Page 1 of 44 UNITED STATES ENVIRONMENTA L PROTECTION A GENCY

WASHINGTON, D.C. 20460 OFFICE OF PREVENTI ON, PESTICIDE

AND TOXIC SUBSTANCES MEMORANDUM Date: February 19 , 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 Tomatoes . PC Code: 123802 DP Barcode: D 373963 Decision No.: 409397 Re gistration No. : 100 - 993 Petition No . : 9F7563 Regulatory Action: New Use/Tolerance 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) THROU GH: Michael Metzger , Branch Chief

Risk Assessment Branch VII Health Effects Division (7509P) TO: Dan Kenn y/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 herbicide fomesafen sodium on potatoes and tomatoes .Page 2 of 44 Table of Contents 1.0 Executive Summary ................................ ................................ ................................ .......... 3 2.0 Ingredient Profile ................................ ................................ ................................ .............. 7 2.1 Summary of Registered and Proposed Uses ................................ ....................... 7 2.2 Structure and Nomenclature ................................ ................................ ............... 9 2.3 Physical and Chemical Properties ................................ ................................ ..... 10 3.0 Hazard Characteriz ation/Assessment ................................ ................................ ........... 10 3.1 Hazard and Dose - Response Characterization ................................ .................. 10 3.1.1 Database Summary ................................ ................................ ................. 10 3.1.2 Toxicological Effects ................................ ................................ ............... 11 3.2 Absorption, Distribution, Metabolism and Excretion ................................ ..... 11 3.3 FQ PA Considerations ................................ ................................ ......................... 11 3.3.1 Adequacy of the Toxicity Database ................................ ....................... 11 3.3.2 Evidence of Neurotoxicity ................................ ................................ ...... 12 3.3.3 Studies Assessing Offspring Sensitivity ................................ ................ 12 3.3.4 Degree of Concern Analysis for Pre and Postnatal Susceptibility ..... 13 3.4 FQ PA Safety Factor for Infants and Children ................................ ................. 13 3.5 Hazard Identification and Toxicity Endpoint Selection ................................ .. 14 3.5.1 Level of Concern for Margin of Exposure ................................ ............ 14 3.5.2 Recommendation for Aggregate Exposure Risk Assessments ............ 14 3.5 .3 Classification of Carcinogenic Potential ................................ ............... 14 3.5.4 Toxicological Doses and Endpoints ................................ ....................... 14 3.6 Endocrine Disruption ................................ ................................ ......................... 15 4.0 Public Health and Pesticide Epidemiology Data ................................ .......................... 16 5.0 Dietary Exposure/Risk Characterization ................................ ................................ ..... 16 5.1 Residues of Concern ................................ ................................ ........................... 16 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 D ietary Exposure/Risk ................................ ................................ . 19 5.3.2 Chronic (Non - Cancer and Cancer) Dietary Exposure/Risk ............... 19 5.4 Anticipated Residue and Percent Crop Treated (%CT) 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 - Occu pational) Exposure ................................ ................................ ... 21 7.0 Aggregate Risk Assessments ................................ ................................ .......................... 21 8.0 Occupational Exposure and Risk ................................ ................................ .................. 21 8.1 Occupational Handler Exposure ................................ ................................ ....... 21 8.1.1 Occupational Handler Risk ................................ ................................ .... 23 8.2 Occupational Post - appl ication Exposure ................................ .......................... 25 9.0 Environmental Justice ................................ ................................ ................................ .... 25 10. 0 Data Needs ................................ ................................ ................................ ........... 26 11.0 References ................................ ................................ ................................ ............................ 27Page 3 of 44

Appendix A: Toxicology Assessment ................................ ................................ ....................... 28 A.1 Toxicology Data Requirements ................................ ................................ .......... 28 A.2 Toxicity Profiles ................................ ................................ ................................ .. 29 Appendix B. Toxicity Summaries ................................ ................................ .............................. 32 Appendix C: Review of Human Resea rch ................................ ................................ ............... 42 Appendix D: Rationale for Toxicology Data Requirements ................................ .................. 43 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 - nitrobenzamide) for the purpose of establishing a tolerance and registering a new use on potatoes and tomatoes . Fome safen 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 residential 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 transplanted tomatoes . 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 tomatoes as a pre - plant non - incorporated pre emergence broadcast applications up to seven days prior to transplanting tomatoes for control of weeds. Hazard Chara cterization The toxicological database for fomesafen is considered complete and adequate for the purposes of this risk assessment. Fomesafen has a low order of acute toxicity by the oral route of exposure (Toxicity

