Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 1 of 48 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION**  **PREVENTION MEMORANDUM**  **Date :**  **Ju ly**  **18 , 2013**  **SUBJECT: Fo**  **mesafen Sodium :**  Human Health Risk Assessment for the Section 3 Registration Action on C antaloupe, Cucumber, Pea (Succulent), Pumpkin, Summer S quash, W inter S quash, W atermelon, S oy bean ( S uccu lent) and L ima Bean (Succulent) **PC Code:** 123803; 123802 **DP Barcode:** 403953, 410795 **Decision No.:** 467057, 477271 **Registration No. :**  100 - 993 **Petition No.:** 2E8061, 3E8167 **Regulatory Action:** Section 3 Registration **Risk Assessment Type:** Single Chemical Aggregate **Case No.:** NA T **XR No.:** NA **CAS No.:** 72178 - 02 - 0 **MRID No.:** NA **40 CFR:** § 180.433
**FROM:** Danette Drew, Chemist

Id eliz Negrón Encarnación, Ph.D., Chemist Alexandra LaMay , Biologist Ronnie Bever, Ph.D. , Toxicologist Branch V/VII Health Effects Division (7509P) **THROUGH:** William Irwin, Ph.D., Toxicologist

Michael Metzger, Branch Chief Branch V/VII Health Effects Division (7509P) **TO:** Laura Nollen, Risk Manager Reviewer

Barbara Madden , Risk Manager Risk Integration, Minor Use & Emergency Response Branch R egistration Divisio n (RD, 7505P)Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 2 of 48 1.0 Executive Summary ................................ ................................ ................................ ............. 4 2.0 HED Recommendations ................................ ................................ ................................ ....... 6 2.1 Data Deficiencies ................................ ................................ ................................ ............. 6 2.2 Tolerance Considerations ................................ ................................ ................................ . 6 2.2.1 Enforcement Anal yt ical Method ................................ ................................ .................. 6 2.2.2 Recommended Tolerances ................................ ................................ ............................ 6 2.2.3 Revisions to Petitioned - For Tolerances ................................ ................................ ........ 7 2.2.4 International Harmonization ................................ ................................ ......................... 7 2.3 Label Recommendations ................................ ................................ ................................ .. 7 2.3. 1 Recommendations from Residue Reviews ................................ ................................ ... 7 2.3.2 Recommendations from Occupational Assessment ................................ ..................... 8 3.0 Introduction ................................ ................................ ................................ .......................... 8 3.1 Chemical Identity ................................ ................................ ................................ ............. 8 3.2 Phy s ical/Chemical Characteristics ................................ ................................ ................... 8 3.3 Pesticide Use Pattern ................................ ................................ ................................ ........ 9 3.4 Anticipated Exposure Pathway s ................................ ................................ ..................... 10 3.5 Consideration of Environmental Justice ................................ ................................ ........ 10 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................ 11 4.1 Summary

of Toxicological Effects ................................ ................................ ................ 11 4.2 Safety

Factor for Infants and Children (FQPA Safety Factor) ................................ ....... 12 4.2.1 Completeness of the Toxicology Database ................................ ................................ 12 4.2.2 Evidence of Neurotoxicity ................................ ................................ .......................... 13 4.2.3 Evidence of Sensitivity /Susceptibility

in the Developing or Young Animal ............. 13 4.2.4 Residual Uncertainty in the Exposure Database ................................ ......................... 13 4.3 Toxicity

Endpoint and Point of Departure Selections ................................ .................... 13 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............ 15 5.1 Residues of Concern Summary and Rationale ................................ ............................... 15 5.2 Food Residue Profile ................................ ................................ ................................ ...... 15 5.3 Water Residue Profile ................................ ................................ ................................ .... 16 5.4 Dietary

Risk Assessment ................................ ................................ ................................ 17 5.4.1 Description of Residue Data Used in Dietary Assessment ................................ ......... 17 5.4.2 Percent Crop Treated Used in Dietary Assessment ................................ .................... 17 5.4.3 Acute Dietary

Risk Assessment ................................ ................................ ................. 17 5.4.4 Chronic Dietary

Risk Assessment ................................ ................................ .............. 18 5.4.5 Cancer Dietary

Risk Assessment ................................ ................................ ................ 18 5.4.6 Summary

Table ................................ ................................ ................................ ........... 18 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ ... 18 6.1 Residential By stander Post - application Inhalation Exposure ................................ ........ 19 6.2 Spray

Drift ................................ ................................ ................................ ...................... 19 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ .......... 19 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ....... 20 9.0 Occupational Exposure/Risk Characterization ................................ ................................ ..... 20 9.1 Short - /Intermediate - Term Handler Risk ................................ ................................ ....... 20 9.2.1 Dermal Post - application Risk ................................ ................................ ..................... 24 9.2.2 Inhalation Post - application Risk ................................ ................................ ................. 25 10.0 References ................................ ................................ ................................ .......................... 26Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 3 of 48 Appendix A. Toxicology Profile and Executive Summaries ................................ ....................... 27 A.1 Toxicology

Data Requirements ................................ ................................ ...................... 27 A.2 Toxicity

Profiles ................................ ................................ ................................ ............. 28 A.3 Toxicity

Summaries ................................ ................................ ................................ ......... 33 Appe ndix B. Phy sical/Chemical Properties ................................ ................................ ................. 47 Appendix C. Review of Human Research ................................ ................................ ................... 48Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 4 of 48 **1.0 Executive Summary**  Fomesafen, 5 - [2 - chloro - 4 - (trifluorometh yl )phenoxy] -N - (methylsulfonyl) - 2 - nitrobenzamide) , is an herbicide used for control of broadleaf weeds , annual grasses, perennial weeds , and sedges . It is in the diphenylether chemical class , and its mode of action is via inhibition of protoporphy

rinogen oxidase (PPO) in the plant. 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). It is currently registered for use on peppers, tomatoes, potatoes, cotton, dry

beans , and field soy

beans. There are no residential uses of fomesafen. The requested Section 3 registration of Reflex  Herbicide (22.8% active ingredient sodium salt of fomesafen) is for new uses on cantaloupe, cucumber, pea (succulent), pumpkin, summer squash, winter squash, watermelon, and soy bean (succulent) (petition #2E8061), and on lima bean (succulent) (peti tion #3E8167). The Health Effects Division (HED) has conducted a human health risk assessment to support the requested use registrations and the establishment of associated tolerances. Assessments were performed for potential dietary (food and drinking water) and occupational worker exposures. The dietary risk assessment takes into account all existing and proposed uses of fomesafen. The toxicity

database for fomesafen is complete. Ge nerally , hyalinization of hepatocy tes provided the most sensitive toxicological endpoint (short, intermediate, and long term) in mammals. Inthe subchronic and chronic toxicity studies in rats and mice , food consumption , food efficiency , body

weight, 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. Neurotoxicity

may occur at the same dose level as s ys temic toxicity . Fomesafen was not considered to be mutagenic. 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 fomes afen should be classified as “Not L ikel y to be Carcinogenic to Humans” (HED Doc No. 0053835 ). Post - implantation loss was noted in the developmental study ; however, n o quantitative or qualitative evidence of increased susceptibility was seen following in u tero exposure to rats or rabbits in developmental studies or in the reproduction study . Fomesafen can result in suppression of anti - SRBC IgM response , but this was not the most sensitive endpoint . Fomesafen has a low order of acute toxicity by the oral , dermal, and inhalation route s of exposure (Toxicity

Category IV ). Fomesafen is minimally irritating to the eye and is not irritating to the skin. It is not a sensitizer. T he fomesa fen risk assessments were based on the most sensitive endpoints in the toxicity database, and the NOAELs selected for risk assessment are considered protective of potential developmental , neurotoxic, and immunotoxic effects for infants and children. Further, highl y conservative exposure estimates were incorporated into the dietary risk assessment and there are no residential uses; therefore, reduction of the 10x Food Quality Protection Act (FQPA) safety factor to 1x is considered appropriate.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 5 of 48 Sufficient residue data are available to support the proposed tolerance s for residu es of fomesafen on cantaloupe, cucumber, pea (succulent) , pumpkin, summer squ ash, winter squash, watermelon, soy bean (succulent) , and lima bean (succulent). The residue of concern is only the parent, fomesafen. The residue data are supported b y adequate storage stability data , and an anal ytical method is available to support the tolerance s. All residues in the magnitude of residue studies were below the low est limit of method validation (LLMV) , and recommended tolerances are based on this level . Environmental fate data indicate that fomesafen should be very mobile and highl y persistent in terrestrial and aquatic environments. The residue of concern in drinking water is parent fomesafen. Estimated drinking water concentrations (EDWCs) were based on Tier II PRZM EXAMS screening model . Conservative acute and chronic dietary (food and drinking water) assessments were performed using tolerance level residues, assuming 100% crop treated, and incorporating modeled EDWCs. Acute and chronic dietary (food and drinking water) risk estimates are not of concern. Because there are no registered residential uses of fomesafen , aggregate risks are identical to the food and drinking water dietary risk estimates; there are no acute or chronic aggregate dietary ris k estimates of concern. For occupational handlers, dermal and inhalation MOEs above 100 are not of concern. All occupational exposure risk estimates for short - and intermediate - term exposures for handlers are not of concern with single layer dermal PPE (includes long - sleeve shirt and long pants ) or with engineering control enclosed cab (fixed wing aircraft/aerial applicators). Dermal MOEs ranged from 350 to 300,000 , and inhalation MOEs ranged from 410 to 360,000. The applications to most of the propos ed crops are for only pre - emergent or directed ground spray s ; thus , post - application contact with treated foliage is expected to be negligible using these applications. The proposed uses for so yb ean and lima bean include a post - emergent application; there fore, a quantitative dermal post - application exposure assessment was only conducted for the se uses . Post - application worker risk estimates for short - and intermediate - term exposures are not of concern (i.e., dermal MOEs are greater than the LOC of 100). Dermal MOEs ranged from 3,200 to 59,000 for post - application activities. Based on the Agency's current practices, a quanti tative non - cancer occupational post - application inhalation exposure assessment was not performed for fomesafen sodium . I f new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhal ation exposure assessment for fomesafen sodium . Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment (see Section 3.5). See Appendix C for information regarding the use of human research data in this assessment.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 6 of 48 **2.0 HED**  **Recommendations** HED recommends for the registration and associated tolerance s for the use of fomesafen sodium on c antaloupe, cucumber, p ea ( s ucculent), p umpkin, s ummer s quash, w inter s quash, w atermelon, s oy bean ( s ucculent) , and l ima b ean ( succulent) . The specific tolerance recommendations are discussed in 2.2, and label modifications are discussed in section 2.3 below . **2.1 Data**  **Deficiencies** None. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate residue anal yt ical methods are available for the purpose of fomesafen tolerance enforcement for plant commodities . A high performance liquid chromatography method with tandem mass spectrometry detection ( LC/MS/MS ) method (GRM045.01A) has previo usl y been submitted as an enforcement method . The method uses extraction procedures similar to previous methods, SPE cleanup procedures, and the final determination step by L C/MS/MS for analysis of fomesafen residues. The validated limit of quantitation (LOQ) of the method is 0.02 ppm. This method is similar to the data acquisition methods used for fomesafen on cantaloupe , pea (succulent), summer squash , and cucumber , where the LLMV was 0.025 ppm. The requirements for multiresidue method testing data for fomesafen are fulfilled. FDA multi residue methods are not suitable for determining residues of fomesafen. Analy tical standards for fomesafen are currently available in the EPA National Pesticide Standards Repository . **2.2. 2**  **Recommended Tolerances** HED recommends that 40 CFR 180.443 be amended by establishing tolerances for the plant commodities listed in the Table 2.2.2 below. The tolerances for plant commodities should be defined as follows: Tolerances are established for residues of the herbicide fomesafen, including its metabolites and degradates, in or on the following commodities. Compliance with the tolerance levels specified in the table below is to be determined b y measuring onl y fomes afen, 5 - [2 - chloro - 4 - (trifluorometh yl )phenox y] -N - (methylsulfonyl) - 2 - nitrobenzamide, in or on the commodity .Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 7 of 48 **Table 2.2.2**  **. Tolerance Summary for Fom**  **esafen .**  **Comm odity**  **Proposed Tolerance (ppm)**  **HED -**  **Recommended**

