3200 21 - day dermal rabbit 00135632 (1983)

A cceptable/ Guideline 0, 10, 100 or 1000 mg/kg/day NOAEL = 1000 mg/kg/day LOAEL was not observed 870.3700 Prenatal development toxicity - rabbit 00109214 (1981)

Unacceptable/Guideline 0, 2.5, 10 or 40 mg/kg/day At 40 mg/kg/day, does appeared thin and had in creased incidence of stomach erosions. No significant difference between controls and treated animals for developmental abnormalities. Study provided information to assess potential developmental toxicity rabbits, but was classified unacceptable becaus e of bacterial infection in the colony. 870.3700 Prenatal development toxicity - rat 00164903 (1981)

Acceptable/Guideline 0, 50, 100 or 200 mg/kg/day [This study was considered with: 1) Report Nos. CTL/P/656 and CTL/P/656S, MRID #001013016, and 2) information provided by Syngenta in their submission (DP316263, MRID 46527208) in establishing the NOAEL and LOAEL. With the additional information, the following conclusions were made.] Maternal NOAEL = 100 mg/kg/day Maternal LOAEL = 200 mg/kg/day based on th e staining of the ventral fur and significantly decreased body weight gain (>10%) Developmental NOAEL = 100 mg/kg/day Developmental LOAEL = 200 mg/kg/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903) 870.3700 Prenatal developmental toxicity - rat 00103016 (1982)

Acceptable/Guideline 0, 1.0, 7.5 or 50 mg/kg/day [The maternal and developmental toxicity LOAEL and NOAEL were not established in this study. However, in conjunction with 1) another developmental toxicity study in rat s (CTL/P/576, MRID 00164903), and 2) information provided by Syngenta in their submission, DP 316263 (MRID 46527208), the following LOAELs/NOAELs were established for fomesa f

en.] Maternal NOAEL = 100 mg/kg/day Maternal LOAEL = 200 mg/kg/day based on the st aining of the ventral fur and significantly decreased body weight gain (>10%) Developmental NOAEL = 100 mg/kg/day Developmental LOAEL = 200 mg/kg/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903) 870.3800 Reproduction and fertility effects - rat (2 - generation) 00144862 (1984)

Acceptable/Guideline 0, 50, 250 or 1000 ppm (0, 2.5, 12.5 and 50 mg/kg/day) Paternal NOAEL = 250 ppm (12.5 mg/kg/day) Paternal LOAEL = 1000 ppm (50 mg/kg/day) based on liver histopathology in males and fema les of both generations Offspring NOAEL = 250 ppm (12.5 mg/kg/day) Offspring LOAEL = 1000 ppm (50 mg/kg/day) based on increased incidence of liver hyalinization in males Reproductive NOAEL = 1000 ppm (50 mg/kg/day) Reproductive LOAEL was not establishedPage 32 of 48

Guideline No./Study Type MRID No. (year)/

Classification/Doses Results 8 70.4200 Carcinogenicity mice - diet 00131491 (1983)

Acceptable/Guideline 0, 1, 10, 100 or 1000 ppm (0, 0.15, 1.5, 15 and 150 mg/kg/day) NOAEL =10 ppm (1.5 mg/kg/day) LOAEL = 100 ppm (15 mg/kg/day) based on the presence of liver tumors and liver weight incr eases in male and female mice 870.4300 Chronic toxicity/ carcinogenicity rats - feeding 00142125 (1984)

Acceptable/Guideline 0, 5, 100 or 1000 ppm (0, 0.25, 5 and 50 mg/kg/day) NOAEL = 5 ppm (0.25 mg/kg/day) LOAEL = 100 ppm (5 mg/kg/day) based on hyalinization of the liver in malesPage 33 of 48

Appendix B. Toxicity Summaries MRID No. 00103013 Citation Wade, J.; Banham, P.; Chart, I .; et al. (1981) PP021: 90 Day Feeding Study

in Rats: Report No. CTL/P/554. (Unpublished study received May 28, 1982 under 10182 - EX - 30 ; prepared b y Imperial Chemical Industries, Ltd., Eng., submitted by I CIAmericas, In c., Wilmington, DE; CDL :247589 - E). Unpublished. EXECUTIVE SUMMARY - In this subchronic toxicity study (MRID 00103013 ), Fomesafen (97.5% a.i.; PPO21) was administered in the diet for 90 day s to 20 Alderley Park rats/sex/dose at doses of 0, 1, 5, 100 or 1000 ppm (equivalent to 0, 0.1, 0.5, 10 and 100 mg/kg/day). The animals were observed daily for clinical signs of toxicity . Body weights and food consumption were determined initially and at 2 - week intervals, thereafter. Hematology , clinical chemistry and urinaly sis were conducted. At termination, animals were necropsied, organs weighed and representative tissues examined microscopicall y. Election microscop y was cond ucted on selected tissues. No mortality

