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### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM **D ate**  **:** 0 5 - JUN - 20 1 4 **SUBJECT: Sulfentrazone**  **–** Preliminary Human - Health Risk Assessment for Registration Review and the Risk Assessment for the Section 3 Registration Request for a New Use on Apples **PC Code:** 129081 **DP Barcode:** D410365 **Decision Nos.:** 476747, 483232 **Registration Nos.**  **:** 279 - 3370, 279 - 3189, & 279 - 3220 **Petition No.:** 3E8202 **Regulatory Action:** Section 3 and Registration Review Risk Assessments **Risk Assessment Type :**  Single Chemical/Aggregate **Case No.:** 7231 **T XR No.:**  NA **CAS No.:** 122836 - 35 - 5 **MRID No.:** NA **40 CFR:** §180.498 

### F **rom :**  George F. Kramer, Ph.D., Senior Chemist

Kelly M. Lowe, Environmental Scientist Anwar Y. Dunbar, Ph.D., Pharmacologist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED; 7509P) **T hrough**  **:** Charles W. Smith III, Branch Chief

RAB1/HED (7509P) **T o**  **:** Laura Nollen/Barbara Madden, RM 05

Registration Division (RD, 7505P) and Christina Scheltema Pesticide Reevaluation Division (7509P) As part of Registration Review, the Pesticide Re - evaluation Division (PRD) of OPP has requested that HED evaluate the hazard and exposure data and conduct occupational and residential exposure assessments, as needed, to estimate the risk to human health th at will result from the currentl y registered uses of pesticides. This memorandum serves as HED’s Preliminary Registration Review risk assessment of the dietary, occupational and residential handler , post application exposure , and aggregate risk from the registered/proposed uses of sulfentrazone. In addition, the Registration Division (RD) requested that HED conduct an exposure and riskSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### assessment for the proposed new use of sulfentrazone on apples. This memorandum provides HED’s human - health risk assessment conducted in support of th is request to establish tolerances for residues of sulfentrazone and its metabolites HMS ( N - (2,4 - dichloro - 5 - (4 - (difluoromethyl ) - 4,5 - dihydro - 3 - hydrox ym ethyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl )p henyl )methanesulfonamide) and DMS ( N - (2,4 - dichloro - 5 - (4 - (difluoromethyl ) - 4,5 - dihydro - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl )phenyl )methanesulfonamide in/on apples. A summary

of the findings and an assessment of human risk resulting from the registered and proposed u ses are provided in this document. The risk assessment , dietary risk assessment, and residue chemistry

review were provided by George Kramer (RAB1), the o ccupational/residential exposure and risk assessment was provided b y Kelly Lowe (RAB1) , the hazard ch aracterization was provided b y Anwar Dunbar (RAB1), and the drinking water assessment was provided b y Michael Barrett of the Environmental Fate and Effects Division (EFED).Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Table of Contents 1.0 Executive Summary ................................ ................................ ................................ ................................ ........ 5 2.0 Recommendations ................................ ................................ ................................ ................................ ........... 7 2.1 Data Deficiencies/Data Needs ................................ ................................ ................................ ............. 8 2.2 Tolerance Considerations ................................ ................................ ................................ .................... 8 2.2.1 Enforcement Analytical Method ................................ ................................ ................................ .............. 8 2.2.2 Recommended Tolerances ................................ ................................ ................................ ....................... 8 2.2.3 Revisions to Petitioned - For Tolerances ................................ ................................ ................................ . 10 2.2.4 International Harmonization ................................ ................................ ................................ .................. 11 2.3 Label Recommendations ................................ ................................ ................................ ................... 11 3.0 Ingredient Profile ................................ ................................ ................................ ................................ ........... 11 3.1 Chemical Identity ................................ ................................ ................................ .............................. 11 3.2 Phy sical/Chemical Properties ................................ ................................ ................................ ............ 12 3.3 Use Pattern ................................ ................................ ................................ ................................ ........ 12 3.4 Anticipated Exposure Pathways ................................ ................................ ................................ ........ 17 3.5 Consideration of Environmental Justice ................................ ................................ ............................ 17 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................................ ............ 17 4.1 Toxicology Studies Available for Analysis ................................ ................................ ....................... 18 4.2 Absorption, Distribution, Metabolism, & Excretion (ADME) ................................ .......................... 18 4.2.1 Dermal Absorption ................................ ................................ ................................ ................................ 18 4.3 Toxicological Effects ................................ ................................ ................................ ........................ 18 4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ................................ .......................... 20 4.4.1 Com

pleteness of the Toxicology Database ................................ ................................ ............................ 20 4.4.2 Evidence of Neurotoxicity ................................ ................................ ................................ ..................... 20 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ................................ ......... 20 4.4.4 Residual Uncertainty in the Exposure Database ................................ ................................ .................... 20 4.5 Toxicity Endpoints and Point of Departure Selections ................................ ................................ ...... 21 4.5.1 Dose - Response Assessment ................................ ................................ ................................ ................... 21 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ................................ ....... 23 4.5.3 Cancer Classification and Risk Assessment Recommendation ................................ ............................. 23 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human - Health Risk Assessment ... 23 4.6 Endocrine Disruptor Screening Program ................................ ................................ ........................... 25 5.0 Dietary Exposure and Risk Assessment ................................ ................................ ................................ ........ 26 5.1 Metabolite/Degradate Residue Profile ................................ ................................ ............................... 26 5.1.1 Summary of Plant and Animal Metabolism Studies ................................ ................................ .............. 26 5.1.2 Summary of Environmental Degradation ................................ ................................ .............................. 26 5.1.3 Com

parison of Metabolic Pathways ................................ ................................ ................................ ...... 27 5.1.4 Residues of Concern Summary and Rationale ................................ ................................ ....................... 27 5.2 Food Residue Profile ................................ ................................ ................................ ......................... 27 5.3 Drinking Water Residue Profile ................................ ................................ ................................ ........ 28 5.4 Dietary (Food + Drinking Water) Risk Assessment ................................ ................................ .......... 29 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ ................................ 29 6.1 Residential Handler Exposure/Risk Estimates ................................ ................................ .................. 30 6.2 Residential Post - application Exposure/Risk Estimates ................................ ................................ ..... 32 6.3 Residential Risk Estimates for Use in Aggregate Assessment ................................ .......................... 32 6.4 Spray Drift ................................ ................................ ................................ ................................ ......... 33 6.5 Residential Bystander Post - Application Inhalation Exposure ................................ ........................... 34 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ................................ ... 34 7.1 Ac ute Aggregate Risk ................................ ................................ ................................ ....................... 34 7.2 Short - and Intermediate - Term Aggregate Risk ................................ ................................ ................. 34 7.3 Chronic Aggregate Risk ................................ ................................ ................................ .................... 35 7.4 Cancer Aggregate Risk ................................ ................................ ................................ ...................... 36 8. 0 Cumulative Exposure/Risk Characterization ................................ ................................ ................................ . 36 9.0 Occupational Exposure/Risk Characterization ................................ ................................ .............................. 36 9.1 Handler Risk Assessment ................................ ................................ ................................ .................. 36 9.2 Post - Application Risk Assessment ................................ ................................ ................................ .... 41 9.2.1 Inhalation Post - Application Risk Assessment ................................ ................................ ....................... 41 9.2.2 Dermal Post - Application Risk Assessment ................................ ................................ ........................... 41Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 4 of 57 10.0 References ................................ ................................ ................................ ................................ ..................... 42 Appendix A. Toxicology Profile and Executive Summaries ................................ ................................ ...................... 43 Appendix B. Methodologies for HEC Calculations. ................................ ................................ ................................ ... 49 Appendix C. Physical/Chemical Properties ................................ ................................ ................................ ................ 54 Appendix D. International Residue Limits ................................ ................................ ................................ ................. 55Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### 1.0 **Executive Summary**  Sulfentrazone is an aryl triazolinone herbicide used to control a variety of broadleaf weeds. Sulfentrazone acts b y the same mechanism as the diphenyl ether herb icides in which membrane disruption is initiated by

the inhibition of protoporphy rinogen oxidase (PPO) in the chlorophyl l biosy nthetic pathway

and leads to the subsequent build - up of toxic intermediates. Plants emerging from soils treated with sulfentrazo ne turn necrotic and die shortly after exposure to light. This preliminary

risk assessment provides information to support the Registration Review of sulfentrazone , and addresses the exposures and risk estimates associated with all currentl y registered an d proposed uses. Since the last risk assessment, new data have been submitted and policies have changed. This document incorporates changes made to the selected endpoint s, toxicological points of departure (PODs), exposure and risk estimates, recommended tolerances, and the potential for spray- drift exposure. All data requirements previously addressed during the scoping process have been satisfied (K. Lowe, D369064, 09/09/2009). In addition, this document evaluate s the petition submitted by Interregional Research Project No. 4 (IR - 4; PP# 3 E 8202 ) that proposes new tolerances for residues of sulfentrazone and its metabolites on apples. Hazard Assessment: Results of mammalian toxicity studies were consistent with PP O inhibition , given that PPO is an important enzy me in the heme sy

nthetic pathway

in mammals. Specificall y, toxicity

reflective of disruption of heme sy nthesis (hematotoxicity) was observed in mice, rats, and dogs, and this was seen at about the same dose levels in the oral studies across species, except in the case of mice, where the effects were seen at a slightly higher dose. In addition, this hematotoxicity occurred around the same dose level from short - through long - term exposure without increasing in severity . Sulfentrazone caused developmental effects via the oral and dermal routes of exposure. Developmental effects, including decreased fetal body weights and reduced/delayed skeletal ossifications, were observed in both the oral and dermal devel opmental toxicity studies in the rat in the absence of maternal toxicity . In the two - generation reproduction study in rats, offspring effects, such as decreased body weights and decreased litter survival were observed at doses that were maternall y toxic ( decreased body weight during gestation in both generations). In a route - specific 28 - day dermal toxicity study in adult rabbits, there were no effects up the highest dose tested . In the route - specific 26 - day inhalation study , there were portal - of - entry ef fects in the nasal passage and s ys temic effects , including decreased body weights and changes in numerous hematological parameters. Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumor formation due to treatment with sulfentrazone and genotoxicity studies were all negative. F ood Quality Protection Act (F QPA ) Safety Factor (

SF ) Decision: The sulfentrazone risk assessment team concludes that the 1 0X FQPA SF should be reduced to 1X since the toxicology database is adequate for assessment of the registered and proposed uses, selected endpoints are protective of the effects seen in the neurotoxicity studies as well as the increased susceptibility to offspring observed in developmental studies, and the conservative nature of the dietary and residential exposure analyses are unlikel y to underestimate exposure [ tolerance - level residues, 100% crop treated (%CT) ; use of 2012 Residential Standard Operating Procedures (SOPs) ] .Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Dose Response Assessment: The two - generation reproductive toxicity study in rats [ no - observed adverse - effect level (NOAEL) = 14 mg/kg/day] was selected for assessment of acute dietary (females 13 - 49 years old) , chronic dietary , and incidental oral exposure scenarios . The acute neurotoxicity (ACN) study (NOAEL = 250 mg/kg/day) was selected for assessment of acute dietary (all populations excluding females 13 - 49 years old) exposure. The dermal developmental toxicity study in rats (NOAEL= 100 mg/kg/day) was selected for assessment of dermal exposure (all durations). The route - specific 26 - day inhalation study

in rats (NOAEL is 0.256 mg/L) was selected for assessment of inhalation expo sure (all durations). For all exposure scenarios except inhalation , a 10 0X uncertainty factor was applied [ 1 0X interspecies extrapolation ; 1 0X for intraspecies variation ; 1X FQPA SF (when applicable ) ] . For inhalation exposure scenarios, a 3 0X uncertainty factor was applied [ 3X interspecies extrapolation; 1 0X for intraspecies variation; 1X FQPA SF (when applicable) ]. Dietary Risk Estimates (Food + Drinking Water): Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM - FCID, ver. 3.16) which incorporates consumption data from United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA; 2003 - 2008) . The acute and chronic anal ys es assumed tolerance - level residues, 100% %CT, DEEM (ver. 7.81) default processing factors , and modeled drinking water estimates. The resulting acute and chronic dietary

risk estimates are not of concern to HED, and the subgroups with the greatest risk estimates utilized ≤7% of the acute population - adjusted dose (aPAD; females 13 - 49 years old) and ≤7% of the chronic population - adjusted dose (cPAD; children 1 - 2 years old), respe ctivel y. Residential (Non - Occupational) Exposure and Risk Assessment: The proposed use on apples will not result in residential exposure; however, there are currently registered turf uses (e.g., residential turf, golf courses) that were assessed as part of Registration Review . All dermal and inhalation exposure risk estimates for residential handlers are not of concern [ i.e., margins of exposure (MOEs) were ≥ 100 for dermal and ≥ 30 for inhalation risk] at baseline for all scenarios ; MOEs were ≥ 560 for dermal and ≥ 1200 for inhalation risk . All residential post application dermal risk estimates are also not of concern (i.e., MOEs ≥ 100); all MOEs were ≥ 610 for adults and ≥ 360 for children. A quantitative spray

drift assessment for sulfentrazone is not required. The turf post - application MOEs are protective for any potential exposures related to spray drift for sulfentrazone. Aggregate -Risk Estimates: In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Acute, chronic, short - , and intermediate - term aggregate assessments were included in this risk assessment. An aggregate cancer risk assessment was not performed because sulfentrazone is not considered to be a carcinogen. Acute and chronic aggregate risks are made up only of dietary

sources; therefore, the exposure estimates provided in the dietary exposure anal ys es represent acute and chronic aggregate exposure, respectivel y. Short - and intermediate term aggregate risks are made up of dietary and non - dietary

sources of exposure. Since sulfentrazone is used on turf, residential handler and post - application exposures are expected. Short - term exposures exist for adults and children from the registered turf application use. In addition, intermediate - term exposures exist for children from incidental soil ingestion. All aggregate sulfentrazone risk estimates are not of concern to HED.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Occupational Exposure and Risk Assessment: A quantitative assessment of occupational exposure has been conducted for all of the registered and proposed uses . The occupational handler exposure and risk estimates indicate that the short - and intermediate - term dermal and inhalation MOEs are not of conc ern to HED (i.e., MOEs were ≥ 100 for dermal and ≥ 30 for inhalation risk), as long as gloves are worn for the highest application rate for mixing/loading liquids and dry

flowables for aerial application to high - acreage crops. Occupational post applicatio n dermal exposure and risk estimates were assessed , and are greater than the level of concern (LOC) of 100 on the day of application (MOEs = 430 to 8,200 ) . Since the post application assessment is not a concern on Day 0 (12 hours following application), the restricted entry interval (REI) is based on the acute toxicity of sulfentrazone technical material. Sulfentrazone is classified as acute Toxicity Category III for acute oral, acute dermal, and acute inhalation toxicity . It is classified as Toxicity Category III for eye irritation potential and Toxicity Category IV for skin irritation potential. It is not a dermal sensitizer. Therefore, the acute toxicity

categories for this chemical require a 12 - hour REI under 40 CFR 156.208(c)(2)(iii). Based on the Agency's current practices, a quantitative non - cancer occupational post - application inhalation exposure assessment was not performed for sulfentrazone at this time. I f new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for sulfentrazone . 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 Lo w - Income Populations.” Review of Human Research : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide H andlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the following Agency website s: http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/p esticides/science/post - app exposure - data.html . 