**Tolerance (ppm) Comments** 

**( correct commodity**  **definition )**  Cantaloupe 0.025 0.025 Cucumber 0.025 0.025 Pea, succulent 0.025 0.025 Pum pkin 0.025 0.025 Squash, summer 0.025 0.025 Winter, Squash 0.025 0.025 Squash, winter Watermelon 0.025 0.025 Vegetable, soybean, succulent 0.05 0.05 Soybean, vegetable, succulent Lima, bean 0.05 0.05 Bean, lima, succulent [It is noted that adequate field trial data for cantaloupe, cucumber , and summer squash is available to establish tolerances for melon, crop subgroup 9 A , and squash/cucumber, crop subgroup 9B. The HED will consider the establishment of tolerances for these two crop subgroup s upon petition from the registrant.] **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** Both the proposed and recommended tolerance level s are the same and are based on the commodity

L LMV , since residues were below this level in the field trial studies. The commodity

names should be changed to reflect the correct commodity definitions. **2.2. 4**  **International Harmonization**  Codex or Mexican MRLs have not been established for residues of fomesafen in/on the registered and proposed commodities; therefore, there are no issues with international harmonization raised by

this action. Canadian MRL ha s been established for residues of fomesafen in/on succulent shelled lima beans at 0.05 ppm which is harmonized with the USA tolerance for lima beans. Canada is also currentl y reviewing a request for the use of fomesafen on cucumbers. **2.3 Label Recommendations**  **2.3.1 Recommendations fr**  **om Residue Reviews** Rotational crop restrictions were not included in the Section B of the petition. The appropriate plant - back intervals (PBIs) for rotated crops should be specified in Section B and in the label of Reflex® Herbicide . Refer to the residue chemistry chapter for PBI s previously established (I. Negron; D407932).Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 8 of 48 **2.3.2 Recommendations**  **from Occupational Assessment** None.
**3.0 In**  **troduction 3.1**  **Chemical Identity T**  **able 3.1**  **. Test Com** **pound Nom enclature.**  Compound

Common name Fomesafen Sodium Company experimental name Not provided. IUPAC name 5 - (2 - chloro - α,α,α - trifluoro -p - tolyloxy) -N - methylsulfonyl - 2 - nitrobenzamide, sodium salt CAS name 5 - [2 - chloro - 4 - (trifluoromethyl)phenoxy] -N - (methylsulfonyl) - 2 - nitro - benzamide, sodium salt CAS registry number 108731 - 70 - 0 Compound

Common name Fomesafen Company experimental name Not provided. 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 registry number 72178 - 02 - 0 End -use product (EP) Reflex® Herbicide, 2 lb ae/gal SL ; EPA Reg. No. 100 - 993 **3.2 Physical/Chemical Characteristics**  Fomesafen is not especially volatile and has a low vapor pressure of 7 .5 x 10 - 7 mm Hg at 5 0 oC. The octanol water partition coefficient (Kow = 790 at pH 1 ) suggests that it is slightly lipophilic. Fomesafen is highl y soluble in water ( 600 g/ L at 2 5 °C and pH of 7 ) and exists as the anionic form at environmental relevant conditions (pKa is 2.7) . Fomesafen is expected to be highly mobile in aquatic environments. A table of the phy sical and chemical properties can be found in Appendix B . F 3 C

Cl O N O 2

O N S C H 3 O O Na+

F 3 C

Cl O N O 2

O N H S C H 3 O OFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 9 of 48 **3.3 Pesticide Use Pattern**  The end - use product relevant to the current petitions is Reflex® Herbicide (EPA Reg. No. 100 - 993), a soluble concentrate liquid (SL) formulation containing 22.8% sodium salt of fomesafen as the active ingredient (equivalent to 2 lb ae/gal of fomesafen). Reflex® is a selective herbicide , which may

be applied preplant surface, pre - emergence, and/or post - emergence for control or partial control of broadleaf weeds, grasses, and sedges. In support of the proposed use s, the petitioner submitted the proposed u se directions of the Reflex® Herbicide in the Section B of the petition . A summary of the proposed use directions is presented in Table 3.3 . See section 2.3 for recommended modifications to the proposed label. Table 3.3 . Summary of Proposed Directions for Use of Reflex Herbicide (EPA Reg. No. 10 - 993) Applic. Timing, Type, and Equip. Form ulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions

and Limitations Cantaloupe (transplants only) Ground equip, prior to transplanting 10 0 - 993 0.25 - 0.375 NS 0.375 35 Cucumber (Direct seeded or transplant) Gound equip, just after seeding but before crop emergence of prior to transplanting 10 - 993 0.25 - 0.375 NS 0.375 42 Peas, succulent Ground or aerial equip, Broadcast, preemergence to weeds and crop 10 0 - 993 0.125 - 0.25 NS 0.375 46 Pum pkin (Direct seeded or transplant) Ground equip , broadcast or direct spray, after seeding but prior to crop emergence or prior to crop transplanting 10 0 - 993 0.25 - 0.375 NS 0.375 32 Summer squash and winter squash (Direct seeded or transplant) Ground equip, broadcast or directed spray, after seeding but prior to crop emergence or prior to transplanting 10 0 - 993 0.25 - 0.375 NS 0.375 32 Watermelon (Direct seeded or transplant) Ground equip, broadcast or directed spray, after seeding but prior to crop emergence or prior to transplanting ; post emergence as directed application to row middles just prior to or at vine runner initiation 10 0 - 993 0.25 - 0.375 NS 0.375 35
Bean, lima, succulentFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 10 of 48 Broadcast, postemergent appl. 1 10 0 - 993 0.125 - 0.25 NS 0.25 3 0 Do not graze treated areas or harvest for forage or hay. Do not utilize hay or straw for animal feed or bedding. Soybean, vegetable, succulent Preplant surface and preemergence appl.; 2 and post emergence appl. 3 10 0 - 993 0.25 - 0.375 NS 0.375 30 Do not graze treated areas or harvest for forage or hay. Do not utilize hay or straw for animal feed or bedding. NS = Not Specified. 1 Do not apply to any field in regions 2, 3, 4 or 5 more than once every two years. 2 Application only allowed in Regions 1, 2, 3 and 4. 3 Applications only allowed in Regions 1, 2, 3, 4 and 5. **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed new use of fomesafen sodium on to cantaloupe , cucumber, pea, pumpkin, squash, watermelon, so ybean (succulent), and lima bean (succulent). Humans may be exposed to fomesafen in food and drinking water, since fomesafen may be applied directly

to growing crops and application may

result in fomesafen reaching surf ace and ground water sources of drinking water. There are no residential uses of fomesafen ; so , there is not likely to be exposure in residential or non - occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application . There is a potential for post - application exposure for workers re - entering treated fields. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new use s of fomesafen but also considers the existing uses as well in regard to the dietary assessment. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.do e.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s (USDA’s) Natio nal Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA ) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionall y, OPP is able to assess dietaryFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 11 of 48 exposure to smaller, specialized subgroups , and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures are evaluated , based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application. Further considerations are currently in development , as OPP h as committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and**  **Dose -**  **Response Assessment** The toxicological database for fomesafen is complete. The last human health risk assessment was performed on October 12, 2010 (A. LaMay , D373600). Since then, several toxicological studies have been received and reviewed . An A cute Toxicity 6 - Pack (MRIDs 46988901 - 46988906) on fomesafen technical (≥98.5% purity) was submitted. An immunotoxicity test was submitted. A subchronic oral toxicity study in rats (MRID 49091201) was received in 2012 , which does not demonstrate an advers e effect at 6x the L OAEL of the previous (1981) subchronic oral toxicity

study in rats (MRID 00103013). A 13 - week subchronic dietary combined toxicity

and neurotoxicity

study in rats (MRID 48996801) was submitted, as well as an acute neurotoxicity

study ( MRID 48973302). The acute neurotoxicity study provided an acute oral endpoint for the general population (including infants and children), but other toxicity endpoints and points of departure (PODs) remained the same as in the 2010 assessment. **4.1 Summ**  **ary of Toxicological Effects** Fomesafen is an herbicide that is absorbed b y leaves and roots and i nhibits protoporphy rinogen oxidase, leading to irreversible cell membrane damage. Generall y, h yalinization of hepatocy tes provided the most sensitive toxicol ogical endpoint (short, intermediate, and long term) in mammals. Inthe subchronic and chronic toxicity studies in rats and mice , food consumption , food efficiency , body

weight, 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). Neurotoxicity (decreased motor activity) may occur at the same dose level as s ys temic toxicity . 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 Committe e (CARC) determined that fomesafen should be classified as “Not L ikel y to be Carcinogenic to Humans” (HED Doc No. 0053835). This decision was based on the weight - ofevidence which supports activation of peroxisome proliferator - activated receptor alpha (PP ARα) as the mode of action for fomesafen - induced hepatocarcinogenesis in mice. Fomesafen was not considered to be mutagenic. Post - implantation loss was noted in the developmental study , but n o quantitative or qualitative evidence of increased susceptibil ity was seen following in utero exposure to rats or rabbits in developmental studies or in the reproduction study . Fomesafen can result in suppression of anti - SRBC IgM response. Fomesafen has a low order of acute toxicity by the oral , dermal, and inhalat ion route s of exposure (Toxicity Category IV ). Fomesafen is minimally irritating to the eye and is not irritating to the skin. Itis not a sensitizer.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 12 of 48 In a metabolism study