occurred. Animals in the 1000 ppm group gained less weight than the controls. Plasma alkaline phosphatase, alanine transaminase and aspartate transaminase were increased 169, 149 and 131%, respectivel y, in males i n the 1000 ppm group. Liver weights were increased in male and females at 1000 ppm. Hyalinization of hepatocy tes, increased eosinophilia and reduced basophilic granulation was observed at 100 and 1000 ppm. Electron microscop y revealed an increase in peroxisomes in centrilobular hepatocy tes at 100 and 1000 ppm. The LOAEL is 100 ppm (10 mg/kg/day) based on hyalinization of hepatocytes, increased eosinophilia, reduced granulation, increased liver weights in males and females, and increases in plasma alka line phosphatase, alanine transaminase and aspartate transaminase in males. The NOAEL is 5 ppm (0.5 mg/kg/day). This study

is classified as Acceptable/Guideline and satisfies the guideline requirements (OPPTS 870.3100; OECD 408) for a 90 - day toxicity study in rats. MRID No. 00103014 Citation Kalinowski AE, Chalmers DT, Chart IS, et al. (1981) PP021: 26 week oral dosing study

in dog. Central Toxicology L aboratory

(Alderley

Park, Cheshire, UK). Laboratory

Report No. CTL/P/591, March 5, 1981. Unpublished . EXECUTIVE SUMMARY - In a 26 - week oral toxicity study (MRID 00103014), fomesafen (97.5% a.i., batch #Y00053/001/005) was administered to 6 Beagle dogs/sex/dose in gelatin capsules at dose levels of 0, 0.1, 1, or 25 mg/kg bw/day . There were no treatment - related effects on survival, clinical parameters, body weight, or food consumption. Mean hemoglobin concentrations and ery

throcy te counts were slightly

decreased in both sexes combined (6 - 10%), relative to controls, at 25 mg/kg from weeks 4 - 20. Mean he matocrit was also slightly decreased (6 - 9%), relative to controls, in both sexes combined at 25 mg/kg during the same period. At 25 mg/kg in both sexes combined, mean platelet counts increased b y 10 - 23% from week 8 - 20, while from weeks 4 - 16 mean prothromb in time was increased onl y slightl y (3 - 4%), relative to controls. Taken together, these results are suggestive of slight anemia at 25 mg/kg.Page 34 of 48

Mean absolute and relative liver weights were increased in males by 10% and 13%, respectively , at 25 mg/kg. The slight increase in liver weights in males was regarded as non - adverse. The adaptive nature of the liver changes was also supported by a 19% (males) and 15% (females) increase in smooth endoplasmic reticulum (SER), indicative of increased protein sy nthesis. Mean plasma cholesterol levels were decreased b y 31 - 40%, relative to controls, in both sexes combined from weeks 1 - 26, while mean plasma trigl ycerides were decreased by 45 - 56% over the same period. A 3 - and 2 - fold increase, relative to controls, in the mean number of peroxisomes in centrilobular hepatocy tes was also observed in males and females, respectively , at 25 mg/kg. Peroxisome proliferation is an adaptive response to hy polipidemic compounds. Changes in the “tinctorial properties of hepato cy tes” was also observed in 4/6 males and 4/6 females at 25 mg/kg; these changes in staining reflect the observed changes at the organelle level, i.e., increase in peroxisome number and SER, and while treatment - related, are considered non - adverse. The LOAEL is 25 mg/kg bw/day, based on hematology (decreased hemoglobin and hematocrit concentrations and erythrocyte count and increased platelet count and prothrombin time). The NOAEL is 1 mg/kg bw/day. This chronic oral toxicity study in the dog is Acceptabl e/Guideline and satisfies the guideline requirements for a chronic oral toxicity study in non - rodents (OPPTS 870.4100; OECD 452). MRID No. MRID 00164903 EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00164903), Fomesafen (97.5% a.i.) was a dministered to 17 - 24 pregnant rats/dose in corn oil by gavage at dose levels of 0, 50, 100 or 200 mg/kg bw/day from day s 6 through 15 of gestation. Maternal toxicity

was evident at dose of 200 mg/kg bw/day (the highest dose tested) and was associated with staining of the ventral fur in 15 of 20 animals and significantly decreased body weight gain (>10%) during the dosing period (Days 7 - 16; Day s16 - 21). Food consumption in the high - dose group was also significantl y decreased as compared to the control gro up during the dosing period (Day s 7 - 16; Day s 16 - 21). However, this study

should be considered with: 1) Report Nos. CTL/P/656 and CTL/P/656S, MRID #001013016, and 2) information provided by S yn genta in their submission (DP 316263, MRID 46527208) in establi shing the NOAEL and L OAEL (see Discussion/Added Information Section). With the additional information, the following conclusions can be made. The ma ternal LOAEL is 200 mg/kg bw/day, based on staining of the ventral fur and significantly decreased body w eight gain (>10%). The maternal toxicity NOAEL is 100 mg/kg bw/day. The developmental LOAEL is 200 mg/kg bw/day based on postimplantation loss. The developmental NOAEL is 100 mg/kg bw/day. This developmental toxicity study is classified Acceptable/G uideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in combination with another developmental toxicity in rat (MRID 001013016).Page 35 of 48

