Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 1 of 24 **UNITED STA TES ENVIRONMENTA**  **L PROTECTION A GENCY**  WA SHINGTON, D.C. 20460 **OFFICE OF CHEMICAL SAFETY AND**  **POLLUTION PREVENTION MEMORANDUM**  **DATE:** 04 - AUG - 20 11 **SUBJECT** : **Saflufenacil.** Human - Health Risk Assessment for Proposed Tolerances for

Residues in/on Imported Coffee, Banana, and Mango . **PC Code:** 118203 **DP Barcode:** D 384602 **Decision No.:** 4 42242 **Registration No. :**  NA **Petition No.:** 0E7806 **Regulatory Action:** Tolerances With No U.S. 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

Chester E. Rodriguez, Ph.D., Toxicologist 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 pesticid es. 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 tolerances fo r residues in/on imported coffee, banana, and mango . The petitioner is BASF . 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 , residue chemistry data review, and dietary

exposure assessment were provided by George Kramer (RAB1), the hazard characterization by Chester Rodriguez (RAB1), and the drinking water assessment by Greg Orrick of the Environmental Fate and Effects Division (EFED).Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 2 of 24 **Table of Contents 1.0 Executive Summary**  **................................ ................................**  **................................ ...............**  **3 2.0 Ingredient Profile**  **................................ ................................**  **................................ ...................**  **6 2.1 Summa**  **ry of Registered/Proposed Uses ................................**  **................................ ...**  **6 2.2 Structure and Nomenclature**  **................................ ................................**  **.................... 7**  **2.3 Physical and Chemical Properties ................................**  **................................ ............**  **8 3.0 Hazard Characterization/Assessment**  **................................ ................................**  **.................. 8**  **3.1 Mode of Action and Toxicological Studies Available for Evaluation ...................**  **8 3.2 Absorption, Distribution, Metabolism, and Elimination (ADME)**  **....................... 8**  **3.3 Hazard Profile ................................**  **................................ ................................**  **............ 9**  **3.4 FQPA Cons iderations**  **................................ ................................**  **.............................. 10**  **3.5 Toxicity Endpoint and Point of Departure Selection ................................**  **............ 11**  **3.6 Endocrine Disruption ................................**  **................................ ..............................**  **12 4.0 D**  **ietary Exposure/Risk Characterization ................................**  **................................ ..........**  **13 4.1 Pesticide Metabolism and Environmental Degradation**  **................................ .......**  **13 4.1.1 Metabolism in Primary Crops**  **................................ ................................**  **. 13**  **4.1.2 Analytical Methodology ................................**  **................................ ............**  **13 4.**  **1.3 Environmental Degradation ................................**  **................................ ....**  **13 4.1.4 Comparative Metabolic Profile**  **................................ ...............................**  **14 4.1.5 Toxicity Profile of Major Metabolites and Degradates**  **......................... 14**  **4.1.6 Pesticide Metabolites and Degradates of Concern ................................**  **. 14**  **4.1.7 Drinking Water Residue Profile ................................**  **.............................. 14**  **4.1.8 Food Residue Profile ................................**  **................................ .................**  **15 4.1.9 International Residue Limits**  **................................ ................................**  **... 15**  **4.2 Dietary Exposure and Risk ................................**  **................................ .....................**  **15 4.2.1 Acute Dietary Exposure/Risk**  **................................ ................................**  **... 15**  **4.2.2 Chronic Dietary Exposure/Risk ................................**  **............................... 16**  **4.2.3 Cancer Dietary Risk ................................**  **................................ .................**  **16 4.3 Anticipated Residue and %CT Information**  **................................ .........................**  **16 5.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **................................ .**  **17 6.0 Aggregate Risk Assessments and Risk Characterization**  **................................ .................**  **17 7.0 Cumulative Risk Characterization/Assessment**  **................................ ................................**  **17 8.0 Data Needs and Label Recommendations**  **................................ ................................**  **......... 17**  **8.1 Toxicology ................................**  **................................ ................................**  **................. 17**  **8.2 Residue Chemistry ................................**  **................................ ................................**  **... 17**  **Appendix A: Toxicology Assessment ................................**  **................................ .......................**  **18 A.1 Toxicology Data Requirements for Saflufenacil**  **................................ ..................**  **18 A.2 Toxicity Profiles**  **................................ ................................**  **................................ .......**  **19 Appendix B**  **: Tolerance Summary Table ................................**  **................................ .................**  **24**Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 3 of 24 **1.0 Executive Summary**  Saflufenacil is a pre - and post - emergence herbicide that acts b y inhibiting protoporphyrinogen IX oxidase, 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 chlorophyll 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 accumu lation of different porphy rins and their precursors in various organs. 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, an d straw of cereal grains (Crop Group 16), cotton, and sunflower. BASF has submitted a petition for tolerances for residues of saflufenacil in/on imported coffee, banana, and mango . **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 i n 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, mice , 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 parameters [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 levels (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 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. These effects also occurred around the same dos e level from short - through long - term exposures without increasing in severit y. 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 maternall y toxic in the developmental study in rats, indicating increased quantitative susceptibility. In rabbits, developmental effects such as increased liver porph yrins were observed at doses (200 mg/kg/ day) that were not maternall y toxic, indicating increasedSaflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 4 of 24 quantitative susceptibility. In the 2 - generation reproductive toxicity study in rats, the reported offspring effects we re more severe than the maternal effects at the same dose level, indicating evidence for increased qualitative susceptibility . For instance, an increased number of stillborn pups, decreased viability