### 2.0 **Recommendations** HED has examined the toxicology and residue chemistry

databases for sulfentrazone. Pending resolution of the deficiencies outlined below, there are no other residue chemistry , residential, occupational, or toxicology data deficiencies that would preclude the continuation of permanent tolerances for residues of sulfentrazone and its meta bolites as outlined in Table 2.2.2.1. For the proposed use on apples, HED concludes that the residue chemistry database supports the establishment of the permanent tolerance listed in Table 2.2.2.1 .Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### 2.1 **Data Deficiencies/Data Needs**  860.1650 Submittal of Analy tical Reference Standards Analy tical standards for sulfentrazone (expiration date 7/1/15) and its metabolites DMS (expiration date 8/1/17) and HMS (expiration date 8/31/18) are currentl y available at the EPA National Pesti cide Standards Repository (personal communication with Theresa Cole, 4/21/14). However, as the existing stocks are depleted, the Repository has requested that the registrant provide additional amounts of sulfentrazone (5 g) and HMS (3 g). They should be sent to the Analy tical Chemistry

L ab, which is located at Fort Meade, to the attention of either Theresa Cole or Thuy Nygen at the following address: USEPA National Pesticide Standards Repository /Anal ytical Chemistry

Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755 - 5350 (Note that the mail will be returned if the extended zip code is not used.) **2.2 Tolerance**  **Considerations 2.2.1**  **Enforcement Analytical Method**  There is an adequate residue anal ytical method for the purposes of tolerance en forcement. A gas chromatography (GC) method for the determination of sulfentrazone and its metabolites DMS and HMS was submitted with a petition for a sulfentrazone tolerance for residues in/on soy beans (PP# 4F04407). A petition method validation (PMV) w as successfully completed by

the Agency ’s Analy tical Chemistry

L aboratory

(ACL). The limit of quantitation (L OQ) and limit of detection (LOD) were determined to be 0.05 ppm and 0.005 - 0.025 ppm, respectively . The method has been forwarded to the Food and Drug Administration (FDA) for inclusion in the Pesticide Analy tical Methods Vol. II (PAM II). The data requirements for multiresidue methods (MRMs) are fulfilled. The FDA MRMs are not suitable as enforcement methods since sulfentrazone residues of concer n were not successfull y recovered b y the FDA MRMs. Samples of raw agricultural and processed commodities from the apple studies were anal yz ed for residues of sulfentrazone and its metabolites DMS and HMS using a liquid chromatograph equipped with tandem m ass spectrometers (LC/MS/MS) method. The validated LOQ was 0.025 - 0.05 ppm for each anal yt e. These methods are adequate for data collection based on acceptable method validation and concurrent recovery

data. **2.2.2 Recommended**  **Tolerances** Permanent tolerances have been established in 40 CFR §180.498 for the combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates in/on various raw agricultural commodities ranging from 0. 05 ppm to 0.6 0 ppm. Table 2 .2.2.1 is a summary of the proposed and HED - recommended tolerances for residues ofSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### sulfentrazone per se . **Table 2.2.2.1 .**  **Tolerance Summary for**  **Sulfentrazone (40 CFR §180.498) .** 

**Comm odity**  **Proposed /**  **Established Tolerance**  **(ppm) HED**  ****

**Recommended Tolerance**  **(ppm) Comments**  (a)(1) General. Tolerances are established for the combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates, in or on the commodities in the table below . Compliance with the tolerance levels specified below

is to be de termined by measuring only the sum of sulfentrazone ( N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide) and its metabolite HMS ( N - (2,4 - dichloro 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone in or on the following commodities. Soy bean, seed 0.05 (2) Tolerances are established for the combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates, in or on the commodities in the table below . Com pliance with the tolerance levels specified below is to be determined by measuring only the sum of sulfentrazone ( N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro 3 - methyl - 5 - oxo - 1 H

- 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide) and its metabolites HMS ( N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide) and DMS ( N - (2 ,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone in or on the following commodities. Apple 0.15 Proposed new use (P P# 3E8202) Asparagus 0.15 Berry and small fruit, group 13 - 07 0.15 Brassica , head and stem, subgroup 5A 0.20 Brassica , leafy greens, subgroup 5B 0.40 Corn, field, forage 0.20 Corn, field, grain 0.15 Corn, field, stover 0.30 Flax 0.15 Correct commodity definition to “Flax, seed” Fruit, citrus, group 10 - 10 0.15 Horseradish 0.20 Melon, subgroup 9A 0.15 Nut, tree, group 14 0.15 Update crop group to “Nut, tree, group 14 - 12 ” Pea and bean, dried shelled, except soybean, subgroup 6C 0.15 Pea, succulent 0.15 Peanut 0.20 Peanut, meal 0.40 Peppermint, tops 0.30 Pistachio 0.15 none Delete, pistachio is member of Nut, tree, group 14 - 1 2 Rhubarb 0.15 Spearmint, tops 0.30 Sugarcane, cane 0.15 Sugarcane, molasses 0.20 Sunflower subgroup 20B 0.20 Turnip, roots 0.15 Turnip, tops 0.60 Vegetable, fruiting, group 8 - 10 0.15Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 10 of 57 **Table 2.2.2.1 .**  **Tolerance Summary for**  **Sulfentrazone (40 CFR §180.498) .** 

**Comm odity**  **Proposed /**  **Established Tolerance**  **(ppm) HED**  ****

**Recommended Tolerance**  **(ppm) Comments**  Vegetable, soybean, succulent 0.15 Vegetable, tuberous and corm, subgroup 1C 0.15 (c) Tolerances with regional registrations. Tolerances with regional registration are established for the combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates, in or on the commodities in the table below . Com

pliance with the tolerance levels specified below is to be determined by measuring only the sum of sulfentrazone (

N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide) and its metabolites HMS (N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide) and DMS (N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazo ne in or on the following commodities. Bean, lima, succulent 0.15 Cow pea, succulent 0.15 Wheat, forage 0.50 Wheat, grain 0.15 Wheat, hay 0.30 Wheat, straw 1.5 (d) Indirect or inadvertent residues. Tolerances are established for inadvertent and indirect combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates, in or on the commodities in the table below . Compliance with the tolerance levels specif ied below is to be determined by measuring only the sum of sulfentrazone (

N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide) and its metabolites HMS (N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide) and DMS (N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone in or on the following commodities when present therein as a result of the application of sulfentrazone to growing crops. Grain, cereal (excluding sweet corn), Hulls 0.30 Grain, cereal, forage, fodder and straw , group 16, except sweet corn; forage 0.2 0.20 Correct number of significant figures to be consistent with HED policy Grain, cereal, forage, fodder and straw , group 16, except sweet corn; hay 0.2 0.20 Grain, cereal, forage, fodder and straw , group 16, except sweet corn; stover 0.1 0.10 Grain, cereal, forage, fodder and straw , group 16, except sweet corn; straw 0.6 0.60 Grain, cereal, group 15, except sweet corn 0.1 0.10 Grain, cereal, group 15, except sweet corn; bran 0.15 

### 2.2.3 **Revisions to Petitioned**  **- For Tolerances**  Based on the proposed uses and the submitted data, no revisions to petitioned - for tolerances are required .Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### 2.2.4 **International Harmonization**  There are no Codex maximum residue limits (MRLs) established for residues of sulfentrazone. The U.S. residue definition s are harmonized with Canada. For those commodities which the US and Canada have in common, the tolerance values are harmonized (asparagus, flaxseeds, horseradish roots, dry

peas and beans, peppermint tops, spearmint tops, sunflower seeds, and cereal grain group 15). For a summary of U.S. tolerances and international MRL s, refer to Appendix D. **2.3 Label**  **Recommendations** Occupational/Residential:  For several occupational handler scenarios, chemical - resistant gloves are necessary to achieve MOEs greater than the LOC. PRD should ensure the appropriate ty pe of glove is listed as required on the label. **3.0 Ingredient**  **Profile 3.1**  **Chemical Identity**  The chemical structure and nomenclature of sulfentrazone and its metabolites are presented in Table 3.1.1. **Table 3.1.1. Nom enclature for Sulfentrazone and its Metabolites.**  Chemical structure

Common name Sulfentrazone Company experimental name F6285; FMC 97285 IUPAC name 2',4' - dichloro - 5' - (4 - difluoromethyl - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl)methanesulfonanilide CAS name N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide CAS registry number 122836 - 35 - 5 End -use product (EP) 4 lb/gal FlC formulation (Spartan® 4F Herbicide; EPA Reg. No. 279 - 3220) and 75% DF formulation (Spartan ® Herbicide; EPA Reg. No. 279 - 3189) Chemical structure of DMS metabolite

Common name 3 - desmethyl sulfentrazone; DMS Cl Cl

N H S O 2 C H 3

N N N O C H 3

C H F 2

Cl Cl

N H S O 2 C H 3

N N N O C H F 2Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 12 of 57 **Table 3.1.1. Nom enclature for Sulfentrazone and its Metabolites.**  Chemical name N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide Chemical structure of HMS metabolite

Common name 3 - hydroxymethyl sulfentrazone; HMS Chemical name N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide 

### 3.2 **Physical /Chemical Properties**  In general, sulfentrazone is persistent and mobile. It has a 545 - day aerobic soil half

- life 1 

### and an average Koc coefficient of 45 mL/g . Additionally , it has a strong potential to leach into groundwater, as indicated in four completed small - scale prospective ground - water monitoring studies, and to move offsite to surface water. It has a low vapo r pressure of 8x10 - 10 

### mm Hg. A detailed description of the physicochemical properties of sulfentrazone is provided in Appendix B. **3.3 Use**  **Pattern** There are numerous end - use product labels registered with sulfentrazone as the active ingredient. These include liquid, dry - flowable, and granular formulations. The labeled use sites include various agricultural crops, Christmas tree farms, golf courses, seedling nurseries, landscape ornamentals, non - crop use sites (such as railroad, highway , roadside, pip eline , and utility rights of - way and industrial areas), residential/commercial turf, and sod farms. Most of the uses are soil - directed, and are applied via either aerial, chemigation, groundboom or handheld equipment . Several labels also allow for applic ation of liquid formulations via dry- bulk fertilizer. The maximum application rate for agricultural crops and turf is 0.375 lb ai/A (0.0086 lb ai/1000 ft2 

### or 0.019 lb ai/gal). The proposed use on apples is as a soil - directed application via groundboom. The maximum rate allowed is 0.375 lb ai/A. One broadcast application can be made per ye ar, and up to two banded applications directed to the base of tree trunk can be made 60 days apart. The REI for all the proposed uses is 12 hours. Based on the prop osed and registered use patterns, it has been determined that the potential exposure scenarios that will need to be assessed include short - and intermediate - term occupational and residential exposures (handler and post - application). A summary

of the regis tered and proposed labels are included in Table 3.3.1 below. All dry bulk fertilizer applications have been assessed at a maximum rate of 3.75 lb ai/ton fertilizer and/or 0.375 lb ai/A. **Table 3.3.1. Summary of Registered and Proposed Uses for Sulfentra zone.**  1 90 th percentile upper confidence interval of the mean half - life. Cl Cl

N H S O 2 C H 3

N N N O C H F 2

O HSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 13 of 57 Crop/Use Site Application Timing and Type of Application Registered

Form ulations Maximum

Application Rate Personal -p rotective Equipment

(PPE) , Restricted - e ntry Interval (REI) , and Preharvest Interval (PHI) Apples (new use) Soil directed; Groundboom Liquid and DF 0.375 lb ai/A PPE = Long - sleeve shirt, long pants, chemical - resistant (CR) gloves, shoes plus socks; REI = 12 hours ; PHI = 14 days Asparagus Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = Single l ayer (SL) w/ CR gloves; REI = 12 hr ; PHI = 14 days Biofuel crops (Napiergrass, Miscane, Napiergrass cross; SLN) Soil directed; aerial or groundboom Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr Berries (Crop group 13 - 07) Soil directed; groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = 3 days Brassica , head and stem Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Brassica , leafy greens Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.2 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Cabbage Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Christmas Tree Farms Soil directed; groundboom/tractor drawn spreader; handheld Liquid 0.0375 lb ai/gal, 0.0086 lb ai/1000 ft2 or 0.375 lb ai/A PPE = SL w/CR gloves (some

labels only list waterproof gloves); REI = 12 hr (some labels do not have REI listed) G 0.375 lb ai/A Citrus fruit Soil directed; groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = 3 days Corn Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12

- 24 hr ; PHI = NA (preemergence only) Cowpeas, succulent Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.19 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Dry shelled peas and beans Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Edamame Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.19 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Fallow cropping systems A pplied prior to planting, early preplant, or preemergence; aerial or groundboom; dry bulk fertilizer Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12 hr Flax Soil directed; aerial, groundboom; chemigation; dry bulk Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only)Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 14 of 57 **Table 3.3.1. Summary of Registered and Proposed Uses for Sulfentra zone.**  Crop/Use Site Application Timing and Type of Application Registered

Form ulations Maximum

Application Rate Personal -p rotective Equipment

(PPE) , Restricted - e ntry Interval (REI) , and Preharvest Interval (PHI) fertilizer Fruiting Vegetables (except cucurbits) and Okra Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Golf Course Fairways and Roughs Aerial, handheld or groundboom/tractor drawn spreader DF 0.375 lb ai/A, 0.008 lb ai/1000 ft2 or 0.019 lb ai/gal PPE = SL w/CR gloves (some

labels only list waterproof gloves); REI = 12 hr (some labels do not have REI listed) G 0.0086 lb ai/1000 ft2

or 0.375 lb ai/A Liquid Grapes Soil directed; groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = 3 days Hardwood seedling nurseries Soil directed; groundboom/tractor drawn spreader ; handheld Liquid 0.0086 lb ai/1000 ft2 or 0.375 lb ai/A PPE = SL w/CR gloves (some

labels only list waterproof gloves); REI = 12 hr (some labels do not have REI listed) G 0.375 lb ai/A Horseradish Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Landscape ornamentals (Container, Field grown Ornamental plantings) Groundboom/tractordrawn spreader or handheld G or Liquid 0.0375 lb ai/gal, 0.0086 lb ai/1000 ft2 or 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12

hr Lima beans Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.19 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Melons Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence only) Mint Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr ; PHI = NA (preemergence/dormant only) Nongrass An imal Feeds Crop Group 18 * (Alfalfa; bean, velvet; clover (Trifolium, Melilotus); kudzu; lespedeza; lupin; sainfoin; trefoil; vetch; vetch, crown; vetch, milk) Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = forage and hay may be harvested or grazed 21 days after application, and crop grown for seed may be harvested as early as 41 days after application. Peanuts Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12

- 24 hr; PHI = NA (preemergence only) Peppers (SLN) Soil directed; groundboom Liquid 0.18 lb ai/A PPE = SL w/ CR gloves and protective eyewear (goggles or face shield); REI = NA (preemergence only)Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 15 of 57 **Table 3.3.1. Summary of Registered and Proposed Uses for Sulfentra zone.**  Crop/Use Site Application Timing and Type of Application Registered

Form ulations Maximum

Application Rate Personal -p rotective Equipment

(PPE) , Restricted - e ntry Interval (REI) , and Preharvest Interval (PHI) Potato Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only) Railroad, Highway, Roadside, Pipeline and Utility Rights of

- Way, Industrial Areas, Fence Rows, and Other listed Non - crop Sites Aerial, handheld or groundboom/tractor drawn spreader DF 0.375 lb ai/A, 0.008 lb ai/1000 ft2 or 0.019 lb ai/gal PPE = SL w/CR gloves (some

labels only list waterproof gloves); REI = 12 hr (some labels do not have REI listed) G 0.0375 lb ai/gal,