in rats, f omesafen wa s readily

absorbed in male and female rats after oral dos ing. The major route of elimination in females wa s in the urine ; fec al excretion was the major route in males, with some enterohepatic recirculation evident . The sex difference wa s not evident at higher doses , where urine wa s the main route of excretion for both sexes. At higher doses, the vast majority wa s excreted unchanged, but at lower doses a lesser amount (60%) wa s excreted unchanged. The major metabolite (10%) wa s 5 - (2 - chloro - α,α,α - trifluoro - tolyloxy) - anthranilic acid. Part, or all, of the metab olism may be due to action b y intestinal microorganisms. 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 predominantly in urine and to a lesser extent in the feces. Most 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. As a dermal penetration study w as not provided, the dermal absorption value of 20% was based on dermal absorption factors for ox yfluorfen and acifluorfen, which have similar structures . **4. 2**  **Safety F**  **actor for Infants and Children (FQPA Safety Factor)** T he FQPA safety factor was reduced to 1X for the reasons described in sections 4.2.1 through 4.2.4 . The toxicity and exposure database s for fomesafen are complete. There is no evidence of increased susceptibility in developing and young animals , and there are no residual uncertainties con cerning pre - or post - natal toxicity . Acute and subchronic neurotoxicity studies are available, and all points of departure used in this risk assessment are protective of any potential neurotoxic , developmental , or immunotoxic effects. The dietary assessm ents are conservative and are based on tolerance level (non - detectable) residues and assume 100% of the crops are treated. There are no residential uses of fomesafen. **4.2.1 Completeness**  **o f**  **the Toxicology Database**  The toxicology

database for fomesafen is complete. The requirement for the subchronic inhalation toxicity

study was waived upon consideration at HASPOC on April 25, 2013 (DOC # 123803TS.001). A weight of evidence approach indicated that the inhalation toxicity study was not necessary

due to low compound volatility, high inhalation MOEs, a conservative oral endpoint upon which the MOEs were based, and low acute toxicity via oral, dermal, and inhalation routes. A lthough the developmental toxicity study in rabbits was classified unacceptable due to mortality from bacterial infections, there was not any evidence of increased susceptibility

of rabbit fetuses due to the treatment with fomesafen. Therefore, the lack of an acceptable developmental toxicity study in non - rodents was not considered a data gap. As a dermal penetration study

was not provided, the dermal absorption value of 20% was based on dermal absorption factors for ox yfluorfen and acifl uorfen, which have similar structures . Consequently , the dermal penetration study is not considered a data gap.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 13 of 48 **4.2.2 Evidence of N**  **eurotoxicity** D ecreased motor activity (horizontal and vertical activity and time in central quadrant) was observed in rats in the acute neurotoxicity screening battery

at the same dose that resulted in general s ys temic toxicity. In the subchronic neurotoxicity test, neither general sy stemic toxicity nor neurotoxicity

was observed at the highest dose tested. **4.2.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There is no evidence of increased susceptibility of rat fetuses to in utero exposure to fomesafen. The 2 - generation reproduction study in rats did not show evidence of increased susceptibili ty to fomesafen. Although the developmental toxicity study in rabbits was classified as 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. **4.2.4 Residual**  **Uncertainty in the Exposure Datab ase**  There are no residential uses of fomesafen. The dietary assessment is based on conservative assumptions, including 100% crop treated and tolerance - level (non - detectable) residues; there are no residual uncertainties in the exposure database. **4. 3**  **Toxicity Endpoint and Point of D**  **eparture Selections** The most recent risk assessment performed for fomesafen was completed on October 12, 2010 (A. LaMay , D373600). That hazard characterization and dose response from that assessment has been revised in the following way s: An Acute Toxicity 6 - Pack (MRIDs 469 88901 - 46988906) on fomesafen technical ( ≥98.5% purity) was submitted and reviewed. Due to the quality of these studies, values from the new 6 - Pack replaced the previous values. A 13 - week dietary combined toxicity and neurotoxicity

study in rats (MRID 489 96801) was submitted, as well as an acute neurotoxicity

study ( MRID 48973302). The acute neurotoxicity study was used to establish an acute oral endpoint for the general population, including infants and children. An acute endpoint was not selected in th e previous assessment. Additionally , a subchronic oral toxicity study in rats (MRID 49091201) was received in 2012 which does not demonstrate an adverse effect at 6x the L OAEL of the previous (1981) subchronic oral toxicity

study in rats (MRID 00103013). MRID 00103013 provides the most protective subchronic POD . T he current inhalation risk estimates, which are based on this protective oral POD, are very low and are not of concern. At this time HED is not electing to use the higher PODs from the 2012 stu dy but may consider them for future assessments. The PODs and toxicity

endpoints selected for various exposure scenarios applicable to this risk assessment are summarized in Table 4.3 (Dietary and Occupational).Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 14 of 48 **Table 4 .**  **3 Summary of Toxicol**  **ogical Doses and Endpoints for Fom**  **esafen for Use in Dietary and**  **O ccupational Hum**  **an Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary (General Population, including Infants and Children) NOAEL =

100 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF = 1 x Ac ute RfD =

1 mg/kg/day aPAD = 1 mg/kg/day Ac ute neurotoxicity test in rat

LOAEL = 250 mg/kg/day based on decreased body weight and motor activity (horizontal and vertical activity and time in central quadrant) in males Ac ute Dietary (Females 13 - 49 years of age) No toxic effects of fomesafen attributable to a single dose and specific to females of ages 13 - 49

were found in the database.
Chronic Dietary (All Populations) NOAEL =

0.25 mg/kg/day UFA = 10x

UFH = 10x FQPA SF = 1x Chronic RfD

= 0.0025 mg/kg/day cPAD = 0.0025 mg/kg/day Chronic toxicity/ carcinogenicity in r at

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%) a UFA = 10x

UFH = 10x Occupational

LOC for MOE = 100 Prenatal developmental in rat

LOAEL = 200 mg/kg/day based on post im plantation loss

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

0.5 mg/kg/day (Inhalation toxicity is assumed to be equivalent to oral toxicity) UFA = 10x

UFH = 10x Occupational

LOC for MOE = 100 Subchronic oral toxicity study in rat

LOAEL = 10 mg/kg/day based on hyalinization of hepatocytes and increased hepatocellular peroxisomes in males. Cancer (oral, dermal, inhalation) Classification: The CARC classified Fomesafen as “Not Likely to be Carcinogenic to Human s” Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. a The dermal absorption value of 20% was b ased on dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 15 of 48 **5.0 Dietary Exposure and Risk Assessment**  **5.1 Residues of Concern Summary and Rationale**  The residues of concern for dietary risk assessment and the toleranc e expression are summarized in Table 5.1. The parent compound , fomesafen , is an adequate indicator of misuse and is the only residue include d in the tolerance expression for plant commodities; there are no livestock tolerances required based on the current or proposed uses of fomesafen. For risk assessment purposes the residue of concern in plant commodities is parent fomesafen. For livestock commodities the residues of concern are fomesafen and its metabolites, 5 - (2 - chloro - α,α,α trifluoro - p - tolyloxy) anthranilic acid and 5 - (2 - chloro - α,α,α - trifluoro - p - tol yl oxy ) -N methylsulfonylanthranilamide. For the purpose of this registration action, there is no reasonable expectation of finite residues of parent fomesafen or its metabolites in liv estock commodities. However, should future registration actions result in the likelihood of measurable residues in animal commodities, an aggregate risk assessment considering these residues may be r equired. M etabolism studies are available for tomatoes, soy beans, and cotto n, as well as a confined rotational crop study. Studies in plants indicate that, in general, fomesafen is absorbed, translocated, and rapidl y and extensively metabolized. Only

trace amounts of the parent were found to be present in plant commodities at harvest. Environmental fate data indicate that fomesafen should be very mobile and highl y persistent in terrestrial and aquatic environments. The residue of concern in drinking water is parent fomesafen. **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 Plants Primary Crop Fomesafen Fomesafen Plants Rotational Crop Fomesafen Fomesafen Livestock Fomesafen , 5 - (2 - chloro - α,α,α trifluoro - p - tolyloxy) anthranilic acid , 5 - (2 - chloro α,α,α - trifluoro - p - tolyloxy) -N methylsulfonylanthranilamide. Not required at this time.
Drinking Water Fomesafen NA Fomesafen is 5 - [2 - chloro - 4 - (trifluoromethyl)phenoxy] -N - (methylsulfonyl) - 2 - nitro - benzamide, sodium salt . **5 .2**  **Food Residue**  **Profile** The submitted crop field trial residue data for cantaloupe, cucumber, summer squash, and succulent peas are adequate to support the proposed use of fomesafen on c antaloupe, cucumbe r, p ea ( s ucculent), p umpkin, s ummer s quash, w inter s quash, and watermelon . The studies reflectFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 16 of 48 the maximum proposed use pattern, and the number and location of the field trials are sufficient . Acceptable methods were used for residue quantitation, and the studies are supported by adequate storage stability data. Residues of fomesafen (the residue of concern) were below the low est limit of method validation (< LLMV ) in all samples of cantaloup e, cucumber, summer squash, or succulent peas when treated with fomesafen sodium at the maximum proposed label rates and minimum PHI s. Residues of fomesafen were also below the LLMV in previously submitted field trials for peppers, potatoes, cotton, dry beans, snap beans , and soy beans (field). T he proposal for the use of the existing field trial data on snap beans to support the establishment of a tolerance for fomesafen on bean, lima, succulent was considered adequate by the Chemistry Science Advisory Council (ChemSAC) provided that a maximum rate per year included in the label is 0.25 lbs ai/A and the PHIis 30 day s. The proposal for the use of snap bean data to support a tolerance for soybean, vegetable, succulent is acceptable as well . In crop subgroup 6A (edible - podded legume vegetables) any succulent cultivar of edible podded bean covers all beans under that group. This group includes snap bean and soy bean, immature seed . For the latter soy bean, vegetable, succulent is the preferred term . There is data to support rotation to other crops beyond those commodities that are currently registere d and proposed as primary crops. Plant back intervals ( PBI s ) for rotational crops were not found in the Section B of the petition. Adequate PBI should be proposed by the registrants and included in the label of the Reflex Herbicide. T here are no new animal feedstuffs associated with the proposed uses. Feedstuffs are associated with succulent soy

bean; however, uses on field soy bean have been registered previousl y. The dietary burdens of fomesafen to beef and dairy cattle were estimated previously according to the 2008 Revised Table 1 of OPPTS Guidelin e 860.1000 for constructing maximum reasonabl y balanced diets (A. LaMay , D373544 , 10/12/2010 ). There is no reasonable expectation of finite residues in livestock commodities , and no tolerances are required for residues of fomesafen in livestock commoditie s. **5.3 Water Residue Profile**  The Environmental Fate and Effect’s Division (EFED) provided e stimated drinking water concentrations (EDWCs) generated using computer modeling methods. The screening model Tier II PRZM - EXAMS was used to calculate the surfac e water EDWCs of **34.8 μg/L**  for peak (acute) , **13.1 μg/L**  for annual average (non - cancer chronic) . Groundwater EDWCs were calculated using the Tier I PRZM - GW (six vulnerable sites modeled) and resulted in the highest acute value of **51.8 μg/L**  and chronic value of **32.3 μg/L**  for groundwater . The groundwater EDWCs were higher than the surface water EDWCs and were therefore selected for use in the fomesafen dietary

assessment. Th e groundwater estimates are very conservative . These estimates are based on the highest proposed application rate for fomesafen (0.375 lb a.i./acre for the crops of cantaloupe, cucumber, pea, succulent, pumpkin, summer squash, watermelon, winter squash, and succulent soy bean vegetable succulent ( i.e. edamame) ). These estimates also reflect results from the most vulnerable site modeled, the “F lorida Citrus scenario .” In addition, theFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 17 of 48 PRZM - GW model is based on a rural drinking water well beneath an agricultural field (a high pesticide use area), which draws water from an unconfined, h igh water - table aquifer. There is ground water monitoring data indicating a maximum concentration of 1 μg/L for fomesafen in ground water source for drinking water from a vulnerable so ybean soil site . However, since fomesafen can be applied to a wide variety of crops, groundwater monitoring from a so ybean soil may