and lactation indices, decreased pre - weaning body weight and/or body weight 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 following reasons:  The concern for increased susceptibility following prenatal or postnatal exposure is low since (1) clear no - observed adverse - effect levels (NOAELs) w ere established for the developmental effects seen in rats and rabbits as well as for the offspring effects seen in the two - generation reproductive toxicity study ; (2) the dose - response relationship for the effects of concern are also well - characterized an d being used for assessing dermal and inhalation risks; (3) none of the effects in the developmental or reproduction studies were attributable to a single exposure and, therefore, are not of concern for acute risk assessment; and ( 4 ) the dose used to evalu ate chronic dietary risks is lower than the NOAELs for fetal/offspring effects in the developmental and reproduction studies and is, therefore, protective of the developmental and offspring effects observed in these studies .  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 an y study in the database including the acute and subchronic neurotoxicity studies.  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 PADSaflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 5 of 24 (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. Since an oral study was used, a dermal absorption factor of 3% was used for the dermal risk assessment. Inhalation toxicity is assumed to be equivalent to oral toxicity . 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 tolerance - 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 dietary 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 population subgroup , all infants (<1 year old) , is 3 1 % 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 + drinking water exposure only . The acute and chronic dietary estimates represent acute and chronic aggregate risk , respectively . **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 Addres s 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 acco rding to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involv eSaflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 6 of 24 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 assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized 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 adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgro ups. **Recommendation for Tolerances** Pending submission of a revised Section F (see requirements under Proposed Tolerances) , there are no residue chemistry

or toxicology

issues that would preclude granting the following permanent tolerances : “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 - (trifluoromethyl) - 1(2H ) - pyrimidinyl] - 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(2 H ) - 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 following commodities.” Coffee, green bean 0.03 ppm Banana 0.03 ppm Mango 0.03 ppm **Note to RD:** These tolerances should include a footnote stating “No U.S. registrations as of [date of FR notice].” Data Gaps See Section 8 .0 for data needs. **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 pet ition for tolerances for saflufenacil residues in/on coffee, banana, and mango imported from Central and South America. BASF has submitted a draft Brazilian label for the 70% water - dispersibleSaflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 7 of 24 granule (WDG) formulation (Heat ® ), which is representative of the Central and South American labels. A summary

of the proposed use patterns is detailed in Table 2.1.2. **Table 2.1.2. Summary of Directions for Use of Saflufenacil.** Applic. Timing, Ty pe, and Equip. Form

ulation App. rate

(lb ai/acre) Max. No.