0.0086 lb ai/1000 ft2 or 0.375 lb ai/A Liquid

Residential/Commercial Turf Handheld or groundboom/tractor drawn spreader DF 0.375 lb ai/A, 0.008 lb ai/1000 ft2 or 0.019 lb ai/gal REI = 12 hr; PPE = SL w/

waterproof gloves DF in WSP 0.0066 lb ai/1000 ft2

OR 0.287 lb ai/A or 0.0033 lb ai/gallon REI = 12 hr; PPE = SL w/

waterproof gloves G 0.0086 lb ai/1000 ft2

or 0.375 lb ai/A; max % ai = 0.4% REI = 12 hr; PPE = SL w/

waterproof gloves Aerial or groundboom, handheld Liquid 0.0086 lb ai/1000 ft2 or 0.375 lb ai/A REI = 12 - 48 hr; PPE = SL w/

waterproof gloves; some labels require CR gloves; some labels require CR apron when mxing/loading Handheld RTU 0.001 lb ai/1000 ft2 Residential labels; no PPE or REI listed Rhubarb Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only)

Sod Farms Aerial, groundboom; chemigation DF 0.375 lb ai/A, 0.008 lb ai/1000 ft2 or 0.019 lb ai/gal PPE = SL w/CR gloves (some

labels only list waterproof gloves); REI = 12 hr (some labels do not have REI listed) Tractor- drawn spreader G 0.0086 lb ai/1000 ft2 or 0.375 lb ai/A Aerial, groundboom; chemigation; dry bulk fertilizer Liquid Soybeans Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only) Strawberry Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only) Succulent peas Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.19 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only) Sugarcane Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = 120 days Sunflower Soil directed; aerial, groundboom; chemigation; dry bulk Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only)Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 16 of 57 **Table 3.3.1. Summary of Registered and Proposed Uses for Sulfentra zone.**  Crop/Use Site Application Timing and Type of Application Registered

Form ulations Maximum

Application Rate Personal -p rotective Equipment

(PPE) , Restricted - e ntry Interval (REI) , and Preharvest Interval (PHI) fertilizer Tobacco Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = 14 days Tree nuts Soil directed; groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.375 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = 3 days Turnips Soil directed; aerial, groundboom; chemigation; dry bulk fertiliz er Liquid and DF 0.25 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only) Wheat Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer Liquid and DF 0.19 lb ai/A PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only) * Use proposed under 1F7838, but not approved due to deficiencies in the residue chemistry database (a ruminant feeding study and additional clover residue data). 1 DF = dry - flowable; G = granular; RTU = ready- to - use. 2 SLN= special local need. **Table 3.3. 2**  **. Plantback Intervals for Use of Sulfentrazone.** Rotational Crop 1 Plantback Interval (months) Alfalfa 12 Barley 4 Cabbage Anytime Canola 24 Cereal Grains (Buckwheat, Oats, Pearl Millet, Proso Millet, Teosinte, Wild Rice) 12 Corn, Field 10 Corn, Pop 18 Corn, Sweet 18 Cotton 18 Dry Shell Peas and Beans Anytime Horseradish Anytime Limas Anytime Mint Anytime Peanuts Anytime Potatoes Anytime Rice 10 Rye 4 Sorghum 10 2 Soy bean Anytime Sugar Beets 36 Sugarcane Anytime Sunflowers Anytime Sweet Potatoes 12 Triticale 4 Tobacco Anytime Turf AnytimeSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 17 of 57 **Table 3.3. 2**  **. Plantback Intervals for Use of Sulfentrazone.** Rotational Crop 1 Plantback Interval (months) Wheat 4 1 For all other crops not listed, the rotation interval is a minimum of 12 months. 2 Sorghum

– 18 - mo nth rotation for rates above 8.0 oz/A. 

### 3.4 **Anticipated Exposure Pathways** Based on the registered and proposed sulfentrazone application scenarios , dietary exposure is an anticipated exposure pathway as residues of sulfentrazone may be found in/on crops, livestock commodities, and drinking water . There are residential uses of sulfentrazone and potential for spray drift, so there is exposure in residential and non - occupational settings. Inan occupational setting, applicators may

be exposed while handling the pesticide prior to application, as well as during application. Ther e is also potential for post - application exposure for workers re - entering treated sites. This risk assessment considers all of the aforementioned exposure pathway s based on the existing and proposed uses of sulfentrazone. **3.5 Consideration**  **of Environmental Justice** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://epa.gov/compliance/ej/resources/policy /exec_order_12898.pdf). As a part of every pesticide risk assessment, the Office of Pesticide Programs (OPP) considers a large variety of consumer subgroups a ccording 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 inv olve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age and ethnic group. Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assess ments 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 treate d areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard**  **Characterization and Dose -**  **Response Assessment** Sulfentrazone belongs to a class of herbicides that inhibit PPO in target photosy nthetic organisms, ultimately

resulting in di sruption of chlorophyll biosy nthesis. In mammals, PPO is also an important enzy

me in heme biosy

nthesis and its inhibition can lead to toxic effects associated with disruption of heme utilization (e.g., red blood cells). Some of the toxicities reported fo r sulfentrazone in mammals are consistent with a PPO inhibition .Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 18 of 57 

### 4.1 **Toxicology Studies Available for Analysis** The toxicological database for sulfentrazone is complete for risk assessment purposes. A 28 - day rat immunotoxicity

study has been submitted to the Agency and reviewed. In addition, HED’s Hazard Science and Policy Council (HASPOC) met on February 16, 2012 (TXR# 0050684) to evaluate the need for a repeated exposure inhalation toxicity study with sulfentraz one and concluded, based on a weight - of - evidence (WOE ) approach, that a s ubchronic rat inhalation study was required. Since then, the subchronic inhalation study has been submitted and reviewed b y the A gency . The results from both studies are included in this hazard assessment. **4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)**  In radiolabel - based studies in the rat, sulfentrazone was well absorbed via the oral route of administration as indicated by the excretion of nearly

all radioactivity

(~84 - 104%) in the urine by 72 hours post - dosing. There was no indication of accumulation ; onl y the carcass, liver, and bone showed detectable levels of radioactivity (<0.5% of the administered) at 72 hours post dosing. The pooled urinary radioactivity

consisted almost entirely of HMS ; the parent chemical was not detected in urine and found o nl y at very l ow levels in feces. There were no apparent sex - dependent differences in ADME behavior noted. **4.2.1 Dermal Absorption**  There are no dermal absorption studies available for sulfentrazone; however, there is a rat 28 - day dermal toxicity

study an d a dermal route - specific rat prenatal developmental toxicity study that can be used to assess risk via the dermal route of exposure. **4.3 Toxicological Effects**  Subchronic and chronic toxicity studies in rats, mice, and dogs identified the hematopoietic s ys tem as the target of sulfentrazone. Sulfentrazone inhibits the enzy me PPO in target plants and the results of subchronic and chronic toxicity studies in mammalian systems are consistent with PPO inhibition . Disruption of heme bios ynthesis was indicated by signs of anemia [decreases in hematocrit (Hct) , hemoglobin (HGB) , and mean corpuscular volume (MCV)] in mice, rats, and dogs at comparable dose levels from short - through long - term exposure without a significant increase in severity. Sulfentrazone c aused developmental effects when administered via the oral (rats and rabbits) and dermal (rat) routes of exposure. Developmental effects in rats and rabbits consisted of reductions in the number of implantations (rats only), increases in early resorptions (rats and rabbits), and reduction in live fetuses per litter (rats and rabbits). Surviving rat fetuses exhibited reduced/delayed skeletal ossifications, and decreased fetal body weights. Developmental effects in rats were seen in the absence of maternal toxicity . In contrast with the rat studies, developmental effects in rabbits were observed at a maternall y toxic dose, where clinical signs of toxicity included hematuria (red blood cells in urine), abortions, and decreased body- weight gains. In the two - gen eration reproductive toxicity study in rats, developmental effects included an increased duration of gestation, reduced prenatal viability (fetal and litter), reduced litter size, and an increased number of stillborn pups. Pup body- weight deficits, al ong with reduced pup and litter postnatal survival, were also observed. All of the offspring effects were reported in the presence of mild maternal toxicity (decreased body

weight and body- weight gain, particularl y inSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 19 of 57 

### F 1 

### females). A published, non - guidel ine developmental toxicity study in the rat [DeCastro VL , Destefani CR , Diniz C , Poli P ., 2007. Evaluation of neurodevelopmental effe cts on rats exposed prenatally to sulfentrazone. Neurotoxicology 28(6):1249 - 59] did not conclusively demonstrate developmental neurotoxicity

and contains several shortcomings that limit its use for regulatory purposes including the lack of a NOAEL. The reported effects involving measures of phy sical and reflex development are likely

secondary

effects reflective of the poor general state of the offspring as reported in the rat two - gen eration reproductive toxicity study at similar dose levels but with a wel l - defined NOAEL [more information on the review of this study can be found in a previous risk assessment (K. Lowe et al. , 22 - DEC - 2010; D364882) and Memo, C. Rodriguez, 19 - DEC 2011, D389975]. No sy stemic toxicity

was seen via the dermal route up to the l imit dose (1,000 mg/kg/day) in a 28 - day dermal toxicity

study in adult non -pregnant rabbits. In a dermal developmental study in rats, there was an increased quantitative fetal susceptibility . While no maternal effects were observed up to the highest dose tested (250 mg/kg/day), fetal effects were observed at this dose, and consisted of decreased body weights, increase d incidences of fetal variations; hy poplastic or wavy ribs, incompletel y ossifi ed lumbar vertebral arches, incomp letel y ossified ischia or pubis, and a reduced number of thoracic vertebral and rib ossification sites. In the 26 - day

inhalation toxicity

study , effects that were considered treatment related and adverse occurred onl y at the highest concentration tested (1.71 mg/L). S ys temic effe cts at this concentration consisted of significant reductions in red blood cell (RBC) parameters including RBC count, HGB concentrations, Hct, MCV, mean corpuscular HGB (MCH), and/or reticulocy tes in both sexes. Portal - of - entry effects consisted of an increased incidence of minimal nasal respiratory epithelial hy perplasia in both sexes as well as minimal lary ngeal epithelial attenuation in all test material exposure groups. The effects on hematological parameters were reversible after 28 days of recovery , while the nasal injury persisted. In an ACN study in rats, effects consisted of an increased incidence of clinical signs of toxicity (staggered gait, splayed hind limbs, and abdominal gripping), changes in functional - observation battery (FOB) parameter s, and decreased motor activity at a high dose level (750 mg/kg bw). Complete recovery

was observed b y day 14, and there was no evidence of neuropathology . In a rat subchronic neurotoxicity (SCN) study , clinical signs of toxicity, increased motor activity, and/or decreased body weights, body- weight gain, and food consumption were also observed with no evidence of neuropathology . In the 28 - day

rat immunotoxicity

study , there were no effects on the immune sy stem and systemic effects consisted of reduced body weight, and increased absolute and relative spleen weights at the highest dose tested. Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumor formation due to treatment with sulfentrazone, and the Cancer Assessment Review Committee (CARC) previously

classified sulfentrazone as “not likely to be carcinogenic to humans” in accordance with EPA proposed Guidelines for Carcinogenic Risk Assessment (April 10, 1996). The available mutagenicity studies indicate that sulfentrazone is weakl y clastogenic in the in vitro mouse ly

mphoma assay

in the absence of S9 activation. There is no evidence that sulfentrazone is mutagenic in bacterial cells or clastogenic in male or female mice in vivo .Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Based on the results of acute toxicity studies in the rat, sulfentrazone was classified as Toxicity Category III ( Toxicity Category

IV being the lowest category) for acute toxicity via the oral, dermal, and inhalation routes of exposure. It was a mild eye irritant ( Toxicity Category III), but not a dermal irritant or sensitizer. **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios. The toxi city database is complete and dietary and residential exposure anal ys es are unlikel y to underestimate exposure . Although effects were seen in neurotoxicity studies and there is evidence of susceptibility to offspring in developmental studies, the effects are well - characterized with clearl y established NOAEL/lowest - observed adverse - effect level (LOAEL) values and selected endpoints are protective for the observed effects. **4.4.1 Completeness of the Toxicology Database**  The existing toxicology

database for sulfentrazone is adequate for FQPA evaluation. Developmental toxicity

studies in rats and rabbits, a two - generation reproduction study in rats, and neurotoxicity

studies in rats are available for FQPA consideration. **4.4.2 Evidence of Neurotoxicity**  In th e ACN and SCN studies, observed effects included changes in motor activity and FOB parameters, clinical signs, and body weight decrements. There is low concern for neurotoxicity since: 1) effects were seen at relativel y high doses; 2) effects occurred in the absence of neuropathology ; 3) there is no evidence of neurotoxicity in other available studies in the toxicity database; 4) effects are well - characterized with clearly established NOAEL/L OAEL values; and 5) the selected PODs are protective of these eff ects. **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  There was evidence for increased (quantitative) susceptibility following oral and dermal exposures in the developmental toxicity studies in rats. Although developmental toxicity was observed at lower doses than maternal toxicity in both studies in the rat, the concern is low based on the following considerations: 1) the toxicology database for assessing pre - and postnatal susceptibility

is complete; 2) there are clear N OAEL s and LOAELs for the developmental effects observed via both the oral and dermal routes; 3) the PODs used for assessing dietary and dermal exposure risks are based on developmental and/or offspring toxicity; 4) the portal - ofentry effects seen in the 2 6 - day inhalation study

are protective of the developmental toxicity ; and 5) there are no residual uncertainties for pre - and/or postnatal toxicity . **4.4.4 Residual Uncertainty in the Exposure Database**  There are no residual uncertainties in the exposure database. The dietary and residential exposure anal ys es are conservative in nature . The dietary exposure assessment used tolerance level residues and assumed 100% CT. The residential exposure assessment uses the 2012 Residential SOPs and is considered he alth -protective. The residential assessment includes an FQPA SF of 10X for inhalation exposures to account for the uncertainty associated with the lack of an appropriate inhalation toxicity study .Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### 4.5 **Toxicity Endpoints and Point of Departure Selections**  **4.5.1 Dose**  **- Response Assessment**  Table 4.5.4 summarizes the toxicological doses and endpoints selected for residential dietary /non - dietary

and occupational risk assessment . The rationale for any changes is provided below and the updated endpoints are included in Table 4.5.4 . The updated endpoints are protective of sulfentrazone’s developmental toxicity , which was the critical effect in the database and observed via both the oral and dermal routes of exposure. Acute Dietary Endpoint ( Females 13 - 49 years old): This acute dietary endpoint is based on increased gestation duration, reduced pre - /postnatal litter and pup survival, reduced litter size, increased number of stillborn pups, reduced postnatal survival (pups and litter), and pup bodywei ght deficits throughout lactation in both generations of offspring observed in the two generation reproductive toxicity study in rats. The developmental effects were reported in the presence of mild maternal toxicity (decreased body

weight and body- weight gain, particularl y in F 1 

### females). Ithas been HED’s practice to consider various forms of developmental toxicity, such as the such as reduced prenatal viability , reduced litter size, and increased number of stillborn pups as single - dose effects and, the refore, relevant for the acute dietary (females aged 13 - 49) exposure scenario in order to protect against potential exposure of pregnant females. It should be noted that the fetal body- weight deficits and retardation in skeletal development (including decreased numbers of caudal vertebral and metacarpal ossification sites) reported in the oral rat prenatal developmental toxicity study were also evaluated for this acute dietary endpoint. However, it was concluded that such effects are unlikel y due to a single - dose effect and are more appropriate for a repeated- exposure scenario. Furthermore, EPA has not traditionally