not be representative of a vulnerable site in an extended fomesafen use area and is not recommended for use in risk assessment. **Table 5. 3**  **. Summary of Estimated Surface Water and Groundwate**  **r Concentrations for Fo**  **mesafen .**  Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute 34.8 51.8 Chronic (non - cancer) 13.1 32.3 a From the Tier II PRZM - EXAMS - Index Reservoir model. b From the Tier I PRZM - GW mo del. (EFED Memo, H.Zhong, D412599, 6/24/13) **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  Acute and chronic aggregate (food and drinking water) dietary exposure s and risk assessment were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database (DEEM - FCID) Version 3.16. This software uses 2003 - 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA). For food, t olerance level residues were assumed in the assessments; the tolerance levels were based on non - detectable residues from the field trials and reflect the method LOQs. For drinki ng water, estimated drinking water concentrations (EDWCs) from highl y conservative surface water modeling based on the highest proposed use rates were used directl y in the assessments. **5.4.2 Percent Crop Treated Used in Dietary Assessment**  An assumption of 100% crop treated (%CT) w as used for all commodities (existing and proposed uses) in the fomesafen dietary assessment. **5.4.3 Acute Dietary Risk Assessment**  A highl y conservative acute dietary risk assessment was conducted which used tolerance level residues, assumed 100% CT for all commodities and screening EDWCs . The estimated exposure (food and drinking water) to the U.S. population and all population subgroups from theFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 18 of 48 established uses and proposed new uses of fomesafen resulted in an estimated risk of <1% of the acute population adjusted dose (aPAD) at the 95 th percentile and are not of concern ( see Table 5.4.6 ) . **5.4.4 Chronic Dietary Risk Assessment**  A highl y conservative chronic dietary risk assessment was conducted which used tolerance level residues, assumed 100% CT for all commodities and screening level EDWCs. The estimated exposure (food and drinking water) to the U.S. population and all population subgroups from the established uses and proposed new uses of fomesafen resulted in risk estimates below the Agency ’s level of concern. The risk estimate for the general U.S. population is 32% of the chronic population adjusted dose (cPAD). The subgroup with the highest chronic exposure and risk estimate is infants. For infants, the exposure for food plus drinking water was 0.0019 15 mg/kg/day , which represents 77% of the cPAD ( see Table 5.4.6 ) . **5.4.5 Cancer Dietary Risk Assessment**  The Cancer Asses sment Review Committee (CARC) classified fomesafen as “Not likely to be carcinogenic to humans;” therefore, a quantitative cancer assessment was not performed. **5.4.6 Summary Table**  **Table 5.4.6 .**  **Summary of Dietary (Food and Drinking Water)**  **Exposure and Risk for Fomesafen.**  **Population Subgroup Acute Dietary**  **( 95th**  **Percentile) Chronic Dietary**  **Cancer Dietary**  **Exposure (m**  **g/kg/day) % aPAD**  **Dietary Exposure**  **(m g/kg/day)**  **% cPAD*** **Dietary Exposure**  **(m g/kg/day)**  **Risk** General U.S. Population 0.002999 <1 0.000787 32 **All Infants (<1 year old)** * 0.009060 <1 **0.0019 15**  **77** N/A N/A Children 1 - 2 years old 0.004827 <1 0.001267 51 Children 3 - 5 years old 0.003915 <1 0.001085 43 Children 6 - 12 years old 0.002951 <1 0.000755 30 Youth 13 - 19 years old 0.002455 <1 0.000588 24 Adults 20 - 49 years old 0.002858 <1 0.000766 31 Adults 50 - 99 years old 0.002597 <1 0.000754 30 Females 13 - 49 years old 0.002938 <1 0.000760 30 The population subgroup with the highest risk estimate is bolded **6.0 Residential**  **(Non -**  **Occupational) Exposure/Risk Characterization** Residential exposures and risk are not assessed because the re are no proposed or registered uses of fomesafen in resi dential settings.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 19 of 48 **6.1 Residential Bystander**  **Post -**  **application Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for fomesafen at this time , primarily because of the low vapor pressure (<7.5 x 10 - 7 mmHg at 50 °C). However, volatilization of pesti cides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticid e Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 1 . The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post - application inhalation exposure into the Agency's risk assessments. I f new policies or procedures are developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for fomesafen . **6.2 Spray Drift**  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 application method employed for fomesafen. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices , State Lead Agencies for pesticide regulation , and other parties to develop the best spray drift management practi ces (see the Agency ’s Spray Drift website for more information 2 ) . The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast , and ground h ydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management p ractices to reduce off - target drift with specific products with significant risk estimates associated with drift. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and ri sks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. There are no residential uses for fomesafen; therefore , the aggregate exposure and risk assessments include acute and c hronic dietary (food and drinking water) only and are shown in

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html 2 Available: http://www.epa.gov/opp00001/factsheets/spraydri ft.htmFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 20 of 48 Sections 5.4.3 and 5.4.4. There are no aggregate risk estimates of concern for the existing and proposed new uses of fomesafen. **8 .0**  **Cumulative Exposure/Risk Characterization** Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to fomesafen and any other substances and fomesafen does not appear to produc e a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fomesafen has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine whic h chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effe cts from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk Characterization**  No chemical - specific handler exposure data were submitted in support of th e proposed fomesafen uses. For assessing the occupational handler and post - application risks, generic surrogate data were used from sources such as PHED 1.1, the AHETF database, and ORETF database . **9.1 Short/Intermediate**  **- Term Handler Risk**  Occupational handler expo sure to the herbicide fomesafen is expected for individuals involved in mixing, appl yi ng , or flagging for the proposed fomesafen sodium applications to cantaloupe , cucumber, pea, pumpkin, squash, watermelon, soybean, and lima bean. Occupational handlers m ay experience short - and intermediate - term dermal and inhalation exposures. The quantitative exposure/risk assessment developed for the proposed uses by occupational handlers is based on the following scenarios:

 Mixing/loading for aerial, groundboom, and chemigation application s  Applying by

aerial or groundboom application s  Flagging in support of aerial application  Mixing/loading/appl yi ng for soil - and ground - directed applications with handheld equipment The maximum application rates for the proposed uses are 0.375 lb ae/acre, except for the proposed use on peas and lima beans; the maximum application rate for peas and lima beans is 0.25 lb ae/acre. Onl y the maximum application rate of 0.375 lb ae/acre was used in the assessment , as this is protective of all proposed uses. The fomesafen product labels direct applic ators and other handlers to wear long - sleeved shirt s,Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 21 of 48 long pants, chemical - resistant gloves, shoes , plus socks, and protective eyewear . Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment (PPE). Exposures were calculated “baseline” , defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The dermal and inhalation routes of exposure were not combined because the points of departure are based on different toxicological endpoints. Occupational dermal and inhalation risk estimates are presented in Table 9.1 below. For occupational handlers, dermal and inhalation MOEs above 100 are not of concern. All occupational exposure risk estimates for short - and intermediate - term exposures f or handlers are not of concern with single layer dermal PPE (includes long - sleeve shirt and long pants) or with engineering control enclosed cab (fixed wing aircraft /aerial applicators ). Dermal MOEs ranged from 350 to 300,000 , and inhalation MOEs ranged f rom 410 to 360, 000.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 22 of 48 **Table 9**  **.1 .**  **Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Fomesafen. Exposure Scenario**  **Crop or Target**  **Derm al Unit** 

**Exposure (μg/lb ai)**  **1 Inhalation Unit** 

**Exposure (μg/lb ai)**  **1 Maximum** 

**Application Rate**  **2 Area** 

**Treated or**  **Am ount**  **Handled Daily**  **3 Derm**  **al Inhalation**  **Mitigation Level: Single**  **Layer Mitigation** 

**Level: No Respirator**  **Dose (m**  **g/kg/day) 4**  **MOE 5**  **Dose**

**(m g/kg/day)**  **6 MOE**  **7** Mixer/Loader M/L, Liquid, Aerial, Broadcast Nursery

220 0.219 0.375 lb ae/acre 60 acres 0.0143 7,000 0.0000616 8,100

Ty pical Field Crop 350 acres 0.0838 1,200 0.000359 1,400 High Acreage Field Crop 1200 acres 0.287 350 0.00123 410 M/L, Liquid, Chemigation Field Crop,

All 350 acres 0.0838 1,200 0.000359 1,400 M/L, Liquid, Groundboom, Broadcast Nursery, Greenhouse 60 acres 0.0143 7,000 0.0000616 8,100 Ty pical Field Crop 80 acres 0.0191 5,200 0.0000821 6,100 High Acreage Field Crop 200 acres 0.0478 2,100 0.000205 2,400 Applicator Applicator, Spray, Aerial Nursery Eng Control: 5 Eng Control:

0.0049 0.375 lb ae/acre 60 acres 0.000328 300,000 0.0000014 360,000 Field Crop, Ty pical 350 acres 0.0019 53,000 0.000008 62,000 Field Crop, High Acreage 1200 acres 0.00652 15,000 0.0000276 18,000 Applicator, Spray, Groundboom Nursery,

Greenhouse 78.6 0.34 60 acres 0.00513 19,000 0.0000956 5,200 Field Crop, Ty pical 80 acres 0.00684 15,000 0.000128 3,900 Field Crop, 200 acres 0.0171 5,800 0.000319 1,600Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 23 of 48 **Table 9**  **.1 .**  **Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Fomesafen. Exposure Scenario**  **Crop or Target**  **Derm al Unit** 

**Exposure (μg/lb ai)**  **1 Inhalation Unit** 

**Exposure (μg/lb ai)**  **1 Maximum** 

**Application Rate**  **2 Area** 

**Treated or**  **Am ount**  **Handled Daily**  **3 Derm**  **al Inhalation**  **Mitigation Level: Single**  **Layer Mitigation** 

**Level: No Respirator**  **Dose (m**  **g/kg/day) 4**  **MOE 5**  **Dose**

**(m g/kg/day)**  **6 MOE**  **7** High Acreage Flagger Flagger Nursery 11 0.35 0.375 lb ae/acre 60 acres 0.000719 140,000 0.0000985 5,100