App. per Season Max. Seasonal

App. Rate (lb ai/acre) PHI

(days) Use Directions and

Limitations Coffee, Banana, and Mango Ground directed to weeds Heat ® 0.022 - 0.044 3 0.131 7 (coffee) 15 (mango) 30 (banana) Applications are to be

made in 16 - 43 gal/acre Note: A non - ionic adjuvant system is required for optimum activity. Conclusions: The submitted use directions for Heat ® are adequate to allow evaluation of the residue data relative to the proposed uses. **2.2 Structure and Nomenclature**  **Table 2.2. Saflufenacil and Metabolite 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 - chloro - 4 - fluoro - 5 - (3 - methyl - 2,6 - dioxo - 4 - (trifluoromethyl) - 3,6 - dihydro - 1(2H ) - pyrimidinyl)benzoyl] -N

- isopropyl -N

- methylsulfamide CAS name 2 - chloro - 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 - chloro - 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 - chloro - 2 - fluoro - 5 - ({[(isopropylamino)sulfonyl]amino}carbonyl)phenyl]urea Cl F N N O

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

Cl F N N H O

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

3 C H 3

Cl F N H O

O N H S N H O O C H3 C H3 N H2Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 8 of 24 **2.3 Physical and Chemical Properties**  **Table 2. 3.**  **Physicochem ical 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 butyrolactone; 2.98 methanol; 0.25 isopropyl alcohol; 0.23 toluene; <0.01 1 - octanol; <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 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 Reference : BA SF Registration Document Number (DocID) 2005/1026464. **3.0 Hazard Characterization/Assessment**  **3.1 Mode of A**  **ction and T**  **oxicological Studies Available for Evaluation** 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 chlorophyll and heme. When protoporphy

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

and mode of action. Its toxicity database is adequate to suppo rt registration. In the last risk assessment (Austin, et al. , 7/22/09; D367317 ), the onl y database deficiency noted was the lack of a guideline immunotoxicity study as part of the revised toxicity data requirements in the 40 CFR Part 158 for conventional pesticide registration . Since then, an immunotoxicity study has been submitted and reviewed b y the Agency . The evaluation of the immunotoxicity study is included in this hazard assessment. **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 concentrations w ere reached within 1 hour of dosing and declined rapidly . Excretion of saflufenacil was essentially complete within 96 hours, with the majority eliminated within the first 24 to 48 hours. The blood and plasma data demonstrated that the majority of the sa flufenacil residues occurred in theSaflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 9 of 24 plasma and were not bound to cellular elements 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 th e major route of elimination in females. The sex - dependent excretion was more pronounced at the low - dose level and resulted in males having up to three fold higher internal exposures than females and being in some cases more sensitive to toxicity than fem ales . 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 resid ues remained very

low in tissues at168 hours after dosing, occurring mainl y in carcass, liver, skin, and gut contents. Exhalation was not a relevant excretion pathway . **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 yrinogen oxidase inhibition and subsequent disruption of heme biosy nthesis, decreased hematological parameters [RBC, Ht, MCV, MCH, MCHC] were seen at ab out 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 lo ng - term exposures without increasing in severity . Effects were also seen in the liver (increased weight, centrilobular fatty

change, and ly

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

hematopoiesis) in rats, and in bo th these organs (increased iron storage 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 severit y. In an acute neurotoxicity

study , a decrease in motor activity was observed on the day of dosing at the limit dose (2000 mg/kg) in males onl y. The finding was not accompanied by an y 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 ys temic 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 susceptibility was observed in the developmental toxicity studies in the rat and rabbit and in the 2 - generation reproduction study in the rat. Devel opmental 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, devel opmental effects such as increased liver porph yrins were observed at doses (200 mg/kg/d ay) that were not maternall y toxic, indicating increased quantitative susceptibility. In the 2 - generation reproductive toxicity study in rats, the reported offspring ef

fects were more severe than the maternal effects at the same dose level, indicating evidence for increased qualitative susceptibility . For instance, an increased number of stillbornSaflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 10 of 24 pups, decreased viability

and lactation indices, decreased pre - weaning bo dy weight and/or body weight 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. In a 28 - day

dermal toxicity

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

up to the limit dose of 1000 mg/kg bw/day . In a recentl y submitted 28 - day immunotoxicity

study , saflufenacil failed to induce toxicity spec ific to the immune sy stem at the highest dose tested (i.e., 52 mg/kg bw/day), indicating that saflufenacil does not directly target the immune system at the dose levels being used for risk assessment . 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.” **3.4 FQPA 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 subchronic neurotoxicity studies (2); and  Immunotoxicity