Category I II), is severely

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

weight/body

weight gain and histopathological changes in the liver were the parameters that were m ost 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 produc ed in the mouse carcinogenicity study; however, HED’s Cancer Assessment Review Committee (CARC) determined that fomesafen should be classified as “Not L ikel y to be Carcinogenic to Humans”. This decision was based on the weight - of - evidence which supports a ctivation 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 quantitat ive or qualitative evidence of increased susceptibility was seen following in utero exposure to rats or rabbits in developmental studies or in the reproduction study . Immunotoxicity , acute neurotoxicity , and subchronic neurotoxicity

studies are now required.Page 4 of 44

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 dos e of fomesafen; therefore, an endpoint for acute dietary risk was not selected. 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 inci dental 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 intermedi ate - 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 applied. The e ndpoint 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 weights in males and females, and increases in liver enzy mes in a 90 - day study in rats. The CARC has classified fomesafen as “Not Likely to be Carcinogenic to Humans”. Residue Data Sufficient residue data are available to support the proposed tolerance in/o n tomatoes. The residue of concern is only the parent, fomesafen. Crop metabolism data are not available to support the proposed tolerance in/on potatoes. A root and tuber metabolism study is needed before HED can recommend for a tolerance. The residue data are supported by adequate storage stability data and an analy

tical method is available to support the proposed tolerance in/on tomatoes. Dietary Exposure and Risk The environmental fate data indicated that fomesafen is likely to be persistent and m obile 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 i n 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 ; sin ce the prospective groundwater moni toring concentration of 1.0 ppb is lower than the surface water value, dietary

assessment using the surface water residue will be protective for residues in groundwater.Page 5 of 44

Acute dietary

risk assessments were not required a s there were no endpoints identified attributable to a single exposure of fomesafen. Additionally , aggregate acute risk assessments were not required. Chronic dietary

risk assessments were conducted for fomesafen sodium using the Dietary Exposure Evalu ation 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 (C SFII) from 1994 - 1996 and 1998. The assumptions of these unrefined asse ssments were tolerance level residues and 100% crop treated. Estimated drinking water concentrations (EDWCs) from the Environmental Fate and Effects Division were also included. The dietary

exposure analy ses in this assessment result in dietary risk esti mates 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 water was 0.000791 mg/k g/day , which is 32% of the chronic population adjusted dose (cPAD ) (D372850, C. Olinger , 1/21/2010 ) . The Cancer Assessment Review Committee (CARC) classified fomesafen as "not likel y to be carcinogenic to humans"; therefore, a cancer risk assessment was not required. 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 - /intermediat e - 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 o f 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 Margi n of Exposure (MOE) for determining 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 . When the MOE is greater than 100, the risks are not of concern. 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 expo sure was evaluated b y following Exposure Science Advisory Council SOPs and data from the Pesticide Handlers Exposure Database (PHED). Data from adult human subjects in the PHED study has received ethical review and all regulatory requirements were met.Page 6 of 44

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 for 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 aircraft). Dermal MOEs ranged from 12,000 to 130,000 and inhalation MOEs ranged from 220 to 5,900. Occupational Post - application Risk : As the herbicide is applied pre - emergence for potato and tomato crops, no occupational post - application exposures are expected. Human Studies : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies , which comprise the Pesticide Handlers Exposure Database (PHED), have been determined to require a review of their ethical conduct, have received that review, and are considered ethicall y and scientifically

acceptable for use in risk assessment. Regulatory Recommendations Pending resolution of the deficiency pertaining to directions for use, there are no residue chemistry issues that would preclude granting a conditional registration for the use of sodium fomesafen on tomatoes and establishing a tolerances for fomesafen in/on tomatoes at 0.025 ppm. Confined rotational crops studies shoul d be required as a condition of registration. At this time, data are not available to support rotation to other crops beyond those commodities that are currentl y registered and proposed as primary crops; therefore, the petitioner must revise the Reflex® H erbicide label to permit immediate replanting of so yb eans, cotton, dry beans, snap beans , and tomatoes onl y (phy totoxicity concerns permitting) with a restriction that other crops can onl y be planted 12 months after treatment or 18 months after treatment i f based on phy totoxicity concerns. The registrant’s most recent Reflex® Herbicide label reflects regional use of fomesafen on tomatoes. 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. Note to PM: 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 degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determin ed b y measuring only fomesafen [5 - [2 - chloro - 4 - (trifluorometh yl )phenox y] -N - (methylsulfonyl) - 2 - nitrobenzamide].” HED cannot recommend for the requested tolerance in/on potatoes due to the lack of an adequate root/tuber metabolism study .Page 7 of 44

Label Recommendati ons The proposed label should be revised to remove the use on potatoes based on lack of an adequate root/tuber metabolism study . The label should be revised to permit immediate replanting of soy beans, cotton, dry

beans, snap beans , and tomatoes only (ph y totoxicity concerns permitting) with a restriction that other crops can onl y be planted 12 months after treatment or 18 months after treatment if based on phy totoxicity concerns. 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 in place for inspectors to validate dail y use p atterns 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 perm anent sy stems outside of center pivot irrigation equipment which are essentially culturally

equivalent (e.g. drip irrigation sy stems for tomatoes in raised bed culture) . 2.0 Ingredient Profile 2.1 Summary of Registered and Proposed Uses Background on Cu rrently 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 sup pression 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 postemergence 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 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 protoporph yrinogen oxidase (PPO) in the plant. Summary of Proposed New Use Pattern: A human health risk assessment has been conducted for the a ctive ingredient fomesafen 5 - [2 - chloro - 4 - (trifluoromethyl)phenoxy] -N - (meth yl sulfonyl) - 2 - nitrobenzamide) for the purpose of registering a new use on potatoes and tomatoes . Reflex  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 tomatoes. 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 tomatoes as a pre - plant non - incorporated pre emergence broadcast applications up to seven days prior to transplanting tomatoes 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.Page 8 of 44

