Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 1 of 35 UNITED STATES ENVIRONMENTA L PROTECTION A GENCY WA SHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION MEMORANDUM DATE: 1 9 - AP R - 20 11 SUBJECT : Saflufenacil . Human - Health Risk Assessment for Proposed Uses in/on

Vegetable, Legume, Subgroup 6C, pea and bean (except soy bean) ; Soy

bean ; Rapeseed Subgroup 20A ; Sunflower Subgroup 20B ; and Cottonseed Subgroup 20C . PC Code: 118203 DP Barcode s : D 380636 , D 38 1292 Decision No s .: 436793, 437943 Registration No . : 7969 - 278 Petition No s. : 0F7744 , 0F7766 Regulatory Action: Sec. 3 Registration Risk Assessment Type: Single Chemical/ Aggregate Case No.: NA T XR No.: NA CAS No.: 372137 - 35 - 4 MRID No.: NA 40 CFR: §180.649 FROM: George F. Kramer, Ph.D., Senior Chemist

Sarah J. L ev y, Chemist Chester E. Rodriguez, Ph.D. , Toxicologist Allison Nowotarski , Biologist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED, 7509P) THROUGH: Dana M. Vogel, Branch Chief

RAB 1/HED (7509P) TO: Kathry

n Montague/Susan Stanton, PM Team 23 Registration Division (RD; 7505P) The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary , occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed uses of saflufenacil in/on vegetable, legume, subgroup 6C, pea and bean (except soy bean) ; soy

bean ; rape seed subgroup 20A ; sunflower subgroup 20B ; and cottonseed subgroup 20C . The petitioner is BASF . This is a shared joint review with the Pest Management Regulatory Agency (PMRA) of Canada. The residue definition and recommended tolerances are harmonized with Canada. A summary

of the findings and an assessment of human - health risk resulting from the proposed uses of saflufenacil are provided in this document. The risk assessment and dietary exposureSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 2 of 35 assessment were provided by George Kramer (RAB1) , the h azard characterization by Chester Rodriguez (RAB1), the residue chemistry data review by

George Kramer and Sarah Lev y (RAB1), the occupational/residential exposure assessment by Allison Nowotarski (RAB1), and the drinking water assessment by Greg Orrick of the Environmental Fate and Effects Division (EFED).Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 3 of 35 Table of Contents 1.0 Executive Summary ................................ ................................ ................................ ............... 4 2.1 Summary of Registered/Proposed Uses ................................ ................................ ... 9 2.2 Structure and Nomenclature ................................ ................................ .................. 11 2.3 Physical and Chemical Properties ................................ ................................ .......... 11 3.0 Hazard Characterization/Assessment ................................ ................................ ................ 12 3.1 Mode of Action and Toxicological Studies Available for Evaluation ................. 12 3.2 Absorption, Distribution, Metabolism, and Elimination (ADME) ..................... 12 3.3 Hazard Profile ................................ ................................ ................................ .......... 13 3.4 FQPA Considerations ................................ ................................ .............................. 14 3.5 Toxicity Endpoint and Point of Departure Selection ................................ ............ 15 3.6 Endocrine Disruption ................................ ................................ .............................. 17 4.0 Public Health and Pesticide Epidemiology Data ................................ ............................... 18 5.0 Dietary Exposure/Risk Characterization ................................ ................................ .......... 18 5.1 Pesticide Metabolism and Environmental Degradation ................................ ....... 18 5.1.1 Metabolism in Primary Crops ................................ ................................ . 18 5.1.2 Metabolism in Rotational Crops ................................ .............................. 18 5.1.3 Metabolism in Livestock ................................ ................................ ........... 19 5.1.4 Analytical Methodology ................................ ................................ ............ 19 5.1.5 Environmental Degradation ................................ ................................ .... 19 5.1.6 Comparative Metabolic Profile ................................ ............................... 20 5.1.7 Toxicity Profile of Major Metabolites and Degradates ......................... 20 5.1.8 Pesticide Metabolites and Degradates of Concern ................................ . 20 5.1.9 Drinking Water Residue Profile ................................ .............................. 20 5.1.10 Food Residue Profile ................................ ................................ ............... 21 5.1.11 International Residue Limits ................................ ................................ . 21 5.2 Dietary Exposure and Risk ................................ ................................ ..................... 22 5.2.1 Acute Dietary Exposure/Risk ................................ ................................ ... 22 5.2.2 Chronic Dietary Exposure/Risk ................................ ............................... 22 5.2.3 Cancer Dietary Risk ................................ ................................ ................. 22 5.3 Anticipated Residue and %CT Information ................................ ......................... 23 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ . 23 6.1 Spray Drift ................................ ................................ ................................ ................ 23 6.2 Residential Bystander Post - application Inhalation Exposure ............................. 23 7.0 Aggregate Risk Assessments and Risk Characterization ................................ ................. 23 8.0 Cumulative Risk Characterization/Assessment ................................ ................................ 24 9.0 Occupational Exposure/Risk Pathway ................................ ................................ ............... 24 9.1 Short -/Intermediate - Term Occupational Handler Risk ................................ ....... 24 9.2 Short -/Intermediate - Term Postapplication Risk ................................ .................. 27 10.0 Data Needs and L abel Recommendations ................................ ................................ ....... 27 10.1 Toxicology ................................ ................................ ................................ ............... 27 10.2 Residue Chemistry ................................ ................................ ................................ . 28 10.3 Oc cupational and Residential Exposure ................................ .............................. 28 Appendix A: Toxicology Assessment ................................ ................................ ....................... 29 A.1 Toxicology Data Requirements for S aflufenacil ................................ .................. 29 A.2 Toxicity Profiles ................................ ................................ ................................ ....... 30 Appendix B: Tolerance Summary Table ................................ ................................ ................. 35Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 4 of 35 1.0 Executive Summary Saflufenacil is a pre - and post - emergence herbicide that acts b y inhibiting protoporphyrinogen IXoxidase, which leads to chlorophyll destruction by photooxidation and causes bleaching of emerging foliar tissue. Protoporphy rinogen IX oxidase is one of the key enzy mes in the porphy rin bios ynthesis for the production of chlorophyll in plants and heme in mammals. It catal yz es the last common step in the biosy nthesis of chloroph yl l and heme. When protoporphy

rinogen IX oxidase is inhibited in mammals, hemoglobin formation is reduced resulting in anemia. In addition, inhibition of the enzy me causes accumulation of different porphy rins and their precursors in various or gans. Saflufenacil is currentl y registered for use on legume vegetables ( Crop Group 06), the foliage of legume vegetables ( Crop Group 07), cereal grains ( Crop Group 15), forage, fodder , and straw of cereal grains ( Crop Group 16), cotton , and sunflower . BASF has submitted a proposal to amend the established tolerances for saflufenacil on cotton, dry bean, dry pea, and soy

bean (PP# 0F7744 ) . The amended tolerances on these crops are the result of the proposed harvest aid/desiccation use pattern for Sharp enTM Powered by Kixor Herbicide (EPA Reg. No. 7969 - 278); the currently- registered uses are for preplant application . In addition, BASF has submitted a proposal for a new use of SharpenTM on Oilseeds, Rapeseed Subgroup 20A as harvest aid/desiccant (PP#0F7744 ). Toxicity/Hazard: Saflufenacil was well absorbed and rapidl y excreted via the oral route in rat metabolism studies. Maximum blood concentrations were reached within one hour and declined rapidly thereafter. Elimination was primaril y urinary in female rats and via the feces in male rats. The sex - dependent excretion resulted in male rats having up to 3 - fold higher internal levels and being in some cases more sensitive to toxicity than females. Saflufenacil exhibited low acute toxicity via the oral, dermal and inhalation routes of exposure (Category III or IV). It was slightl y irritating to the eye (Category III), but neither a dermal irritant nor sensitizer. Subchronic and chronic toxicity studies in rats, m ice and dogs identified the hematopoietic sy stem as the primary

target of saflufenacil. Consistent with its proposed mode of action involving protoporph yrinogen oxidase inhibition and subsequent disruption of heme biosy nthesis, decreased hematological par ameters [ red blood cells (RBC), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) ] were seen at about the same dose level [ lowest - observed adverse - effect level s (LOAEL s ) of 13 - 39 mg/kg/day] across species, except in the case of the dog, where the effects were seen at a slightly higher dose (LOAELs of 50 - 100 mg/kg/day). These effects occurred around the same dose level from short - through long - term exposures without incre asing in severity . Effects were also seen in the liver (increased weight, centrilobular fatty

change, ly

mphoid infiltrate) in mice, the spleen (increased spleen weight and extramedullary

hematopoiesis) in rats, and in both these organs (increased iron sto rage in the liver and extramedullary

hematopoiesis in the spleen) in dogs. These effects also occurred around the same dose level from short - through long - term exposures without increasing in severity.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 5 of 35 In creased fetal susceptibility was observed in the developmental toxicity studies in the rat and rabbit and in the 2 - generation reproduction study in the rat. Developmental effects such as decreased fetal body weights and increased skeletal variations occurred at doses (20 mg/kg/day) that were not matern all y toxic in the developmental study in rats, indicating increased quantitative susceptibility. In rabbits, developmental effects such as increased liver porphyrins were observed at doses (200 mg/kg/d) that were not maternally toxic, indicating increased quantitative susceptibility. In the 2 - generation reproductive toxicity study in rats, the reported offspring effects were more severe than the maternal effects at the same dose level, indicating evidence for increased qualitative susceptibility . For ins tance, an increased number of stillborn pups, decreased viability

and lactation indices, decreased pre - weaning body weight and/or bodyweight gain, and changes in hematological parameters occurred at the same dose level as maternal decrements in food intake, body weight, body- weight gain, and changes in hematological parameters and organ weights indicative of anemia. Saflufenacil was weakly

clastogenic in the in vitro chromosomal aberration assay in V79 cells in the presence of S9 activation; however, the response was not evident in the absence of S9 activation. It was neither mutagenic in bacterial cells nor clastogenic in rodents in vivo. Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumors at the tested doses. Saflufenacil is classified as “not likely carcinogenic to humans.” Saflufenacil was negative in neurotoxicity testing (acute and subchronic studies), a 28 - day dermal toxicity

study , and failed to induce toxicity specific to the immune sy stem in a recentl y submitted immunotoxicity study. Dose - Response and Food Quality Protection Act (FQPA) Assessments: The saflufenacil risk assessment team recommends that the 10X FQPA S afety F actor (SF) for the protection of infants and children be reduced to 1X for the f ollowing reasons:  The concern for increased susceptibility following prenatal or postnatal exposure is low since (1) clear no - observed adverse - effect level s (NOAEL s ) / LOAE L s were established for the developmental effects seen in rats and rabbits as well as for the offspring effects seen in the tw o - generation reproductive toxicity study ; (2) the dose - response relationship for the effects of concern are also well - characterized and being used for assessing dermal and inhalation risks; and (3) the dose being us ed for the overall risk assessments would be protective of the developmental and offspring effects.  An immunotoxicity