MRID No. 00103016 Citation Wickeramaratne, G.A., Richards, D., Babham, P.B. (1982) Fomesafen: Teratogenicity

study in the rat. CTL/P/656 and CTL/P/656S prepared by Central Toxicology

L aboratory , Imperial Chemical Industries PL C, Alderley Park, Macclesfield, Cheshire, UK. Unpublished Study . EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00103016), Fomesafen (97.5% a.i.) was administered to 19 - 21 pregnant rats/dose in corn oil by gavage at dose levels of 0, 1.0, 7.5 or 50 mg/kg bw/day from day s 6 through 15 of gestation. There was no maternal and/or fetal toxicity evident at any

dose level tested. However, this study should be considered with: 1) Report No. CTL/P/576, MRID #00164903, and 2) information provided b y S yn genta in their submission (DP 316263, MRID 46527208) in establishing the NOAEL and LOAEL (see Discussion/Added Information Section). With the additional information, the following conclusions can be made. The maternal LOAEL is 200 mg/kg bw/day, based on staining of the ventral fur and significantly decreased body weight gain (>10 %). The maternal toxicity NOAEL is 100 mg/kg bw/day. The developmental LOAEL is 200 mg/kg bw/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903). The developmental NOAEL is 100 mg/kg bw/day. This developmental toxicity stu dy is classified Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in combination with another developmental toxicity in rat (CTL/P/576, MRID 00164903). MRID No . 00109214 Citation Wickeramaratne, G. A., Richards, D., Imartin, M., Doss, A., Ishmail, J., Taylor, D., Forbes, D., smf Godley , W.J. PP021: Teratogenicity Study in the Rabbit. Unpublished Report No. CTL/P/578. Central Toxicology L aboratory , Imperial Chemical Industries PLC, Alderley Park, Macclesfield, Cheshire, UK. Unpublished. EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00109214), fomesafen (97.5% a.i.) was administered to at least 13 pregnant Dutch rabbits/group orally (in gelatin capsul es) at dose levels of 0, 2.5, 10, or 40 mg/kg/day from day s 6 through 18 of gestation. Due to the low number of pregnant does in the low and high dose groups after the initial mating, 6 mated rabbits were added to the control, low, and mid dose groups and 7 to the high dose group. The remaining does were sacrificed on GD 29; their fetuses were removed by cesarean section and examined. A total of 17 animals died on study. Total mortality (including sacrifice in extremis) was 3/24, 3/24, 4/24, and 7/25 at 0, 2.5, 10, and 40 mg/kg/day , respectively . The incidence of mucous around the nose and/or forepaws increased in a dose - dependent manner: 3/24, 3/24, 4/24 and 8/25 at 0, 2.5, 10 and 40 mg/kg/day , respectively . Pasteurella multocida was isolated from tw o animals found dead or removed from the study prior to GD 29. However, no other animal was tested for infection with Pasteurella multocida. In the high dose group onl y, 6/25 does appeared thin, although body weight gain was not affected overall. Mean f ood consumption was 34% higher (p<0.05) than controls in the 40 mg/kg/day group during days 20 -Page 36 of 48

29. An increased incidence (6/25) of erosion of the stomach (hemorrhagic foci) was observed macroscopically

in high dose females versus 1/24 in controls, 2/24 at 2.5 mg/kg/day , and 0/24 at 10 mg/kg/day . Erosion of the stomach was also observed in a separate, preliminary study at 75 and 150 mg/kg/day

with an incidence of 7/12 animals at each dose. The maternal LOAEL was unable to be determined due to the occurre nce of an apparent bacterial infection in the animal colony. There was no significant difference between the control and treated groups in pregnancy rate or abortions. While the mean number of implantations/dam was similar across dose, the number of corp ora lutea/dam was significantly (p<0.05) increased in the high dose group (10.6) relative to controls (7.7). This resulted in an increase in pre - implantation loss at the high dose onl y. This observation was not considered toxicologicall y significant, bec ause it suggested that dosing took place before the completion of implantation, resulting in maternal - stress - induced embryo lethality . Earl y and late fetal deaths increased in the mid - dose group onl y (7/24, 3/24, respectivel y) relative to controls (4/24, 1/24, respectively). There was an increased frequency of partially ossified h yoid (7.1%) and right vestigial rib (#13, 5.4%) at 40 mg/kg/day relative to controls (2.9 and 0%, respectivel y). However, these variants are not regarded as toxicologicall y sign ificant. The developmental LOAEL was unable to be determined due to the occurrence of an apparent bacterial infection in the animal colony. Because of an apparent bacterial infection in the animal colony ; individual animal data were not reported; all fetuses were not examined for both soft tissue and skeletal alterations; and historical control data were not provided, the developmental toxicity study in the rabbit is classified Unacceptable/guideline . This study does not satisfy