considered delays in ossification (and related fetal body- weight deficits) to be single - dose effects. The conventional 100 - fold uncertainty factor (10X inter- , and 10X intraspecies) was applied to the NOAEL (14 mg/kg bw/day). The FQPA SF was reduced to 1X (see Section 4.4). Thus, the acute reference dose (aRfD) and aPAD are equivalent at 0 .14 mg/kg bw/day . Acute Dietary Endpoint ( General population, including infants and children): This acute endpoint is based upon increased incidence of clinical signs, FOB findings, and decreased motor activity at the LOAEL of 750 mg/kg bw seen followin g a single oral administration in the ACN study . The aRfD and aPAD are equivalent at 2.5 mg/kg bw/day based on the NOAEL of 250 mg/kg/day

from the ACN study

and a 100 - fold uncertainty factor ( 10X interspecies, 10X intraspecies, 1X FQPA) . Chronic Dietary Endpoint ( All populations): The chronic dietary endpoint is based on increased gestation duration, reduced pre - /postnatal litter and pup survival, and pup body- weight deficits throughout lactation in both generations of offspring observed at the LOAEL of 33 and 40 mg/kg/day

in males and females, respectivel y in the rat two - generation reproductive toxicity study . This LOAEL is based on developmental toxicity, the most sensitive endpoint, and is protective of developmental and chronic effects seen in other studies. The chronic reference dose (cRfD) and cPAD are equivalent at 0.14 mg/kg bw/day based on the NOAEL of 14 mg/kg/day

in the two - generation reproductive toxicity study and a 100 - fold uncertainty factor ( 10X interspecies, 10X intraspecies, 1X FQPA) . Incidental Oral Endpoint (Short- and intermediate - term): This endpoint is based on offspringSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### toxicity observed in the rat two - generation reproductive toxicity study in the form of reduced pre - /postnatal litter and pup survival, and pup body- weight defic its throughout lactation in both generations of offspring observed at the LOAEL of 33 and 40 mg/kg/day in males and females, respectivel y (lowest NOAEL= 14 mg/kg/day for males). The effects seen in the offspring are appropriate for the population (infant s and children) and durations (short - and intermediate - term) of concern. The LOC for incidental oral risk estimates is for MOEs less than 100, which includes the 10X inter- and 10X - intraspecies factor s . The FQPA SF was reduced to 1X (see Section 4.4). Dermal Endpoints (Short- and intermediate- term): The dermal developmental toxicity study in rats was selected to assess dermal exposures (NOAEL=100 mg/kg/day). The LOAEL is based on developmental toxicity. This endpoint is appropriate since the develop mental effects were seen after repeated exposure via the dermal route. The LOC for occupational and non occupational dermal risk estimates is for MOEs less than 100, which includes the 10X inter- and 10X intraspecies factors. The FQPA SF was reduced to 1 X (see Section 4.4). Inhalation Endpoints (Short- and intermediate- term) : The short - and intermediate - term inhalation endpoints were derived from the route specific 26 - day inhalation study

in rats where the NOAEL is 0.256 mg/L. The LOAEL is 1.71 mg/L fo r both sexes based on significant reductions in RBC parameters, including RBC count, HGB, Hct, MCV, MCH, and/or reticulocy tes in male and female rats following 26 day s of inhalation exposure to the test material. Portal - of

- entry effects at this dose were also observed and manifested as an increased incidence of minimal nasal respiratory epithelial hy

perplasia in both sexes as well as minimal lary ngeal epithelial attenuation in all test material exposure groups. As described below, human equivalent concentrations and doses (HECs and HEDs) were calculated based this subchronic inhalation study . This inhalation study is protective for the systemic effects (including developmental effects seen in the oral studies ) for the following reasons: 1) the dose spread in the inhalation study

between the NOAEL and LOAELis large (40 to 600 mg/kg/day) and the effects in the nasal passage likel y start a lower dose than the LOAEL; 2) the reference concentration (RfC) methodology calculations include a 15 - fold lower regional deposited dose ratio for portal - of

- entry effects (0.213) compared to sy stemic effects ( 3.129 ) ; and 3) the estimated inhalation HEDs are lower or equivalent (depending on the exposure scenario being assessed) than the oral NOAEL from th e developmental study . HECs derived from this study were based upon the increased incidence of minimal nasal respiratory

epithelial hy

perplasia in male and female rats . The resulting HECs are 0.04 and 0.05 mg/L for occupational handler and residential handler. Portal - of - entry effects were used to generate HECs and are protective for any s ys temic effects (portal - of - entry HEC = 0.04 mg/L vs. systemic RBC HEC = 0.60 mg/L for occupational, and portal - of - entry HEC = 0.05 mg/L vs. systemic RBC HEC = 0.801 mg/L). HEDs were subsequently calculated for occupational handler exposure scenarios based upon ventilation rates of 8.3, 16.7, and 29 L/min (2.317, 4.661 , and 8.094 mg/kg/day) and residential - handler exposure scenarios based upon a ventilation rate of 16.7 L/min (1.55 mg/kg/day). For details regarding the calculation of the HECs and HEDs, see Appendix B. These HEDs are protective of the systemic effects observed through the inhalation route. This study

is thus appropriate for the route and duration of expo sure, and a s described above in Section 4.3, use of this inhalation study is protective of any potential developmental effects seen in the oral rat developmental study . The LOC is 30 which includes interspecies (3X) and intraspecies (10X) uncertainty factors. TheSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### interspecies factor was reduced from 10X to 3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies differences. **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  The Agency

must consider risks from individual routes of exposure (oral, dermal, and inhalation) and perform combined exposure and risk assessments if a common toxicity endpoint is established across different routes of exposure. Since developmental effects (fetal body- w eight deficits and skeletal effects) were observed in the studies used to select the PODs for the dermal and oral exposure routes, these routes should be combined. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  The CARC has classified sulfentrazone as “not likely to be carcinogenic” to humans (TXR #: 011910) in accordance with EPA proposed Guidelines for Carcinogenic Risk Assessment (April 10, 1996). **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human**  **- Health**  **Risk Assessment**  **Table 4.5.4.1 .**  **Summ ary of Toxicological Doses and Endpoints for Sulfentrazone for Use in Residential and** 

**Dietary Hum**  **an -**  **Health Risk Assessment.** Exposure Scenario POD Uncertainty/ FQPA SFs RfD, PAD, LOC

for Risk Assessment Study and Toxicological Effects Ac ute Dietary (Females 13 - 49) NOAEL = 14

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X aRfD = aPAD =

0.14 mg/kg/day Two - g eneration Reproductive

Toxicity Study - Rat Offspring Toxicity LOAEL = 33 (M) and 40 (F) mg/kg/day based on reduced prenatal viability (fetal & litter), reduced litter size, increased no. of stillborn pups, reduced pup and litter postnatal survival, and decreased pup body weights throughout lactation. Ac ute Dietary (General population including infants and children) NOAEL = 250

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X aRfD =aPAD =

2.5 mg/kg/day ACN Study - Rat

LOAEL = 750 mg/kg/day based on increased incidence of clinical signs and FOB parameters and decreased mo tor activity. Chronic Dietary (all populations) NOAEL = 14

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X cRfD = cPAD =

0.14 mg/kg/day Two - g eneration Reproductive

Toxicity Study - Rat Offspring Toxicity LOAEL = 33 (M) and 40 (F) mg/kg/day based on reduced prenatal viability (fetal & litter), reduced litter size, increased no. of stillborn pups, reduced pup and litter postnatal survival, and decreased pup body weights throughout lactation . Short - (1 - 30 day s) and Intermediate Term (1 - 6 months) Incidental Oral Offspring

NOAEL = 14 mg/kg/day UF A = 10X

UF H = 1 0X FQPA SF = 1X Residential LOC

for MOE = 100 Two - Generation Reproductive

Toxicity Study - Rat Offspring LOAEL = 33 mg/kg/day based on decreased pup body weightsSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 24 of 57 **Table 4.5.4.1 .**  **Summ ary of Toxicological Doses and Endpoints for Sulfentrazone for Use in Residential and** 

**Dietary Hum**  **an -**  **Health Risk Assessment.** Exposure Scenario POD Uncertainty/ FQPA SFs RfD, PAD, LOC

for Risk Assessment Study and Toxicological Effects

and reduced postnatal survival in both generations. Short - (1 - 30 day s), Intermediate - (1 - 6 mo nths), and Long - Term

(>6 mo nths) Dermal NOAEL =

100 mg/kg/day UF A = 10X

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

for MOE = 100 Dermal Developmental Study - Rat

LOAEL = 250 mg/kg/day based on decreased fetal body weight; increased incidences of fetal skeletal variations: hypoplastic or wavy ribs, incompletely ossified lumbar vertebral arches, and incompletely ossified ischia or pubes; and reduced number of thoracic vertebral and rib ossification sites. Short - (1 - 30 day s), Intermediate - (1 - 6 mo nths), and Long - Term

(>6 mo nths) Inhalation Portal - of - entry NOAEL = 0.256 mg/L, HEC = 0.054 mg/L, HED = 1.55 mg/kg/day UF A = 3X

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

for MOE = 30 Portal - of - entry LOAEL = 1.71 mg/L based on an increased incidence of minimal nasal respiratory epithelial hyperplasia in male and female rats. Cancer (oral, dermal, inhalation) **Classification:** Sulfentrazone is classified as “not likely to be carcinogenic to humans.” NOAEL = no - observed adverse - effect level. LO AE L = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = extrapolation for use of a LOAEL in the absence of a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population - adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. **Table 4.5.4.2 .**  **Summ ary of Toxicological Doses and**  **Endpoints for Sulfentrazone for Use in Occupational**

**Hum an**  **- Health Risk Assessment.**  Exposure Scenario POD Uncertainty/ FQPA SFs RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects Short - (1 - 30 day s), Intermediate - (1 - 6 mo nths), and Long Term (>6 months) Dermal NOAEL =

100 mg/kg/day UF A = 10X

UF H = 10X Occupational

LOC for MOE = 100 Dermal Developmental Study - Rat

LOAEL = 250 mg/kg/day based on decreased fetal body weight; increased incidences of fetal skeletal variations: hypoplastic or wavy ribs, incompletely ossified lumbar vertebral arches, and incompletely ossified ischia or pubes; and reduced number of thoracic vertebral and rib ossification sites. Short - (1 - 30 day s), Intermediate - (1 - 6 mo nths), and Long Term (>6 months) Inhalation Portal - of - entry NOAEL = 0.256 mg/L HEC = 0.041 mg/L HED (8.3 L/min) = 2.317 mg/kg/day HED (16.7 L/min) = 4.661 UF A = 3X

UF H = 10X Occupational

LOC for MOE = 30 Portal - of - entry LOAEL = 1.71 mg/L based on an increased incidence of minimal nasal respiratory epithelial hyperplasia in male and female rats.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 25 of 57 **Table 4.5.4.2 .**  **Summ ary of Toxicological Doses and**  **Endpoints for Sulfentrazone for Use in Occupational**

**Hum an**  **- Health Risk Assessment.**  Exposure Scenario POD Uncertainty/ FQPA SFs RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects mg/kg/day HED (29 L/min) = 8.094 mg/kg/day Cancer (oral, dermal, inhalation) **Classification:** Sulfentrazone is classified as “not likely to be carcinogenic to humans.” 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). UF L = extrapolation for use of a LOAEL in the absence of a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population - adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. 

### 4.6 **Endocrine Disruptor Screening Program** As required b y Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic, and chronic toxicity, including assessments of carcinogenicity , neurotoxicity, developmental, reproductive, and general or system ic toxicity . These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology , organ weights, estrus cyclicity , sexual maturation, fertility , pregnancy rates, reproductive loss, an d sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its Registration Review decision for sulfentrazone, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), sulfentrazone is subject to the endocrine screening part of th e Endocrine Disruptor Screening Program (EDSP). EPA has developed the 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 b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate. ” The EDSP employs a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potenti al of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. 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 n ext stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine - related effects caused by the substance, and establish a dose - respons e relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. 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. A second list of chemicals identified for EDSP screening was published on June 14, 2013 2 

### and includes some pesticides 2 See http://www.regulations.gov/#!documentDetail;D=EPA - HQ - OPPT - 2009 - 0477 - 0074 for the final second list of chemicals.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### scheduled for registration review and chemicals found in water. Neith er of these lists should be construed as a list of known or likely endocrine disruptors. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery , please visit our website. 3 

### 5.0 **Dietary Exposure and Risk Assessment**  D415626 , G. Kramer , 05 - JUN - 2014 (residue chemistry summary for the current action) D417172 , G. Kramer, 05 - JUN - 2014 (dietary exposure analysis for the current action) 

### 5.1 **Metabolite /Degradate Residue Profile**  **5.1.1 Summary**  **of Plant and Animal Metabolism Studies** The nature of the residue in plants is adequatel y understood. Data concerning the metabolism of sulfentrazone following preemergent applications in soy beans and confined rotational crops were submitted in conjunction with the soy bean petition (PP#4F04407). The HED Metabolism Committee determined that the parent compound, sulfentrazone, and the metabolite HMS are the residues of concern in soy beans, and that sulfentrazone and the metabolites HMS and DMS are the residues of concern in rotational crops (G. Kramer, 14 - JUN - 1996; D226434). In addition, HED concluded that the results of the rotational crop metabolism studies may

be translat ed to support preemergent uses on all types of crops (G. Kramer, 13 - MAR - 1996; D220548). Data concerning the metabolism of sulfentrazone following postemergent applications in corn, soy bean, and radish were submitted in conjunction with recent petitions (D 389972, 5/9/12, G. Kramer). The metabolism of sulfentrazone following postemergent application was similar to that seen in rotational crops and following preemergent application to soy bean; no additional major metabolites were identified. HED concludes m etabolism data are now available to support postemergence applications and that sulfentrazone and its metabolites HMS and DMS (free and conjugated) are the residues of concern in all crops except soy bean seed, where the residues of concern are sulfentrazon e and the metabolite HMS. The nature of the residue in livestock is adequately understood based on acceptable ruminant and poultry

metabolism studies. The metabolism of sulfentrazone in livestock differs from that in plants as metabolism proceeds onl y b y oxidation of the 3 - methyl group to HMS, followed b y further oxidation to form sulfentrazone carboxyl ic acid, which is decarbox yl ated to DMS. Sulfentrazone per se and its metabolites HMS and DMS were identified as the residues of concern in meat, milk, poultry , and eggs. **5.1.2 Summary**  **of Environmental Degradation** Sulfentrazone is expected to be persistent under most environmental conditions. Sulfentrazone half - lives in aerobic soil metabolism, anaerobic aquatic metabolism, and terrestrial field dissipation studies are one ye ar or longer (1.5 ye ars, 9 ye ars , and 1 to 2 years, respectively). Sulfentrazone is stable towards abiotic hydrolysis. Direct photolysis in water appears to be the only transformation pathway with observed half

- lives of 12 hours at pH 5 and 1 hour at pHs 7 and 9. Many of the photoly tic products are formed by cleavage of the C to N bond between the phenyl and triazolo

3 See http://www.epa.gov/endo/ .Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### rings. Although methyltriazole was the major degradate detected in the aqueous photolysis study , the fate of this degradate in the natural environment is unknown because the field dissipation and the groundwater monitoring studies did not monitor this degradate. However, photoly tic breakdown would be more significant in shallow waters of low turbidity than in deep waters of high turbidity . The major transformation product observed in soils is the carboxylic acid of sulfentrazone (3 - carbox ylic acid sulfentrazone). This degradate, together with parent sulfentrazone, has been detected in groundwater so far in prospective ground - water monitoring studies. In a variety of soils ranging in texture from sand to silty clay loam, sulfentrazone is very mobile (Kd, 

### 0.2 to 0.8; average Koc 

### 43). The pKa 

### of sulfentrazone is 6.5 and, therefore, sulfentrazone would be more mobile in neutral to alkaline soils than in acidic soils. The pKa 