study as part of the revised 40 CFR Part 158 toxicology data requirements has been submitted and reviewed b y the Agency . The results of the study indicate that saflufenacil does not directl y target the immune system at the dose levels being used for risk assessment.  There was no evidence of neurotoxicity or neuropathology

in the acute and subchronic neurotoxicity

study . In the acute neurotoxicity study , a decrease in motor activity was observed on the first day

of dosing at the limit dose (2000 mg/kg/d ay) in males only . The finding was not accompanied by any other neuropathological changes and was considered a reflection of a mild an d transient general s ys temic toxicity and not a substance - specific neurotoxic effect. Additionally, it was not corroborated in the subchronic neurotoxicity

study . There is also no other indication of neurotoxici ty in an y study in the database . In the subchronic neurotoxicity study , s ys temic toxicity

was seenSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 6 of 35 at 1000 (66.2 mg/kg/day) and 1350 (101 mg/kg/day) ppm in males and females, respectivel y.  There are also no additional residual uncertainties with respect to exposure data. The dietary food exposure assessment utilizes recommended tolerance - level residues and assumed 100% crop treated (CT) for all commodities. By using these screening - level assessments, acute and chronic exposures/risks will not be underestimated. The dietary drinking water assessm ent utilizes values generated by model and associated modeling parameters that are designed to provide conservative, health - protective, high - end estimates of water concentrations. There is no potential for residential exposure. A 100 - fold uncertainty

f actor (UF) (10 X for interspecies extrapolation and 10 X for intraspecies variation) was incorporated into the acute reference dose (aRfD, 5.0 mg/kg) and chronic RfD (cRfD, 0.046 mg/kg/day) . The acute population - adjusted dose (aPAD) and the chronic PAD (cPAD) are equal to the acute and chronic RfDs, respectivel y, divided b y the FQPA SF (1X). Saflufenacil is classified as “ not likely carcinogenic to humans ” by all relevant routes of exposure based on adequate studies in two animal species; therefore, cancer risk assessments are not required. In estimating margins of exposure (MOEs), the level of concern (LOC) is for MOEs < 100 for the dermal and inhalation risk assessments. A 3 % dermal - absorption factor and a 100% inhalation - absorption factor were used in the route - to - route extrapolation. The toxicological doses relevant to this human - health risk assessment are summarized below. acute dietary (general population, including infants and children) NOAEL = 500 mg/kg/day acute RfD and aPAD = 5.0 mg/kg/day chronic dietary NOAEL = 4.6 mg/kg/day chronic RfD and cPAD = 0. 0 4 6 mg/kg/day short - , intermediate - , and long - term dermal and inhalation oral NOAEL = 5.0 mg/kg/day LOC for MOEs <100 (occupational) Dietary Risk Estimates (Food + Drinking Water): Acute and chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database (DEEM - FCID TM , Version 2.03), which uses food consumption data from the U.S. Department of Agriculture's (USDA’s) Continuing Survey s of Food Intakes by Individuals (CSFII) from 1994 - 1996 and 1998. The acute and chronic analy se s assumed 100% CT, DEEM TM 7.81 default processing factors, and to lerance - level or higher residues for all foods. Drinking water was incorporated directly into the dietary

assessment using the concentration for ground water generated by the Tier II Pesticide Root Zone Model Ground Water (PRZM GW ) . The resulting acute dietary (food + drinking water) risk estimates using the DEEM - FCID TM model at the 95 th percentile [ <1% aPAD for all infants (<1 ye ar old), the most highly exposed population subgroup ] , are not of concern (<100% aPAD). The chronic diet ary risk assessment shows that the chronic dietary risk estimates are not of concern (i.e., <100% cPAD). For the U.S. population , the exposure for food and water utilized 9.2 % of the cPAD. The chronic dietary risk estimate for the highest exposed populat ion subgroup , all infants (<1 year old) , is 30 % of the cPAD. Residential Exposure : There are no residential uses proposed or currently registered for saflufenacil . Therefore, a residential risk assessment was not conducted. Aggregate Risk: There are no uses of saflufenacil that are expected to result in residential exposures. Therefore, the aggregate exposure assessment takes into consideration dietary food +Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 7 of 35 drinking water exposure only . The acute and chronic dietary estimates represent acute and chronic aggregate risk , respectively . Occupational Exposure/Risk : There is potential for occupational handler and postapplication short - and intermediate - term exposure resulting from the proposed uses of saflufenacil. Potential occupational h andler exposure scenarios include mixing/loading liquids for aerial and ground applications, applications via aerial and ground equipment, and flagging. There is no expectation of occupational post - application exposure associated with the proposed uses. No chemical - specific handler exposure data were submitted in support of this Section 3 registration. It is the policy of HED to use data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in PHED Surrogate Exposure Guide (8/98) to assess handler exposures for regulatory

actions when chemical - specific monitoring data are not available (HED Science Advisory

Council for Exposure (ExpoSAC) Draft Standard Operating Procedure (SOP) # 7, dated 1/28/99). In addition, no chemical - specifi c post - application data were submitted; therefore, exposures during post - application activities were estimated using default assumptions and dermal transfer coefficients from HED’s ExpoSAC Policy Number 3.1 “Agricultural Transfer Coefficients” (August 2000 ). All risks for occupational handlers are above the target MOE of 100 with the use of gloves, and do not exceed the LOC as the proposed labels already require the use of protective gloves as personal protective equipment. Saflufenacil is classified as T oxicity C ategory III for acute oral toxicity , acute dermal toxicity , and acute eye irritation. It is classified as toxicity C ategory IV for acute inhalation toxicity and acute dermal irritation. It is not a dermal sensitizer. The restricted - entry interval (REI) of 12 hours appearing on the SharpenTM label complies with the Worker Protection Standard (WPS) . Environmental Justice Considerations: 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.hss.energy .gov/nuclearsafety/ env/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 patter ns 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 USDA under CSFII and are used in pesticide risk as sessments 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 . Additionally , OPP is able to assess dietary exposure to smaller, specia lized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and a dults entering or playingon treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to theSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 8 of 35 development of specialized software and models that consider exposure to by st anders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. Review of Human Research: This assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED and the Agricultural Reentry Task Force (ARTF) Database . EPA has reviewed al l the studies in these multi - pesticide generic exposure databases and , based on available evidence , has found them to be neither fundamentall y unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied. Recommendation for Tolerances and Regi stration: Pending submission of a revised Section F (see requirements under Proposed Tolerances), and the submission of reference standards for the saflufenacil metabolites (see requirements under Submittal of Analy

tical Reference Standards) , there are no residue chemistry , occupational exposure , or toxicology

issues that would preclude granting an un conditional registration for the requested use s of s aflufenacil on the requested crops. The proposed uses and the submitted data support: “Tolerances are established for residues of saflufenacil, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of saflufenacil (2 - chloro - 5 - [3,6 - dihydro - 3 - methyl - 2,6 - dioxo - 4 - (trifluorometh yl ) - 1(2H ) - py rimidinyl] - 4 - fluoro -N

- [[methyl(1 - methylethyl)amino]sulfonyl]benzamide) and its metabolites N

- [2 - chloro - 5 - (2,6 - dioxo - 4 - (trifluoromethyl) - 3,6 - dihydro - 1(2H ) - py rimidinyl) - 4 - fluorobenzoyl] -N

' - isopropylsulfamide and N - [4 - chloro - 2 - fluoro - 5 - ({[(isopropylamino)sulfonyl]amino}carbon yl )phenyl]urea, calculated as the stoichiometric equivalent of saflufenacil, in or on the commodities.” Cotton, gin byproducts 0.45 ppm Cottonseed Subgroup 20C 0.20 ppm Sunflower Subgroup 20B 1.0 ppm Pea, hay 17 ppm Grain, aspirated fractions 10 ppm Soy bean, hulls 0.50 ppm Soy bean, seed 0.10 ppm Pea and bean, dried shelled, except soybean, subgroup 6C 0.30 ppm Rapeseed Subgroup 20A 0.45 ppm Note to RD: In conjunction with establishing these tolerances, the existing tolerance for “ Vegetable, foliage of legume, group 7 ” should be modified to “Vegetable, foliage of legume, group 7 (except pea hay)” ; the existing tolerance for “ Vegetable, legume, group 6 ” should be replaced with " Vegetable, legume, edible podded, subgroup 6A " plus " Pea and bean, succulent shelled, subgroup 6B " ; and the existing tolerance s for “ Sunflower, seed ” and " Cotton, undelinted seed " should be deleted.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 9 of 35 The proposed uses and the submitted data also support: “Tolerances are established for residues of saflufenacil, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by meas uring only saflufenacil, 2 - chloro - 5 - [3,6 - dihydro - 3 - methyl - 2,6 - dioxo - 4 - (trifluoromethyl) - 1(2H ) - py rimidinyl] - 4 - fluoro -N

- [[methyl(1 - methylethyl)amino]sulfonyl]benzamide, in or on the commodities.”

Cattle, liver 2.5 Cattle, meat byproducts, except liver 0.05 Goat, liver 2.5 Goat, meat byproducts, except liver 0.05 Sheep, liver 2.5 Sheep, meat byproducts, except liver 0.05 Horse, liver 2.5 Horse, meat byproducts, except liver 0.05 Data Gaps See Section 10.0 for data needs and label recommendations . 2.0 Ingredient Profile 2.1 Summary of Registered/Proposed Uses Saflufenacil is currentl y registered for use on legume vegetables ( Crop Group 06), the foliage of legume vegetables ( Crop Group 07), cereal grains ( Crop Group 15), forage, fodder , and straw of cereal grains ( Crop Group 16), cotton , and sunflower . BASF has submitted a proposal to amend the established tolerances for saflufenacil on cotton, dry bean, dry pea, and soy

bean (PP# 0F7744 ) . The amended tolerances on these crops are the re sult of the proposed harvest aid/desiccation use pattern for SharpenTM Powered by Kixor Herbicide (EPA Reg. No. 7969 - 278); the currently

registered uses are for preplant application . In addition, BASF has submitted a proposal for a new use of SharpenTM on Oilseeds, Rapeseed Subgroup 20A as harvest aid/desiccant (PP#0F7744). BASF has submitted draft labels dated 6 /24 / 1 0 for the 2.85 lb ai/gal SC formulation [ SharpenTM Powered b y Kixor Herbicide (EPA Reg. No. 7969 - 278) ] . Information pertaining to the propose d end - use product is listed in Table 3. A summary of the proposed use patterns on legume vegetables and oilseeds is detailed in Table 2.1.2. Table 2.1.1. Summary of Proposed End - Use Product s . Trade Name Reg.