Field Crop, All 350 acres 0.00417 24,000 0.000574 870 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2013 ); Level of mitigation: Baseline; Eng. Controls for aerial applicators. 2 Based on p roposed label. 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) × DAF (%) ÷ BW (kg). 5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = Dermal Un it Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg). 7 Inhalation MOE = I

nhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 8 10 gallons per acre assumed.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 24 of 48 **9.2.1 Dermal Post**  **- application Risk**  Post - application dermal exposure is not anticipated for the majority of the proposed fomesafen uses since, based on the label directions, it is not likely that the pesticide will contact the foliage. The proposed label states that the product is applied as follows: (1) to cantaloupe as a directed spray to row middles prior to transplanting; (2) to cucumber as a directed spray to row middles just after seeding but before crop emergence or just prior to transplanting; (3) to succulent peas as a broadcast pre - emergence application; (4) to pumpkin, squash, and watermelon as a broadcast or directed spray to row middles after seeding but prior to crop emergence or prior to transplanting; and (5 ) to watermelon also as a directed post - emergence application to row middles. Therefore, a quantitative post - application dermal exposure assessment was not conducted for these proposed uses. This risk assessment for fomesafen sodium evaluates the potenti al risks associated with its pre plant/pre - emergent uses on vegetables . There is a low potential for occupational post - application exposure associated with the use of pre - plant/pre - emergent herbicides because there are no hand labor activities ty

pically a ssociated 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. There is a possible concern that some level of soil contact could occur during mechanic ally assisted transplanting activities ; however, this is likely to result in negligible exposures as outlined in HED Exposure SAC Policy 8. Th e rationale is that transplanting activities involve moving starter plants onto a rotating wheel while riding upo n an implement being moved across a field. In such cases , there would be minimal contact with machinery that has field soil on it , because of the possibility of mechanical injury . These conclusions are appropriate even though fomesafen sodium has a long half - life in soil (i.e., ~390 days). The applications to the proposed crops are for pre - emergent or directed ground spray s; thus, contact with treated foliage is expected to be minimal, except for soy beans and lima beans. Therefore, a quantitative derm al post - application exposure assessment was only conducted for the proposed new uses with post - emergent applications (i.e., soy beans and lima beans). The proposed application rate on soy beans is 0.375 lb ae/acre and for lima beans is 0.25 lb ae/acre. A ll occupational exposure risk estimates for short - and intermediate - term exposures for post application workers are not of concern (i.e., dermal MOEs are greater than the LOC of 100). Dermal MOEs ranged from 3,200 to 59,000 for post - application workers (s oy bean and lima bean activities).Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 25 of 48 **Table 9.2.1**  **. Occupational Post**  **- application**  **Non -**  **Cancer Exposure and Risk Estimates for Fom esafen**  **. Crop/Site**  **Activities Transfer Coefficient**  **(cm 2**  **/hr) DFR/TTR**  **1 Dermal Dose**  **(m g/k** **g/day) 2**  **MOE 3**  Short and Intermediate - term Soybean Hand Weeding 70 1.05 0.002 59,000

Scouting 1100 0.027 3,700 Lima Beans Scouting 1100 0.7 0.018 5,600

Irrigation 1900 0.031 3,200 1 DFR = Application Rate × F × (1 - D) t × 4.54E8 μg/lb × 2.47E - 8 acre/cm2 ; where F = 0.25 and D = 0.10 per day 2 Daily Dermal Dose = [DFR (μg/cm2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)]  BW (kg). 3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm 2 ) × TC × 0.00 1 mg/μg × 8 hrs/day × dermal absorption factor (%) ]  BW (kg) . Restricted Entry

Interval The current label specifies a 24 - hour REI . Fomesafen has a low order of acute toxicity by the dermal route of exposure (Toxicity Category IV ). Fomesafen is minimally irritating to the eye and is not irritating to the skin. Itis not a sensitizer. Short - and intermediate - term post application risk estimates were not a concern on D ay 0 (12 hours following application) for all post - application activities. Und er 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute IV for acute dermal, eye irritation or primary skin irritation are assigned a 12 - hour REI . Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post - application exposures to fomesafen. The REIon the label meets the minimum requirement. **9.2.2 Inhalation Post**  **- application Risk**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for fomesafen at this time primarily because of the low vapor pressure ( <7.5 x 10 - 7 mmHg at 50 °C ) . However, there are multiple potential sources of post application inhalation exposure to individuals performing post - application activities in previously

treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that c ontain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final repo rt on March 2, 2010 3 . The Agency is in the process of evaluating the SAP report , as well as available post - application inhalation exposure data generated b y the ARTF and may , as appropriate, develop policies and procedures, to identify the need for and the way to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for fomesafen .

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 26 of 48 Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from appl ication of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of the fomesafen occupational post application inhalation exposure scenarios. **10.0 References**  I. Negrón Encarnación, In Process , D407932, Fomesafen Sodium. Petition for the Establishment of Tolerances and Registration of New Uses on Cantaloupe, Cucumber, Pea (Succulent), Pumpkin, Summer Squash, Watermelon, Winter Squash, Soy bean (Succulent) and Fresh Lima Bean: Summary

of Analy tical Chemistry and Residue Data . D. Drew, D410439 , 7/11/13, Fomesafen Sodium, Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Cantaloupe, Cucumber, Pea (Succulent), Pumpkin, Summer Squash, Winter Squash, Watermelon, Soy

bean (Succulent) and Li ma Bean (Succulent) . A. LaM ay , In Process , D407933, Fomesafen Sodium. Occupational and Residential Expos ure Assessment for Proposed Uses on Cantaloupe, Cucumber, Pea, Pumpkin, Squash, Watermelon, Soy bean, and Lima Bean . A. LaMay , 10/12/10, D373600, Fomesafen Sodium: Human Health Risk Assessment for the Establishment of Tolerances and Registration of New Use s of Fomesafen Sodium on Potatoes and Peppers. H. Zhong, 6/24/13, D412599, Revised Fomesafen Drinking Water Assessment to Include IR - 4 Use on L ima Bean and Groundwater EDWCs Using a Tier - I PRZM - GW Model.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 27 of 48 **A ppendix**  **A .**  **Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR 158.340) for the food use for fomesafen are in the table below . Use of the new guideline numbers does not imply that the new (1998) guideline protocols we re used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Acute Eye Irritation ................................ ....................... 870.2500 Acute Dermal Irritation ................................ ................. 870.2600 Skin Sensitization ................................ .......................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90 - Day

Oral Toxicity in Rodents ................................ .. 870.3150 90 - Day

Oral Toxicity in Nonrodents ............................. 870.3200 21/28 - Day Dermal Toxicity ................................ ........... 870.3250 90 - Day

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

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

yes yes

-

- 870.3700a Prenatal Developmental Toxicity (rodent) ..................... 870.3700b Prenatal Developmental Toxicity (nonrodent) ............... 870.3800 Reproduction and Fertility Effects ................................ . yes yes yes yes

no a yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Carcinogenicity (rat) ................................ ...................... 870.4200b Carcinogenicity (mouse) ................................ ................ 870.4300 Combined Chronic Toxicity/Carcinogenicity ................ yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Bacterial Reverse Mutation Test ... 870.5300 Mutagenicity

—Mammalian Cell Gene Mutation Test 870.5375 Mutagenicity

—In Vitro Chromosomal Aberrations 870.5385 Mutagenicity

—Mammalian Chromosomal Aberrations 870.5395 Mutagenicity

—Micronucleus Test 870.5450 Mutagenicity

—Dominant Lethal Assay 870.5550 Mutagenicity

— Unscheduled DNA Synthesis yes yes yes yes yes no no yes

yes yes yes c yes

-

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

Neurotoxicity Screening Battery (rat) ............... 870.6300 Developmental Neurotoxicity ................................ ........ y es yes no yes

yes

- 870.7485 Metabolism and Pharmacokinetics ................................ 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

no b yes a Although the developmental toxicity study in rabbits was classified unacceptable due to mortality from bacterial infections, there was not any evidence of increased susceptibility of rabbit fetuses due to the treatment with fomesafen. Therefore, the lack of an acceptable developmental toxicity study in non - rodents was not considered a data gap. b As a dermal penetration study was not provided, the dermal absorption value of 20% was based on dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures. Consequently, the dermal penetration study is not considered a data gap. c Two studies were Not Classified (because there were no mutagenicity guidelines when the study was conducted), and one study was Unacceptable/Guideline. H owever, there are mutagenicity studies which evaluate both somatic and germinal cells, which is considered sufficient to satisfy CFR requirements.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 28 of 48 **A.2 Toxicity Profile**  **s Table A.2.1**  **Acute Toxicity Profile -**  **Fo mesafen**  **Guideline No. Study Type**  **MRID(s) Results**  **Toxicity Category** 870.1100 Ac ute oral [rat] 46988901 LD 50 Females >5000 mg/kg bw IV 870.1200 Ac ute dermal [rat] 46988902 LD 50 Com bined > 5050 mg/kg bw IV 870.1300 Ac ute inhalation [rat] 46988903 LC 50 Com bined >2.63 mg/L IV 870.2400 Ac ute eye irritation [rabbit] 46988904 Minimally irritating I V 870.2500 Ac ute dermal irritation [rabbit] 46988905 No irritation IV 870.2600 Skin sensitization [guinea pig] 46988906 Not a sensitizer N/A **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Fomesafen Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.3050 28 - Day Oral Toxicity in Rodents 40786709 (1980) Acceptable/Non Guideline 0, 5, 15, 50, 150, 500, 1500 or 1500 ppm M: 0, 0.71, 2.13, 7.20, 20.7, 68.9, 209.1, or 917.2 mg/kg/day) F: 0, 0.94, 2.87, 8.30, 27.1, 83.4, 246.8, 1247.6 mg/kg/day NOAEL = 209/247 mg/kg/day in M/F LOAEL = 917/1247 mg/kg/day in M/F based on decreased body weights and body weight gains, decreased food efficiency, hematology (decrease d 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 Oral Toxicity in Rodents 00103013 (1981) Acceptable/ Guideline 0, 1, 5, 100 or 1000 ppm (0, 0.1, 0.5, 10 and 100 mg/kg/day) NOAEL = 0.5 mg/kg/day LOAEL = 10 mg/kg/day based on hyalinization of hepatocytes and increased hepatocellular peroxisomes 870.3100 + 870.6200b Com bined 90 - Day

oral Toxicity and Neurotoxicity Screening Battery in Rodents 48996801 (2012) Acceptable/Guideline 0, 100/300, 300/100, or 1000/3000 ppm in M/F M: 0, 6.4, 20.3, 67.0 mg/kg/day F: 0, 23.1, 74.2, 233.2 mg/kg/day NOAEL = 67.0/233.2 mg/kg/day in M/F LOAEL was not ob served