### of the carbox yl ic acid of sulfentrazone is not known, but it may be comparable to that of parent sulfentrazone and exhibit a similar behavior as the parent in neutral - alkaline soils. The HED Metab olism Assessment Review Committee (MARC) concluded that parent and 3 - carbox yl ic acid sulfentrazone are the residues of concern for the drinking - water assessment (Memo, G. Kramer et al. , 10 - APR - 2003; D288713). HED continues to consider the given metabolite s and degradates to be the residues of concern for risk assessment. **5.1.3 Comparison**  **of Metabolic Pathways** In plants, sulfentrazone is metabolized via four different pathway s: (1) Oxidation of the 3 - methyl group to form 3 - hydrox ymethyl sulfentrazone or HMS, followed by further oxidation to form sulfentrazone carbox yl ic acid which is decarbox yl ated to 3 - desmethylsulfentrazone or DMS. (2) Hydrolysis of the trifluoromethyl group to form desdifluoromethyl sulfentrazone which is oxidized and decarbox yl ated to form desdifluoromethyldesmethyl sulfentrazone. (3) Hydrol ys is of the sulfonamide group to form desmethyl sulfonyl sulfentrazone. (4) Scission of the phenyl and triazole rings to produce methyl triazole. The corresponding phenyl metabolites are believed to remain bound. The metabolism of sulfentrazone in animals (livestock and rats) differs from that in plants as metabolism proceeds onl y b y oxidation of the 3 - methyl group to form HMS, followed by further oxidation to form sulfentrazone carboxyl ic acid which is decarbox yl ated to DMS. Sulfentrazone carbox yl ic acid was also the major transformation product obs erved in soils. **5.1.4 Residues**  **of Concern Summary and Rationale** The residues of concern in primary crops, rotational crops, livestock, and drinking water, as identified by

the MARC, are shown in Table 5.1.4 below. **Table 5.1.4. Residues of Concern in**  **Crops, Livestock, and Drinking Water.** Matrix Tolerance Expression Residues for Risk Assessment Primary Crops, except soybean seed sulfentrazone, HMS, DMS (free and conjugated) sulfentrazone, HMS, DMS (free and conjugated) Soybean, seed sulfentrazone, HMS sulfentrazone, HMS Rotational Crops sulfentrazone, HMS, DMS (free and conjugated) sulfentrazone, HMS, DMS (free and conjugated) Livestock sulfentrazone, HMS, DMS sulfentrazone, HMS, DMS Water n ot applicable. sulfentrazone, 3 - carboxylic acid sulfentrazone 

### 5.2 **Food Residue Profile**  A tolerance is currently

established under 40 CFR §180.498(a)(1) for the combined residues of sulfentrazone and its major metabolite, HMS, in/on soy bean seed at 0.05 ppm. In addition, permanent tolerances are esta blished under 40 CFR §180.498(a)(2) for the combined residues ofSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### sulfentrazone and its metabolites HMS and DMS in/on several food commodities; these established tolerances range from 0.15 ppm (various plant commodities) to 0. 6 0 ppm (turnip tops ). Toleranc es for the combined residues of sulfentrazone and its metabolites HMS and DMS have been established under 40 CFR §180.498(c) in connection with regional registrations; these include tolerances for residues in/on succulent lima bean, succulent cowpea, and wheat grain at 0.15 ppm. Finally , tolerances are established under 40 CFR §180.498(d) for inadvertent and indirect combined residues of sulfentrazone and its metabolites HMS and DMS in/on cereal grain (excluding sweet corn) bran, forage, grain, hay , hulls, stover, and straw at 0.1 - 0.6 ppm as a result of the application of sulfentrazone to growing crops. Pending uses are for the nongrass animal feeds crop group 18 (PP#1F7838) and apples (PP#3E8202). Additional residue data and a ruminant feeding study are required for proposed use on nongrass animal feeds (Memo, G. Kramer , D 389972 , 09 - MAY - 2012 ) . The submitted field trial residue data for all registered crops are adequate. The recentl y submitted field trial residue data apple are also adequate. The field trial data reflect the proposed use patterns; an adequate number of trials were conducted in the appropriate geographic regions; and samples were anal yz ed for the residue of concern using validated data - collection methods. The storage intervals were also validated. However, an additional six clover trials are required to support the proposed use on nongrass animal feeds (Memo, G. Kramer , D 389972 , 09 - MAY - 2012 ). HED previousl y determined that, based on the established sulfentrazone tolerances for soy bean and cereal grain commodities and the results of the livestock metabolism studies, conventional feeding studies are not required. However, a ruminant feeding study is required to support the proposed use on nongrass animal feeds crop group 18 (Mem o, G. Kramer , D 389972 , 09 - MAY 2012 ) . Rotational crop studies for corn, rice, sorghum, and wheat were submitted in conjunction with the soy bean petition (PP#4F04407). Permanent tolerances have been established for indirect or inadvertent residues of sulfentrazone and its metabolites, HMS and DMS, in cereal grains (excluding sweet corn), bran, forage, grain, hay , hulls, stover, and straw. The labeled rotational crop restrictions (Table 3.3.2) are adequate for use rates up to 0.375 lb ai/A . **5.3 Drinking**  **Water Residue Profile** Drinking water residues provided b y EFED (Memo, M. Barrett, 21 - MAY - 2014; D415627) were incorporated directl y into the acute and chronic dietary analyses as “water, direct, all sources” and “water, indirect, all sources.” The estimated drinking water concentrations (EDWCs) were Tier 1 estimates for ground water using the Pesticide Root Zone Model - Ground Water (PRZM GW) model version 1.07 (Screening Concentration In Ground Water) and surface water using the Pesticide Root Zone Model/Exposure Analy sis Modeling Sy stem (PRZM/EXAMS) model. The proposed use on apples carries the maximum single and annual application rates for all currentl y registered uses (0.375 lb ai/ A). Previous estimates of sulfentrazone residues in drinking water were done separatel y for parent and the 3 - carbox yl ic acid sulfentrazone degradate. Sulfentrazone and 3 - carbox yl ic acid sulfentrazone have a potential to reach both surface and ground waters that may be used as drinking water sources. This revise d assessment has now taken a total toxic residues (TTR) approach to assessing exposure, instead of providing values for each compound individually .Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### For surface water, the highest acute (peak) sulfentrazone value is 37.3 ppb and the 10 - ye ar average value i s 5.3 ppb. For ground water, the highest dail y value (peak) sulfentrazone value is 134 ppb and the post - breakthrough - average value is 98 ppb. EDWCs of 0.134 ppm and 0.098 ppm were used in the acute and chronic anal ys es, respectivel y. **Table 5.3**  **. Estim ated Tier 1 Concentrations of Sulfentrazone and 3**  **- Carboxylic Acid Sulfentrazone in**  **Drinking Water Due to the Use of Sulfentrazone**  **.**

Scenario Surface Water (ug/L) Groundwater (ug/L) Ac ute Chronic Ac ute Chronic FL Sugarcane 37.3 3.2 - - LA Corn 31.3 5.3 - - Delmarva Sweet C orn - - 134 98 

### 5.4 **Dietary (Food + Drinking Water)**  **Risk Assessment** Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM - FCID, ver. 3.16 which incorporates consumption data from the USDA NHANES/WWEIA; 2003 - 2008. The acute and chronic anal ys es assumed toleran ce - level residues, 100% CT, DEEM (ver. 7.81) default processing factors, and modeled drinking water estimates. The highest acute exposure estimate was for the population subgroup all infants <1 ye ar old, which utilized 1.1% of the aPAD for sulfentrazone. Females 13 - 49 years old have a lower aPAD than the general population. As a result, even though the exposure estimate for females 13 - 49 years old was lower than the estimate for infants <1 year old, females 13 - 49 years old is the population subgroup with the highest risk estimate (≤7% aPAD). The highest chronic exposure estimate was for the population subgroup children 1 - 2 years old , which utilized 7 .1% of the c PAD for sulfentrazone. **Table 5.4.1. Summary of Acute and Chronic Dietary (Food and Drinkin g Water) Exposure and Risk** 

**for Sulfentrazone. 1**  Population Subgroup 95 th Percentile cPAD (mg/kg/day) Exposure

(mg/kg/day) %cPAD aPAD (mg/kg/day) Exposure

(mg/kg/day) %aPAD General U.S. Population

2.5 0.011114 <1.0

0.14 0.003973 2.8 **All Infants (<1 year old)**  0.026754 1.1 0.008577 6.1 **Children 1 -**  **2 years old** 0.022692 <1.0 **0.009881 7.1**  Children 3 - 5 years old 0.017984 <1.0 0.007889 5.6 Children 6 - 12 years old 0.011833 <1.0 0.004817 3.4 Youth 13 - 19 years old 0.008607 <1.0 0.003225 2.3 Adults 20 - 49 years old 0.009187 <1.0 0.003498 2.5 Adults 50 - 99 years old 0.008301 <1.0 0.003314 2.4 **Females 13 -**  **49 years old** 0.14 **0.009363 6.7**  0.003450 2.5 1 The populations with the greatest risk and exposure estimates are bolded. 

### 6.0 **Residential (Non**  **- Occupational) Exposure/Risk Characterization**  D417171, K. Lowe, 05 - JUN - 2014 

### The proposed use on apples is not expected to result in residential exposure. The previous exposure assessment for sulfentrazone assessed the registered residenti al uses on turfgrass using the 2012 Residential SOPs (Memo, K. Lowe, D389974, 17 - MAY - 2012) and covers most of the scenarios necessary

for Registration Review. Residential handler and post - application scenariosSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### were assessed at a maximum application rate o f 0.375 lb ai/A for liquid, granular, and dry flowable formulations (identified in the 2009 scoping document for sulfentrazone; Memo, K. Lowe et al ., D369064, 09 - SEP - 2009). There were no residential risk estimates of concern identified. Updated risk estimate tables have been included in this memo for residential handlers since the inhalation POD and LOC for sulfentrazone has been changed since the previous assessment. In addition, updated risk estimates have been included for the post- application episodic granular ingestion scenario based on a revised maximum percent active ingredient for granular formulations identified during the label review of registered sulfentrazone labels. **6.1 Residential**  **Handler Exposure/Risk Estimates** Tabl e 6 .1.1 provides a summary of the residential handler exposures and risk estimates for sulfentrazone. All dermal and inhalation exposure risk estimates for residential handlers are not of concern (i.e., MOEs ≥ 100 for dermal and MOEs ≥ 30 for inhalation) at baseline for all scenarios.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 31 of 57 **Table 6.1.1. Residential Handler Non -**  **cancer Exposure and Risk Estim ates for Sulfentrazone.**  Exposure Scenario Level of

Concern Dermal Unit

Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Maximum

Application Rate 1 Area Treated or

Amount Handled Daily 2 Dermal

(LOC = 100) Inhalation (LOC = 100) Dose (mg/kg/day) 3 MOE 4 Dose (mg/kg/day) 5 MOE 6 **Loader/Applicator for Granules** Push - type spreaders 100 0.81 0.0026 0.375 lb ai/A 0.5 A 0.0022 45,000 0.0000061 250,000 Belly grinders 360 0.039 0.0000086 lb ai/ft2 1200 ft2 0.054 1,900 0.000005 310,000 Spoon 6.2 0.087 100 ft2 0.000077 1,300,000 0.00000094 1,700,000 Cup 0.11 0.013 0.0000014 73,000,000 0.00000014 11,000,000 Hand dispersal 160 0.38 0.002 50,000 0.0000041 380,000 Shaker can 0.11 0.013 0.0000014 73,000,000 0.00000014 11,000,000 **Mi xer/Loader/Applicator for Liquids**  Manually- pressurized handwand 100 63 0.018 0.019 lb ai/gallon 5 gallons 0.087 1,200 0.000021 73,000 Hose - end sprayer 13.4 0.022 0.375 lb ai/A 0.5 A 0.036 2,700 0.000052 30,000 Backpack 130 0.14 0.019 lb ai/gallon 5 gallons 0.18 560 0.00017 9,300 Sprinkler can 13.4 0.022 0.0000086 lb ai/ft2 1000 ft2 0.0017 60,000 0.0000024 660,000 **Mi xer/Loader/Applicator for Dry Flowables**  Manually- pressurized handwand 100 69 1.1 0.019 lb ai/gallon 5 gallons 0.095 1,100 0.0013 1,200 Hose - end sprayer 13.4 0.022 0.375 lb ai/A 0.5 A 0.036 2,700 0.000052 30,000 Backpack 69 1.1 0.019 lb ai/gallon 5 gallons 0.095 1,100 0.0013 1,200 Sprinkler can 13.4 0.022 0.000008 lb ai/ft2 1000 ft2 0.0016 64,000 0.0000022 700,000 1 Based on registered labels (see Table 3.3.1 ). 2 Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential - exposure - sop.html). 3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ Body Weight (69 kg). 4 Dermal MOE = Dermal NOAEL (100 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 5 Inhalation Dose = I

nhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ Body Weight (80 kg). 6 Inhalati on MOE = I

nhalation NOAEL (1.55 mg/kg/day) ÷ I nhalation Dose (mg/kg/day).Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### 6 **.2 Residential Post** **- application Exposure/Risk Estimates**  Table 6 .2.1 provides a summary of the residential post - application exposures and risk estimates for sulfentraz one. All risk estimates for post - application exposure are not of concern (i.e., MOEs ≥ 100); all MOEs were ≥ 610 for adults and ≥ 360 for children. **Table 6.2.1. Short**  **- Term** **Residential Post -**  **application Exposure and Risk Estimates for Sulfentrazone.** Lifestage Post - application Exposure Scenario Dose (mg/kg/day) 1 MOEs 2 Combined MOEs **Liquid formulation** Adult Turf

Liquid formulation 0.375 lb ai/A Dermal Physical Activities on Turf 0.16 610 N/A Mowing 0.0033 30,000 Golfing 0.013 7,800 Child 11 to < 16 years old Dermal Mowing 0.0033 30,000 Golfing 0.013 7,800 Child 6 to < 11 years old Dermal Golfing 0.015 6,600 Child 1 to< 2 year old Dermal Physical Activities on Turf 0.28 360 310 Hand to Mouth 0.0057 2,500 Object to Mouth 0.00017 81,000 N/A Short - and Intermediate - term Incidental Soil

Ingestion 1.3 x 10 - 5 1,100,000 **Granular formulation** Adult Turf

Granular formulation 0.375 lb ai/A Dermal Physical Activities on Turf 0.036 2,800 N/A Mowing 0.00066 150,000 Golfing 0.0026 39,000 Child 11 to < 16 years old Dermal Mowing 0.00066 150,000 Golfing 0.0026 39,000 Child 6 to < 11 years old Dermal Golfing 0.0030 33,000 Child 1 to < 2 year old Dermal Physical Activities on Turf 0.061 1,600 1,500 Hand to Mouth 0.00057 25,000 Object to Mouth 0.000035 400,000 N/A Short - and Intermediate - term Incidental Soil

Ingestion 1.3 x 10 - 5 1,100,000 0.4% ai Episodic Granular Ingestion 0.11 130 1 Dose (mg/kg/day) equations provided in Appendix B . 2 MOE = POD ( d ermal = 100 mg/kg/day and i ncidental oral = 14 mg/kg/day) ÷ Dose (mg/kg/day). LOC = 100. 