No. ai (% of formulation) Form

ulation Ty pe Target Crops Target Pests Label Date SharpenTM Powered by Kixor Herbicide 7969 -

278 29.74 SC legume vegetables, oilseeds Broadleaf

weeds Draft label s

submitted 6/24/10Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 10 of 35 Table 2.1. 2 . Summary of Directions for Use of Saflufenacil . Applic. Timing, Ty pe, and Equip. Form

ulation [EPA Reg. No.] App. Rate

(lb ai/ acre ) Max. No.

App. per Season Max. Seasonal

App. Rate (lb ai/ acre ) PHI

(days) Use Directions and

Limitations Oilseeds, Rapeseed Subgroup 20A Preharvest Desiccation Broadcast, Ground or aerial SharpenTM

Herbicide 2 . 85 lb/gal S C [ 7969 - 278 ] 0.0225 -

0.045 2 0. 045 3 Applications are to be made in ≥ 10 gal/ acre ( ground) or ≥ 3 gal/ acre ( aerial ) . Oilseeds, Sunflower Subgroup 20B Preharvest Desiccation Broadcast, Ground or aerial SharpenTM

Herbicide 2 . 85 lb/gal S C [ 7969 - 278 ] 0.0225 -

0.045 2 0. 090 7 Applications are to be made in ≥ 10 gal/ acre ( ground) or ≥ 3 gal/ acre ( aerial ) . Oilseeds, Cottonseed Subgroup 20C Preharvest Desiccation Broadcast, Ground or aerial SharpenTM

Herbicide 2 . 85 lb/gal S C [ 7969 - 278 ] 0.0112 -

0.045 2 0. 045 5 Applications are to be made in ≥ 10 gal/ acre ( ground) or ≥ 5 gal/ acre ( aerial ) . Dry Edible Beans Preharvest Desiccation Broadcast, Ground or aerial SharpenTM

Herbicide 2 . 85 lb/gal S C [ 7969 - 278 ] 0.0225 -

0.045 2 0. 045 2 Applications are to be made in ≥ 10 gal/ acre ( ground) or ≥ 3 gal/ acre ( aerial ) . Do not graze or feed treated hay or straw to livestock. Dry P ea s Preharvest Desiccation Broadcast, Ground or aerial SharpenTM

Herbicide 2 . 85 lb/gal S C [ 7969 - 278 ] 0.0225 -

0.045 2 0. 045 3 Applications are to be made in ≥ 10 gal/ acre ( ground) or ≥ 3 gal/ acre ( aerial ) . Desiccation treated pea vines may be grazed or fed to livestock Soy b eans Preharvest Desiccation Broadcast, Ground or aerial SharpenTM

Herbicide 2 . 85 lb/gal S C [ 7969 - 278 ] 0.0225 -

0.045 2 0. 045 3 Applications are to be made in ≥ 10 gal/ acre ( ground) or ≥ 3 gal/ acre ( aerial ) . Do not graze or feed treated hay or straw to livestock. Note: Thorough spray coverage and a methylated seed oil (MSO) plus ammonium - based adjuvant system is required for optimum desiccation activity. Conclusions : The submitted use directions for SharpenTM Herbicide are adequate to allow evaluation of the residue data relative to the proposed use s .Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 11 of 35 2.2 Structure and Nomenclature T able 2.2. Saflufenacil and Metabolite s Nom enclature. Chemical Structure

Common name Saflufenacil Company experimental name BAS 800 H (synonyms : AC 433 379, BASF Reg. No. 4054449) IUPAC name N ' - [2 - C hloro - 4 - fluoro - 5 - (3 - methyl - 2,6 - dioxo - 4 - (trifluoromethyl) - 3,6 - dihydro - 1(2H ) - pyrimidinyl)benzoyl] -N

- isopropyl -N

- methylsulfamide CAS name 2 - C hloro - 5 - [3,6 - dihydro - 3 - methyl - 2,6 - dioxo - 4 - (trifluoromethyl) - 1(2H ) - pyrimidinyl] - 4 - fluoro -N - [[methyl(1 - methylethyl)amino]sulfonyl]benzamide CAS registry number 372137 - 35 - 4 End - use product (EP) Sharpen TM Powered by Kixor Herbicide (EPA Reg. No. 7969 - 278 ) ( 2.85 lb ai/gal SC formulation) Chemical Structure

Common name M800H11 Chemical name N - [2 - C hloro - 5 - (2,6 - dioxo - 4 - (trifluoromethyl) - 3,6 - dihydro - 1(2H ) -pyrimidinyl) - 4 - fluorobenzoyl] -N

' - isopropylsulfamide Chemical Structure

Common name M800H35 Chemical name N - [4 - C hloro - 2 - fluor o - 5 - ({[(isopropylamino)sulfonyl]amino}carbonyl)phenyl]urea 2.3 Physical and Chemical Properties T able 2.3. Physicochemical Properties of Technical Grade Saflufenacil. Parameter Value Melting point Average = 189.9 ° C, peak max = 193.4 ° C pH 4.43 of 1% solution at 25 ° C Bulk Density (ambient temp.) 0.661 kg/L (free fall), 0.736 kg/L (packed) Water solubility (20°C) in g/100 - mL: 0.0025 in water (pH = 5) ; 0.0014 in pH 4 buffer ; 0.21 in pH 7 buffer ; not determined due to degradation in pH 9 buffer Solvent solubility (20°C) in g/100 - mL: 19.4 acetonitrile ; 24.4 dichloromethane ; 55.4 N,N - dimethylformamide ; 27.5 acetone ; 6.55 ethyl acetate ; 36.2 tetrahydrofuran ; 35.0 butyr olactone ; 2.98 methanol ; 0.25 isopropyl alcohol ; 0.23 toluene ; <0.01 1 - octano l; <0.005 n - heptane Vapor pressure at 20/25°C 20 °C = 4.5 x 10 - 15 Pa 25°C = 2.0 x 10 - 15 Pa Cl F N N O

O C H 3 F F F O N H S N O O C H3 C H3 C H

3

Cl F N N H O

O F F F O N H S N H O O C H3 C H3

Cl F N H O

O N H S N H O O C H3 C H3 N H 2Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 12 of 35 T able 2.3. Physicochemical Properties of Technical Grade Saflufenacil. Parameter Value Dissociation constant (pKa) 4.41 Octanol/water partition coefficient Mean Log P ow = 2.6 (P ow = 368.3) UV/visible absorption spectrum wavelength maximum: λma x = 271.6 nm extinction coefficient: ε = 9709 L/mol - cm 3.0 Hazard Characterization/Assessment 3.1 Mode of A ction and T oxicological S tudies Available for Evaluation Saflufenacil is a pre - and post - emergence herbicide that acts b y inhibiting proto porphy rinogen IXoxidase which leads to chloroph yl l destruction by photooxidation and causes bleaching of emerging foliar tissue. Protoporphy rinogen IX oxidase is one of the key enzy mes in the porphy rin bios ynthesis for the production of chlorophyll in plants and heme in mammals . It catal yz es the last common step in the biosy nthesis of chlorophyll and heme. When protoporphy

rinogen IX oxidase is inhibited in mammals, hemoglobin biosy nthesis is reduced , resulting in anemia and accumulation of different porphy rins and their precur sors in various organs. Saflufenacil has been evaluated extensively for its toxicity

and mode of action. It s toxicity database is adequate to support registration. In the last risk assessment (Austin , et al. , 7/22/09; D 367317 ), the onl y database defic iency noted was the lack of a guideline immunotoxicity study as part of the new toxicity data requirements in the 40 CFR Part 158 for conventional pesticide registration . Since then, an immunotoxicity study has been submitted and reviewed by the Agency . The evaluation of the immunotoxicity study is included in this hazard assessment. For additional information, see Austin , et al. ( 7/22/09; D 367317 ). 3.2 Absorption, Distribution, Metabolism, and Elimination (ADME) In rat metabolism/pharmacokinetic studies via the oral route, saflufenacil was well absorbed and rapidly excreted. Regardless of the dose administered, maximum blood concentration s were reached within 1 h our of dosing and declined rapidly . Excretion of saflufenacil was essentially comple te within 96 h ours , with the majority eliminated within the first 24 to 48 h ours . The blood and plasma data demonstrated that the majority of the saflufenacil residues occurred in the plasma and w ere not bound to cellular eleme nts of the blood. Following single or repeated low and high - dose administration, the main route of elimination in male rats was via the feces, whereas urinary

excretion was the major route of elimination in females. The sex - dependent excretion was more pronounced at the low - dose l evel and resulted in m ales having up to three fold higher internal exposures than females and being in some cases more sensitive to toxicity than females . There was significantl y higher biliary excretion of saflufenacil residues in males than in females. In creasing the dose b y a factor of 25 resulted in an increase of the AUC - values by a factor of 6.1 in males and 12.4 in females. Saflufenacil residues remained very low in tissues at 168 h ours after dosing, occurring mainl y in carcass, liver, skin , and gut contents. Exhalation was n ot a relevant excretion pathway .Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 13 of 35 3.3 Hazard Profile Saflufenacil exhibited low acute toxicity via the oral, dermal, and inhalation routes of exposure (Category III or IV). It was slightl y irritating to the eye (Category III ) , but not a dermal irritant nor a sensitizer. Subchronic and chronic toxicity studies in rats, mice and dogs identified the hematopoietic sy stem as the primary

target of saflufenacil. Consistent with its proposed mode of action involving protoporph yrino gen oxidase inhibition and subsequent disruption of heme biosy nthesis, decreased hematological parameters [RBC, Ht, MCV, MCH, MCHC] were seen at about the same dose level (L OAELs of 13 - 39 mg/kg/day) across species, except in the case of the dog, where the effects were seen at a slightl y higher dose (LOAELs of 50 - 100 mg/kg/day). These effects occurred around the same dose level from short - through long - term exposures without increasing in severity . Effects were also seen in the liver (increased weight, centrilobular fatty

change, ly

mphoid infiltrate) in mice, the spleen (increased spleen weight and extramedullary

hematopoiesis) in rats, and in both these organs (increased iron storage in the liver and extramedullary

hematopoiesis in the spleen) in dogs. Th ese effects also occurred around the same dose level from short - through long - term exposures without increasing in severity. In an acute neurotoxicity

study , a decrease in motor activity was observed on the day of dosing at the limit dose (2000 mg/kg/day) in males only. The finding was not accompanied by any neuropathological changes and was considered a reflection of a mild and transient general sy stemic toxicity

and not a substance - specific neurotoxic effect. In the subchronic neurotoxicity study , s y stemic toxicity