the guideline requirement for a developmental toxicity

study [OPPTS 870.3700; §83 - 3(b)] in the rabbit. MRID No. 00131491 Citation Colley , J.; Slater, N.; Hey wood, R.; et al. (1983) Fomesafen: 2 - Year Feeding Study in Mice: HRC Report No. I CI318/82754; Sponsor's Study No. PM 0 386; CTL/C/1207A through E. Final rept. (Unpublished study received Oct 13, 1983 under 10182 - EX - 33; pre - pared by Huntingdon Research Centre, Eng., submitted by I CI Americas, Inc., Wilmington, DE; CDL :071999 - A; 072000; 072001). Unpublished. EXECUTIVE SU MMARY - In a chronic feeding/oncogenicity study (MRID 00131491), Fomesafen (Batch No. P28 and I CIPart No. Y00053/001/007, 97.2%) was administered in the diet to CD - 1 mice (52/sex/group; control group contained 104 mice/sex) for up to 104 weeks at doses of 0, 1, 10, 100 or 1000 ppm (equivalent to 0, 0.15, 1.5, 1.5 or 15 mg/kg/day). An interim sacrifice was scheduled at 52 weeks utilizing additional groups of 12 mice/sex, except for the control group which contained 24 mice/sex. Male mice in the 1000 p pm group were terminated after 80 treatment weeks (80% survival) and female mice were terminated after 90 treatment weeks (70% survival). No significant increases in mortality

were observed at the lower treatment doses. There was a high incidence of mal ePage 37 of 48

and female mice with swollen abdomens in the 1000 ppm group b y terminal sacrifice. Ery throcy te counts, hemoglobin levels and hematocrits were decreased in male and female mice in the 1000 ppm group at terminal sacrifice. AP and GPT activities were si gnificantly increased in males and females in the 100 and 1000 ppm groups at 52 weeks. Liver weights and liver- to body weight ratios were significantl y increased in both sexes receiving 100 and 1000 ppm F omesafen. Kidney , adrenal, and heart weights were significantl y increased at 1000 ppm. Because the organ - to - body weight ratios were not significantl y different from the controls, fomesafen was not considered to have a significant toxicological affect on these organ weights. The incidence of liver masses was significantl y increased in males receiving 1, 100 and 1000 ppm fomesafen and in females receiving 100 and 1000 ppm fomesafen. The increase in liver masses was accompanied by increases in enlarged and discolored livers and by increases in eosinophilic hepatocy

tes and pigmented macrophages and/or Kupffer cells. The incidence of malignant liver cell tumors was signif icantl y (p< 0.001) increased in males and females receiving 1000 ppm fomesafen. The LOAEL is 100 ppm (equivalent to 1.5 mg/kg/day) based o n the presence of liver tumors and liver weight increases in male and female mice. The NOAEL is 10 ppm (equivalent to 0.15 mg/kg/day). The submitted study

is classified as Acceptable/Guideline and does satisfy the requirements for a chronic feeding/oncoge nicity study in mice (OPPTS 870.4300; OECD 453). MRID No. 00135632 Citation Henderson, C., Parkinson, G., Oliver, G., et al. (1983) Subacute Dermal Toxicity in Rabbits. Imperial Chemical Industries, PL C Central Toxicology L aboratory , UK. Laboratory

Rep ort Number CTL/P/555, March 15, 1983. Unpublished. EXECUTIVE SUMMARY - In a 21 - day dermal toxicity

study (MRID 00135632), fomesafen (90.8% a.i.; Batch/Lot # P 21 C4915/26/1) in propylene glycol suspension was applied to shaved intact or abraded skin of N ew Zealand white rabbits (10/sex/dose; 5 intact and 5 abraded skin/sex) at dose levels of 0, 10, 100, or 1000 mg/kg bw/day (limit dose), 6 hours/day , 5 day s/week for 3 weeks. No treatment - related effects were observed on mortality , body weight, body

weight gain, food consumption, hematology , clinical chemistry and urinaly sis at any dose in either sex. Clinical signs (subdued behavior) was observed only in the high - dose animals immediately after the application of test material. Clinical signs in the high - dose group were not considered as toxicologically

significant since they

were observed immediately after treatment. A slight reduction in food consumption and an increase in thy roid weight were also observed. However, these effects were not considered treatment - related, since there was no dose response. Fomesafen produced moderate to severe skin reactions manifested as ery thema, edema, scaling and crust in the treated area in the 100 and 1000 mg/kg/day dose groups. The systemic toxicity LOAEL was not observed in this study. The systemic toxicity NOAEL is 1000 mg/kg/day (limit dose). This study

is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3200; OECD 410) for a 21 - day dermal toxicity

study in rats.Page 38 of 48

MRID No . 00142125 Citation Milburn, G., Banham, et al. (1984) Fomesafen: 2 ye ar feeding in rats: Report no. CTL/P/863. Unpublished study prepared by