study (1). The saflufen acil 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 were established for the developmental effects seen in rats and rabbits as well as for the offspring effects seen in the two - 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; (3) none of the effects in the developmental or reproduction studies were attributable to a single exposure and, therefore, are not of concern for acute risk assessment; and ( 4 ) the dose used to evaluate chronic dietary

risks is lower than the N OAEL s for fetal/offspring effects in the developmental and reproduction studies and is, therefore, protective of the developmental and offspring effects observed in these studies . .  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 n europathology

in an y study in the database including the acute and subchronic neurotoxicity studies.  There are also no additional residual uncertainties with respect to exposure data. The dietary food exposure assessment utilizes recommended tolerance - l evel residues andSaflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 11 of 24 100% 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 m odeling parameters that 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 extrapolation (10X) and intraspecies variation (10X). Thus, the aPAD is calculat ed to be 5.0 mg/kg bw (NOAEL of 500 mg/kg bw divided by 100). Acute Dietary Endp oint (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 wavy ribs) observed in the prenatal developmental 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 b y 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 se veral 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 extrapolation (10X) and intraspecies variation . Thus, the cPAD is 0.046 mg/kg bw/day

(NOAEL of 4.6 divided by 100) (Table 3.5). **Table 3.5. Summ ary of Toxicological Doses and Endpoints for Safl**  **ufenacil for Use in Dietary Hum an**  **- Health**  **Risk Assessments. Exposure**  **Scenario Point of** 

**Departure Uncertainty/** 

**FQPA SFs 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 **aRfD** = 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.Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 12 of 24 **Table 3.5. Summ ary of Toxicological Doses and Endpoints for Safl**  **ufenacil for Use in Dietary Hum an**  **- Health**  **Risk Assessments.** Chronic Dietary (All Populations) NOAEL = 4.6

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X **cRfD** = 0.046

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

NOAEL = 4.6 mg/kg bw/day. 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: Not 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 dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower envir onmentally 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. **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 similar to an effect produced by a “naturally

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations . Tier 1 consists of a battery of 11 screening assay s to identify the p otential 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 potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify an y adverse endocrine related effects caused by the substance, and establish a dose - r esponse relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Thi s list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application agricultural scenarios. This list should not be construed as a list of known or likely e ndocrine disruptors. 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 screen all pesticide chemicals. Accordingl y, EPA anticipates issuing f uture 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/.Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 13 of 24 **4 .0**  **Dietary Exposure/Risk Characterization** The following references apply to this section: Residue Chemistry

Summary - D390922 , G. Kramer, 04 - AUG - 2011 Dietary Exposure - D390923 , G. Kramer, 04 - AUG - 2011 Drinking Water Degradates Identification - D 356619, G. Orrick, 01 - DEC - 2008 Estimated Drinking Water Concentrations (EDWCs) - D 349860, G. Orrick, 1 5 - APR - 200 9 **4 .1**  **Pesticide Metabolism and Environmental Degradation 4**  **.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 pre - plant/pre - emergence application. The main reactions involved in the metabolic pathway of saflufenacil were N

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

- methyl -N

- isopropyl group, hydrol yt ic cleavage of the uracil ring generating a urea side chain, and hydroxylation of the phenyl ring. The HED Residues of Concern Knowle dgebase 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 ). This conclusion was translated to perennial crops (i.e., tre e fruits and tree nuts) where saflufenacil application is directed to the weeds on the orchard floor (Memo, G. Kramer, 7/22/09; D 349938 ). As the proposed use on coffee, banana, and mango is also directed to weeds at the base of the plants, HED concludes that the residues of concern for the tolerance expression and risk assessment also consist of saflufenacil, M800H11, and M800H35 for these crops. **4 .1.**  **2 Analytical Methodology**  BASF Method D0603/02 is the current enforcement method for determination of residues of saflufenacil and its metabolites M800H11 and M800H35 in different plant matrices. Residues of saflufenacil and its metabolites M800H11 and M800H35 were extracted with methanol:water (70:30; v:v). The methanol extract was evaporated and recons tituted in methanol:water (50:50; v:v) for liquid chromatography /mass spectroscopy/mass spectroscopy (LC - MS/MS) analy sis. Two transitions per anal yte were monitored for the quantitation and confirmation of saflufenacil, M800H11 and M800H35. The residues of each analy te were expressed as parent equivalents using a molecular weight conversion factor (1.0 for saflufenacil, 1.06 for M800H11, and 1.42 for M800H35). The limit of quantitation (L OQ) was 0.01 ppm for each anal yt e. The limit of detection (LOD) wa s reported to be 3X the standard deviation (SD) at the LOQ for each anal yt e (0.002 - 0.003 ppm) . Recovery samples, prepared at levels of LOQ and 10X LOQ in each matrix, were generally