(anemia) was seen at 1000 (66.2 mg/kg/day) and 1350 (101 mg/kg/day) ppm in males and females, respectivel y. There was no evidence of neurotoxicity or neuropathology

in either the acute or subchronic neurotoxicity study . In creased fetal su sceptibility was observed in the developmental toxicity studies in the rat and rabbit and in the 2 - generation reproduction study in the rat. Developmental effects such as decreased fetal body weights and increased skeletal variations occurred at doses (20 mg/kg/day) that were not maternall y toxic in the developmental study in rats, indicating increased quantitative susceptibility. In rabbits, developmental effects such as increased liver porphyrins were observed at doses (200 mg/kg/d) that were not matern ally toxic, indicating increased quantitative susceptibility. In the 2 - generation reproductive toxicity study in rats, the reported offspring effects were more severe than the maternal effects at the same dose level, indicating evidence for increased qual itative susceptibility . For instance, an increased number of stillborn pups, decreased viability

and lactation indices, decreased pre - weaning body weight and/or bodyweight gain, and changes in hematological parameters occurred at the same dose level as m aternal decrements in food intake, body weight, body- weight gain, and changes in hematological parameters and organ weights indicative of anemia. In a 28 - day

dermal toxicity

study in rats, saflufenacil did not induce any ty pe of dermal or sy stemic toxici ty

up to the limit dose of 1000 mg/kg bw/day .Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 14 of 35 In a recentl y submitted 28 - day i mmunotoxicity

study , saflufenacil failed to induce toxicity specific to the immune sy stem at the highest dose tested (i.e., 52 mg/kg bw/day). Saflufenacil was weakly

clastogenic in the in vitro chromosomal aberration assay in V79 cells in the presence of S9 activation; however, the response was not evident in the absence of S9 activation. It was neither mutagenic in bacterial cells nor clastogenic in rodents in vivo . Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumor s at the tested doses. Saflufenacil is classified as “not likely carcinogenic to humans. ” 3.4 FQ PA Considerations The toxicology

database for saflufenacil is complete and adequate for FQPA consideration . The following acceptable studies are available:

 Developmental toxicity study in rats and rabbits (2) ;  Two - generation reproduction study in rats (1) ;  Acute and s ubchronic n eurotoxicity s tudies ( 2) ; and  Immunotoxicity

study (1). The saflufenacil risk assessment team recommends that the FQPA SF be reduced to 1X for the following reasons:  The concern for increased susceptibility following prenatal or postnatal exposure is low since (1) clear NOAELs /L OAELs were established for the developmental effects seen in rats and rabbits as well as for the offspring effects seen in the tw o - generation reproductive toxicity study ; (2) the dose - response relationship for the effects of concern are also well - charact erized and being used for assessing dermal and inhalation risks; and (3) the dose being used for the overall risk assessments would be protective of the developmental and offspring effects.  An immunotoxicity

study as part of the revised 40 CFR Part 158 t oxicology data requirements has been submitted and reviewed b y the Agency . The results of the study indicate that saflufenacil does not directl y target the immune system at the dose levels being used for risk assessment.  There was no evidence of neurotoxi city or neuropathology

in the acute and subchronic neurotoxicity

study . In the acute neurotoxicity study , a decrease in motor activity was observed on the first day

of dosing at the limit dose (2000 mg/kg/d ay) in males only . The finding was not accompanied by any other neuropathological changes and was considered a reflection of a mild and transient general s ys temic toxicity and not a substance - specific neurotoxic effect. Additionally, it was not corroborated in the subchronic neurotoxicity

study . There is also no other indication of neurotoxici ty in an y study in the database . In the subchronic neurotoxicity study , s ys temic toxicity

was seen at 1000 (66.2 mg/kg/day) and 1350 (101 mg/kg/day) ppm in males and females, respectivel y.  There are also no additional residual uncertainties with respect to exposure data. The dietary food exposure assessment utilizes recommended tolerance - level residues and 100% CT information for all commodities. By using these screening - level assessments, acute and chronic exposures/risks will not be underestimated. The dietary drinking water assessment utilizes values generated b y model and associated modeling parameters whichSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 15 of 35 are designed to provide conservative, health - protective, high - end estimates of water concentrations. Additionally , there is no potential for residential exposure. 3.5 Toxicity Endpoint and Point of Departure Selection Acute Dietary Endpoint (General population including infants and children) : An acute dietary endpoint was established for this population group based on decreased motor activity observed at the L OAEL of 2000 mg/kg bw in male rats in the acute neurotoxicity study. The NOAEL was 500 mg/kg bw. A combined UF of 100 was applied to account for interspecies (10X) and intraspe cies (10X) extrapolation. Thus, the aPAD is estimated as the NOAELof 500 mg/kg bw divided by

100 or 5.0 mg/kg bw. Acute Dietary Endpoint (Females 13 - 49 years old) : An acute dietary endpoint was considered but not established for this subpopulation group because developmental effects resulting from a single dose of saflufenacil could not be identified in the database. The skeletal variations (e.g., misshapen bones, delay s in ossification, and wav y ribs) observed in the prenat al d evelopmental study in the rat are not considered to be the result of a single dose. The process of bone deposition begins with cartilage deposition followed by calcification and does not occur during a single day . Unlike supernumerary ribs or missing bones, which may be caused by

the activation or inactivation of genes and could be the outcome of a single exposure, the process of bone depositi on occurs over several day s and , therefore, is not considered appropriate for establishing an aRfD for females of 13 - 49 years old . Chronic Dietary Endpoint: This endpoint was based on decreases in red blood cells, hemoglobin, and hematocrit as well as porph yri a observed in males in the satellite group (sacrificed at 10 months) at the LOAEL of 13.8 mg/kg bw/day in a mouse chronic/carcinogenicity s tudy . The NOAEL is 4.6 mg/kg bw/day . This study provides the lowest NOAEL in the toxicity database for saflufenacil. A combined UF of 100 was applied to account for interspecies (10X) and intraspecies (10X) extrapolation. Thus, the cPAD is estimated as 4.6 divided by 100 or 0.046 mg/kg bw/day (Table 3.5a). Incidental Oral (Short- and Intermediate - Term): Selection of this endpoint is not warranted since residential uses of saflufenacil are not expected. Dermal (Short- and Intermediate - Term): Although a 28 - day dermal toxicity

study with non pregnant adult rats yielded no evidence of toxicity (dermal or s ys temic), there is concern for developmental toxicity

following exposure to saflufenacil. Decreased fetal wei ghts and increased skeletal variations were observed in the rat oral prenatal developmental toxicity study at the LOAEL of 20 mg/kg/day (NOAEL was 5 mg/kg/day). The concern for developmental toxicity is also supported by

findings at higher doses from the rabbit developmental toxicity study and the rat 2 - generation reproductive toxicity study. In the previous risk assessment (Austin , et al. , 7/22/09; D 367317 ), a dermal - absorption factor of 3% was used based on a dermal - penetration study. Thus, the equival ent dermal NOAEL based on the rat prenatal developmental toxicity

study can be estimated as 5 mg/kg/day / 0.03 or 166.7 mg/kg/day . The LOC is for a MOE <100, based on a combined UF of 100 to account for interspecies (10X) and intraspecies (10X) extrapolati on.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 16 of 35 Inhalation (Short- and Intermediate - Term): Besides the required acute inhalation toxicity study that resulted in only

minimal toxicity

(Category

I V), no other inhalation toxicity studies are available for saflufenacil. Based on the available toxicity database and the Agency's current practices, the inhalation risk for saflufenacil is being assessed using the rat oral prenatal developmental toxicity

study with a 100% absorption assumption . The Agency sought expert advice and input on issues re lated to this route - to - route extrapolation approach (i.e. , the use of oral toxicity

studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency r eceived the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, re - examine and develop new policies and procedures for co nducting inhalation risk assessments, including route - to - route extrapolation of toxicity

data. If any

new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for saflufenacil and/or a re - examination of th e inhalation toxicity

risk assessment. Table 3.5a . Summary of Toxicological Doses and Endpoints for Saflufenacil for Use in Dietary Hum an - Health Risk Assessments. Exposure Scenario Point of

Departure Uncertainty/

FQPA SF s RfD and PAD Study and Toxicological Effects Ac ute Dietary (General Population, including Infants and Children) NOAEL = 500

mg/kg bw UF A = 10X

UF H = 10X FQPA SF = 1X a RfD = 5.0

mg/kg aPAD = 5.0 mg/kg Ac ute Neurotoxicity Study .

NOAEL = 500 (M) and 2000 (F) mg/kg bw . LOAEL was 2000 mg/kg bw (males) based on the decreased motor activity representing mild and transient systemic toxicity. LOAEL was not established for females. Chronic Dietary (All Populations) NOAEL = 4.6

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X c RfD = 0.046

mg/kg/day cPAD = 0.046 mg/kg/day Chronic/Carcinogenicity (mouse) .

NOAEL = 4.6 mg/kg bw/d ay . LOAEL = 13.8 mg/kg bw/d based on decreased red blood cells, hemoglobin, and Ht and porphyria observed in the satellite group. Cancer (oral, dermal, inhalation) Classification: N ot likely carcinogenic to humans based on the lack of tumors in the mouse and rat

carcinogenicity studies and lack of mutagenicity. Point of Departure (POD) = A data point or an estimated point that is derived from observed d ose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no - observed adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population - adjusted dose (a = acute, c = chronic). RfD = reference dose.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 17 of 35 Table 3.5b. Summary of Toxicological Doses and Endpoints for Saflufenacil for Occupational Hum an - Health Risk Assessment. Exposure/ Scenario Point of

Departure UFs LOC for Risk Assessment Study and Toxicological Effects Dermal Short and Intermediate Term (1 - 30 days and 1 - 6 mo nths, respectively) NOAEL=5

mg/kg/day Dermal absorption factor = 3% UF A = 10X

UF H = 10X FQPA SF = 1X Occupational LOC

for MOE = 100 Developmental study

– Rat .

NOAEL = 5 mg/kg bw

/day. LOAEL = 20 mg/kg bw/day based on decreased fetal bodyweight and increased skeletal variations. Inhalation Short - and Intermediate Term (1 - 30 days and 1 - 6 mo nths, respectively) NOAEL=5

mg/kg/day Inhalation absorption rate = 100% UF A = 10X

UF H = 10X FQPA SF = 1X Occupational LOC

for MOE = 100 Developmental study

– Rat .

NOAEL = 5 mg/kg bw

/day. LOAEL = 20 mg/kg bw/day based on decreased fetal bodyweight and increased skeletal variations. Cancer (oral, dermal, inhalation) Classification: Not likely carcinogenic to humans based on the lack of tumors in the mouse and rat

carcinogenicity studies and lack of mutagenicity.