The draft label specifies that use is restricted 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 alternate ye ars in Region 3, 0.25 lb ae/A in alternate years in Region 4, and 0.18 75 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 tomatoes are either pre - emergence or pre - transplant, the use of surfactants is not needed when Reflex® is applied to these crops. Application eq

uipment : Ground applications 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 an y 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 p roducts registered for use on potatoes and tomatoes : The draft label provides mixing procedures for tank mixes but does not specify specific tank mix partners for potatoes and tomatoes. The use directions state that, for tank mix combinations, the recomm endations, restrictions, 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 potatoes. For pre - plant non - incorporated pre - emergence applications prior to transplanting tomatoes, Reflex® may

also be tank mixed with other pesticide products registered for use in this way and timing in tomatoes. Table 2 .1 . U se Pa ttern Summary of Proposed New Use of Fo mesafen on Potatoes and Tomatoes 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 Tomato: 1.5 pt/A (0.375 lb ae/A) ; Max 1.5 pt /A/season Frequency No minimum rotation interval for potatoes and transplanted tomatoes Pre - Harvest Interval ( PHI ) Potatoes and tomatoes should not be harvested within 70 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 an d loaders handling more than 140 gallons of Reflex ® Herbicide in a single workday must wear: dust/must filtering NIOSH - approved respiratorPage 9 of 44 with any N, R, P or HE filter. (Note: it is recommended that this requirement be removed from the label). Restric ted 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. Tomato: Broadcast pre - plant non - incorporated pre - emergence application up to 7 days prior to transplanting tomatoes. Refer to Syngenta’s Regional Use Map for Reflex® 1 (summarized in the ‘General Us e Directions’ below) 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 seasona l 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 esafen 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.Page 10 of 44

Table 2.2b. Sodium Salt of Fom esafen Nomenclature. Compound Chemical Str ucture F 3 C

Cl O N O 2

O N S C H 3 O O Na+

Common name Sodium Salt of Fomesafen Company experimental 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 C AS 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. Trichilo 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 for hazard characterization.Page 11 of 44

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 moderatel y irritating to the skin. In the subchronic and chronic toxicity studies in rats and mic e 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 carcinogenicity study ; however , HED’s Cancer Assessment Review Committee (CARC) determined that fo mesafen 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 dev elopmental 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 w a 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 at higher doses where the urine wa s the main route of excretion for both sexes. At higher doses, the vast majority w a 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 microorganis ms. 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. Mo st 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. 3.3 FQ PA Considerations 3.3.1 Adequacy of the Tox icity Database The toxicology

database for fomesafen is adequate for FQPA assessment. The following acceptable studies are available: • Developmental toxicity study in rats • 2 - Generation reproduction toxicity studies in ratsPage 12 of 44

An unacceptable developmental toxicity study in rabbits provide d information that fomesafen does not pose a hazard to the developing embryo. 3.3.2 Evidence of Neurotoxicity No neurot oxicity

was observed in the studies. Acute and subchronic neurotoxicity studies are now required un der 40 CFR Part 158. 3.3.3 Studies Assessing Offspring Sensitivity Developmental Toxicity

Studies in Rat s (MRID 00164903) 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. The maternal LOAEL was 200 mg/kg bw/day , the highest dose tested, based on staining of the ventral fur and significantly decreased body weight gain (>10%). The maternal toxicity NOAEL was 100 mg/kg bw/day . The developmental L OAEL was 200 mg/kg bw/day based on postimplantation loss. The developmental NOAEL was 100 mg/kg bw/day. This developmental toxicity study 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 (MRID 001013016). Developmental Toxicity Study in Rabbits (MRID 00109214) In a developmental toxicity study (MRID 00109214), fomesafen (97.5% a.i.) was administered to at least 13 pregnant Dutch rabbits/group orall y at doses 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 dos e groups and 7 to the high dose group. In the high dose group only , 6/25 does appeared thin, although body weight gain was not affected overall. An increased incidence of erosion of the stomach was observed in high dose females. Mortality due to a bac terial infection was 3/24, 3/24, 4/24, and 7/25 in the respective dose groups. There was no significant difference between the control and treated groups in pregnancy

rate or abortions or for developmental abnormalities. This study

provided information to assess potential developmental toxicity rabbits, but was classified unacceptable because of bacterial infection in the colony . Reproductive Toxicity