within the acceptable range of 70 - 120%. **4 .1.**  **3 Environmental Degradation**  Saflufenacil 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 readil y h ydrolyzed 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 Human - Health Risk Assessment DP Number : 384602

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Page 14 of 24 Saflufenacil biodegrades in 1 to 5 weeks in aerobic soil (half - lives of 8.5 - 34 day s) and less quickly in a erobic aquatic 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. Dissipation occurred with half - live s 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 d egradates 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 majo r 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, Table B.1.2 of Austin, et al. , 7/22/09; D367317 ). **4 .1.**  **4 Comparative Metabolic Profile**  The primary

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

- methyl -N

- isopropyl group, and hydroly tic 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. **4 .1.**  **5 Toxicity**  **Profile of Major Metabolites and Degradates** T oxicity data w ere not submitted for the metabolites of saflufenacil. **4 .1.**  **6 Pesticide Metabolites and Degradates of Concern**  **Table 4**  **.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 + M800H01, M800H02, M800H07, M800H08, M800H15, M800H22, Product 8 Not Applicable **4 .1.**  **7 Drinking Water Residue Profile**  The EDWCs 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 incorporatedSaflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 15 of 24 directly into the DEEM - FCID TM in the food categories “water, direct, all sources” and “water, indirect, all sources.” Screening EDWCs ( Table 4 .1.9 ) of saflufenacil were generated with FQPA Index Reservoir Screening Tool (FIRST) for surface water 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 4 .1.8 ). **Table 4**  **.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 (used in acute analysis) 173 (used in chronic analysis) **4 .1.**  **8 Food Residue Profile**  The submitted magnitude of the residue data for coffee, banana, and mango are adequate. There are also adequate storage stability data to validate the storage conditions and intervals of samples collected from the field trials. Quantifiable residues were not found in coffee RAC samples (green beans) e ven after application of saflufenacil at exaggerated rates (~3X); therefore, anal ys is of coffee processed fractions (roasted beans, instant coffee) was not necessary and separate tolerances for processed fractions are not required. Analy tical standards of saflufenacil (expiration date: 2/1/13), M800H11 (expiration date: 7/1/14), and M800H35 (expiration date: 7/1/14) are currently available in the National Pesticide Standards Repository

[source: personal communication with T. Cole of Analy tical Chemistry Laboratory

(ACL)/Biological and Economics Analy sis Division (BEAD), 6/20/11]. A summary

of the recommended tolerances for the current petition are listed in Appendix C: Tolerance Reassessment Summary . The petitioner should submit a revised Section F reflecting the recommended tolerances and commodity definitions presented in Appendix C. **4 .1.**  **9 International Residue Limits**  There are no Canadian or Codex maximum residue limits (MRL s) established for residues of saflufenacil and its metabolites in coffee, banana, and mango commodities. Harmonization is thus not an issue for this petition. **4 .2**  **Dietary Exposure and Risk 4**  **.2 .1**  **Acute Dietary Exposure/Risk** The unrefined acute analysis assumed 100% CT, DEEM TM 7.81 default concentration factors, and t olerance - level residues for all commodities [except for cottonseed; sunflower subgroup 20B;Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 16 of 24 soy bean, seed; vegetable, legume, subgroup 6C, pea and bean (except soy bean); and rapeseed subgroup 20A for which the recommended tolerance levels were multiplied b y 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