No long - term

uses are expected for saflufenacil . 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 - obs erved adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). A dermal - absorption factor of 3% wa s estimated from a dermal - penetration study (See last risk as sessment ( Austin, et al. , 7/22/09; D367317 )) UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of concern. 3.6 Endocrine Disruption As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife simil ar to an effect produced b y a “naturally

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations . Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or th yroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the p otential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify an y adverse endo crine related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 chemicals, which c ontains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application agricultural scenari os. This list should not be construed as a list of known or likely endocrine disruptors.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 18 of 35 Saflufenacil is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must sc reen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call - ins for all pesticide active ingredients . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. 4.0 Public Health and Pesticide Epidemiology Data No public health/epidemiology data were used in developing this risk assessment. Since saflufenacil is a new chemical, data are not available. 5.0 Dietary Exposure/Risk Characterization The following references apply to this section: Residue Chemistry

Summary - D 381129 , G. Kramer, 24 - MAR - 2011 Dietary Exposure - D 381976 , G. Kramer, 24 - MAR - 2011 Drinking Water Degradates Identification - D 356619 , G . Orrick , 01 - DEC - 2008 Estimated Drinking Water Concentrations - D 349860 , G . Orrick , 1 5 - APR - 200 9 5.1 Pesticide Metabolism and Environmental Degradation 5.1.1 Metabolism in Primary Crops The previousl y submitted metabolism data for corn, soy bean, and tomato were adequate to elucidate the nature of the residue in plants resulting from preplant/preemergence application. The main reactions involve d in the metabolic pathway of saflufenacil we re N

- demethylation at the uracil ring , s tepwise degradation ( N - dealkylation) of the N

- methyl -N

- isopropyl group, hydrol yt ic cleavage of the uracil ring generating a urea side chain , and h ydrox yl ation of the phenyl ring. The HED Residues of Concern Knowledg ebase Subcommittee (ROCKS) determined that residues of concern for the tolerance expression and risk assessment consist of saflufenacil, M800H11, and M800H35 ( Memo, B. Daiss , 1/6/09; D 359645 ) . The proposed metabolic pathway

of radiolabeled saflufenacil in soy bean following post - emergence treatment follows the same initial pathway s, but is not as extensive. No new metabolites were observed following post - emergence treatment ; however, an additional major metabolite ( M800H02 ), that is not included in the tol erance expression, was observed in so ybean seed. As the structure of M800H02 is closely

related to the parent compound and it is the precursor of the regulated metabolite M800H11, HED concludes that M800H02 is a residue of concern for risk - assessment purp oses in seed crops following post - emergence treatment. 5.1.2 Metabolism in Rotational Crops The metabolism of saflufenacil in rotational crops appears to be consistent with the pathway observed in the plant metabolism studies. Unless the petitioner requests plantback intervalsSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 19 of 35 (PBIs) shorter than 4 months, no additional data are required, and to lerances for inadvertent residues in/on rotational crops need not be established in conjunction with the currently proposed uses. 5.1.3 Metabolism in Livestock The nature of the residue in livestock is adequately understood based on acceptable metabolism studies conducted on lactating goats and laying hens. Saflufenacil was metabolized by several dealkyl ation steps occurring at two different sites in the molecul e ( N - isopropyl -N

methylsulfamide side chain and at the uracil ring) and via hydrol yt ic opening of the uracil ring (goat only) . In the ruminant metabolism study , s aflufenacil was a major residue in all matrices. M800H04 , a ring opening product, was the on ly significant metabolite (>10% total radioactive residue , TRR) found (liver). In the poultry metabolism study , s aflufenacil was a major residue in all matrices and no significant metabolites were found . 5.1.4 Analytical Methodology The petitioner ha s submitted two liquid chromatography /mass spectroscopy/mass spectroscopy (L C - MS/MS) anal yt ical methods for the determination of residues of the parent and its metabolites in/on plant and livestock commodities. BASF Method D0603/02 was developed for deter mination of residues of saflufenacil and its metabolites M800H11 and M800H35 in different plant matrices using LC - MS/MS. The limit of quantitation (L OQ) was 0.01 ppm for each anal yt e in food matrices and 0.025 ppm for each analy te in feed matrices. BASF analy tical Method No. L 0073/01 was developed for determination of saflufenacil in livestock matrices using LC - MS/MS. The LOQ was 0.01 ppm in all matrices . These methods were used as the data - collection methods in the anal ys is of samples for residues of c oncern from the various studies associated with the current petition. Each method has been adequately validated by

the petitioner as well as b y i ndependent laboratories. Method No. L 0073/01 was also adequatel y radiovalidated using weathered samples obtai ned from metabolism studies. HED has determined that Methods D0603/02 and L0073/01 are suitable enforcement methods for plant and livestock commodities, respectively , as defined in S O P No. ACB - 019 ( 9 /1 5 /08). 5.1.5 Environmental Degradation Saflufenac il is slowly

photoly zed in water (half

- life of 57 day s at pH 5) and on soil (half - lives of 83 and 87 day s) at 22°C. Inaddition , the compound is relatively stable to hydrol ys is at pH 5, almost stable at pH 7 (half - life of 248 day s), and readily hydrolyzed at pH 9 (half - life of 4.9 day s). Therefore, alkaline hydroly sis is a major degradation route for saflufenacil in high pH environments. Saflufenacil biodegrades in 1 to 5 weeks in aerobic soil (half - lives of 8.5 - 34 day s) and less quickly in aerobic aquat ic environments of pH 5.6 to 6.4 (half - lives of 50 and 107 day s). Therefore, aerobic soil metabolism is another major degradation route for saflufenacil that will operate in the environment at any pH value.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 20 of 35 Dissipation occurred with half - lives of 2.4 to 22 day s in terrestrial field dissipation studies conducted in the continental U . S . , which is consistent with the submitted, laboratory- derived data. Dissipation was slower in Canadian field plots (half - lives of 25 day s and >>20 day s). Major degradates that are structurally similar to the parent compound include M01, M02, M04, M07, M08, M15, M22, and the soil photolysis product number 8. Major cleavage products of saflufenacil include M26, trifluoroacetic acid , M31, M33, and TFP . Another major aqueous photoly sis product was isolated as well (unknown 3/4/7/6), but not identified. Major degradates that did not decline in amount in unsterile study conditions include M7, M29, and product 8 (see Appendix B: Metabolism Assessment, T able B.1.2 of Austin, et al. , 7/22/09; D367317 ). 5.1.6 Comparative Metabolic Profile The primary

route s of metabolism in animals and plants and degradation in the environment w ere basicall y the same: N - demethylation at the uracil ring , s tepwise degradation ( Ndealkyl ation) of the N

- methyl -N

- isopropyl group, and hydrol yt ic cleavage of the uracil ring . Unique environmental pathway s included the addition of hydrogen to the double bond in the uracil ring and the formation of trifluoroacetic acid. 5 .1.7 Toxicity Profile of Major Metabolites and Degradates T oxicity data w ere not submitted for the metabolites of saflufenacil. 5.1.8 Pesticide Metabolites and Degradates of Concern Table 5. 1 .8 . Summary of Metabolites and Degradates to be included in the Risk Assessment . Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crops (preplant

application) Saflufenacil + M800H11, M800H35 Saflufenacil + M800H11, M800H35 Primary Seed Crops (post - emergence ) Saflufenacil + M800H11, M800H02 , M800H35 Rotational Crops Saflufenacil + M800H11, M800H35 Livestock Ruminants Saflufenacil Saflufenacil

Poultry Drinking Water Saflufenacil + M800H 0 1, M800H 0 2, M800H 07, M800H 0 8, M800H 15, M800H 22, P roduct 8 Not Applicable 5.1.9 Drinking Water Residue Profile The Estimated Drinking Water Concentrations (EDWC s ) used in the dietary exposure risk assessment were provided by EFED in a memorandum dated 4/15/09 (Memo, G . Orrick ; DP# 349860 ) . Water residues were incorporated directly into the DEEM - FCID TM in the food categories “water, direct, all sources” and “water, indirect, all sources.”Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 21 of 35 Screening EDWC s ( Table 5.1.9 ) of saflufenacil were generated with FQPA Index Reservoir Screening Tool (FIRST) for surface wat er and with PRZM GW for ground water. Modeled application rates represent the maximum use patterns of five proposed end - use labels with selected uses on row crops, orchard trees, vineyards, tree plantations, and non - agricultural areas . Remaining model input parameters were chosen according to current guidance (USEPA, 2002). EDWCs reflect exposure to saflufenacil and all degradates of concern in drinking water ( Table 5.1.8 ). Table 5. 1 .9 . Tiered EDWCs for Proposed Saflufenacil Uses. Source (Tier: Model) 1 - in - 10 -year Peak Exposure ( ppb ) 1 - in - 10 -year Annual Mean Exposure ( ppb ) Surface water (Tier I: FIRST) 37.3 23.8 Ground water (Tier II: PRZM GW) 180 173 5.1.10 Food Residue Profile The submitted magnitude of the residue data for the raw and processed commodities of cotton, dry bean, dry pea, canola, and soy

bean are adequate. There are also adequate storage stability data to validate the storage conditions and intervals of samples co llected from the field and processing trials. With the exception of soy bean hulls and aspirated grain fractions (AGF s ), no concentration of the total saflufenacil residue was found in any processed commodity , separate tolerances for residues in/on processed commodities are not required. An adequate dairy

cow feeding study

has been submitted; this study is acceptable for determining tolerance levels for ruminant commodities. The increased reasonably- balanced dietary burdens (RBDBs) resulting from the proposed uses necessitate that the established tolerances be increased to 2.5 ppm for residues in liver and 0.05 ppm for residues in meat by products except liver of cattle, goats, horses, and sheep. Analy tical standards of saflufenacil, M800H11, and M8 00H35 are currently available in the National Pesticide Standards Repository [source: personal communication with T. Cole of Analy tical Chemistry