Study Rat 2 - Generation Reproduction Study (MRID 00144862)Page 13 of 44

In a two - generation reproduction toxic ity study (MRID 00144862) Fomesafen (P28; 97.5% a.i.) was administered in diet to 30 Wistar rats (Alderley Park - derived)/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. At 1000 ppm, an increased incidence of liver alterations was 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). 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). The offspring LOAEL = 1000 ppm (50 mg/kg/day), based on increased incidence of liver hyalinization in F1b male pups . The offspring NOAEL = 250 ppm (12.5 mg/kg bw/day). No treatment - related reproductive parameters were affected due to treatment with fomesafen. The reproductive NOAEL = 1000 ppm (50 mg/kg/day) , the highe st dose tested. The study is classified Acceptable/Guideline and satisfies the guideline requirement for a reproduction toxicity

(OPPTS 870.3800; OECD 416) for a two - generation reproduction study in the rat. 3.3.4 Degree of Concern Analysis for Pre and Postn atal Susceptibility 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 susceptib ility 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 was not any evidence of increased susceptibility of rabbit f

etuses 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 sus ceptibility . 3.4 FQ PA Safety Factor for Infants and Children EPA began requiring functional immunotoxicity testing of all food and non - food use pesticides on December 26, 2007. Since this requirement went into effect after the tolerance petition was submitted, these studies are not yet available for fomesafen. In the absence of specific immunotoxicity

studies, the toxicity

database was e valuated to determine whether a database uncertainty factor is n eeded to account for 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. Since this requirement went into effect after the tolerancePage 14 of 44

petition was submitted, these studies are not yet available for fomesafen. The toxicity database was evaluated for evidence of neurotoxicity and no evidence for neurotoxicity was found in the database. Itwas therefore concluded that a database uncertainty factor is not needed to account for potential n eurotoxicity . For the above reasons, and because there are no concerns and/or residual uncertainties for pre - and/or postnatal increased susceptibility , the FQPA safety factor was reduced to 1X. 3.5 Hazard Identification and Toxicity Endpoint Selection 3.5.1 Level of Concern for Margin of Exposure A summ ary

of the levels of concern for risk assessment may be found in Table 3. 5. 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 3.5.1 . Lev els of Concern for Risk Assessment. Route Short - Term (1 - 30 Days) Intermediate - 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 . 3.5.2 Recommendation for Aggregate Exposure Risk Assessments No residential uses are proposed for fomesafen at this time. Therefore, aggregate risk consists of exposure from food an d drinking water sources only . Onl y chronic aggregate risk was assessed since no acute toxicity

is likely to result from exposure to fomesafen. 3.5.3 Classification of Carcinogenic Potential In a ccordance 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. Whi le the proposed mode of action for liver tumors 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 quanti fication of risk is not required. 3.5.4 Toxicological Doses and EndpointsPage 15 of 44

A summary

of the hazard endpoints selected may be found in Table 3. 5.4. TABLE 3. 5.4 Toxicological Doses and Endpoints for Fom esafen Human Health Risk Ass essments. 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 fo me safen were fo und in the database. Ac ute Dietary (General US Pop.) - - No toxic effects attributable to a single dose of fo me safen 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 = 1 X (cPAD) = 0.00025 mg/kg/day Chronic toxicity

– rat

LOAEL = 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 = 10 0 (Occupational) LOC for MOE = 100 (Residential) Prenatal 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 absorption rate = 10 0% oral equivalent) 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 in creases 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%)* LOC for MOE = 100 (Occupational) LOC for MOE = 100 (Residential) Chroni c 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” Point of Departure (POD) = A data point or an e stimated 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. 3.6 E ndocrine 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 wildl ife similar to an effect produced b y 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 requiredPage 16 of 44

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 have 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 an y adverse endocrine related effects cause d 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 is issuing test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide ac tive 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 scenarios. This list should n ot 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 Ti er 1 screening battery , please visit our website: http://www.epa.gov/endo/. In the available toxicity

studies on fomesafen, there was no estrogen, androgen, and/or thy roid mediated toxicity . 4.0 Public Health and Pesticide Epidemiology Data At this time th ere is no information in the incident reports that affect this risk assessment. 5.0 Dietary Exposure/Risk Characterization 5.1 Residues of Concern The registrant submitted a new tomato metabolism study in support of this petition that is acceptable and supports the proposed use on tomatoes. The metabolism in tomatoes is submitted to the previously submitted studies on soy beans and cotton. HED generally recommends that three metabolism studies on diverse crops be conducted when a pesticide is to be used on several different commodities. Although three metabolism studies have been submitted, soy

beans and cotton are not sufficiently diverse to support the proposed use on potatoes. A potato metaboli sm study , in which both the root and tops/foliage are analyzed, is requi red to support the proposed use on potatoes. HED cannot recommend for a tolerance in/on potatoes until an adequate metabolism study is submitted. The residues of concern for food and drinking w ater are summarized in Table 5. 1 below.Page 17 of 44

Table 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 Pl ants Primary Crop Fomesafen Fomesafen Plants Rotational Crop Not determined 1 Not determined 1 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 requir ed at this time. 2