### 6.3 **Residential Risk Estimates for Use in Aggregate Assessment** Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggreg ate assessment for sulfentrazone.  The recommended residential exposure for use in the adult short- term aggregate assessment reflects dermal exposure from applications to turf via backpack sprayer.  The recommended residential exposure for use in the children 1 < 2 years old short - term aggregate assessment reflects dermal and hand- to - mouth exposures from post - application exposure to turf applications.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 33 of 57 **Table 6**  **.3.1. Recommendations for the Residential Exposures for the Sulfentrazone Aggregate Assessment.** Lifestage Exposure

Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation 3 Oral Total Dermal Inhalation 3 Oral Total **Short -**  **term** Adult Male Handler

–

MLA liquids via backpack 0.18 N/A N/A **0.18** 560 N/A N/A **5 6**  **0**

Child 11 < 16 years old Post application exposure from golfing (liquid formulation) 0.013 N/A N/A **0.013** 7,800 N/A N/A **7,800**

Child 6 < 11 years old Post application exposure from golfing (liquid formulation) 0.015 N/A N/A **0.015** 6,600 N/A N/A **6,600**

Child 1 < 2 year old Post application exposure from activities on turf (liquid formulation) 0.28 N/A 0.0057 **0.28** 360 N/A 2,500 **310**

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + incidental oral (where applicable). 2 MOE = the MOEs associated with the highest residential doses. 3 Inhalation risk estimates were not combined with dermal or oral risk estimates in this assessment since the toxicological eff ects in the inhalation toxicological study were portal - of - entry and different from those seen in the dermal and oral toxicological studies. 

### 6.4 **Spray Drift** Off - target movement of pesticides can occur via many types of pathways and it is governed b y a variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact . They

can also deposit on surfaces where contact with residues can eventually lead to exposures (e.g., children playing on lawns where resi dues have deposited next to treated fields) . The potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for residential risk assessments for turf products. The approach to be used for quantitativ el y incorporating spray drift into risk assessment include assessing exposures for children (1 to <2 ye ars old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an exposure scenario. Aside from the predicted residues available for transfer, the routes of exposure and assessment methodology

is analogous to how exposures to turf products are considered in risk assessment. Several sulfentrazone products have existing labels for use on turf , thus it was considered whether the risk assessment for turf may be considered protective of any ty pe of exposure resulting from spray

drift. If the maximum application rate on crops adjusted by the amount of drift expected is less than or equal to existing turf application rates, the existing turf assessment is considered protective of spray drift exposure. The proposed maximum single application rate of sulfentrazone for several registered agricultural crops is 0.375 lb ai/A . The highest fraction of spray drift noted for any application method immediately adjacent to a treated field results in aSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### deposition fraction of 0.26 4 

### of the application rate. A quantitative spray drift assessment for sulfentrazone is not required because the maximum application rate for a crop/target site multiplied by

the adjustment factor for drift of 0.26 is less than the maximum direct spray residential turf application rate (0.375 lb ai/A) 5 

### for any sulfentrazone products. The turf post application MOEs are protective for any potential exposures related to spray drift for sulfentrazone and have previously been discussed in Section 5.2. **6.5 Residential Bystander Post**  **- Application Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for sulfentrazone at this time primarily because of the low acute inhalation toxicity

( Toxicity Category III) and the low vapor pressure (8 x 10 - 10 

### mm Hg). However, volatilization of pesticides may be a sourc e of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009, and receiv ed the SAP’s final report on March 2, 2010 6 

### . 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 developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for sulfentrazone. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. **7.1 Acute Aggregate Risk**  Acute aggregate risk results from exposure to residues in food and drinking water alone. The acute dietary

exposure analysis included both food and drinking water. Therefore, acute aggregate risk is equivalent to the acute dietary risk, as discussed in S ection 5.4, above. All risk estimates are not of concern . **7.2 Short** **- and Intermediate**  **- Term Aggregate Risk**  Short - and intermediate - term aggregate exposure takes into account short - and intermediate - term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). Sulfentrazone is currentl y registered for uses that could result in short - and intermediate - term residential exposure, and RAB1 has determined that it is appropriate to aggregate chronic exposure through food and water with short - and intermediate - term residential exposures to sulfentrazone. For short - and intermediate - term exposures, incidental oral and 4 Tier 1 output from the aerial application using fine to medium spray quality based on AgDrift® output files 5 0.375 lb ai/A x 0.26 ≤ 0. 375 lb ai/A 6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### dermal exposure risk assessments are appropriate to aggregate due to similarities in the toxicity endpoints observed between the oral and dermal routes. The short - and intermediate - term incidental oral and dermal exposures are combined with chronic dietary (food and water) exposure for determination of aggregate short - and intermediate - term exposures. HED uses chronic dietary

exposure when conducting short - and intermediate - term aggregate assessments as they have determined that these will more accurately reflect exposure from food over the HED defined short - and intermediate - term interval than will acute exposure. Adults may

potentiall y be exposed to sulfentrazone through dermal, inhalation, and dieta ry (food and drinking water) routes. It was appropriate to aggregate handler dermal exposures with dietary (food and water) exposures for the short - and intermediate - term duration . The backpack scenario for mixing and loading liquids is the exposure scen ario with the greatest risk estimate; therefore, the exposure estimates for this scenario are protective of other exposure scenarios. For yo ung children, due primarily to their hand - to - mouth activities, short - term oral (non - dietary) exposures are expected along with dermal and dietary (food and drinking water) exposures; therefore, it was appropriate to aggregate these exposures for the short - and intermediate - term duration. Children 1 - 2 years old represent the population subgroup for children with the greatest exposure; therefore, the exposure estimates for children 1 - 2 years old are protective of other children population subgroups. The LOC is 100; therefore MOEs <100 are risk estimates of concern. Tables 7.2.1 and 7.2.2 summarize the short - and intermediate - term aggregate exposures and risk estimates for 1 - 2 year olds and adults. The aggregate short - and intermediate - term MOEs are >1 00 for adults and children; therefore, aggregate exposures to sulfentrazone are not of concern to HED. **Table 7.2.1. Short**  **- and Interm**  **ediate -**  **term Aggregate Risk Calculations for Children 1**  **- 2 Years Old.**  Population LOC Background Dietary + Incidental Oral Exposures Residential Exposures Aggregate MOE (food, water, and residential) 4 Chronic Food and Water Exposure (mg/kg/day) Incidental

Oral Exposure (mg/kg/day) 1 Oral MOE 2 Dermal Exposure (mg/kg/day) Dermal

MOE 3 Children 1 - 2 years old 100 0.009881 0.0057 900 0.28 360 260 1 Short -term I

ncidental Oral Exposure = Hand - to - m outh exposure. 2 Oral MOE = NOAEL (14 mg/kg/day) ÷ (chronic food/water exposure + incidental oral exposure). 3 Dermal MOE = NOAEL (100 mg/kg/day) ÷ (dermal exposure). 4 Aggregate MOE = 1/[(1/oral MOE) + (1/dermal)]. **Table 7.2. 2**  **. Short -**  **Term Aggregate Risk Calculations**  **for Adults.** Population Dietary Exposure 1 Dermal Residential Exposure 2 Aggregate MOE (food, water, and residential) 3 Chronic Food and Water Exposure (mg/kg/day) MOE Dermal Exposure (mg/kg/day) MOE General U.S. Population 0.003973 3500 0.18 560 480 1 MOE dietary = [(short - or intermediate - term oral NOAEL = 14 mg/kg/day)/(chronic dietary exposure)]. 2 MOE dermal = [(short - or intermediate - term dermal NOAEL = 100 mg/kg/day)/(high - end dermal residential exposure)]. 3 Aggregate MOE = 1/[(1/dietary M OE) + (1/dermal MOE) + (1/inhalation MOE)]. 

### 7.3 **Chronic Aggregate Risk** The chronic aggregate risk assessment results from long - term exposure to residues in food and drinking water, as there are no residential scenarios that result in long - term exposure. The chronic dietary

exposure anal ys is included both food and drinking water and, therefore, theSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### chronic aggregate risk assessment is equivalent to the chronic dietary risk assessment discussed in Section 5.4, above. All risk estimates are not of concern . **7.4 Cancer Aggregate Risk**  An aggregate cancer risk assessment was not performed because sulfentrazone is not considered to be a carcinogen. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not ma de a common mechanism of toxicity finding as to sulfentrazone and any other substances and sulfentrazone 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 sulfentrazone 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 Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mech anism on EPA’s website at http://www.epa.gov/pesticides/cumulative/ . **9.0 Occupational Exposure/Risk Characterization**  D 417171 , K. Lowe , 05 - JUN - 2014 

### 9.1 **Handler Risk Assessment** The occupational handler exposure and risk estimates indicate that the short - and intermediate term dermal and inhalation MOEs are not of concern to HED (i.e., MOEs > 100 for dermal and MOEs > 30 for inhalation), as long as gloves are worn for the highest application rate for mixing/loading liquids and dry flowables for aerial application to high - acreage crops. HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long - sleeve shirt, long pants, shoes, and socks); per the Agency ’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators. The Agency

matches quantitative occupational exposure assessment with appropriate characterization of exposure potential . While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades . According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of Global Positioning System (GPS) for swath guidance in agricultural aviation has grown steadily from the mid - 1990s. Over the same time period, the u se of human flaggers for aerial pesticide applications has decreased steadil y from ~15% in the late 1990s to only 1% in the most recent (2012) NAAA survey . The Agency will continue to monitor all available information sources to best assess and characteri ze the exposure potential for human flaggers in agricultural aerial applications.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 37 of 57 **Table 9.1.1. Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Sulfentrazone** . Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation (LOC = 100) Mitigation Level = baseline unless indicated otherwise Mitigation Level

= baseline unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) Mixer/Loader

Aerial application of dry flowable Nursery (ornamentals,

vegetables, trees, container stock) 227

51.6 (SL w/ gloves) 8.96 0.375 60 0.0741 1,300 0.00253 Sod 350 0.432 230 0.0148 Field crop, typical acreage 8 Field crop, high acreage 9 1,200 1.48 0.336 (SL w/ gloves) **68**

300 (SL w/ gloves) 0.0504 0.25 0.987 100 0.0336 0.19 0.751 130 0.0255 0.16 0.632 160 0.0215 Chemigation application of dry flowable Sod 227 8.96 0.375 350 0.432 230 0.0148

Field crop, typical and high - acreage 8,9 Nursery (ornamentals, vegetables, trees, container stock) 60 0.0741 1,300 0.00253

Groundboom application of a dry flowable Golf course (fairways, tees, greens)

227 8.96 0.375 40 0.0494 2,000 0.00168 Field - grown ornamental crops Nursery (ornamentals, vegetables, trees, container stock) 60 0.0741 1,300 0.00253 Sod 80 0.0987 1,000 0.00336 Field crop, typical acreage 8 Field crop, high acreage 9 200 0.246 410 0.0084 Commercial Impregnation of Dry Flowable Formulation on Dry Bulk Fertilizers (closed

system) 9.8 (EC) 0.24 (EC) 3.75 lb ai/ton 960 tons 0.512 200 0.0108 On - farm Im

pregnation of Dry Flowable Formulation on Dry Bulk Fertilizers 227 8.96 0.375 160 0.246 410 0.0084 Loading/applying granular for tractor - drawn spreader application Golf course (fairways, tees, greens) 8.4 1.7 0.375 40 0.00183 55,000 0.000319 Sod 80 0.00365 27,000 0.000638 Christmas tree farms Nursery (ornamentals, vegetables, trees, container stock) 60 0.00274 36,000 0.000479

Aerial application of liquid formulation Nursery (ornamentals,

vegetables, trees, container stock) 220

37.6 (SL w/ gloves) 0.219 0.375 60 0.0717 1,400 0.0000616 Sod 350 0.419 240 0.000359 Field crop, typical acreage 8 Field crop, high acreage 9 1200 1.43 0.245 (SL w/ gloves) **70**

410 (SL w/ gloves) 0.00123 0.25 0.957 100 0.000821Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 38 of 57 **Table 9.1.1. Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Sulfentrazone** . Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation (LOC = 100) Mitigation Level = baseline unless indicated otherwise Mitigation Level

= baseline unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 0.19 0.728 140 0.000624 Chemigation application of a liquid formulation Sod 220 0.219 0.375 350 0.419 240 0.000359

Field crop, typical and high - acreage 8,9 Nursery (ornamentals, vegetables, trees, container stock) 60 0.0717 1,400 0.0000616

Groundboom application of liquid formulation Golf course (fairways, tees, greens)

220 0.219 0.375 40 0.0478 2,100 0.0000411 Field - grown ornamental crops Nursery (ornamentals, vegetables, trees, container stock) 60 0.0717 1,400 0.0000616 Sod 80 0.0957 1,000 0.0000821 Field crop, typical acreage 8 Field crop, high acreage 9 200 0.239 420 0.000205 Commercial Im

pregnation of Liquid Formulation on Dry Bulk Fertilizers (closed system) 8.6 (engineering control) 0.083

(engineering control) 3.75 lb

ai/ton 960 tons 0.449 220 0.00374 On - farm Impregnation of Liquid Formulation on

Dry Bulk Fertilizers 220 0.219 0.375 160 0.191 520 0.000164 Applicator Aerial spray application Nursery (ornamentals, vegetables, trees, container stock) 2.08

(engineering control) 0.0049

(engineering control) 0.375 60 0.000678 150,000 0.00000138 Sod 350 0.00396 25,000 0.00000804 Field crop, typical acreage 8 Field crop, high acreage 9 1200 0.0136 7,400 0.0000276

Groundboom spray application Golf course (fairways, tees, greens)

78.6 0.34 0.375 40 0.0171 5,800 0.0000638 Field - grown ornamental crops Nursery (ornamentals, vegetables, trees, container stock) 60 0.0257 3,900 0.0000956 Sod 80 0.0342 2,900 0.000128 Field crop, typical acreage 8 Field crop, high acreage 9 200 0.0855 1,200 0.000319 Mechanically- pressurized handgun Rights - of - way (e.g., utilities, railroad, roadways) 1,300 3.9 0.019 lb ai/gallon 1000

gallons 0.358 280 0.000926

Tractor- drawn Spreader granular application Golf course (fairways, tees, greens) 9.9 1.2 0.375 40 0.00216 46,000 0.000225 Sod 80 0.0043 23,000 0.00045 Christmas tree farms Nursery (ornamentals, vegetables, trees, 60 0.00323 31,000 0.000338Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 39 of 57 **Table 9.1.1. Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Sulfentrazone** . Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation (LOC = 100) Mitigation Level = baseline unless indicated otherwise Mitigation Level

= baseline unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) container stock) Flagger Flagger for aerial spray application Nursery (ornamentals,

vegetables, trees, container stock) 11 0.35 0.375 60 0.00359 28,000 0.0000985 Sod 350 0.0209 4,800 0.000574 Field crop, typical and high - acreage 9,10 Mixer/Loader/Applicator Dry Flowables via Backpack Railroad, Highway,

Roadside, Pipeline and Utility Rights of

- Way, Industrial Areas, Fence Rows, and Other listed Non - crop Sites 8,260 2.58 0.019 lb ai/gallon 40 gallons 0.091 1,100 0.0000245 Landscaping, turf (lawns, athletic fields, parks, etc.) Dry Flowables via Manually- Pressurized Handwand Landscaping, turf

(lawns, athletic fields, parks, etc.) 100,000 30 0.019 lb ai/gallon 40 gallons 1.1

0.00474 (SL w/ gloves) **91**

21,000 (SL w/ gloves) 0.000285 Dry Flowables via Mechanically- pressurized Handgun Golf course (fairways,

tees, greens) 1,960 42 0.375 5 0.0533 1,900 0.000985 Landscaping, turf (lawns, athletic fields, parks, etc.)