L aboratory

(AC L ) /Biological and Economics Analy sis Division (BEAD) , 10/28/10]. However, since the standards for M800H11 and M800H35 expired on 10/ 1 /10 , the petitioner is requested to provide a new suppl y to the Repository . A summary

of the recommended tolerances for the current petition are listed in Appendix C: Tolerance Reassessment Summary . The petitione r should submit a revised Section F reflecting the recommended tolerances and commodity definitions presented in Appendix C. 5.1.11 International Residue Limits There are no Codex maximum residue limits (MRLs) established for residues of s aflufenacil and its metabolite s in crop or livestock commodities. Canadian MRL s are established for vegetable, legume, subgroup 6c ; cotton, undelinted seed ; and livestock commodities, all at levels lower than those recommended to support the current action. Canada is currentl y in the process of reviewing the proposed harvest - aid uses use of saflufenacil . EPA and Canadian tolerance/MRL recommendations are harmonized as a result of the joint - review process.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 22 of 35 5.2 Dietary Exposure and Risk 5.2 .1 Acute Dietary Exposu re/Risk The unrefined acute analysis assumed 100% CT, DEEM TM 7.81 default concentration factors, and tolerance - level residues for all commodities [ except for cottonseed; sunflower subgroup 20 B ; soy bean, seed; vegetable, legume, subgroup 6C, pea and bean (except soy bean); and rapeseed subgroup 20A for which the recommended tolerance level s w ere multiplied by a correction factor to account for a metabolite of concern which is not included in the tolerance expression ]. Drinking water was i ncorporated directly into the dietary

assessment using the concentration for ground water generated by the Tier II PRZM GW model . The acute dietary exposure and risk estimates (food + water) are 0.010370 mg/kg/day for the general U.S. population (<1% of the aPAD) and 0.038353 mg/kg/day (<1% of the aPAD) for the most highly exposed population subgroup [ all infants (<1 year old) ] and are , thus , below HED’s LOC (<100% aPAD ; Table 5.2 ). 5.2.2 Chronic Dietary Exposure/Risk The unrefined chronic analy sis assumed 100% CT, DEEM TM 7.81 default concentration factors, and tolerance - level residues for all commodities [ except for cottonseed; sunflower subgroup 20 B ; soy bean, seed; vegetable, legume, subgroup 6C, pea and bean (except soy bean); and rapeseed subgroup 20A for which the recommended tolerance level s w ere multiplied by a correction factor to account for a metabolite of concern which is not included in the tolerance expression] . Drinking water was incorporated directly into the dietary as sessment using the concentration for ground water generated b y PRZM GW (173 ppb) . The chronic dietary exposure and risk estimates (food + water) are 0.004219 mg/kg/day for the general U.S. population ( 9.2 % of the cPAD) and 0.013999 mg/kg/day ( 30 % of the c PAD) for the most highly exposed population subgroup [ all infants (<1 year old) ] and are , thus , below HED’s LOC (<100% cPAD ; Table 5.2 ). Table 5.2 . Summ ary of Dietary (Food and Drinking Water) Exposure and Risk for Saflufenacil . Population Subgroup Ac ute Dietary (95 th Percentile) Chronic Dietary Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD General U.S. Population 0.010370 <1 0.004219 9.2 All Infants (<1 year old) 0.038353 <1 0.013999 30 Children 1 - 2 years old 0.017102 <1 0.007234 16 Children 3 - 5 years old 0.015406 <1 0.006506 14 Children 6 - 12 years old 0.010475 <1 0.004370 10 Youth 13 - 19 years old 0.008429 <1 0.003159 6.9 Adults 20 - 49 years old 0.009246 <1 0.003811 8.3 Adults 50+ years old 0.008373 <1 0.003945 8.6 Females 13 - 49 years old 0.009310 <1 0.003793 8.2 5.2.3 Cancer Dietary Risk Saflufenacil is classified as “ not likely carcinogenic to humans . ” Therefore, c ancer risk is not a concern for this chemical.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 23 of 35 5.3 Anticipated Residue and %CT Information The acute and chronic dietary exposure analy ses were based on tolerance - level or higher residues and the assumption of 100% CT. Anticipated residues and percent CT estimates were not incorporated into the assessments. 6.0 Residential (Non - Occupational) Exposure/Risk Characterization Saflufenacil has no registered or proposed residential uses ; therefore, a quantitative non occupational exposure assessment was not performed. 6.1 Spray Drift Spray drift is alway s a potential source of exposure to resid ents nearb y spraying operations. This is particularl y 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 saflufenacil . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State L ead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical - by- chemical basis, the Agency is no w requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants , and is developing a policy on how to appropriatel y apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose f urther refinements in spray drift management practices to reduce off - target drift with specific products with significant risks associated with drift. 

### 6.2 Residential Bystander Post - application Inhalation Exposure Based on the Agency's current practices , a quantitative residential by stander post - application inhalation exposure assessment was not performed for saflufenacil at this time . However, volatilization of pesticides may be a potential source of post - application inhalation exposure to individuals nearb y to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP /meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, 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. If new policies or procedures are put into place, then the Agency

may revisit the need for a quantitative post - application inhalation exposure assessment for saflufenacil . 7.0 Aggregate Risk Assessments and Risk Characterization Aggregate exposure and risk assessments were assessed b y incorporating the drinking water directly into the dietary- exposure assessment for the following scenarios: acute and chronic aggregate exposure (food + drinking water). Short - , i ntermediate - , and long - term aggregate - riskSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 24 of 35 assessments were not performed because there are no registered or proposed uses of saflufenacil that result in residential exposures. A cancer aggregate - risk assessment was not performed because saflufenacil is n ot a carcinogen and cancer risk is not a concern. 8.0 Cumulative Risk Characterization/Assessment 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 saflufenacil and an y other substances and saflufenacil does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that saflufenacil has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

E PA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 Occupational Exposure/Risk Pathway The following reference applies to this section: Occupational and Residential Exposure Assessment - D381978 , A. Nowotarski , 24 - FEB - 2011 A risk assessment has already been performed for sunflower subgroup 20B, soy bean, dry peas, cottonseed subgroup 20C, and dry edible beans (Austin, et al. , 7/22/09; D367317 ). The maximum use rate has not increas ed for the proposed new use and , therefore, the previous assessment still covers any occupational handler/postapplication exposure from use on these crops. An assessment for rapeseed subgroup 20A (canola) is included below since this use has not been assessed previously . 9.1 Short -/Intermediate - Term Occupational Handler Risk Potential occupational exposure scenarios include: 1) mixing/loading liquids for aerial application; 2) mixing/loading liquids for groundboom application; 3) applicators using aerial equipment; 4) open - cab groundboom equipment; and 5) flaggers. Handler exposure is expected to be short - and intermediate - term based on information provided on proposed labels (e.g., maximum application rate of 0.0445 lb ai/A). Ty pically , HED completes short - and intermediate - term assessments for occupational scenari os in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify deleting intermediate - term scenarios. Based on use data and label instructions, HED believes that occupational exposures may occur over a single day

or up to weeks at a time for many use - patterns and that intermittent exposure over several weeks may also occur. Some applicators may

appl y these products over a period of weeks, because they are commercial applicators who are completing multiple applications for multiple clients. The average adult body weight of 60 kg was used for estimating dermal and inhalation dose because the endpoint isSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 25 of 35 from a developmental study and was observed in offspring. Long - term exposures are not expected ; ther efore, a long - term assessment was not conducted. No chemical - specific data are available with which to assess potential exposure to pesticide handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data available in PHED (August , 1998). For pesticide handler s, it is HED standard practice to present estimates of dermal exposure for “baseline ; ” that is, for workers wearing a single layer of work clothing consisting of a long - sleeved shirt, long pants, shoes plus socks and n o protective gloves , as well as for “baseline” and the use of protective gloves or other personal - protective equipment (PPE) as might be necessary . The proposed product label involved in this assessment directs applicators and other handlers to wear prote ctive eyewear, long - sleeved shirt and long pants, socks, shoes, and chemical - resistant gloves . Daily handler exposures are estimated for each applicable handler task with the application rate, the area treated in a day , and the applicable unit exposure u sing the following formula: Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x Application Rate (lbs ai/area) x Daily Area Treated (area/day) Where: Daily Exposure = Amount (mg ai/day) inhaled that is available for inhalation absorption; Unit Exposure = Unit exposure value (mg ai/lb ai) derived from August 1998 PHED data; Application Rate = Normalized application rate based on a logical unit treatment, such as acres; and Daily Area Treated = Normalized application area base d on a logical unit treatment such as acres (A/day). The daily dermal or inhalation dose is calculated by normalizing the daily

exposure by

body weight and adjusting, if necessary , with an appropriate inhalation absorption factor using the following formu la: Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x (Absorption Factor (%/100)) / Body Weight (kg) Where: Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg ai/kg body weight/day); Daily Exposure = Amount (mg ai/day) deposited on surface of skin that is available for dermal absorption, or the amount inhaled that is available for inhalation absorption; Absorption Factor = A measure of the amount of chemical that crosses a biological b oundary such as the skin or lungs (% of the total available absorbed); and Body Weight = Body weight determined to represent the population of interest in a risk assessment (kg). Non - cancer dermal and inhalation risks for each applicable handler scenario are calculated using an MOE , which is a ratio of the NOAEL to the daily dose. All MOE values were calculated using the formula below: MOE= NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day) Table 9.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers. An MOE ≥100 is adequate to protect occupational pesticide handlers. Since all theSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 26 of 35 estimated MOEs are >100 with baseline protection or the addition of gloves (as already required by the label), the proposed uses are not of concern for HED.

a Application rates are the maximum application rates determined from proposed labels for saflufenacil . b Amount handled per day values are HED estimates of acres treated per day or gallons handled per day based on ExpoSAC SOP #9

“Standard Values for Daily Acres Treated in Agriculture,” industry sources, and HED estimates. c Baseline Dermal: Long - sleeve d shir t, long pants, and no gloves. Table 9.1 . Occupational Dermal and Inhalation Exposures and Risks. Crop or Target App. Rate

(lb ai/A) a Area

Treated Daily or Amount Handled (acres or gallons per day) b Dermal and Inhalation

Unit Exposures (mg/lb ai) Short - and Intermediate Term Doses (mg/kg/day) e MOEs f

Short - and Intermediate Term Com

bined Dermal and Inhalation Mixer/Loader for Aerial Applications Rapeseed subgroup 20A (canola) 0.0445 1200 Dermal Baseline c : 2.9 PPE - G: 0.023 Dermal Baseline: 0.078 PPE - G g : 0.00062 Dermal Baseline: 64 PPE - G: 8,100 Baseline

Dermal +Baseline Inhal: 63 PPE - G Dermal + Baseline Inhal: 2,900 Inhalation Baseline d : 0.0012 Inhalation Baseline: 0.0011 Inhal. Baseline: 4,600 Mixer/Loader for Groundboom Applications Rapeseed subgroup 20A (canola) 0.0445 200 Dermal Baseline c : 2.9 Dermal Baseline: 0.013 Dermal Baseline: 380 Baseline

Dermal + Baseline Inhal: 380 Inhalation Baseline d : 0.0012 Inhalation Baseline: 0.00018 Inhal. Baseline: 28,000 Applying Sprays via Groundboom Equipment Rapeseed subgroup 20A (canola) 0.0445 200 Dermal Baseline: 0.014 Dermal Baseline: 0.000063 Dermal Baseline: 79,000 Baseline