ICIAmericas, Inc. 550p. Unpublished. EXECUTIVE SUMMARY - In this combined chronic toxicity /carcinogenicity

s tudy (MRID 00142125), Fomesafen (97.5% a.i.; CTLReference No. Y00053/001; Batch No. P28) was administered in the diet for 2 years to 52 Wistar albino rats/sex/dose at doses of 0, 5, 100 or 1000 ppm (equivalent to 0, 0.25, 5 and 50 mg/kg/day). In addition , groups of 12 rats/sex received the same dietary

concentrations for up to 52 weeks (interim sacrifice).The actual concentrations of fomesafen in the test diets were in the acceptable range of 10% of the nominal concentrations. There was an increased in cidence of coat staining in males treated with 100 and 1000 ppm fomesafen and in all females treated with fomesafen. Body weights were significantl y decreased in males in the 1000 ppm group from weeks 3 through 76. Decreased food utilization efficiencies were observed in males treated with 100 and 1000 ppm fomesafen during the first 14 weeks of the study. Significant increases in the activities of plasma alkaline phosphatase, alanine transaminase and aspartate transaminase, and in plasma albumin were ob served in male rats treated with 1000 ppm fomesafen. Significant reductions in plasma cholesterol and trigl ycerides were observed in males and females treated with 1000 ppm fomesafen. Male and female rats treated with 1000 ppm fomesafen had depressed protein excretion in urine. Mean liver weights were significantly

increased in males and females administered 1000 ppm fomesafen in the diet. Hyalinization of the liver was observed in rats administered 100 and 1000 ppm fomesafen in the diet. Biliary

hy pe rplasia, bile duct dilatation and portal fibrosis were decreased in groups treated with 1000 ppm fomesafen. Pigmentation of portal macrophages, Kupffer cells, and hepatocy tes was substantially

increased in males and slightl y i ncreased in females treated w ith 1000 ppm fomesafen. The LOAEL is 100 ppm (5 mg/kg/day), based on hyalinization of the liver in males. The NOAEL is 5 ppm (0.25 mg/kg/day). This study

is classified as Acceptable/Guideline and satisfies the guideline requirements (OPPTS 870.4300; OEC D 453) for a combined chronic toxicity /carcinogenicity

study in rats. MIRD No. 00144862 Citation Tenston, D.J. et al (1984) Fomesafen: Two - Generation Reproduction Study in the Rat. Central Toxicology L aboratory , Imperial Chemical Industries PLC, Alderl ey Park, Macclesfield, Cheshire, UK. Study number RR0199, 1984. Unpublished. EXECUTIVE SUMMARY - In a two - generation reproduction toxicity study (MRID 00144862) Fomesafen (P28; 97.5% a.i.) was administered in diet to 30 Wistar rats (Alderley Park - derive d)/sex/dose at dose levels of 0, 50, 250, or 1000 ppm (equivalent to 0, 2.5, 12.5, or 50 mg/kg/day) , for 2 generations. The F1A pups were weaned on postnatal day (PND)22 and F1B, F2B and F2A pups were weaned PND 29. Thirty F1B females and 15 males were selected to become F1 parents and produced F2B litters. Brother - sister matings were avoided in each parental generation.Page 39 of 48

In the parental animals, no treatment - related effects were observed on body weights, or food consumption. At 1000 ppm, increased in cidences of liver alterations were seen male and female F0 and F1 parents. These include congestion (M & F), multifocal necrosis (M), Kupffer cell pigmentation (M), h yalinization (diffuse and centrilobular; M & F) and biliary hyp erplasia (M & F). An increased incidence of liver hyalinization was observed in the livers of F1b males, however, these effects are considered to be of s ys temic effect rather than offspring toxicity . No liver alteration s were observed at 250 ppm. The parental LOAEL = 1000 ppm (50 mg/kg bw/day), based on liver histopathology in males and females of both generations. The maternal toxicity NOAEL = 250 ppm (12.5 mg/kg bw/day). An increased incidence of liver hyalinization was observed in the livers of F1b male pups. [Although, representative samples of liver from pups in the mid - and low - dose groups were not microscopicall y examined, hyalinization would not be expected to be observed since it was not observed in the livers of the parental animals in the low - and mid - dose groups.] The offspring LOAEL = 1000 ppm (50 mg/kg/day), based on increased incidence of liver hyalinization in males. The offspring NOAEL = 250 ppm (12.5 mg/kg bw/day). No treatment - related reproductive parameters were affected due to treatment with fomesafen. R eductions of litter size (15 - 20%) was observed in F1and F2 A litter at 250 ppm. A significant reduction 20% in litter size was observed at 1000 ppm F2B litters, however, there was no reduction in litter sizes in other 3 1000 ppm groups. A 13% reduction in litter size was also observed at 50 ppm in F1 B litters. These litter reductions were sporadic, not dose - related, and therefore, considered to be of no toxicological significance. At 1000 ppm, an increased incidence of h ya linization of the liver was observed in F1B pups in the 1000 ppm group. The reproductive NOAEL = 1000 ppm (50 mg/kg/day). The LOAEL was not established. The study is classified Acceptable/Guideline and satisfies the guideline requirement for a reproduction toxicity

(OPPTS 870.38 00; OECD 416) for a two - generation reproduction study in the rat. MRID No. 00164903 Citation Wickeramaratne, G.A., Richards, D., Babham, P.B. (1981) PP021: Teratogenicity

study in the rat. CTL/P/576 and CTL/P/567S prepared by Central Toxicology

L aborato ry , Imperial Chemical Industries PL C, Alderley Park, Macclesfield, Cheshire, UK. Unpublished. EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00164903), Fomesafen (97.5% a.i.) was administered to 17 - 24 pregnant rats/dose in corn oil by gavage at dose levels of 0, 50, 100 or 200 mg/kg bw/day from day s 6 through 15 of gestation.Page 40 of 48