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 0.010415 mg/kg/day for the general U.S. population (<1% of the aPAD) and 0.038388 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 4 .2 ). **4 .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 cott onseed; sunflower subgroup 20B; soy bean, seed; vegetable, legume, subgroup 6C, pea and bean (except soy bean); and rapeseed subgroup 20A for which the recommended tolerance levels were 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 assessment using the concentration for ground water generated b y PRZM GW (173 ppb) . The chronic dietary exposure and risk estimates (food + wat er) are 0.004232 mg/kg/day for the general U.S. population ( 9.2 % of the cPAD) and 0.014043 mg/kg/day ( 3 1 % of the cPAD) for the most highly exposed population subgroup [ all infants (<1 year old) ] and are , thus , below HED’s LOC (<100% cPAD ; Table 4 .2 ). **Tabl e**  **4 .2. Summ**  **ary of Dietary (Food and Drinking Water) Exposure and**  **Risk for Saflufenacil.** 1 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 0.010415 <1 0.004232 9.2 All Infants (<1 year old) **0.038388** <1 **0.014043 31**  Children 1 - 2 years old 0.017262 <1 0.007290 16 Children 3 - 5 years old 0.015438 <1 0.006535 14 Children 6 - 12 years old 0.010471 <1 0.004383 10 Youth 13 - 19 years old 0.008451 <1 0.003164 6.9 Adults 20 - 49 years old 0.009266 <1 0.003821 8.3 Adults 50+ years old 0.008388 <1 0.003959 8.6 Females 13 - 49 years old 0.009336 <1 0.003802 8.3 1 The population subgroup with the greatest exposure is in bold. **4 .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 (a cancer dietary risk assessment was not conducted) . **4 .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.Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 17 of 24 **5 .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 .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 - , intermediate - , and long - term aggregate - risk 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 not a carcinogen an d cancer risk is not a concern. **7 .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 findi ng 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

EPA’s Office of Pes ticide 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/. **8 .0**  **Data Needs and Label Recommendations 8**  **.1 Toxicology** 

 none **8 .2**  **Residue Chemistry** 860.1550 Proposed Tolerances The petitioner is requested to submit a revised Section F specifying the following:

 Revised tolerance l evels and commodity definitions , as presented in Appendix B : Tolerance Summary

Table. cc: G. Kramer (RAB1) RDI: RAB1 ( 8 / 3 /11) G.F. Kramer:S10957:PY - S:(703)305 - 5079:7509P:RAB1Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 18 of 24 **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 Neurotoxicity Screening Battery (rat) ................. 870.6200b 90 - Day Neurotoxicity Screening Battery (rat) ............... 870.6300 Developmental Neurotoxicity ................................ ........ 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 : 384602

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Page 19 of 24 **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 Saflufenacil.** 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, 112/153.1, 335/446, 882/1630 mg/kg bw/day. LOAEL = 36.6 mg/kg bw/day (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/day. LOAEL = 153.1 mg/kg bw/day (females) based on moderate centrilobular fatty change in the liver. NOAEL = 63.4 mg/kg bw/day. 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/day . LOAEL = 39.2 mg/kg bw/day (males) based on decreased Hb, MCV, and MCH. NOAEL =13.4 mg/kg bw/day. LOAEL = 130.4 mg/kg bw/day (females) based on decreased Hb, Ht, MCV, and MCH. NOAEL = 43.6 mg/kg bw/day. 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 /day (males) based on multiple hematological changes, liver - weight increases with centrilobular fatty change and lymphoid infiltrate in males. NOAEL = 12.4mg/kg bw/day. LOAEL = 156.6 mg/kg/day (females) based on increased liver weight with centrilobular fatty change and lymphoid infiltrate. NOAEL = 51.8 mg/kg/day.Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 20 of 24 **Table A.2.2. Subchronic, Chronic ,**  **and Other Toxicity Profile for Saflufenacil.** 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, 12.6, 110.5, 344.7 mg/kg bw/day. LOAEL = 32.3 mg/kg bw/day (M) and 110.5 mg/kg bw/day (F) based on multiple hematological effects and increased spleen weight and extramedullary hematopoiesis. NOAEL = 10.5 (M), 12.6 mg/kg bw/day (F). 870.3150 28 - Day Oral Toxicity feeding dog 47128112 (2005) Acceptable/non - guideline 0, 30, 100, or 300 mg/kg bw/day. LOAEL = 100 mg/kg bw /day 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/day. 870.3150 90 - Day Oral Toxicity feeding dog 47128113 (2006) Acceptable/guideline 0, 10, 50, or 150 mg/kg bw/day . LOAEL = 50 mg/kg bw/day based on lower MCV and MCH values in both sexes. NOAEL = 10 mg/kg bw/day. 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 /day. 870.3700a Prenatal developmental in (rat) 47128115 (2007) Acceptable/guideline 0, 5, 20, or 60mg/kg/day . **Maternal** NOAEL = 20 mg/kg/day. LOAEL = 60 mg/kg/day based on decreased 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 (rabbi t) 47128116 (2006) Acceptable/guideline 0, 50, 200, or 600 mg/kg/day . **Maternal** NOAEL = 200 mg/kg bw/day. LOAEL = 600 mg/kg bw /d based on mo rtality and increased necropsy findings. **Developm ental**  NOAEL = 50 mg/kg/day LOAEL = 200 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/day . **Parental System ic**  NOAEL = 15 mg/kg/day. **Parental System ic**  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/day. **Offspring** LOAEL = 50 mg/kg/day based on decreased 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 : 384602