Dermal + Baseline Inhal: 29,000 Inhalation Baseline: 0.00074 Inhalation Baseline: 0.00011 Inhal. Baseline: 45,000 Applying Sprays via Aerial Equipment Rapeseed subgroup 20A (canola) 0.0445 1200 Dermal Eng conth : 0.005 Dermal

Eng cont: 0.00014 Dermal Eng cont: 37,000 Eng cont

Dermal + Eng cont Inhal: 25,000 Inhalation Eng cont: 0.000068 Inhalation

Eng cont: 0.000061 Inhalation Eng cont: 82,000 Flagger Rapeseed subgroup 20A (canola) 0.0445 350 Dermal Baseline: 0.011 Dermal Baseline: 0.000087 Dermal Baseline: 58,000 Baseline

Dermal + Baseline Inhal: 28,000 Inhalation Baseline: 0.00035 Inhalation Baseline: 0.000092 Inhalation Baseline: 54,000Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 27 of 35 d Bas eline I

nhalation: no respirator. e Dose (mg/kg/day) = Unit E xposure(mg/lb ai) x A pp . R ate (0.0445 lb ai/acre) x Ar ea Treated (acres/day) or Amount Handled (gallons) / Body W eight (60 kg) . f MOE = NOAEL/Dose ; where the short - and intermediate - term dermal NOAEL = 5 mg/kg/day ; short - and intermediate - term

inhalation NOAEL = 5 mg/kg/day . g PPE - G = long - sleeve shirt, long pants, and gloves. h Engineering control: enclosed cockpit and baseline attire (long - sleeve shirt, long pants, shoes, and socks) . 9.2 Short -/Intermediate - Term Postapplication Risk Dermal The proposed use is for application of saflufenacil as a pre - harvest desiccant. As such, postapplication exposure to foliage is not expected because harvesting is done mechanically . Therefore, occupational post - application dermal exposure was not assessed at this time. Inhalation Based on the Agency's current practices, a quantitative occupational post - application inhalation exposure assessment was not performed for saflufenacil at this time. 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 contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational post - application inhalatio n 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 saflufenacil . RE I Saflufenacil is class ified as acute T oxicity C ategory I II for acute dermal toxicity and primary eye irritation . It is classified as T oxicity C ategory IV for primary

skin irritation . Therefore, the interim WPS REIof 12 hours is adequate to protect agricultural workers from p ost - application exposures to saflufenacil. 10.0 Data Needs and Label Recommendations 10.1 Toxicology

 noneSaflufenacil Human - Health Risk Assessment DP Number 380636

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Page 28 of 35 10.2 Residue Chemistry 860.1650 Submittal of Analy tical Reference Standards

 Analy tical standards of saflufenacil, M800H11, and M800H35 are currently available in the National Pesticide Standards Repository [source: personal communication with T. Cole of ACL/BEAD, 10/28/10]. However, since the standards for M800H11 and M800H35 expired on 10/ 1 /10 , the petitioner is requested to provide a new suppl y to the Repository . 860.1550 Proposed Tolerances The petitioner is requested to submit a revised Section F specifying the following:

 Revised tolerance levels and commodity definitions are presente d in Appendix B : Tolerance Summary

Table. 10.3 Occupational and Residential Exposure

 none

cc: G. Kramer (RAB1) RDI: RAB1 (3/ 16 /11) G.F. Kramer:S10 95 7:PY - S :(703)305 - 5079:7509P:RAB1Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 29 of 35 Appendix A: Toxicology Assessment A.1 Toxicology Data Requirements for S aflufenacil Test Technical Required Satisfied 870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

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

Dermal ................................ .............................. 870.3465 90 - Day Inhalation ................................ .......................... yes yes yes no no yes

yes yes

-

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

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

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

—Gene Mutation - mammalian ................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

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

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

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotox icity Screening Battery (rat) ................. 870.6200b 90 - Day Neurotox icity Screening Battery (rat) ............... 870.6300 Developmental Neurotox icity ................................ ........ no no yes yes no -

- yes yes no 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

yes yes Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. - -Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 30 of 35 A.2 Toxicity Profiles Table A.2.1. Acute Toxicity Profile – Saflufenacil. Guideline No. Study Type MRID(s) Results Toxicity Category Purity 870.1100 Ac ute oral [rat] 47128101 LD 50 wa s >2000 mg/kg bw III 93.8% 870.1200 Ac ute dermal [rat] 47128102 LD 50 >2000 mg/kg III 93.8% 870.1300 Ac ute inhalation [rat] 47128103 LC 50 >5.3 mg/L IV 93.8% 870.2400 Ac ute eye irritation [ White New

Zealand rabbit] 47128105 minimal irritation III 93.8% 870.2400 Ac ute eye irritation [ White New

Zealand rabbit] 47128104 minimal irritation III 93.8% 870.2500 Ac ute dermal irritation [rabbit] 47128106 slightly irritating IV 93.8% 870.2600 Skin sensitization [Guinea Pig] 47128107 not a sensitizer N/A 93.8% Table A.2.2. Subchronic, Chronic , and Other Toxicity Profile for S a flufenacil . Guideline No./ Study Type MRID (yr . )/Classification/Doses Results 870.3100 28 - Day Oral Toxicity feeding mice 47128110 (2007) Acceptable/non - guideline 0, 50, 150, 450, 1350, or 4050 ppm . M\F: 0, 12.8/17.9, 36.6/63.4, 112/15 3.1, 335/446, 882/1630 mg/kg bw/day . LOAEL = 36.6 mg/kg bw/d ay (males) based on increased alanine aminotransferase, aspartate aminotransferase , urea and total bilirubin , decreased hemoglobin and Ht and increased liver weight and centrilobular fatty change . NOAEL = 12.8 mg/kg bw/d ay . LOAEL = 153.1 mg/kg bw/d ay (females) based on moderate centrilobular fatty change in the liver. NOAEL = 63.4 mg/kg bw/d ay . 870.3100 28 - Day Oral Toxicity feeding - rat 47128108 (2007) Acceptable/non - guideline 0, 5 0, 150, 450, 1350, or 4050 ppm . M = 0, 4.5, 13.4, 39.2, 117, 357; F = 0, 5.0, 15.9, 43.6 , 130.4, 376 mg/kg bw/d ay . LOAEL = 39.2 mg/kg bw/d ay (males ) based on decreased Hb, MCV, and MCH. NOAEL =13.4 mg/kg bw/d ay . LOAEL = 130.4 mg/kg bw/d ay (females) based on decreased Hb, Ht , MCV, and MCH. NOAEL = 4 3.6 mg/kg bw/d ay . 870.3100 90 - Day Oral Toxicity feeding mice 47128111 (2007) Acceptable/guideline 0, 15 (males only), 50, 150, 450 , and 1350 (females only) ppm . M = 0, 3.6, 12.4, 36.7, 109.1; F = 0, 17.6, 51.8, 156.6, 471.2 mg/kg bw/ day . LOAEL = 36.7mg/kg bw /d ay (males ) based on multiple hematological changes, liver - weight increases with centrilobular f atty change and lymphoid infiltrate in males. NOAEL = 12. 4 mg/kg bw/d ay . LOAEL = 156.6 mg/kg/d ay (females) based on increased liver weight with centrilobular fatty chang e and lymphoid infiltrate. NOAEL = 51.8 mg/kg/d ay .Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 31 of 35 Table A.2.2. Subchronic, Chronic , and Other Toxicity Profile for S a flufenacil . Guideline No./ Study Type MRID (yr . )/Classification/Doses Results 870.3100 90 - Day Oral Toxicity feeding - rat 47128109 (2007) Acceptable/guideline 0, 50, 150, 450 ( males), 1350, or 4050 (females ) ppm . M = 0, 3.5, 10.5, 32.3, 94.7 . F = 0, 4.3, 1 2.6, 110.5, 344.7 mg/kg bw/d ay . LOAEL = 32.3 mg/kg bw/d ay (M ) and 110.5 mg/kg bw/d ay

(F) based on multiple he matological effects and increased spleen weight and extramedullary hematopoiesis . NOAEL = 10.5 (M) , 12.6 mg/kg bw/d ay (F) . 870.3150 28 - Day Oral Toxicity feeding dog 47128112 (2005) Acceptable/non - guideline 0, 30, 100, or 300 mg/kg bw/d ay . LOAEL = 100 mg/kg bw /d ay based decreased mean corpuscular volume, MCH , and MCHC , bone marrow hyperplasia, increased iron storage in the liver and extramedullary hematopoiesis in the spleen . NOAEL = 30 mg/kg bw/d ay . 870.3150 90 - Day Oral Toxicity feeding dog 4712 8113 (2006) Acceptable/guideline 0, 10, 50, or 150 mg/kg bw/d ay . LOAEL = 50 mg/kg bw/d ay based on lower MCV and MCH values in both sexes . NOAEL = 10 mg/kg bw/d ay . 870.3200 21/28 - Day dermal toxicity (rat) 47128114 (2006) Acceptable/guideline 0, 100, 300, or 1000 mg/kg . LOAEL was not established. NOAEL = 1000 mg/kg bw /d ay . 870.3700a Prenatal developmental in (rat) 47128115 (2007) Acceptable/guideline 0, 5, 20 , or 60 mg/kg/ day . Maternal NOAEL = 20 mg/kg/day . LOAEL = 60 mg/kg/day based on decrease d hemoglobin and Ht , mean corpuscular volume and MCH . Developm ental NOAEL = 5 mg/kg/day . LOAEL = 20 mg/kg/day based on decreased fetal body weights and increase in skeletal variations. 870.3700b Prenatal developmental in (rabbit) 47128116 (2006) Acceptable/guideline 0, 50, 200 , or 600 mg/kg/day . Maternal NOAEL = 2 00 mg/kg bw/d ay . LOAEL = 600 mg/kg bw /d based on mo rtality and increased necropsy findings . Developm ental NOAEL = 5 0 mg/kg/day LOAEL = 2 00 mg/kg/day based on increased liver porphyrins . 870.3800 Reproduction and fertility effects (rat) 47128117 (2007) A cceptable/guideline 0, 5, 15, or 50 mg/kg bw/d ay . Parental Systemic NOAEL = 15 mg/k g/d ay . Parental Systemic LOAEL = 50 mg/kg/day based on decreased food intake, body weight, body weight gain and changes in hematological parameters and organ weights indicative of anemia. Reproduction NOAEL = M/F 50 mg/kg/day . Reproduction LOAEL was not established. Offspring NOAEL = 15 mg/kg/d ay . Offspring LOAEL = 50 mg/kg/d ay based on decrease d number of live born pups, increased number of stillborn pups, decreased viability and lactation indices, decreased pre - we aning body weight and/or body - we ight gain and changes in hematological parameters .Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 32 of 35 Table A.2.2. Subchronic, Chronic , and Other Toxicity Profile for S a flufenacil . Guideline No./ Study Type MRID (yr . )/Classification/Doses Results 870.4300b Chronic Toxicity (dog) 47128118 ( 2007 ) Acceptable/guideline 0, 5, 20, or 80 mg/kg bw/d ay . LOAEL = 80 mg/kg bw/d ay based on decreased albumin, MVH, and MCH . NOAEL = 20 mg/kg bw/d ay . 870.4300 Chronic/Carcinogenicity (rat) 47128120 (2007) Acceptable/guideline 0, 20, 100, 250 ( males ), 500 or 1000 ( females ) ppm . M = 0, 0.9, 4.8, 12.0, 24.2 . F = 0, 1.3, 6.2, 31.4, 63.0 mg/kg bw /d ay . LOAEL = 31.4 mg/kg bw/d ay (females ) based on decreased hemoglobin, Ht , MCV and MCH . NOAEL = 6.2 mg/kg bw/d ay (females). LOAEL was not established in males. NOAEL = 24.2 mg/kg bw/d ay . No evidence of carcinogenicity . 870.4300 Chronic/Carcinogenicity (mouse) 47128119 (2007) Acceptable/guideline 0, 1 ( males ), 5, 25, 75, or 150 ( females) ppm . M = 0, 0.2, 0.9, 4.6, 13.8 . F = 0, 1.2, 6.4, 18.9, 38.1 mg/kg bw /d ay . satellite groups : M = 0, 14.2 . F = 0, 39.0 mg/kg bw/d . NOAEL = 4.6 mg/kg bw/d ay ( males ) and 18.9 mg/kg bw/d ay