Drinking Water Fomesafen NA 1 The nature of the residue in rotational crops has not been adequately delineated. For this action rotation is limited only to the primary crops that are the subject of this action. 2 HED has determined that use of fomesafen on the primary crops that are the subject of this action will not likely result in finite residues in livestock commodities (180.6 (a)(3)). 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) and 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). Environmental fate data indicate that fomesafen should b e 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 modeling 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 representative 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 application rate s of 0.375 lbs ae/A for soy bean, dry and snap bean, cotton, and tomato; 0.25 lbs ae/A for potato; and 0.5 lb ae/ A for nursery crop . Fomesafen 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.Page 18 of 44

EFED conducted a ground water assessment using the available environmental fate data and the SCI - GROW model. EFED notes that 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 ground water were not expected to exceed 11.2 μg/L (ppb) . No USGS groundwater monitoring data were located for fomesafen, however, th e 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 dete ction 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 soy beans 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 at er 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 applicatio n , with a concentration of 10 ppb, adjusted for a Percent Crop Area (PCA) of 0.87. This value was used directly in the dietary

exposure assessment.

 Sy ngenta submitted a prospective ground water monitoring study for fomesafen use on soy beans. EFED recomm ended 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 Twelve crop field trials were submitted in support of the proposed tolerance in/on tomatoes. Residues in all trials were non - detectable at a limit of quantitation of 0.025 ppm. This is consistent with trials on other crops. Processing factors could not be calculated for tomatoes as residues were non - detectable in/on the raw and processed commodities. The metabolism, crop field trial, and processing studies are supported b y adequate storage stability studies. The multi residue methods are not suitable for the anal ys is of fomesafen. An adequate anal yt ical method is available for the enforcement of tolerances. Sy ngenta submitted a new LC/MS/MS method (GRM045.01A) for analy sis of fomesafen residues, which has been adequately validated in various crop commodities. Confined rotational crop data remain outstanding. Limited rotational crop field trials reflectingPage 19 of 44

anal ys is of only

the parent compound are available. There are no livestock feed items associated with the use on tomatoes. The existing uses of fomesafen result in a 180.6 ( a)(3) situation, that there is no reasonable expectation of finite residues and no tolerances in/on livestock commodities are needed. 5. 3 Dietary Exposure and Risk Please see DP Barcode: D372850, Fomesafen Sodium: Chronic Dietary Exposure Assessment to Support Proposed New Use on Tomatoes, January 21, 20 10 by Christine Olinger for the complete fomesafen sodium dietary assessment. Chronic dietary

risk assessments were conducted using the Dietary Exposure Evaluation Mo del (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 support a propos ed new use of fomesafen sodium (commonly called fomesafen) on tomatoes. See Table 5.2 below for a summary of fomesafen chronic dietary exposure risk estimates for food and drinking water. 5. 3 .1 Acute Dietary Exposure/Risk No toxic affects attributable to a single dose of fomesafen were found in any study ; therefore no acute dietary

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

exposure assessments were performed for fomesafen . 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. F or non - cancer exposure, the highest exposure and risk estimates were for all infants (<1 ye ar old ), with a cPAD of 32 % including food and drinking water. Table 5. 3.2 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fomesafen . Popul ation 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) Risk General U.S. Population NA NA 0.000282 11.3 NA NA All Infants (< 1 year old) 0.000791 32 Children 1 - 2 years old 0.000480 19 Children 3 - 5 years old 0.000441 18 Children 6 - 12 years old 0.000302 12Page 20 of 44

Youth 13 - 19 years old 0.000221 8.8 Adults 20 - 49 years old 0.000258 10 Adults 50+ years old 0.000260 10 Females 13 - 49 years old 0.000255 10 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 percent 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 a new proposed enforcement method, Method GRM045.01A, which is entitled “Fomesafen Analy tical Method for the Determination of Residues of Fom esafen in Crop Commodities by L C - MS/MS.” This high performance liquid chromatography with tandem mass spectrometry detection (LC/MS/MS) method is based on previously submitted gas chromatography with nitrogen phosphorus detection (GC/NPD) methods (refer t o 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% hydrochloric acid in acetonitrile . An aliquo t 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 spectra and linearity data were submitted demonstrating adequate se nsitivity . 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 ation Sufficient residue data are available to suppor t a tolerance of 0.025 ppm in/on tomatoes. Processed commodity

tolerances are not needed since detectable residues were not found in either raw or processed tomato commodities. According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. K nizner), the tolerance expression for fomesafen should be revised to state: “Tolerances are established for residues of fomesafen, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levelsPage 21 of 44

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 International Harmonization No Codex, Canadian, or Mexican MRL s have been established for residues of f omesafen in/on tomato. 6.0 Residential (Non - Occupational) Exposure There are no residential uses for fomesafen sodium; therefore, an evaluation of exposures resulting from home uses was not required. 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 Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by 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

Drif t 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 reduce off - target drift with specific products with significant risks associated with drift. 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 a nd 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 A dd New Uses on Potatoes and Tomatoes , Alexandra LaMay , February 19 , 2010 , for the complete fomesafen occupational exposure and risk assessment. This section describes the occupational exposure and risk assessments conducted to support applications of fom esafen on potatoes and tomatoes . 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 ExposurePage 22 of 44