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Page 21 of 24 **Table A.2.2. Subchronic, Chronic ,**  **and Other Toxicity Profile for Saflufenacil.** 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/day . LOAEL = 80 mg/kg bw/day based on decreased albumin, MVH, and MCH. NOAEL = 20 mg/kg bw/day. 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 /day . LOAEL = 31.4 mg/kg bw/day (females) based on decreased hemoglobin, Ht, MCV and MCH. NOAEL = 6.2 mg/kg bw/day (females). LOAEL was not established in males. NOAEL = 24.2 mg/kg bw/day. **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 /day . satellite groups: M = 0, 14.2 . F = 0, 39.0 mg/kg bw/d . NOAEL = 4.6 mg/kg bw/day (males) and 18.9 mg/kg bw/day (females). LOAELs = 13.8 mg/kg bw/day (males) and 38.1 mg/kg bw/day (females) based on decreased red blood cells, hemoglobin, and Ht and porphy

ria observed in the satellite group. **No evidence of carcinogenicity.** Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 47128121 (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 870.5300 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 47128124 (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 was not clastogenic in the absence of metabolic activation. Cy togenetics - other 870.5395 In Vivo Mammalian Cy togenetics - Ery

throcyte Mi cronucleus 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. Sy stemic NOAEL = 500 (M) and 2000 (F)Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 22 of 24 **Table A.2.2. Subchronic, Chronic ,**  **and Other Toxicity Profile for Saflufenacil.** Guideline No./ Study Type **MRID (yr.)/Classification/Doses Results**  mg/kg bw. There 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/day. Sy stemic LOAEL = 66.2 (males) and 101 (females) mg/kg bw/day based on decreased hemoglobin, Ht, mean corpuscular volume , and MCH. There was no evidence of neurotoxicity. 870.7485 Metabolism an d 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 the 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 signifi cantly higher biliary excretion of saflufenacil residues in males 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 was metabolized 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 sulfonylamid e 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 : 384602

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Page 23 of 24 **Table A.2.2. Subchronic, Chronic ,**  **and Other Toxicity Profile for Saflufenacil.** Guideline No./ Study Type **MRID (yr.)/Classification/Doses Results**  870.760 0 Dermal penetration (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 - guideline 0, 10, 50, or 1000 ppm ( ♂ = 0, 0.8, 4.1, 80.6; ♀ = 0, 0.9, 4.6, 89.5 mg/kg bw/day, 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/day) . 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 feca l porphyrin only in males. There were no effects on hematology parameters.Saflufenacil Human - Health Risk Assessment DP Number : 384602

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Page 24 of 24 **Appendix B: Tolerance Summary Table Table B.1. Tolerance Summary for Saflufenacil.**  Commodity Proposed Tolerance (ppm) HED - Recommended

Tolerance (ppm) Correct Commodity

Definition/Comments Coffee, green bean 0.03 0.03 Banana, whole fruit 0.03 0.03 Banana Mango, fruit 0.03 0.03 Mango **Note to RD:** These tolerances should include a footnote stating “No U.S. registrations as of [date of FR notice].”