Maternal toxicity

was evident at dose of 200 mg/kg bw/day (the highest dose tested) and was associated with staining of the ventral fur in 15 of 20 animals and signifi cantly decreased body weight gain (>10%) during the dosing period (Days 7 - 16; Day s16 - 21). Food consumption in the high - dose group was also significantl y decreased as compared to the control group during the dosing period (Day s 7 - 16; Day s 16 - 21). Howeve r, this study

should be considered with: 1) Report Nos. CTL/P/656 and CTL/P/656S, MRID #001013016, and 2) information provided by S yn genta in their submission (DP 316263, MRID 46527208) in establishing the NOAEL and L OAEL (see Discussion/Added Information Section). With the additional information, the following conclusions can be made. The ma ternal LOAEL is 200 mg/kg bw/day, based on staining of the ventral fur and significantly decreased body weight gain (>10%). The maternal toxicity NOAEL is 100 mg/ kg bw/day. The developmental LOAEL is 200 mg/kg bw/day based on postimplantation loss. The developmental NOAEL is 100 mg/kg bw/day. This developmental toxicity study is classified Acceptable/Guideline and satisfies the guideline requirement for a devel opmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in combination with another developmental toxicity in rat (MRID 001013016). MRID No. 40786709 Citation Colley , J., Cladee, S., Street, A., Hey wood, R., Gibson, W., Prentice, D., Buckley , P., and Offer, J. (1980) Preliminary Assessment of PP 021 Toxicity to Mice by Dietary Administration for 4 weeks. Huntingdon Research Center, Huntingdon, U.K. Study No. ICI/317/80148, September 13, 1980. Unpublished. EXECUTIVE SUMMARY - In a 28 - day range f inding oral toxicity

study (MRID 40786709), fomesafen (94% a.i., Batch/L ot # P 21 and ICI TSC No. Y00053/001/004) was administered to CD - 1 mice (10/sex/dose) in the diet at doses of 0, 5, 15, 50, 150, 500, 1500, or 5000 ppm (equal to 0/0, 0.71/0.94, 2.13/2.87, 7.20/8.30, 20.7/27.1, 68.9/83.4, 209.1/246.8, or 917.2/1247.6 mg/kg/day

[M/F]) for up to 28 day s. Clinical signs consisting of emaciation were noted in two females in the high dose group (5000 ppm) and in one female in the 150 ppm dose group. Since there was no dose response, the effect was not considered treatment - related. Mortality was seen in one male at 15 ppm in week 2, one male at 50 ppm during week 4 and one female at 5000 ppm during week 4. Statistically significant decreased body weights and body weight gains were observed in high - dose animals only . Food efficiency

was also decreased in high - dose animals only . Clinical chemistry parameters were not evaluated in this study . A slight decrease in ery throcytes, hemoglobin, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) was observed in high - dose females, while decreased MCH and a slight increase in ery throcy tes were seen in high - dose males. These changes in hematological parameters were indicative of slight anemia and w ere therefore regarded as toxicologicall y significant. Statistically significant increases in liver weights were observed in males at ~50 ppm and in females at ~150 ppm. Enlarged hepatocy tes were also observed. However, since there were no corroborating adverse histopathological findings, these effects were considered adaptive changes. All high - dose animals exhibited bile duct hy perplasia. Small seminal vesicles were observed in 2/10 high -Page 41 of 48

dose males, while small uteri were observed in 4/10 females at 1500 ppm and in 9/10 high - dose females. Under the conditions of this study, the LOAEL was 5000 ppm (equal to 917/1247 mg/kg/day in M/F) based on decreased body weights and body weight gains, decreased food efficiency, hematology (decreased erythrocyte cou nt, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), bile duct hyperplasia, decreased uterine size in females, and decreased size of the seminal vesicles in males. The NOAEL is 1500 ppm (equal to 209/247 mg/kg/day in M/F). This 28 - d ay

oral study is acceptable/non - guideline , because treatment was less than 90 day s (or 10% of the animal’s lifespan), as required b y Guideline OPPTS 870.3100 for a subchronic oral toxicity study in rodents. MRID No. 44569805 Citation Howard, C.A., Richardson, C.R. (1989) Fomesafen: An evaluation in the in vitro cy togenetic assay

in human ly

mphocy tes. Central Toxicology

L aboratory , Alderley Park, Macclecsfield, Cheshire, UK SK104TJ. L aboratory Project ID: CTL/P/2378, April 4, 1988. Unpublished. EXECUTI VE SUMMARY - In a mammalian cell cy togenetics assay