Liquids via Backpack Christmas Tree farm

8,260 2.58 0.0375 lb ai/gallon 40 gallons 0.18 560 0.0000484 Railroad, Highway, Roadside, Pipeline and Utility Rights of

- Way, Industrial Areas, Fence Rows, and Other listed Non - crop Sites Nursery (ornamentals, vegetables, trees, container stock) Landscaping, turf (lawns, athletic fields, parks, etc.) 0.019 lb ai/gallon 0.091 1,100 0.0000245 Liquids via Manuallypressurized Handwand Landscaping, turf (lawns, athletic fields, parks, etc.) 100,000 30 0.019 lb ai/gallon 40 gallons 1.1

0.00474 (SL w/ gloves) **91**

21,000 (SL w/ gloves) 0.000285

Liquids via Mechanicallypressurized Handgun Golf course (fairways, tees, greens) 1,140 1.9 0.375 5 0.031 3,200 0.0000445 Landscaping, turf (lawns, athletic fields, parks, etc.) Nursery (ornamentals, vegetables, trees, container stock) 1,300 3.9 0.0375 lb ai/gallon 1000

gallons 0.707 140 0.00183 Granulars via Backpack Christmas Tree farm 15 23.8 0.375 5 0.000407 250,000 0.000112Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 40 of 57 **Table 9.1.1. Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Sulfentrazone** . Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation (LOC = 100) Mitigation Level = baseline unless indicated otherwise Mitigation Level

= baseline unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) Nursery (ornamentals, vegetables, trees, container stock) Water Soluble Packets via Backpack Residential/

Commercial Turf 8,260 2.58 0.0033 lb ai/gallon 40 gallons 0.0158 13000 0.00000426 Water Soluble Packets via Manually- Pressurized Handwand 100,000 30 0.191 140000 0.0000495 Water Soluble Packets via Mechanically- Pressurized Handgun 1,350 18 0.287 lb ai/A 5 0.0281 11000 0.000323 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, Eng. Controls. 2 Based on registered and proposed labels. 3 Exposure Science Advisory Council Policy #9.1 and Registrant information. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre) × Area Treate d (A/day) ÷ BW (69 kg). 5 Dermal MOE = Dermal NOAEL (100 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = I

nhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW (80 kg). 7 Inhalation MOE = I

nhalation NOAEL (2.317, 4.661, or 8.094 mg/kg/day) ÷ I nhalation Dose (mg/kg/day). 8 Field crops, typical acreage category covers the following crops: apples, asparagus, Brassica head and stem, Brassica leafy greens, cabbage, citrus fruits, tree nuts, grapes and berries, edamame, fallow cropping systems, flax, fruiting vegetables, okra, horseradish, lima beans, melons, rhubarb, strawberry, succulent peas, tobacco, turnips, Christmas tree farms (where applicable) . 9 Field crops, high - acreage crops category covers the following crops: corn, dry shelled peas and beans, mint, peanuts, peppermint, spearmint, potato, soybeans, sugarcane, sunflower, wheat.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### 9.2 **Post -** **Application Risk Assessment 9.2.1**  **Inhalation Post** **- Application Risk Assessment**  Based on the Agency's current practices, a quantitative post - application inhalation exposure asses sment was not performed for sulfentrazone at this time primarily because of the low acute inhalation toxicity

( Toxicity Category III) and the low vapor pressure (8 x 10 - 10 

### mm Hg). However, there are multiple potential sources of post - application inhalatio n 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, and received the SAP’s final report on March 2, 2010 7



### . The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated by the ARTF and may , as appropriate, develop policies and procedures, to identify the need for and, subsequentl y, the way to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assess ment for sulfentrazone . Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application inhalation exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. **9.2.2 Dermal Post**  **- Application Risk Assessment**  Most of the registered uses and the proposed use on apples are soil - directed preplant or preemergent uses where no crop foliage is present. Currently , HED has no transfer coefficients or other data to assess post - application dermal exposures to soil by occupational workers. In general, such exposures are considered to be negligible. Therefore, for the soil - directed uses, post - application exposures and risks to occupational workers were not assessed. The registered uses on turf (golf courses and sod farms) and ornamentals are not specifically soil directed and, therefore, could result in potential post - application exposures. The short - and intermediate - term post - application exposure scenarios associated with the registered uses of sulfentrazone are summarized in Table 9.2.2.2. All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 430 to 8,200 ) on day 0 (12 hours after application) and, therefore, are not of concern to H ED.

7 Available: http://www.epa.gov/sc ipoly/SAP/meetings/2009/120109meeting.htmlSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 42 of 57 **Table 9.2.2.2. Occupational Post -**  **application Non -**  **Cancer Exposure and Risk Estimates for Sulfentrazone.** Crop/Site Activities Transfer Coefficient (cm2/hr) Application

Rate (lb ai/A) DFR 1 Dermal Dose

(mg/kg/day) 2 MOE 3

(LOC = 100) Short - and Intermediate - term Landscape ornamentals (Container, Field grown Ornamental plantings) Hand Harvesting, Hand Pruning,

Transplanting, Hand Harvesting, Hand Pr uning, Scouting, Container Moving, Hand Weeding, Transplanting,

Pinching 230 0.375 1.05 0.028 3,200 Handset Irrigation 1,900 0.232 430 Golf Courses Maintenance, greens only 2,500 0.375 0.042 0.012 8,200 Maintenance 3,700 0.018 5,500 Sod Maintenance, Slab Harvesting,

Transplanting/Planting 6,700 0.033 3,100 1 DFR = Application Rate × F × (1 - D) t × 4.54E8 μg/lb × 2.47E - 8 acre/cm2 ; where F = 0.25 and D = 0.10 per day. 2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day]  BW (69 kg). 3 MOE = POD (100 mg/kg/day) / Daily Dermal Dose. 

### Restricted - Entry

Int erval The REI specified on the proposed label is based on the acute toxicity of sulfentrazone. Sulfentrazone is classified as acute Toxicity Category III for acute oral, acute dermal, and acute inhalation toxicity . It is classified as Toxicity Category III for eye irritation potential and category IV for skin irritation potential. It is not a dermal sensitizer. Short - and intermediate term post - application risk estimates were not a concern on day 0 (12 hours following application) for all post - application activities. Under 4 0 CFR 156.208 (c) (2) (iii), ai s classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12 - hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REIof 12 h ours is adequate to protect agricultural workers from post - application exposures to sulfentrazone. **10.0 References**  Recent RA J. Van Alstine , et al. , 14 - JUN - 2012 ; D389082 Scoping Document K. Lowe, et al. , 09 - SEP - 2009 ; D369064 HASPOC Memo D. Smegal, 02 - MAR - 2012; TXR # 0050684; and Re - Classification of Peer - Reviewed Developmental Neurotoxicity Study in Rats: C. Rodriguez, 19 - DEC - 2011; D389975. ORE Memo K. Lowe, D417171; 05 - JUN - 2014 Dietary Memo G. Kramer, D417172; 05 - JUN - 2014 cc: G. Kramer (RAB1) RDI: RAB1 ( 5 / 14 /14) G.F. Kramer:S10957:PY - S:(703)305 - 5079:7509P:RAB1Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 43 of 57 

### Appendix A. Toxicology Profile and Executive Summaries The requirements (40 CFR 158.340) for food uses for sulfentrazone are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Table A.1. Toxicological Data Requirements for Sulfentrazone.** Study 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 28 - Day

Dermal ................................ .............................. 870.3465 28 - Day

Inhalation ................................ .......................... yes yes yes yes yes

yes yes yes 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700a Dermal Developmental Toxicity (rodent) ...................... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes 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 Neurotoxicity (hen) ............................... 870.6100b 90 - Day

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

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

-- yes yes

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

-- yes **Table A.2. Acute Toxicity Profile**  **– Sulfentrazone.**  Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute oral [rat] 41911605 LD 50 = 2855 (M & F) mg/kg III 870.1200 Ac ute dermal [mice] 41911606 LD 50 = 711 (M & F) mg/kg III 870.1200 Ac ute dermal 42286400 LD 50 >2000 mg/kg/day III 870.1300 Ac ute inhalation [rat] 42471002 4 - hour, whole body exposure; LC 50 >4.13 mg/L III 870.2400 Ac ute eye irritation

[rabbit] 41911608 Corneal opacity, iritis, diffuse irritation within 24, clearing by day 4 III 870.2500 Ac ute dermal irritation

[rabbit] 41911609 Non - irritating IV 870.2600 Skin sensitization

[Guinea Pig] 41911610 Not a Dermal Sensitizer N/A **Table A.3. Toxicity Profile for Sulfentrazone**Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 44 of 57 Guideline No./ Study T ype MRID No.

(year)/Classification/ Doses Results 870.3100 90 - Day oral toxicity (rat) 43004601 (1990)

Acceptable/Guideline 0, 300, 1000, 3000, & 7000 ppm , M: 0, 3.3, 6.7, 19.9, 65.8, 199.3, & 534.9 mg/kg/day F: 0, 4, 7.7, 23.1, 78.1, 230.5, & 404.3 mg/kg/day Sy stemic Toxicity NOAEL = 19.9 mg/kg/day in males and 23.1 mg/kg/day in females. Sy stemic Toxicity LOAEL = 65.8 mg/kg/day in males and 78.1 mg/kg/day in females, based on clinical signs of anemia (reduced Hct , HGB , MCV , and MCH values during treatment). 870.3100 90 - Day oral toxicity (mice) 43616517 (1993) Acceptable/Guideline 0, 50, 1 00, 300, 550, 1000, & 3000 ppm M: 0, 10.3, 17.8, 60, 108.4, & 194.4 mg/kg/day F: 0, 13.9, 29, 79.8, 143.6, & 257 mg/kg/day Sy stemic Toxicity NOAEL = 60 mg/kg/day in males and 79.8 mg/kg/day in females. Sy stemic Toxicity LOAEL = 108.4 mg/kg/day in males and 143.6 mg/kg/day in females, based on decreased body weights, body - weight gains, red blood cells, HGB , Hct , and severity of splenic micropathology (increased incidence and severity of extramedullary hematopoiesis). Four - week recovery period reversed all the treatment related effects except extramedullary hematopoiesis; however, severity was reduced. 870.3150 90 - Day oral toxicity (dog) 42932102 (1992)

Acceptable/Guideline 0, 300, 800 & 2000 ppm M/F: 0/0, 10/10, 28/28, & 57/73 mg/kg/day Sy stemic Toxicity NOAEL = 28 mg/kg/day for males and females. Sy stemic Toxicity LOAEL = 57/73 mg/kg/day (M/F), based on decreased body weights (7 - 10%) and body - weight gains during first 5 weeks of study; decreased HGB , Hc t , MCV , and MCH concentration, and increased absolute liver weights and alkaline phosphatase levels, and microscopic changes in the liver and spleen (pigmented sinusoidal microphages in the liver, swollen centrilobular hepatocytes and pigmented reticuloendothelial cells in the spleen). 870.3200 28 - Day dermal toxicity (rabbit) 44248301 (1996) Acceptable/Guideline 0, 10, 30, 100, 300, & 1000 mg/kg/day Sy stemic and Dermal Toxicity NOAEL = 1000 mg/kg/day (highest dose tested or HDT). Sy stemic and Dermal Toxicity LOAEL was not established. 870.3465 26 - Day inhalation toxicity with 28 days of recovery (rat) 49253902 (2013) Acceptable/Non - Guideline 0, 0.085, 0.256 and 1.71 mg/L (0, 20, 40, 600 mg/kg/day [M/F]) NOAEL = 0.256 mg/L. LOAEL = 1.71 mg/L based on significant reductio n in RBC parameters, including RBC count, HGB, Hct , MCV, MCH, and/or reticulocytes in male and female rats following 26 days inhalation exposure to the test material. Portal - of - entry NOAEL = 0.25 6 mg/L. Portal - of - entry LOAEL = 1.71 mg/L based on an incre ased incidence of minimal nasal respiratory epithelial hyperplasia in male and female rats. 870.3700a Prenatal Developmental (rat) 42932104 (2013) Acceptable/Guideline 0, 1, 10, 25 & 50 mg/kg/day Maternal NOAEL = 25 mg/kg/day. Maternal LOAEL = 50 mg/kg/day, based upon increased relative splenic extramedullary hematopoiesis. Developmental NOAEL = 10 mg/kg/day. Developmental LOAEL = 25 mg/kg/day, based upon decreased mean fetal weights, and retardation in skeletal development evidenced by an increase d number of litters with any variation and by decreased number of caudal vertebral and metacarpal ossification sites.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 45 of 57 **Table A.3. Toxicity Profile for Sulfentrazone** Guideline No./ Study T ype MRID No.

(year)/Classification/ Doses Results 870.3700 Prenatal developmental (rat) 43651003 (1992) Acceptable/Non - Guideline 0, 25, & 50 mg/kg/day Study was conducted to evaluate exte rnal and cardiac abnormalities. Maternal NOAEL = 25 mg/kg/day. Maternal LOAEL = 50 mg/kg/day, based on decreased mean body weights during gestation, and decreased litter size. Developmental NOAEL = 25 mg/kg/day. Developmental LOAEL = 50 mg/kg/day, based on significant reductions in the number of im plantations and percentage of live fetuses, increase in the percentage of early resorptions, and decreased fetal body weights. Supplemental study to the 1992 Developmental Toxicity Study in Rats (MRID 42932104) . 870.3700 Prenatal dermal developmental (rat) MRID 42932105 (1992) Acceptable/Guideline 0, 5, 25, 50, 100, & 250 mg/kg/day Maternal NOAEL >250 mg/kg/day. Maternal LOAEL was not established. Developmental NOAEL = 100 mg/kg/day. Developmental LOAEL = 250 mg/kg/day, based on decreased fetal body weight; increased incidence of fetal variations: hypoplastic or wavy ribs, incompletely ossified lumbar vertebral arches, and incompletely ossified ischia or pubis; and reduced number of thoracic vertebral and rib o ssification sites. 870.3700b Prenatal Developmental (rabbit) MRID 42932106 (1993) Acceptable/Guideline 0, 100, 250, & 375 mg/kg/day Maternal NOAEL = 100 mg/kg/day. Maternal LOAEL = 250 mg/kg/day, based on increased abortions, clinical signs (hematuria and decreased feces), and reduced body- weight gain. Developmental NOAEL = 100 mg/kg/day. Developmental LOAEL = 250 mg/kg/day, based on increased resorptions, decreased live fetuses per litter, and decreased fetal weights. 870.3800 Two - Generation reproductio n and fertility effects (rat) 43345408 (1994) Acceptable/Guideline 0, 200, 500, & 700 ppm M/F: 0, 14/16, 33/40, & 46/56 mg/kg/day Parental Toxicity NOAEL =14 (M) and 16 (F) mg/kg/day. Parental Toxicity LOAEL = 33 (M) and 40 (F) mg/kg/day based on decreased maternal body weight/body- weight gain during gestation in both generation (P & F 1 ) and reduced premating body weight gain in second - generation (F 1 ) males. Reproductive Toxicity NOAEL = 14 (M) and 16 (F) mg/kg/day. Reproductive Toxicity LOAEL = 33 (M) and 40 (F) mg/kg/day, based on increased duration of gestation in females and degeneration and/or atrophy of the germinal epithelium of the testes and oligospermia and intratubular degenerated seminal material in the epididymis of F 1 males. Offspring Toxicity NOAEL = 14 (M) and 16 (F) mg/kg/day. Offspring Toxicity LOAEL = 33 (M) and 40 (F) mg/kg/day, based on reduced prenatal viability (fetal & litter), reduced litter size, increased no. of stillborn pups, reduced pup and litter postnatal survival and decreased pup body weights throughout lactation. 870.3800 43869101(1995) Sy stemic/Developmental Toxicity NOAEL = 20 (F)Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 46 of 57 **Table A.3. Toxicity Profile for Sulfentrazone** Guideline No./ Study T ype MRID No.