870.3150 90 - Day Oral Toxicity in Nonrodents 00103014 (1981) Acceptable/Guideline 0, 0.1, 1.0, 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)Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 29 of 48 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Fomesafen Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.3200 21/28 - Day Dermal Toxicity 00135632 (1983) Acceptable/ Guideline 0, 10, 100, 1000 mg/kg/day NOAEL = 1000 mg/kg/day LOAEL was not observed 870.3700a Prenatal developmental in (rodent) 00164903 (1981) Acceptable/Guideline 0, 50, 100, 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 LOAEL = 200 mg/kg/day based on the staining of the ventral fur and significantly decreased body weight gain (>10%) **Developm ental**  NOAEL = 100 mg/kg/day LOAEL = 200 mg/kg/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903) 870.3700a Prenatal developmental in (rodent) 00103016 (1982) Acceptable/Guideline 0, 1.0, 7.5, 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 foll owing LOAELs/NOAELs we re established for fomesafen.] **Maternal** NOAEL = 100 mg/kg/day LOAEL = 200 mg/kg/day based on the staining of the ventral fur and significantly decreased body weight gain (>10%) **Developm ental**  NOAEL = 100 mg/kg/day LOAEL = 200 mg/kg/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903) 870.3700b Prenatal developmental in (nonrodent) 00109214 (1981) Unacceptable/Guideline 0, 2.5, 10, 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. The s tudy provided information to assess potential developmental toxicity rabbits, but was classified unacceptable because of bacterial in fection in the colony. 870.3800 Reproduction and fertility effects 00144862 (1984) Acceptable/Guideline 0, 50, 250, 1000 ppm (0, 2.5, 12.5, 50 mg/kg/day) **Parental/System ic**  NOAEL = 12.5 mg/kg/day LOAEL = 50 mg/kg/day based on liver histopathology in ma les and females of both generations **Reproductive** NOAEL = 50 mg/kg/day LOAEL was not established **Offspring** NOAEL = 12.5 mg/kg/day LOAEL = 50 mg/kg/day based on increased incidence of liver hyalinization in malesFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 30 of 48 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Fomesafen Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.4200b Carcinogenicity (mouse) 00131491 (1983) Acceptable/Guideline 0, 1, 10, 100, 1000 ppm (0, 0.15, 1.5, 15, 150 mg/kg/day) NOAEL = 1.5 mg/kg/day LOAEL = 15 mg/kg/day based on the presence of liver tumors and liver weight increases in male and female mice **evidence of carcinogenicity** 870.4300 Com bined Chronic Toxicity/Carcinogenicity 00142125 (1984) Acceptable/Guideline 0, 5, 100, 1000 ppm (0, 0.25, 5, 50 mg/kg/day) NOAEL = 0.25 mg/kg/day LOAEL = 5 mg/kg/day based on hyalinization of the liver in males **no evidence of carcinogenicity** Genetic Toxicity Test 870.5300 In vitro mammalian cell gene mutation test 40910804 Acceptable/Guideline

- S9: 0, 450, 475, 500, 525, 550, 575, 600 μg/mL +S9: 0, 325, 350, 375, 400, 425, 450, 475 μg/mL A technical grade preparation containing 97 percent fo me safen was tested for mutagenicity against L5178Y mo use lymphoma cells, both in the presence and absence of S - 9 metabolic activation at concentrations ranging between 325 to 600 μg/mL. T wo tests were performed and each test was performed in duplicate fo r each concentration. There was no indication of mutagenicity at any dose level tested, both in the presence or absence of metabolic activation. The positive controls, including ethylmethanesulphonate, a direct mutagen and N nitrosodimethylamine, which required metabolic activation, were both responsive in these tests. Genetic Toxicity Test 870.53 7 5 In Vitro M ammalian C hromosome A

berration T est 44569805 Acceptable/Guideline

- S9: 0, 150, 500, 1000 μ g/mL +S9: 0, 75, 150, 250 μg/mL There was no evidence of chromosome aberrations induced over background.
Genetic Toxicity Test 870.5375 In Vitro Mammalian Chromosome Aberration Test 4456980 6 Acceptable/Guideline ±S9: 0, 10, 100, 1000 μg/mL There was no evidence of chromosome aberrations induced over background. Genetic Toxicity Test 870.5385 Mammalian Bone Marrow Chromosomal Aberration Test 00135628 Not Classified 0, 125, 250 mg/kg The mitotic index is significantly decreased by 250 mg/kg Fomesafen, indicating toxicity. The percent of cells with chromosome abnormalities in cluding gaps is significantly increased by 250 mg/kg Fomesafen. Both 125 and 250 mg/kg Fomesafen slightly (but not statistically significantly) increased the number of cells with chromosome abnormalities excluding gaps. Fomesafen is conside red to be a weak mutagen. Genetic Toxicity Test 870.5385 Mammalian Bone Marrow Chromosomal Aberration Test 00164907 Not Classified 0, 125, 250 mg/kg The product induced statistically significant increase of cells with abnormalities at the 125 and 250 mg/kg dose level. The responses were similar to the ones observed in the cells of animals treated with the positive control EMS , and they include gaps and other than gaps as well as breaks and fragments. The product induced chromosome damage in the bone marrow of the rat cells at oral doses of 125 and 250 mg/kg.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 31 of 48 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Fomesafen Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  Genetic Toxicity Test 870.53 8 5 Mammalian Bone Marrow Chromosomal Aberration Test 45048208 Unacceptable/Guideline 0, 25, 125, 250 mg/kg Fomesafen technical up to 250 mg/kg dose level is not clastogenic in this in vivo test system . Genetic Toxicity Test 870.539 5 Mammalian Ery

throcyte Micronucleus T est 40910805 Acceptable/Guideline M: 0, 175, 279 mg/kg F: 0, 215, 344 mg/kg Fomesafen does not appear to be clastogenic in the mo use micronucleus test system. Genetic Toxicity Test 870.5450 Rodent D ominant L ethal A ssay 00103019 Not Classified 0, 25,100, 250 mg/kg/day Fomesafen possesses no dominant lethality at any one of the dose levels assayed . Genetic Toxicity Test 870.5 550 Unscheduled DNA S ynthesis in M ammalian C ells in C ulture 40786703 Unacceptable/Guideline Up to 1000 μg/mL At 1000 μg/mL, the compound was toxic to the cells. It is difficult to interpret the UDS results as provided.
870.6200a Ac ute Neurotoxicity Screening Battery 48973302 (2012) Acceptable/Guideline 0, 100, 250, 800 mg/kg NOAEL = 100 mg/kg LOAEL = 250 mg/kg based on decreased motor activity (horizontal and vertical activity and time in central quadrant) in males 870.6200b + 870.3100 Com bined 90 - Day

oral Toxicity and Neurotoxicity Screening Battery in Rodents 48996801 (2012) Acceptable/Guideline 0, 100/300, 300/100, 1000/3000 ppm in M/F M: 0, 6.4, 20.3, 67.0 mg/kg/day F: 0 , 23.1, 74.2, 233.2 mg/kg/day NOAEL = 67.0/233.2 mg/kg/day in M/F LOAEL was not observedFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 32 of 48 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Fomesafen Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.7485 Metabolism and Pharmacokinetics in Rat 00103017 (1982) 00135633 (1983) 00164904 (1982) 00164905 (1982) 00164906 (1982) 00164939 (1982) Not C lassified or Acceptable/Guideline The overall mean recovery of radioactivity by D ay 7 wa s 99.9% for males and 98.5% for females in MRID 00103017 . The study, MRID 00135633, is acceptable to prove that no meaningful accumulation of the material was left in th e body; most (up to 95%) was ex creted via urine, feces or bile. The liver did not accumulate the material in meaningful amounts. In MRID 00164904, there was not a great difference between male and female rats in the excretion of (1 4C) - PP021 , and most of the material was excreted. The liver was the organ with more accumulation, ± 0.5% males. ± 0.4% females. In MRID 00164905, widespread tissue distribution of radioactivity was observed throughout the 28 day dosing period (5 mg/kg d oses). Radioactivity in the liver was increased as dosing proceeded and decreased progressively after the 21 or 28 last dose. In MRID 00164939, Animals were treated with a s ingle dose by intravenous injection (5 mg/kg), and r ecovery wa s 9 4 % in both sexes . T here wa s a difference observed in fomesafen excretion between male and female rats. The liver was the organ with the most residues. MRID 00164906 and its DER were not found. 870.7485 Metabolism and Pharmacokinetics in Dog 00135634 (1983) Acceptable/Guideline Fomesafen is excreted via urine or feces. The feces showed a large amount of biliary product elimination. No substantial differences were observed between male and female dogs. The largest part of the product or the metabolite was e liminated via urine. The only metabolite found was the same product, fomesafen. 870.7485 Metabolism and Pharmacokinetics in Marmoset 00141525 (1984) Not evaluated; MRID nor DER were found.
870.7485 Metabolism and Pharmacokinetics in Mouse 00144861 (1983) Not evaluated; MRID nor DER were found.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 33 of 48 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Fomesafen Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.7485 Metabolism and Pharmacokinetics in Ham ster 40910803 (1984) Supplementary 5 mg/kg/day A single dose of radio labeled compound ( 5 mg/kg ) was administered orally to three male and three female hamsters. Urinary and fecal samples were collected at 24 - hour intervals for 3 days. The animals were killed at 72 hours to collect tissues and carcass for analysis of radioactivity. In males, excretio n based on dose of radioactivity recovered, amounted to 55 percent in urine and 28 percent in feces; in females, 47 percent wa s excreted in urine and 27 percent in feces. There were no differences in amount excreted by either route between the two sexes. W ithin the first 24 hours, about 36 percent of the dose was recovered in urine and 15 percent of the dose in feces for both the male and female. At 72 hours, radioactivity remaining in the entire organism amounted to about 3.0 percent in males and 2.5 perce nt in females; no sex differences. Of the four tissues in which radioactivity was measured, including liver, kidneys, lung, and blood, uptake was highest by the liver, based on percent of dose in the entire organ and μg equivalents/g of tissue. 870.7800 I mmunotoxicity 48762301 (2011) Acceptable/Guideline 0, 100, 1000 , 4000 ppm (0, 16, 176, 791 mg/kg/day) NOAEL = 16 mg/kg/day LOAEL = 176 mg/kg/day based on dose - related suppression of anti - SRBC IgM response

**A.3 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 CIAmerica s, In c., Wilmington, DE; CDL :247589 - E). Unpublished. **EXECUTIVE SUMMARY** - In this subchronic toxicity study (MRID 00103013), Fomesafen (97.5% a.i.; PPO21) was administered in the diet for 90 day s to 20 Alderley Park rats/sex/dose at doses of 0, 1, 5, 10 0, or 1000 ppm (approximately equivalent to 0, 0.1, 0.5, 10, and 100 mg/kg/day

using a conversion factor of 0.1). The animals were observed daily for clinical signs of toxicity . Body

weights and food consumption were determined initially and at 2 - week i ntervals, thereafter. Hematology , clinical chemistry and urinal ys is were conducted. At termination, animals were necropsied, organs weighed and representative tissues examined microscopicall y. Election microscop y was conducted on selected tissues. No m ortality

occurred. Animals in the 1000 ppm group gained less weight than the controls. Plasma alkaline phosphatase, alanine transaminase and aspartate transaminase were increased inFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 34 of 48 males in the 1000 ppm group. L iver weights were increased in male and f emales at 1000 ppm. Hyalinization of hepatocy tes, characterized by

increased eosinophilia and reduced basophilic granulation and reduced vacuolization, was observed at 100 and 1000 ppm. Electron microscop y revealed an increase in peroxisomes in centrilob ular hepatocy tes at 100 and 1000 ppm. **The LOAEL is 100 ppm ( 10**  **mg/kg/day) based on hyalinization of hepatocytes and**  **increased hepatocellular peroxisomes**  **in males .**  **The NOAEL is 5 ppm (0.5 mg/kg/day).** This study

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

in dog. Central Toxicology L aboratory (Alderley

Park, Cheshire, UK). Laboratory

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

throcy te counts were slightly

decreased in both sexes combined (6 - 10%), relative to controls, at 25 mg/kg from weeks 4 - 20. Mean hematocrit was also slightly decreased (6 - 9%), relative to controls, in both sexes combined at 25 mg/kg during the same period. At 25 mg/kg in both sexes combined, me an platelet 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% (fe males) increase in smooth endoplasmic reticulum (SER), indicative of increased protein sy nthesis. Mean plasma cholesterol levels were decreased b y 31 - 40%, relative to controls, in both sexes combined from weeks 1 - 26, while mean plasma trigl ycerides were d ecreased 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 ada ptive response 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 p eroxisome 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 tim e). The NOAEL is 1 mg/kg bw/day.** Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 35 of 48 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 **EXECUTIV E SUMMARY**  - In a developmental toxicity study (MRID 00164903), Fomesafen (97.5% a.i.) was administered to 17 - 24 pregnant rats/dose in corn oil by gavage at dose levels of 0, 50, 100 or 200 mg/kg bw/day from day s 6 through 15 of gestation. Maternal toxici ty