Occupational handler scenarios include handling of Reflex  during mixing, loading, and applying processes . The proposed label states load ers, applicators, and other handlers must wear a long - sleeved shirt, long pants, shoes plus socks and chemical - resistant gloves as personal protective equipment (PPE) . Therefore , these scenarios were assessed. Also, for aerial applications, mixers/loader s handling more that 140 gallons of product per day must wear a dust/ mist filtering NIOSH respirator (80% protection factor, PF5) according to the proposed label. For the uses on potatoes and tomatoes, it is assumed that a mixer/loader would not handle m ore 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 - te rm exposures may occur; long term exposures are not expected. Exposure and risk were evaluated using the Pesticide Handlers Exposure Database (PHED). 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 scenari os were assessed for agricultural workers: Mixer/Loaders (M/L) : (1) M/L liquids for Aerial Application/ Chemigation ; (2) M/L liquids for Groundboom 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 tomatoes. Maximum applicati on rates have been assessed in this document to more inform risk managers about the specific conditions of the proposed label amendments . The adverse affects for short - and intermediate - term dermal risk assessment are female - specific; therefore the body we ight of an average female (60 kg) was used to estimate dermal exposure. Since the adverse effects for the short - and intermediate - term inhalation endpoints are not gender specific, the body weight of an average adult (70 kg) was used to estimate inhalatio n 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 be 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.Page 23 of 44

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 Tomato 0.375 Liquid: Aerial Applicator Potato 0.25 350 Tomato 0.375 Liquid: Groundboom Mixer/Loader; Applicator Potato 0.25 80 Tomato 0.375 Flagging Potato 0.25 350 Tomato 0.375 Risks were calculated as a MOE, which is a ratio of the toxic ological 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 we ight. 8.1.1 Occu pational Handler Risk The proposed label indicates that applications are made pre - emergence to potatoes and tomatoes . The proposed label allows for liquid application with a groundboom or an enclosed fixed wing aircraft. See Table 8.1.1 be low. For mixer/loaders at single layer dermal PPE (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 tomatoes : 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 tomatoes , 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 ,000 and the inhalation MOE is 1,500 . o For mixer/loader for groundboom application on tomatoes , the dermal MOE is 43 ,000 and the inhalation MOE is 970 . For applicators at single layer dermal PPE (gloves, no respirator) for groundboom applicators 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 tomatoes : 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 .Page 24 of 44 o For applicators using engineering control of enclosed fixed wing aircraft application on tomatoes, the d ermal MOE is 4 2 ,000 and the inhalation MOE is 3,900 . o For applicators using groundboom open c ab on potatoes , the dermal MOE is 11 0,000 and the inhalation MOE is 2,400 . o For applicators using groundboom open cab on tomatoes , the dermal MOE is 71 ,000 and the inhalation MOE is 1,600 . For flagging at single layer dermal PPE (gloves, no respirator) :  Fo r 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 tomatoes: o For flaggers op e n cab for t omatoes , the dermal MOE is 29 ,000 and the inhalation MOE is 1,100 . o For flaggers op e n cab for tomatoes , 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. Table 8 .1 .1 . Short - and Intermediate - Term Fomesafen Sodium Occupatio nal 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 Mixer/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 To mato 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

To mato 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 To mato 0.375 0.0024 0.00013 42,000 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 To mato 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 To mato 0.375 0.00525 0.00066 19,000 760 1 Application rates are based on maximum values found on the label .Page 25 of 44 2 Minimum P PE 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 Absor ption (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 Application by fixed - wing aircraft has engineering control of enclosed cab. 8.2 Occupational Post - application Exposure As the proposed label states that the prod uct 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 broa dcast application prior to transplanting tomatoes; post - application exposures are not anticipated for this use ; therefore a quantitative post - application exposure assessment was not conducted. This risk assessment for fomesafen sodium evaluates the pote ntial risks associated with its pre plant/pre - emergent uses on tomatoes 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 activiti es ty picall y associated with the production of crops that would require significant contact with treated soil and no foliage is present that could also lead to exposure via contact including potatoes and tomatoes. There is a possible concern that some lev el of soil contact could occur during mechanically assisted tomato transplanting activities, however, but this is likely to result in negligible exposures as outlined in HED Exposure SAC Policy 8. This is because transplanting activities involve moving st arter plants onto a rotating wheel while riding upon an implement being moved across a field. In such cases there would be minimal contact with machinery that has small amounts of field soil on it because of the possibility

of mechanical injury . Also, co mmercial tomato cultivation is ty pically 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 approp riate even though fomesafen sodium has a long half - life in soil (i.e., mean soil half life of ~390 days). 9 .0 Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk ass essment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) ty pically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but n ot limited to, people who obtain drinking water from sources near agricultural areas, the variability of dietsPage 26 of 44

within the U.S., and people who may be exposed when harvesting crops. Should these high exposures indicate potential risks of concern, OPP furth er 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 De rmal 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 Pro vided the following deficiencies are addressed as a condition of the registration, HED concludes that the residue chemistry database is sufficient to support requested Section 3 registration and establishment of tolerances for residues of fomesafen sodium in/on tomatoes . 860.1200 Directions for Use