(chromosomal aberrations) (MRID 44569805), human ly mphocy tes (obtained from one male and one female donor) in culture were exposed to fomesafen (96.7% a.i.) in dimethyl sulfoxide (DMSO) at concentrations of 0, 150, 500, and 1000 μ g/ml in the absence of S9 - mix and 75, 150, and 250 μ g/ml in the presence of S9 mix for 3 - 3.5 hours and harvested 72 hours after the beginning of treatment. Two - hundred cells (100 per duplicate coded slide) were evaluated for met aphases with structural aberrations. The S9 - fraction was obtained from Aroclor 1254 induced male Sprague Dawley

rat liver. Fomesafen was tested at concentrations ranging from 150 - 1000 μ g/mL(S9) and 75 - 250 μ g/mL (+S9). A significant increase in chromoso me fragments was observed in l ymphocytes from donor 1 at 1000 μ g/mL (S9). However, the clastogenic response is most likely secondary

to cy totoxicity as the MI was reduced b y 57% in these cells. In the repeat experiment (S9, donor 1), the MI decreased b y 56% and clastogenicity was not observed. Proper experimental protocol was followed and the solvent and positive control values were appropriate. There was no evidence of chromosome aberrations induced over background. This study

is classified as Accepta ble/Guideline and satisfies the guideline requirement for Test Guideline OPPTS 870.5375; OECD 473 for in vitro cy togenetic mutagenicity

data. MRID No. 44569806 Citation Mellano, D., Berruto, G. (1984) Fomesafen: In vitro study of chromosome aberration induced b y fomesafen in cultured human lymphocytes. Istituto Di Ricerche Biomediche, “Antoine Marxer” S.p.A., Casella Postale 226, 10015 Ivrea. Laboratory Project ID: CTL/C/1262, May 16, 1984. UnpublishedPage 42 of 48

EXECUTIVE SUMMARY - In an in vitro mammalian cell cy togenetics assay

(Chromosomal aberrations) (MRID 44569806), human ly mphocy tes (obtained from 1 male donor) in culture were exposed to fomesafen (97.5% a.i.) in dimethyl sulfoxide (DMSO) at concentrations of 0, 10, 100, and 1000 μ g/ml in the absence and presence of metabolic activation for 3 hours and harvested 26 hours after the beginning of treatment. One - hundred cells (duplicate slides) were evaluated for metaphases with structural aberrations. The S9 - fraction was obtained from Aroclor 1254 induc ed male Sprague Dawley rat liver. Fomesafen was tested up to a cy totoxic concentration for this assay . Cy totoxicity was observed at 1000 μ g/ml with and without S - 9 mix. No statistically or biologicall y significant increases in chromosomal damage were ob served at any of the dose levels either in the presence or absence of metabolic activation. The solvent and positive controls induced the appropriate response. There was no evi dence of chromosome aberrations induced over background. This study

is classi fied as Acceptable/Guideline and satisfies the guideline requirement for Test Guideline OPPTS 870.5375; OECD 473 for in vitro cy togenetic mutagenicity

data.Page 43 of 48

Appendix C : Review of Human Research This asse ssment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide. These studies, listed below, have received the appropriate ethical review.

 The PHED Task Force, 1998. The Pesticide Handler Exposure Database (PHED), Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency , the California Department of Pesticide regulation, and the American Crop Protection Association, released August 1998.  ARTF Studies. Agricultural Reentry Task Force (ARTF). Reviewed b y HED, ExpoSAC SOP No. 003 (May

7 th , 1998 - Revised August 7 th , 2000).Page 44 of 48

Appendix D: Rationale for Toxicology Data Requirements Guideline Number : 870.7800 Study Titl e: Immunotoxicity Rationale for Requiring the Data The immunotoxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for reg istration of a pesticide (food and non - food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immunotoxicity. Practical Utility of the Data How will the data be used? Immunotoxicity studies p rovide critical scientific information needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited and are inad equate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8 - tetrachlorodibenzo -p - dioxi n) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). How could the data impac t the Agency's future decision - making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. Guideline Number : 870.7200 Study Title: Acute and Subchronic Neurotoxicity Rationale for Requiring the Data Acute and subchronic neurotoxicity studies are now required under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide for (food and non - food uses). The Neurotoxicity Test Guideline (OPPTS 870.6200) require a functional observational battery, motor activity, and neuropathology evaluation . The functional observational battery consists of noninvasive procedures designed to detect gross functional deficits in animals and to better quantify behavioral or neurological effects detected in other studies. The motor activity test uses an automated device that measures the level of activity of an individual animal. The neuropathological techniques are designed to provide data to detect and characterizePage 45 of 48

histopathological changes in the central and peripheral nervous system. This battery is designed to be used in conjunction with general toxicity studies and changes should be evaluated in the context of both the concordance between functional neurological and neuropatholgical effects, and with respect to any other toxicological effects seen. Practical Utility of the Data How will the data be used? Neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population of neurotoxicity from pesticide exposure. How could the data impact the Agency's future decision - making? If the neurotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the risk assessments' s conclusion, the risk assessments for the test material may need to be revised to refl ect the magnitude of potential risk derived from the new data.Page 46 of 48

Appendix E. Confined Rotational Crop Summary Table Analyte Structure Major Residue 1 Minor Residue 1 Fomesafen F 3 C