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 consump tion 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 Inform ation 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 1**  **00 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.** 00103016 **Citation :**  Wickeramaratne, G.A., Richards, D., Babham, P.B. (1982) Fomesafen: Teratogenicity study in the rat. CTL/P/656 and CTL /P/656S prepared by

Central Toxicology

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

dose level tested . However, this study should be considered with: 1) Report No. CTL/P/576, MRID #00164903, and 2) information provided b y S yn genta in their submission (DP 316263, MRID 46527208) in establishing the NOAEL and LOAEL (see Discussion/Added Information Section) . With the additional information, the following conclusions can be made. **The maternal LOAEL is 200 mg/kg bw/day, based on staining of the ventral fur and significantly decreased body weight gain**  **(> 10%). The maternal toxicity NOAEL is 100 mg/kg bw/day. The developmental** Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 36 of 48 **LOAEL is 200 mg/kg bw/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903). The developmental NOAEL is 100 mg/kg bw/day.**  This developmental toxicity s tudy is classified **Acceptable/Guideline** and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in combination with another developmental toxicity in rat (CTL/P/576, MRID 00164903). **MRID No** . 001092 14 **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 Chemic al 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 cap sules) 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, 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, 2/2 4 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 occu rrence of an apparent**  **bacterial infection in the animal colony.** There was no significant difference between the control and treated groups in pregnancy rate or abortions. While the mean number of implantations/dam was similar across dose, the number of c orpora lutea/dam was significantly (p<0.05) increased in the high dose group (10.6) relative to controls (7.7). This resulted in an increase in pre - implantation loss at the high dose onl y. This observation was not considered toxicologicall y significant, 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 (4/2 4, 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 s ignificant.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 37 of 48 **The developmental LOAEL was unable to be determined due to the occurrence of an apparent bacterial infection in the animal colony.**  Because of an apparent bacterial infection in the animal colony ; individual animal data were not reported; all fetuses were not examined for both soft tissue and skeletal alterations; and historical control data were not provided, the developmental toxicity study in the rabbit is classified **Unacceptable/guideline** . This study does not satisfy

the guideline requirem ent 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 - p ared by Huntingdon Research Centre, Eng., submitted by I CI Americas, 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. 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 mortality

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 and females in the 100 and 1000 ppm groups at 52 weeks. Liver weights and l iver - to body weight ratios were significantl y increased in both sexes receiving 100 and 1000 ppm Fomesafen. Kidney , adrenal, and heart weights were significantl y increased at 1000 ppm. Because the organ - to - body weight ratios were not significantl y different from the controls, fomesafen was not considered to have a significant toxicological affect on these organ weights. The incidence of liver masses was significantl y increased in males receiving 1, 100 and 1000 ppm fomesafen and in females receiving 100 and 1000 ppm fomesafen. The increase in liver masses was accompanied by increases in enlarged and discolored livers and by increases in eosinophilic hepatocy

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

is classified as **Acceptable/Guideline** and does satisfy the requirements for a chronic feeding/oncogenicity study in mice (OPPTS 870.4300; OECD 453).Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 38 of 48 **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 1 000 mg/kg bw/day (limit dose), 6 hours/day , 5 day s/week for 3 weeks. No treatment - related effects were observed on mortality , body weight, body

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

significant since they

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

is class ified 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. CT L/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 administere d 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 phosphatase, 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 yceridesFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 39 of 48 were observed in males and females treated with 1000 ppm fomesafen. Male and female rats treated with 1000 ppm fomesafen had depressed protein excretion in urine. Mean liver weights were significantly

increased in males and females administ ered 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 fomesaf

en. 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 male**  **s. The NOAEL is 5 ppm (0.25 mg/kg/day).** This study

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

study in rats. **MIRD No.** 00144862 **Citation :**  Ten ston, 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) 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. The F1A pups were weaned on postnatal day (PND)22 and F1B, F2B and F2A pups were weaned PND 29. Thirty F1B females and 15 males were selected to become F1 parents and produced F2B litters. Brother - sister matings were avoided in each parental generation. In the parental animals, no treatment - related effects 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 yalinization (diffuse and centrilobular; M & F) and biliary hyp erplasia (M & F). An increased incidence of liver hyalinization was observed in the livers of F1b males, however, these ef fects are considered to be of s ys temic effect rather than offspring toxicity . No liver alterations 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 hyalinizati**  **on in males. The offspring NOAEL = 250 ppm (12.5 mg/kg bw/day).**Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 40 of 48 No treatment - 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 reduction 20% in litter size was observed at 1000 ppm F2B litters, however, there was no reduction in litter sizes in other 3 1000 ppm groups. A 13% reduction in litter size was also observed at 50 ppm in F1 B litters. These litter reductions were sporadi c, not dose - related, and therefore, considered to be of no toxicological significance. At 1000 ppm, an increased incidence of h ya linization of the liver was observed in F1B pups in the 1000 ppm group. **The reproductive NOAEL = 1000 ppm (50 mg/kg/day). The LOAEL was not established.**  The study is classified **Acceptable/Guideline** and satisfies the guideline requirement for a reproduction toxicity

(OPPTS 870.3800; 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. **EXECUTIVE SUMMARY** - In a developmental toxicity study (MRID 00164903), Fomesafen (97.5% a.i.) was administered to 17 - 24 pregnant rats/dose in corn oil by gavage at dose levels of 0, 50, 100 or 200 mg/kg bw/day from day s 6 through 15 of gestation. Maternal toxicity

was evident at dose of 200 mg/kg bw/day (the highest dose tested) and was associated with staining of the ventral fur in 15 of 20 animals and significantly decreased body weight gain (>10%) during the dosing period (Days 7 - 16; Day s16 - 21). Food consumption in the high - dose group was also significantl y decreased as compared to the control 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 #00101301 6, 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**  **terna l 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 de velopmental 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.** 40786709Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 41 of 48 **Citation :**  Colley , J., Cladee, S., Street, A., Hey wood, R., Gibson, W., Prentice, D., Buckley , P., and Offer, J. (1980) Preliminary Assessment of PP 021 Toxicity to Mice by Dietary Administratio n for 4 weeks. Huntingdon Research Center, Huntingdon, U.K. Study No. ICI/317/80148, September 13, 1980. Unpublished. **EXECUTIVE SUMMARY** - In a 28 - day range finding oral toxicity study (MRID 40786709), fomesafen (94% a.i., Batch/L ot # P 21 and ICI TSC N o. Y00053/001/004) was administered to CD - 1 mice (10/sex/dose) in the diet at doses of 0, 5, 15, 50, 150, 500, 1500, or 5000 ppm (equal to 0/0, 0.71/0.94, 2.13/2.87, 7.20/8.30, 20.7/27.1, 68.9/83.4, 209.1/246.8, or 917.2/1247.6 mg/kg/day

[M/F]) for up to 28 day s. Clinical signs consisting of emaciation were noted in two females in the high dose group (5000 ppm) and in one female in the 150 ppm dose group. Since there was no dose response, the effect was not considered treatment - related. Mortality was se en 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 decrea sed 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 de creased MCH and a slight increase in ery throcy tes were seen in high - dose males. These changes in hematological parameters were indicative of slight anemia and were therefore regarded as toxicologicall y significant. Statistically significant increases in liver weights were observed in males at ~50 ppm and in females at ~150 ppm. Enlarged hepatocy tes were also observed. However, since there were no corroborating adverse histopathological findings, these effects were considered adaptive changes. All high - dose animals exhibited bile duct hy perplasia. Small seminal vesicles were observed in 2/10 high 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 hyperplasi a, decreased uterine size**  **in females, and decreased size of the seminal vesicles in males. The NOAEL is 1500 ppm (equal to 209/247 mg/kg/day in M/F).**  This 28 - 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 subchronic oral toxicity study in rodents. **MRID No.** 44569805 **Citation :**  Howard, C.A., Richardson, C.R. (1989) Fomesafen: An evaluation in the in vitro cy togenetic assay

in human ly

mphoc yt es. Central Toxicology L aboratory , Alderley Park, Macclecsfield, Cheshire, UK SK104TJ. L aboratory Project ID: CTL/P/2378, April 4, 1988. Unpublished.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 42 of 48 **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 were exposed to fomesafen (96.7% a.i.) in dimethyl sulfoxide (DMSO) at concentrations of 0, 150, 500, and 1000 μg/ml in the absence of S9 - mix and 75, 150, and 250 μg/ml in the pre sence 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 m ale Sprague Dawley

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

to cy totoxicity as the MI was reduced b y 57% in these cells. In the repeat experiment (S9, donor 1), the MI decreased b y 56% and clastogenicity was not observed. Proper experimental protocol was followed and the so lvent 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.** 44569806 **Citation :**  Mellano, D., Berruto, G. (1984) Fomesafen: In vitro study of chromosome aberration induced b y fomesafen in cultured human lymphocytes. Istituto Di Ricerche Biomediche, “Antoine Marxer” S.p.A., Casella Postale 226, 10015 Ivrea. Laboratory Project ID: CTL/C/1262, May 16, 1984. 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 dimethyl sulfoxide (DMSO) at concentrations of 0, 10, 100, and 1000 μg/ml in the absence and presence of metabolic activation for 3 hours and harvested 26 hours after the beginning of treatment. One - hundred cells (duplicate slides) were evaluated for metaphases with structural aberrations. The S9 - fraction was obtained from Aroclor 1254 induced male Sprague Dawley rat liver. Fomesafen was test ed up to a cy totoxic concentration for this assay . Cy totoxicity was observed at 1000 μg/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 presen ce or absence of metabolic activation. The solvent and positive controls induced the appropriate response. **There was no evi dence of chromosome aberrations**  **induced over background.** This study

is 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.** 48762301 **Citation :**  Donald L ., Marr C., (2011). Fomesafen