· At this time, data are not available to support rotation to other crops beyond those commodities that are currently registered and proposed as primary crops; therefore, the petitioner must revise the Reflex® Herbicide label to permit immediate replanting of soy beans, cotton, dry

beans, snap beans , and tomatoes only with a restriction that other crops can onl y be planted 12 months after treatment or 18 months after treatment if based on phy totoxicity concerns. 860.1850 Confined Accumulation in Crops

· The ongoing confined rotational crop study, which was expected to be completed by 12/2009, should be submitted. Based on this future submission, HED will determine the terminal residues of concern in rotational crops and will re - evaluate the existing field rotational crop studies for determination of appropriate plantback restrictions. HED cannot recommend for the requested tolerance in/on potatoes due to the lack of an adequate root/tuber metabolism study . T he following study must be submitted to support the proposed tolerance.Page 27 of 44

860.1300 Plant Metabolism

· A potato metabolism study in which both the roots and tops are anal yz ed is required to support the proposed use and tolerance on potatoes. 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 37396 1 , A. LaMay , 2/ 19 /20 10. Dietary : 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 Bean. Summary of Anal yt ical Chemistry

and Residue Data, D365199, C. Olinger, 1/21 /2010. Fomesafen Sodium: Chronic Dietary Exposure Assessment to Support Proposed New Use on Tomatoes, D372850, C. Olinger, 1/21 /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, soy beans, dry

beans, snap beans, potato and tomato , D365204 , J. L in, 12/10/20 09 . Endpoint Selection : Fomesafen: Second Report of the Cancer Assessment Review Committee, 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 expos ure assessment, D337945, W. Phang and M. Llo yd, 4/29/08.Page 28 of 44

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 ................................ .................. 870.1 300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary 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 (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenic ity

—Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

—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 Neur otox. (hen) ................................ ..... 870.6100b 90 - Day

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

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

- no no

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

no noPage 29 of 44

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 - 2000 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 Irriation - 870.2500 (§ 81 - 5) Primary Dermal Irritation 00247589 Moderate Irriation - 870.2600 (§ 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 4078 6709 (1980)

Acceptable/Non - Guideline 0, 5, 15, 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 vesicles 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 o n 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 30 of 44

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

Classification/Doses Results 87 0.3200 21 - day dermal rabbit 00135632 (1983)

Acceptable/ 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 increased incidence of stomach erosions. No significant difference between controls and treated animals for developmental abnormalities. Study provided information to assess potential developmental toxicity r abbits, but was classified unacceptable because 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 the 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/5 76 (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 rats (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 fomesagen.] Maternal NOAEL = 100 mg/kg/day Maternal LOAEL = 200 mg/kg/day based on the 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) 870.3800 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) b ased on liver histopathology in males and females 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 31 of 44

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

Classification/Doses Results 870.4200 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 increases 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) LO AE L = 100 ppm (5 mg/kg/day) based on hyalinization of the liver in malesPage 32 of 44

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 subchron ic 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 conducted on selected tissues. No mortality

occurred. Animals in the 1000 ppm group gained less weight than the controls. Plasma alkaline phosphatase, alanine transaminase an d aspartate transaminase were increased 169, 149 and 131%, respectivel y, in males in 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 granul ation, increased liver weights in males and females, and increases in plasma alkaline 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 satis fies 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

(Alderle y P ark, 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 gelati n 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 hematocrit was also slightly decreased (6 - 9%), relative to controls, in both sexes combined at 25 mg/kg during the same period. At 25Page 33 of 44

mg/kg in both sexes combined, mean plate let counts increased b y 10 - 23% from week 8 - 20, while from weeks 4 - 16 mean prothrombin 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. 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) i ncrease 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 re sponse to hy polipidemic compounds. Changes in the “tinctorial properties of hepatocy 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 peroxisom e 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 Acceptable/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 SUMMAR Y - 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. Maternal toxicity

was e vident 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 group 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 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.Page 34 of 44

This developmental toxicity study 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 (MRID 001013016). 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, bas ed 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 001649 03). The developmental NOAEL is 100 mg/kg bw/day. This developmental toxicity study 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 an other 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 capsules) 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 two animals found dead or removed from the study prior to GD 29. However,Page 35 of 44

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 food consumption was 34% higher (p<0.05) than controls in the 40 mg/kg/day group during days 20 - 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 occurrence 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. Whi le the mean number of implantations/dam was similar across dose, the number of corpora 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 hi gh dose onl y. This observation was not considered toxicologicall y significant, because 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 significant. 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 classi fied 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 0386; 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 America s, Inc., Wilmington, DE; CDL :071999 - A; 072000; 072001). Unpublished. EXECUTIVE SUMMARY - 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.Page 36 of 44