( females ) . LOAELs = 13.8 mg/kg bw/d ay (males ) and 38.1 mg/kg bw/day (females ) based on decreased red blood cells, hemoglobin, and Ht and porphyria observed in the satellite grou

p. No evidence of carcinogenicity . Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 4712812 1 (2005) Acceptable/guideline 0, 20, 100, 500, 2500, or 5000 μg/plate (saflufenacil hydrate) . There was no evidence of induced mutant colonies over background. Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 47128122 (2005) Acceptable/guideline 0, 20, 100, 500, 2500, or 5000 μg/plate (saflufenacil anhydrate) . There was no evidence of induced mutant colonies over background. Gene Mutation 870.5 3 00 In vitro Mammalian Cells Gene Mutation (Chinese Hamster Ovary Cells) 47128123 (2005) Acceptable/guideline 0, 312.5, 625, 1250, 2500, or 5000 μg/mL . There was no evidence of induced mutant colonies over background. Cy togenetics 870.5375 In vitro Mammalian Cytogenetics chromosomal aberration assay V79 cells 4712812 4 (2005) Acceptable/guideline 0, 5, 10, and 20 ug/ml without S9 activation . 0, 10, 20, and 40 ug/ml with S9 activation . Saflufenacil was considered clastogenic in vitro in V79 cells in the presence of S9 metabolic activation. Saflufenacil wa s not clastogenic in the absence of metabolic activation. Cy togenetics - other 870.5395 In Vivo Mammalian Cy togenetics - Ery

throcyte Micronucleus assay in mice 47128125 (2005) Acceptable/ guideline 0, 500, 1000, or 2000 mg/kg bw. There was no increase in the frequency of micronucleated immature erythrocytes in mo use bone marrow . 870.5550 Other Genotoxicity -In vivo unscheduled DNA synthesis (rat) 47128126 (2005) Acceptable/guideline single oral dose of 1000 or 2000 mg/kg bw . Negative 870.6200a Ac ute neurotoxicity battery (rat) 47128127 (2007) Acceptable/Guideline 0, 125, 500, or 2000 mg/kg bw . Sy stemic LOAEL was 2000 mg/kg bw ( males ) based on the decreased motor activity representing mild and transient systemic toxicity. Sy stemic LOAEL was not established for females .Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 33 of 35 Table A.2.2. Subchronic, Chronic , and Other Toxicity Profile for S a flufenacil . Guideline No./ Study Type MRID (yr . )/Classification/Doses Results Sy stemic NOAEL = 500 (M) and 2000 (F) mg/kg bw . The re was no evidence of neurotoxicity. 870.6200b Subchronic neurotoxicity (rat) 47128128 (2007) Acceptable/Guideline 0, 50, 250, 1000 ( males ), or 1350 ( females ) ppm . M = 0, 3.3, 16.6, 66.2 . F = 0, 3.9, 19.4, 101.0 mg/kg bw /d . Sy stemic NOAEL = 16.6 (males) , 19.4 (females) mg/kg bw/d ay . Sy stemic LOAEL = 66.2 (males) and 101 (females) mg/kg bw/d ay based on decreased hemoglobin, Ht , mean corpuscular volume and MCH. There was no evidence of neurotoxicity. 870.7485 Metabolism and pharmacokinetics (rat) 47128130 , 47128129 (2007) 4, 20, or 100 mg/kg bw (single oral dose) . 5 or 100 mg/kg bw

(single dose) 100 mg/kg for 14 days . Saflufenacil was rapidly absorbed, distributed, and excreted. Regardless of the dose administered, maximum concentration of saflufenacil in blood and plasma was reached within 1 h of dosing and declined rapidly after 24 h. Excretion of orally dosed saflufenacil was essentially complete within 96 h; the majority was eliminated within the first 24 to 48 h. Demonstrating that th e majority of the saflufenacil residues occurred in the plasma and was not bound to cellular elements of the blood. There was a sex dependent difference in the excretion of orally administered saflufenacil . Following single low - and high - dose administration or a repeat high - dose administration, the main route of elimination in male rats was via the feces, while urinary excretion was the major route of elimination in females. There wa s s ignificantly higher biliary excretion of saflufenacil residues in mal es than in females. Exhalation was not a relevant excretion pathway of saflufenacil . At 168 h after dosing, saflufenacil residues remaining in tissues were very low , and occurred mainly in carcass, liver, skin, and gut contents. Saflufenacil wa s metaboli zed by three major transformation steps: demethylation of the uracil ring system, degradation of the N - methyl -N

isopropyl group to NH 2 , and cleavage of the uracil ring, forming a sulfonylamide group. The predominant metabolites were M800H01, M800H03, M800H07 and the parent compound. Other minor metabolites were M800H05, M800H16, M800H17, M800H18, M800M19, and M800M20. There were no significant sex differences in metabolic profiles.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 34 of 35 Table A.2.2. Subchronic, Chronic , and Other Toxicity Profile for S a flufenacil . Guideline No./ Study Type MRID (yr . )/Classification/Doses Results 870.7600 Dermal p enetration (rat) 47128214 (2007) Acceptable /guideline 1.1723 mg/cm2 , 0 . 1172 mg/cm2 , and 0.0117 mg/cm2

. 11.723, 1.172 , and 0.117 mg/rat . Dermal absorption is 3 % .

870.7800 Immunotoxicity (mice) 48233701 (2010) Acceptable/guideline 0, 50, 125, and 250 ppm (0, 10, 27, and 52 mg/kg/day) . LOAEL for systemic toxicity was 125 ppm (or 27 mg/kg bw/day) based on significant changes in pathological and clinical pathology parameters . The NOAEL for systemic toxicity was 50 ppm (10 mg/kg bw/day) . The LOAEL for immunotoxicity was not identified. The NOAEL for immunotoxicity is the highest dose tested of 250 ppm (52 mg/kg bw /day) . Com parative Bioavailability/Toxicity Study (rat) 47128133 (2005) Acceptable/non - guideline 0 or 1350 ppm . The bioavailability and toxicity potential of the hydrated and anhydrated forms of saflufenacil were similar. Mechanistic study

– total porphyrin analysis in rat 47128132 (2006) Acceptable/non - guidel ine 0, 10, 50, or 1000 ppm ( ♂ = 0, 0.8, 4.1, 80 .6; ♀ = 0, 0.9, 4.6, 89.5 mg/kg bw/d ay , respectively) . Total porphyrins in feces and liver provided the most reliable and sensitive data. Statistically significant effects on porphyrin metabolism could be detected at exposure concentrations well below those associated with adverse hematological effects. NOAEL= 4.1 mg/kg/day. LOAEL = 80.6 mg/kg/day based on decreased hemoglobin, Ht, MCV, MCH , and MCHC. Mechanistic study - porphyrin analysis supplementary (rat) 47128131 (2005) Acceptable/non - guideline 0, 1, 5, or 25 ppm ( ♂ = 0, 0.1, 0.4, 2.0; ♀ = 0, 0.1, 0.5, 2.3 mg/kg bw/d ay . Dietary administration of saflufenacil at 25 ppm caused an increase in porphyrin in feces of male (237%) and female (61%) rats, while saflufenacil at 5 ppm caused an increase in fecal porphyrin only in males. There were no effects on hematology parameters.Saflufenacil Human - Health Risk Assessment DP Number 380636

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Page 35 of 35 Appendix B: Tolerance Summary Table Table B.1 . Tolerance Su mmary for Saflufenacil . Commodity Proposed Tolerance (ppm) HED - Recommended

Tolerance (ppm) Correct Commodity

Definition

/Comments Oilseeds, Cottonseed Subgroup 20C, gin byproducts 3.5 0.45 Cotton, gin byproducts Oilseeds, Cottonseed Subgroup 20C, undelinted seed 0.2 0.20 Cottonseed Subgroup 20C Oilseeds, Sunflower Subgroup 20B, seed 1.0 1.0 Sunflower Subgroup 20B Pea, vines 8.0 17 Pea, hay Soy bean, aspirated grain fractions 4.52 10 Grain, aspirated fractions Soy bean, hulls 0.42 0.50 Soy bean, seed 0.1 0.10 Vegetable, Legume, Subgroup 6C, beans, dry 0.5 0.30 Pea and bean, dried shelled, except soy bean, subgroup 6C Vegetable, Legume, Subgroup 6C, peas, dry 0.1 Oilseeds, Rapeseed Subgroup 20A, seed 0.8 0.45 Rapeseed Subgroup 20A Cattle, liver - 2.5 Cattle, meat by

products , except liver - 0.05 Goat, liver - 2.5 Goat, meat by

products , except liver - 0.05 Sheep, liver - 2.5 Sheep, meat by

products , except liver - 0.05 Horse, liver - 2.5 Horse, meat by

products , except liver - 0.05 Note: In conjunction with establishing these tolerances, the existing tolerance for “Vegetable, foliage of legume, group 7 ” should be modified to “Vegetable, foliage of legume, group 7 (except pea hay)”; the existing tolerance for “ Vegetable, legume, group 6 ” should be replaced with " Vegetable, legume, edible podded, subgroup 6A " plus " Pea and bean, succulent shelled, subgroup 6B "; and the existing tolerances for “ Sunflower, seed ” and " Cotton, undelinted seed " should be deleted.