– A 28 Day Immunotoxicity

Study of Fomesafen by Oral (Die tary) Administration in Mice using Sheep Red Blood Cells as the AntigenFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 43 of 48 Charles River Laboratories, Tranent, Edinburgh EH 33 2NE, UK. Study number 520005, October 31 , 2011. MRID 48762301 . Unpublished. **EXECUTIVE SUMMARY** - In an immunotoxicity study (MRID 48762301 ) , Fomesafen (98.8%, Batch/Lot no. 517927) was administered to female CD - 1mice (10/group) in diets at dose levels of 0, 100, 1000 or 4000 ppm (0, 16, 176, 79 1 mg/kg/day , respectively) for 28 consecutive day s. Positive control group consisted of 10 females received cyclophosphamide (CPH) by oral gavage (10 mg/kg/day) for 28 consecutive day s. All animals in all groups received a single intravenous injection of the antigen, 2x10 8 sheep red blood cells (SRBC) in Earles balanced salt solution, on Day 25. On day 29, blood samples were collected from the orbital sinus under isoflurane anesthesia. Measurement of the SRBC IgM antibody level s were pe rformed with an Enzy me Linked Immunobsorbent Assay ( ELISA ) . The anim als were monitored for mortality and for treatment related s ymptoms daily . Body weights were recorded twice weekl y from Day ( - 7) until necropsy . Additionally , all animals were assessed by gross pathology ; the weights of liver (with gall bladder) , spleen and thy mus were measured. There w ere no treatment related signs and s ymptoms and no differences in food consumption. There were no deaths during the study period. Body weights were not affected in animals in 100 or 1000 ppm groups. However, treatment related lower body weight and body

w eight gain occurred in 4000 ppm group . Animals in positive control group that received (CPH) showed statistically

significant lower body weight and body weight gain (p<0.05) . In creased liver weights (p<0.01) w ere found at 100 ppm and above groups. L ower s pleen and thy mus weights were observed in animals at 4000 ppm. Histologically , mild to mark diffuse or centrilobular hepatocy

tes hy pertrophy was found in animals at 100 ppm and above groups . There was a dose response in severity of histopathology . These findings correlated with higher liver wei ghts and macroscopic findings. The selected doses were approved by the HED Dose Adequacy and Review Team (DART, TXR No. 0055484, dated 14 September 2010). **The systemic NOAEL is not established (<100 ppm). The**  **systemic LOAEL wa s 100 ppm**  **(equivalent to 16**  **mg/kg/day) based on increased liver weights and histological changes**  **.** For immunotoxicity, there is a dose - dependent suppression of the immune response to sheep red blood cells after the treatment with Fomesafen . IgM levels in animals at 1000 and 4000 ppm groups were approximately 2 - 3 folds lower than that of the control animals. A high inter individual variability

was noted in all the treatment groups as well as in the control group. Evaluation of individual an imal data of this study show ed a distribution and trend that demonstrate d a significant suppression of anti - SRBC IgM response. Animals in positive control group showed decreased antibody re sponse which confirmed the ability of the test sy stem to detect immunosuppre ssive effects and validated the study design. The Natural Killer (NK) cells activity was not evaluated. However, under the HED guidance when the tes t substance produces dose - related suppression of the TDAR ( anti - SRBC response ), then the test su

bstance is considered as immunotoxic and no further study is required. NK cells activity assay is not required.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 44 of 48 **Under conditions of this study, the immunotoxicity NOAEL is 100**  **ppm (equivalent to**  **16 mg/kg/day).**  **The LOAEL is 1000 ppm (equivalent to 176 mg/k g/day) based on dose**  **- related**  **suppression of anti -**  **SRBC IgM response.** T his immunotoxicity

study is classified **acceptable guideline** and satisfies the guideline requirement for an immunotox icity study (OPPTS 870.7800) in mice
. **MRID No.** 48973302 **Citation :**  Rached, E. 2012. Fomesafen technical - Acute oral (gavage) neurotoxicity study in rats. Harlan laboratories, Ltd. Itingen, Switzerland. L aboratory Report No. D41528, October 16, 2012. MRID 48973302. Unpublished. Rached, E. 2012. Fomesafen t echnical - preliminary acute oral (gavage) neurotoxicity study in rat. Harlan laboratories, Ltd. Itingen, Switerland. L aboratory Report No. D41517, October 12, 2012. MRID 48973301. Unpublished. **EXECUTIVE SUMMARY -**  In an acute neurotoxicity study ( MRID 48973302), fomesafen ( 98.8 % a.i., Batch No. 517927 ) was administered in a single oral gavage dose to 10 non - fasted Wistar rats/sex/group at dose levels of 0, 100, 250, or 800 mg/kg bw in 0.5% (w/v) aqueous carbox ym eth yl cellulose (10 mL/kg) . The anim als were observed for 15 days after dosing , and the survivors were sacrificed on Day 16 . Neurobehavioral assessments , consisting of a modified functional observational battery (FOB) and locomotor activity testing , were performed on all animals of both sex es before dosing and on Day s 1 (day of dosing), 8 , and 1 5 . Cholinesterase activity was not determined in this study . At study termination, 5 rats /sex/group were anesthetized and perfused in situ for neuropathological examination. The tissues from the perfused animals in the control and 800 mg/kg groups were subjected to histopathological evaluation of brain, spinal cord, and peripheral nervous sy stem tissues. No adverse, treatment - related ef fects were observed on mortality , clinical signs, or gross or microscopic pathology . No treatment - related effects were observed during the brain weight or neuropathology

assessments. Sy stemic toxicity

was noted in the males for a day or two after treatme nt, but recovery did occur. In the 800 mg/kg male rats, a net loss in body weight was observed on Day 2 ( - 13.2 g in treated group vs 2.98 g in controls) and Day 3 ( - 9.39 g in treated group vs 7.61 g in controls). Body weights at Day

15 and overall (Days 1 - 15) body weight gains in the 800 mg/kg males were similar to controls. Body weights were affected to a lesser degree in the 250 mg/kg males. A net loss of weight was observed in the 250 mg/kg males on Day 2 ( - 7 g in treated group); however, body weights at Day

3 and later were similar to controls. Body weights in the 100 mg/kg males and in all treated female groups were similar to controls. During the first 24 hours after treatment, mean food consumption was decreased (statistical anal ys is not performe d) by 62% in the 800 mg/kg males and by 22% and 43% in the 250 and 800 mg/kg females, respectivel y. No notable effect was observed on food consumption during Day s 8 - 9 and 14 - 15 in the treated groups. Food consumption as a mean of means over the treatment period was decreased b yFomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 45 of 48 17 - 18% in the 800 mg/kg group. The effect on food consumption in the females was not considered adverse due to the transient nature and the minimal impact on body weight. Neurotoxicity

was observed, but not in the absence of s ys t emic toxicity . Inthe 250 and 800 mg/kg males on Day

1, decreased (p ≤0.05, except as noted) motor activity compared to controls was observed as follows: (i) horizontal activity by 36 - 41%; (ii) time in central quadrant b y 46 - 59% (not statistically

signifi cant [NS] at 250 mg/kg); and (iii) vertical activity by 61 - 64%. The e ffect on the females was much less apparent. In the 800 mg/kg females on Day 1, horizontal activity

was decreased (NS) by

24%, and vertical activity was decreased (NS) b y 28%. Motor ac tivities in all other animals on Day 1 and in all animals on Day s 8 and 15 were similar to controls. Habituation was demonstrated, and unaffected b y treatment. Reduced activity and decreased rearing was also assessed during the FOB; however, these findin gs demonstrated an equivocal effect on Day 1, marginal increases in incidence or severity without an effect that was clearly related to dose. At 800 mg/kg on Day

1, one male rat had a hunched posture (#34) and piloerection (#34), and another rat had a r educed righting response (#31). Piloerection, hunched posture, and abnormal gait were observed in one female (#72). These findings were not observed in other animals at any other time. As s ys temic toxicity was noted at this dose, these findings were con sidered equivocall y treatment - related. **The LOAEL**  **was 250 mg/kg, based on decreased body weight and motor activity (horizontal and vertical activity and time in central quadrant) in males.**  **The NOAEL is 100 mg/kg**  **.** This study

is classified as **acceptable/g uideline**  and sati sfies the guideline requirement (870.6200; OECD 424 ) for an acute neurotoxicity study in rats . **MRID No.** 48996801 **Citation :**  Rached, E. (2012) Formesafen technical

– 13 - week dietary combined toxicity

and neurotoxicity

study in Wistar rats. Harlan Laboratories Ltd., Itingen, Switzerland. Laboratory Project ID: D41541, November 15, 2012. MRID 48996801. Unpublished. **EXECUTIVE SUMMARY** - In a subchronic neurotoxicity and oral toxicity study (MRID 49091201, replacing MRID 48996801 ), fom esafen ( 98.8 % a.i., Batch No. 517927 ) was administered in the diet to 15 Wistar rats/sex/group at dose levels of 0, 100/300, 300/100 0 , or 1000/3000 ppm in males/females (equivalent to 0/0, 6.4/23.1 , 20.3/74.2 , and 67.0/233.2 mg/kg/day

[M/F], respectively) for 13 weeks. Neurobehavioral assessment (functional observational battery

[FOB] and motor activity testing) was performed prior to treatment and during Weeks 2, 5, 9, and 13 on 10 rats/sex/group. At study termination, 5 rats /sex/group were anesthetized and perfused in situ for neuropathological examination. The tissues from the perfused animals in the control and 1000 (males)/3000 (females) ppm groups were subjected to histopathological evaluation of brain, spinal cord, and peripheral nervous system tis sues. Additionally , required evaluations for a subchronic dietary toxicity study were fulfilled. Standard toxicity

observations (such as body weight) were recorded for all animals (n=15). Clinical diagnostics and standard histopathology were performed on 10 rats/sex/group.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 46 of 48 No adverse, treatment - related effect was observed on mortality , clinical signs, body weight, body weight gains, food consumption, food utilization, ophthalmoscopic examination, hematology , clinical chemistry , urinaly sis, or gross or microscopic pathology . No treatment - related effect was observed during the functional observational battery , motor activity , brain weight or neuropathology

assessments. There were no deaths or clinical signs of toxicity in either sex. Slight decreases i n terminal body weight s (Day

92) and body

weight gains (Day s 1 - 85) were observed in males at 300 ppm ( decr 4 - 5%) and 1000 ppm ( decr 6 - 7%), but the magnitude of the reduction s were not considered adverse. Female body weights were comparable among the groups. The liver appears to be the target organ, as evidenced by the dose - related increase in liver weight in both sexes. Adjusted (for terminal body weight) liver weights were increased (p<0.01) dose - dependently in all treated male groups b y 14 - 42% and in the 1000 and 3000 ppm females by 12 - 28%. Absolute and relative to body liver weights were also similarl y increased dose - dependently in both sexes. At 1000 ppm, enlarged livers were seen in 4 of 10 males, and minimal centrilobular hypertrophy was seen in 1 of 10 males. These responses were considered treatment - related, but adaptive in the absence of other pathological or clinical chemistry findings. **The systemic and neurotoxicity LOAELs were not observed .**  **The systemic and**  **neurotoxicity NOAEL**  **s are**  **10 00/3000**  **ppm (equivalent to 67.0/233.2**  **mg/kg/day in**  **M/F) .**  The study is classified as **a cceptable/guideline**  and satisfies the guideline requirement ( OPPTS 870.6200b ; OECD 424 ) for a subchronic neurotoxicity study in rats and the guideline requirement ( OPPTS 870. 3100; OECD 408 ) for a subchronic toxicity study in rats . Although a LOAEL was not determined, previous studies in rats with this test compound have demonstrated toxic effects at lower doses. Consequently , the dose selection was considered justified.Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 47 of 48 **Appendix B**  **. Physical/Chemical Properties** 
**T able B.1 P**  **hysicochem ical 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 mm Hg 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 available 1 The Pesticide Manual, A World Compendium, The British Crop Protection Council ( toxnet.nlm.nih.gov).Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 48 of 48 **Appendix C**  **. Review of Human Research**  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 data, which include studies from PHED 1.1; the AHETF database ; and the ARTF database , are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethi cs requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 4

.

4 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html