Male mice in the 1000 ppm group were terminated after 80 treatment weeks (80% survival) and female mice were terminated after 90 treatment weeks (70% survival). No significant increases in mortal ity

were observed at the lower treatment doses. There was a high incidence of male 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 significantly increased in males females in the 100 and 1000 ppm groups at 52 weeks. Liver weights and liver- to - body weight ratios were significantly increased in both sexes receiving 100 and 1000 ppm Fomesafen. Kidney , adrenal, and heart weights were significantly 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 signif icant toxicological affect on these organ weights. The incidence of liver masses was significantly 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 accompanie d by

increases in enlarged and discolored livers and b y increases in eosinophilic hepatocy tes and pigmented macrophages and/or Kupffer cells. The incidence of malignant liver cell tumors was significantly (p< 0.001) increased in. males and females receivi ng 1000 ppm fomesafen. The LOAEL is 100 ppm (equivalent to 1.5 mg/kg/day) based on 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 A cceptable/Guideline and does satisfy the requirements for a chronic feeding/oncogenicity 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

Report 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 New 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 an y dose in either sex. Clinical signs (subdued behavior) was observed only in the high - dose ani mals 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).Page 37 of 44

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. 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

study (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 incidence 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 phosphat ase, alanine transaminase and aspartate transaminase, and in plasma albumin were observed 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 p pm 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 perplasia, 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 with 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 a s Acceptable/Guideline and satisfies the guideline requirements (OPPTS 870.4300; OECD 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, Alderley Park, Macclesfield, Cheshire, UK. Study number RR0199, 1984. Unpublished. EXECUTIVE SUMMARY - In a two - generation reproduction toxicity study (MRID 00144862) Fomesafe n (P28; 97.5% a.i.) was administered in diet to 30 Wistar rats (Alderley Park - derived)/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 toPage 38 of 44

become F1 parents and produced F2B litters. Brother - sister matings were avoided in each parental generation. In the parental animals, no treatment - related ef fects were observed on body weights, or food consumption. At 1000 ppm, increased incidences 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 yalin ization (diffuse and centrilobular; M & F) and biliary hy perplasia (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 toxici ty . 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 treatm ent - related reproductive parameters were affected due to treatment with fomesafen. Reductions of litter size (15 - 20%) was observed in F1and F2 A litter at 250 ppm. A significant reduct ion 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 s ignificance. 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/Guideli ne and satisfies the guideline requirement for a reproduction toxicity

(OPPTS 870.3800; 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 aboratory , Imperial Chemical Industries PL C, Alderley Park, Macclesfield, Cheshire, UK. Unpublished.Page 39 of 44

EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00164903), Fomes afen (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. 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 comp ared to the control group 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, M RID 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 signif icantly 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 developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in combination with another developmental toxicity in rat (MRID 001013016). MRID No. 40786709 Citation Coll ey , 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/3 17/80148, September 13, 1980. Unpublished. EXECUTIVE SUMMARY - In a 28 - day range finding 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 i n 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 male s. These changes in hematological parameters were indicative of slight anemia and were therefore regarded as toxicologicall y significant. Statistically significant increases inPage 40 of 44

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 ob served in 2/10 high 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 count, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), bile duct hyperplasia, decreased uterine size in females, and decreased size of the seminal vesic les in males. The NOAEL is 1500 ppm (equal to 209/247 mg/kg/day in M/F). This 28 - day

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 subchron ic 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. EXECUTIVE 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 w ere exposed to fomesafen (96.7% a.i.) in dimethyl sulfoxide (DMSO) at concentrations of 0, 150, 500, and 1000 ug/ml in the absence of S9 - mix and 75, 150, and 250 ug/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 metaphases 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 ug/mL (!S9) and 75 - 250 ug/mL (+S9). A significant increase in chromosome fragments was observed in l ymphocytes from donor 1 at 1000 ug/mL(!S9). However, the clastogenic response is most likely secondary

to cy totoxicity as the MI was reduce d by 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 Acceptable/Guideline and satisfies the guideline requirement for Test Guideline OPPTS 870.5375; OECD 473 for in vitro cy togenetic mutagenicity

data. MRID No. 44569806Page 41 of 44

Citati on 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. Unpublished 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 di methyl sulfoxide (DMSO) at concentrations of 0, 10, 100, and 1000 ug/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 metaph ases with structural aberrations. The S9 - fraction was obtained from Aroclor 1254 induced male Sprague Dawley rat liver. Fomesafen was tested up to a cy totoxic concentration for this assay . Cy totoxicity was observed at 1000 ug/ml with and without S - 9 mix . No statistically or biologicall y significant increases in chromosomal damage were observed 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 w as no evi dence of chromosome aberrations induced over background. This study

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

data.Page 42 of 44

Appendix C : Review of Human Research In the PHED study , adult human subjects were intentionally exposed to a pesticide and it has been determined that a review of their ethical conduct is required.

 The PHED Task Force, 1995. The Pesticide Handler Exposure Database (PHED), Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency , and the National Agricultural Chemicals Association, released February 1995. The PHED study

has received th e appropriate ethical review .Page 43 of 44

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 registration 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 endpoint s 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 provide 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 inadequate 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 immunotoxici ty in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8 - tetrachlorodibenzo -p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin ox ide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). How could the data impact 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 give n 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 be havioral 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 characteri zePage 44 of 44

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 neurologic al 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 ris k assessments' 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.