Cl O N O 2

O N H S C H 3 O O Wheat Forage (NP) 90/224/270

–

65.2/68.4/70.4 Wheat Forage (TMP) 90/224/270

– 36.1 / 11. 8/ 35.9 Wheat Hay (NP) 90/224/270

– 63.9 / 50.7 /48.0 Wheat Hay (TM P) 90/224/270

– 51.9 / 14.9 /21.2 Wheat Straw (NP) 90/224/270

– 30.4 / 3 8 .1 /43.2 Wheat Straw (TMP) 90/224/270

– 35.3 /24.3 / 34.6 Wheat Grain (NP) 90/224/270

– 44.4 / 33.3 / 33.3 Wheat Grain (TM P) 90/224/270

– 25 / 16.7 / 16.7 Potato Foliage (N P) 9 1 day

– 18.5 Potato Root (N P) 9 1 day

– 25.0 Potato Root (TM P) 9 1 day

– 25.0 Immature Spinach (NP) 224/270

– 57.9/62.5 Immature Spinach (TMP) 270 day

– 32.5 Mature Spinach (NP) 224 /270

– 60.0/53.8 Mature S pinach (TMP) 270 day

– 20.7 Radish Foliage (N P) 224 day

– 78.6 Radish Foliage (TM P) 224 day

– 19.4 Radish Root (TMP) 224 day

– 44.4 Carrot Foliage (N P) 270 day

– 30.9 Carrot Foliage (TM P) 270 day

– 19.5 Carrot Root (N P) 270 day

– 25.0 Carrot Foliage (TM P) 2 70 day

– 19.5 Carrot Root (TM P) 270 day

– 10.0 Soybean Forage (NP) 9 1 day

– 3.4 Soybean Hay (NP) 9 1 day

– 1.8 Soybean Forage (TM P) 9 1 day

– 0.7 Potato Foliage (TM P) 9 1 day

– 6.6 Immature Spinach (TMP) 224 day

– 4.2 Mature Spinach (TMP) 224

– 4.0Page 47 of 48

Analyte Structure Major Residue 1 Minor Residue 1 R052850 C onjugate O H Cl C O O H Soybean Forage (TM P) 9 1 day

– 14.1 (0.02 ppm) Soybean Hay (TM P) 9 1 day

– 16.8(0.061 ppm) Wheat Straw (TMP) 90/224/270

– 3.6 / ND / ND (<0.031 ppm) TFAA Conjugates O O H F F F Wheat Forage (TMP) 90/224/270

– 20 / 73.5 / 51.3 (<0.03 ppm) Wheat Hay (TMP) 90/224/27 0

– 12.6 / 64.9 /45.1 (<0.051 ppm) Wheat Straw (TMP) 90/224/270

– 9.9 /28.7 / 17.8 (<0.086 ppm) Wheat Grain (TMP) 90/224/270

– ND / 33.3 / 33.3 (<0.004 ppm) Soybean Forage (TM P) 9 1 day

– 26.0 (0.037 ppm) Soybean Hay (TM P) 9 1 day

– 37.4(0.136 ppm) Potato Foliage (TM P ) 9 1 day

– 37.7 (0.023 ppm) Potato Root (TM P) 9 1 day

– 50.0 (0.004 ppm) Immature Spinach (TMP) 224/270

– 79.2/52.5 (<0.021ppm) Mature Spinach (TMP) 224/270

– 92.0/55.2 (<0.023 ppm) Radish Foliage (TM P) 270 day

– 74.2 (0.023 ppm) Radish Root (TM P) 270 day

– 3 3.3 (0.003 ppm) Carrot Foliage (TM P) 270 day

– 19.5 (0.017 ppm) Carrot Root (TM P) 270 day

–40.0 (0.004 ppm) Soybean Seed (TM P) 9 1 day

– 20.0 (0.005 ppm)Page 48 of 48

Analyte Structure Major Residue 1 Minor Residue 1 R290493 2 - amino - 3 - (3

– methanesulfonyl amin o - carbonyl - 4 - nitro phenylsulfany 1) - propionic acid N O 2

O N H S C H 3 O O S N H 2 O H O Soybea n Forage ( N P) 9 1 day

– 27.6 (0.016 ppm absolute) Potato Foliage (N P) 9 1 day

– 25.9 (0.007 ppm) Potato Root (N P) 9 1 day

– 12.5 (0.001 ppm) Immature Spinach (NP) 224 day

– 10.5 (0.002 ppm) Wheat Forage (NP) 90/224/270

– 1.4/2.6/3.7 Wheat Straw (NP) 90/224/270

– ND / 3.3 /2.2 Soybean Hay ( N P) 9 1 day

– 8.9 (0.015 ppm) Immature Spinach (NP) 270 day

– 4.2 (<0.001 ppm) Mature Spinach (NP) 270 day

– 7.7 (0.001 ppm) Radish Foliage (N P) 224 day

– 7.1 (<0.001 ppm) 1 These columns include the matrix, radiolabel posi tion [nitrophenyl (NP) or trifluorometh ylphenyl (TMP)], plant - back interval, % of Total Radioactive Residues, and for the metabolites, residue level in ppm.