(year)/Classification/ Doses Results One - Generation reproduction and fertility effects (rat) Acceptable/Nonguideline 0, 50, 100, 200, & 500 ppm F 0 M/F: 0, 3.9/4.1, 7.8/13.4, 16/16, & 40/43 mg/kg/day F 1 M/F: 0/0, 4.5/5 .0, 9.2/10.1, 18/20, & 45/51 mg/kg/day mg/kg/day. Sy stemic/Developmental Toxicity LOAEL = 51 (F) mg/kg/day, (F 1 females), based on decrease in pre mating body - weight gain (10%). Offspring and Reproductive Toxicity NOAEL = 16 mg/kg/day (M/F) mg/kg/day. Offspring and Reproductive Toxicity LOAEL F 1 = 40 (M/F) mg/kg/day, based on reduced gestation day - 20 fetal weights; decreased postnatal day 0, 4, and 7 pup weights; decreased pup survival; delayed vaginal pate ncy; reduced epididymal, prostate, and testicular weights. Additional information supports the conclusions reached in the two - generation reproduction study (MRID 43345408). 870.4100b Chronic toxicity (dog) 43345406 (1994) Acceptable/Guideline 0, 300, 800 , and 1800 ppm M/F: 0, 9.9/10.4, 24.9/29.6, & 61.2/61.9 mg/kg/day Sy stemic Toxicity NOAEL = 24.9/29.6 mg/kg/day for males/and females. Sy stemic Toxicity LOAEL = 61.2/61.9 mg/kg/day (M/F), based upon compensated normochromic microcytosis. 870.4200 Carcinogenicity rodents (mouse) 43345407 (1994) Acceptable/Guideline 0, 300, 600, 1000, & 2000 ppm M/F: 0, 46.6/58.0, 93.9/116.9, 160.5/198.0 & 337.6/407.1 mg/kg/day Sy stemic Toxicity NOAEL = 93.9 mg/kg/day for males and 116.9 mg/kg/day for females. Sy stemic Toxicity LOAEL = 160.5 mg/kg/day for males and 198.0 mg/kg/day for females, based on dose - related decreases in HGB and Hct by study termination. No evidence of carcinogenicity. 870.4300 Com bined chronic toxicity/carcinogenicity rodents (rat) 433 45409 (1994) Acceptable/Guideline M: 0, 600, 1000, 2000, & 3000 ppm F: 0, 300, 600, 1000 & 2000 ppm M/F: 0/0, 24.3/20, 40/36.4, 82.8/67, & 123.5/124.7 mg/kg/day Sy stemic Toxicity NOAEL = 40 mg/kg/day for males and 36.4 mg/kg/day for females. Sy stemic Toxicity LOAEL = 82.8 mg/kg/day for males and 67 mg/kg/day for females, based on dose - related decreased body weights (11 & 19%), body- weight gains (13 & 26%), food consumption (13 & 19%), HGB , Hct , MCV , and MCH . Increased nucleated red blood cells and reticulocytes in bone of females at 124.7 mg/kg/day. No evidence of carcinogenicity. 870.5100 Gene Mutation: Ames assay Gene Mutation: HGPRT 41911611 (1986) Acceptable/Guideline Salmonella typhimurium strains TA 1535, TA1538, TA1537, TA 98, and TA10 0 were exposed to sulfentrazone technical (95.5%) at concentrations of 100 - 10,000 ug/plate with or without S9 activation (both trials). No evidence of compound - induced cytotoxicity wa s evident either in presence or in absence of S9 activation. The positiv e controls induced the expected mutagenic responses in the appropriate tester strain. Sulfentrazone was considered not mutagenic under any test condition.

870.5300 In vitro mammalian cell gene mutation assay (mouse lymphoma) 43004604 (1992) Acceptable/Guideline Mouse lymphoma (L5178Y TK+/ - CHO) cells were exposed to sulfentrazone In a forward gene - m utation assay, sulfentrazone at precipitating levels were equivocally positive in the absence of S9 activation. This response was not repeated at doses up to 1800 g/mL in the presence of S9 activation.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 47 of 57 **Table A.3. Toxicity Profile for Sulfentrazone** Guideline No./ Study T ype MRID No.

(year)/Classification/ Doses Results technical (94.2%) in non activated dose ranges of 424 - 1308 ug/mL (Trial 1) and 1308 - 3000 ug/mL (Trial 2); With S9 activation dose ranges of 424 - 1407 ug/mL (Trial 1) and 915 - 1800 ug/mL (Trial 2). 870.5395 Mammalian erythrocyte micronucleus test 430 04605 (1992) Acceptable/Guideline Groups of 5 male and 5 female ICR mice received single intraperitoneal injection of 85, 170, and 340 mg/kg sulfentrazone technical (94.2%). Test material was administered in corn oil and bone marrow cells harvested at 24, 48, and 72 hours post - dosing. Cyclophosphamide at 30 mg/kg was used as positive control. The test was negative in mice administered single intraperitoneal doses of 85 - 340 mg/kg. The 340 mg/kg dose was estimated to be approximately 80% of the LD50/7. No evidence of a cytotoxic effect on the target organ and no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow cells.

870.5450 Dominant lethal assay - rodent 44248302 (1996) Acceptable/Guideline In dominant lethal assay, male rats were dosed at 0, 100, 225, or 450 mg/kg/day for 5 days, and mated to untreated females sequentially for 10 weeks to determine the level of fetal deaths due to dominant lethal mutations. There were no significant differences from negati ve controls in the proportion of early dead: total im plants, and (total) dead: total implants. Based on the results, sulfentrazone is considered negative for inducing dominant lethal mutations in pre - meiotic, meiotic, and post - meiotic germ cells of male rats under conditions of this assay up to the estimated maximum tolerable dose (MTD). 870.6200 ACN Study 43345405 (1994) Acceptable/Guideline 0, 250, 750, & 2000 mg/kg Sy stemic Toxicity NOAEL = 250 mg/kg/day. Sy stemic Toxicity LOAEL = 750 mg/kg/day, based upon increased incidence of clinical signs, FOB findings, and decreased motor activity which was reversed by day 14 post dose. No evidence of neuropathology at any dose. 870.6200 SCN Study 43345405 (1994) Acceptable/Guideline 0, 500, 2500, or 5000 ppm (0 /0, 30/37, 150/180, or 265/292 mg/kg/day [M/F]) NOAEL = 500 ppm (30/37 mg/kg/day). LOAEL = 2500 ppm (150/180 mg/kg/day) based on increased incidence of clinical signs (M&F), decreased BW, BWG, and FC (F), and increased mo tor activity at week 13 only (F). No evidence of neuropathology at any dose. 870.7485 Metabolism and pharmacokinetics (rat) 43345410 (1994) Acceptable/Guideline Phenyl 14 C sulfentrazone (98% pure.) was administered to Sprague Dawley rats ( five animals/sex/dose) by gavage Sulfentrazone was readily absorbed and 84 to 104% of the administered dose was excreted in urine and feces within 72 hours. There were no major sex differences in the pattern of excretion. Almost all the radioactivity in the urine was HMS (84 - 104% of the administered dose). In the feces, HMS accounted for 1.26 - 2.55% of the administered dose.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 48 of 57 **Table A.3. Toxicity Profile for Sulfentrazone** Guideline No./ Study T ype MRID No.

(year)/Classification/ Doses Results as a single dose at levels of 50 and 500 mg/kg, or as a single dose of 50 mg/kg following a 14 - day pretreatment with non radioactive sulfentrazone (50 mg/kg/day). The proposed metab olic pathway appeared to be conversion of the parent compound mainly to HMS (excreted in the urine). A small amount of HMS wa s also converted to sulfentrazone 3 - carboxylic acid (excreted in the urine and feces). 870.7800 Immunotoxicity (rat) 48748601 (20 12) Acceptable/Guideline 0, 500, 1000, or 2000 ppm (0, 42, 87, or 163 mg/kg/day[F]) Sy stemic NOAEL = 1000 ppm (87 mg/kg/day) . Sy stemic LOAEL = 2000 ppm (163 mg/kg/day) based on reduced body weight, and increased absolute and relative spleen weights. Immunotoxicity NOAEL = 2000 ppm (equivalent to 163 mg/kg/day) . Immunotoxicity LOAEL was not established. Published literature 47749201 (2009) De Castro, et al ., (2007) Acceptable/non - guideline 0, 25, or 50 mg/kg bw/day Dose - dependent, statistically signif icant delayed ear opening, decreased grip response and rearing frequency, and increased surface righting reflex reaction time observed at ≥25 mg/kg/day; no effect on maternal body weight (only parameter tested in dams) during gestation. The results of thi s non guideline study were published in the open literature. Due to limitations in study conduct and reporting of the statistical analysis, the study is of limited value in risk assessment.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 49 of 57 

### Appendix B. Methodologies for HEC Calculations. The RfC methodology

applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also the phy sicochemical properties of the inhaled compound, the ty

pe of toxicity

observed ( e.g. , systemic vs. portal - of - entry) and the pharmacokinetic (PK) **but not pharmacodynamic** (PD) differences between animals and humans. Based on the EPA’s RfC guidance (1994), the methodology for RfCs derivation is an estimate of the quantitative dose - response assessment of chronic non - cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species specific relationships of exposure concentration to deposited/delivered dose . This adjustment is influenced b y the phys icochemical properties of the inhaled compound as well as the ty pe of toxicity observed ( e.g. , systemic vs. portal - of - entry), and takes into consideration the PK differences between animals and humans. Though the RfC methodology was developed to estimate toxicity

of inhaled chemicals o ver a lifetime, it can be used for other inhalation exposures ( e.g. , acute and short - term exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition that can be applied to shorter duration of exposures provided the assumptions underlying the methodology are still valid. These assumptions, in turn, vary depending on the type of toxicity observed. Thus the derivation of a HEC for inhaled gases is described b y the following equation: Where: POD study 

### : Point of departure identified in the critical toxicology study D animal exposure 

### : Duration of animal exposure (hrs/day; day s/wk) D anticipated exposure 

### : Anticipated human duration of exposure (hrs/day ; days/wk) RGDR: Regional Gas Dose Ratio Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerodyn amic diameter [MMAD]) and the geometric standard deviation (σ g

### ), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the rth region or target tissue. RDDR

r 

### = (RDD r 

### /Normalizing Factor) A 

### (RDD r 

### /Normalizing Factor) H 

### As with calculations for gase s, the r regions and potential target tissues are the three respiratory regions (ET, TB, PU). The RDDR is easily calculated by

using a software program designed specificall y for computing the RDDR from the MMAD and σ g 

### defined from an aerosol inhalation study . The values for the species - specific parameters used to calculate the RDDR are provided in the EPA document “Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry .” 

# HEC = POD * D

D * W

W * RGDR study animal exp

osure (hrs / day) human expo

sure (hrs / day) animal exp osure (day s / wk) human expo

sure (days / wk)Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 50 of 57 

### Regional Deposited Dose Ratio (RDDR) for **S ulfentrazone**  MMAD = 2.3 Sigma g = 2.0 Body Minute SPECIES Weight (g) Ventilation (VE, ml)

----------------------------------------------------------------------------- rat 236 171.5 human 70000 13800.0

-----------------------------------------------------------------------------

Extrathoracic SA (m^2) deposited fraction

-------------------------------------------------------------------------------- rat 15 0.439 human 200 0.341

--------- ----------------------------------------------------------------------- RATIO 0.075 1.288 RDDR = (VE/SA) animal

### /(VE/SA) human 

### * deposited fraction animal

### /deposited fractionhuman 

### = (171.5/15) animal

### /(13800/200) human 

### * 0.439 /0.341 = 0.213 The magnitude of the UFs applied is dependent on the methodology used to calculate risk. The RfC methodology

takes into consideration the PK differences **but not the PD differences** . Consequently , the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X. Thus, the UF when using the RfC methodology

is customarily

30X. **B.1. HEC Calculations for Short** **- and Intermediate**  **- term Residential Exposure:**  Assume residents will be exposed for 24 hrs/day and 7 days/week: HEC = NOAEL study 

### * (daily duration of exposure animal

### /daily duration of exposure human

### ) * (days/week of exposure animal

### /days/week of exposure human

### ) * RDDR Residential Handler Outdoor HEC = 0 .256 mg/L* 0.213 = 0.054 mg/L Residential Handler Outdoor HEC = 0.256 mg/L* (5/7) * 0.213 = 0.038 mg/L Indoor Postapp. Handler Outdoor HEC = 0.256 mg/L * (6/18) * (5/7) * 0.213 = 0.0129 mg/L Bystander HEC = 0.256 mg/L * (6/24) * (5/7) * 0.213 = 0.00974 mg/LSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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Page 51 of 57 **Table B.1. HEC Array for Residential Risk Assessment.** Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF Short - & Intermediate - Term Exposure

Inhalation

– Rat (MRID 49253902 ) 26 - day ET 1.71 0.256 See equations listed above table 0.213 Handler/Out door Postapp. - 0.054 mg/L 3 10 NA Indoor Posapp. - 0.038 mg/L Indoor Postapp. (Adults and Children) - 0.0013 mg/L Bystander 0.00974 mg/L Long - Term

Exposure: Not appropriate for sulfentrazone . **Key for Array Tables** LOAEL : Lo we st - observed adverse - effect level NOAEL : No - observed adverse - effect level Da : Daily animal exposure (hrs/day) Dh : Anticipated daily human exposure (hrs/day) Wa : Weekly animal exposure (days/week) Wh : Anticipated weekly human exposure (days/week) RRDR : Regional Deposited Dose Ratio HEC : Human - Equivalent Concentration inter : Interspecies extrapolation UF intra : Intraspecies variation UF UF: Other UF(s) ET: Extra - thoracic region 

### Route **- to**  **- Route**  **Extrapolation** More information and details in: Memo, “Route - to - Route Extrapolations” J. Whalen and H. Pettigrew, 10/10/98. HED’s route - to - route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral equivalent doses. The equation uses a single conversion factor to account for default body weights and respiratory volumes. An activity factor is used to account for increased exposure resulting from increased respiration. Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: HED (mg/kg/day) = Dose (s ys temic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kg Where: A = absorption: ratio of deposition and absorption in respiratory tract compared to absorption by

the oral route. CF = conversion f actor; a L/hr/kg factor which accounts for respiratory volume and body weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98). D = duration; duration of daily animal or human exposure (hours). AF = activity

factor; animal default is 1. For humans with a ventilation rate of 16.7Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### L/min, the value is 1.2. Therefore, the residential HED for sulfentrazone is calculated as follows: **Residential Handler and Outdoor Postapplication HED:** (0.05427 mg/L) x 1.2 x 11.8 L/hr/kg x 2 hr x 1 = 1.554 mg/kg/day **B.2. HEC Calculations for Short** **- and Intermediate**  **- term Occupational Exposure:**  Assume workers will be in the field for 8 hrs/day and 5 days/week: HEC = NOAEL study 

### * (daily duration of exposure animal

### /daily duration of exposure human

### ) * (days/week of exposure animal

### /days/week of exposure human

### ) * RDDR HEC = 0.256 mg/L * (6/8) * (5/5) * 0.213 = 0.041 mg/L. **Table B.1. HEC Array for Occupational Risk Assessment.**  Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF Short - & Intermediate - Term Exposure Inhalation

– Rat (MRID 49253902 ) 26 - day ET 1.71 0.256 6 8 5 5 0.213 0.041 3 10 NA Long - Term

Exposure: Not appropriate for sulfentrazone . **Key for Array Tables** LOAEL : Lowest - observed adverse - effect level NOAEL : No - observed adverse - effect level Da : Daily animal exposure (hrs/day) Dh : Anticipated daily human exposure (hrs/day) Wa : Weekly animal exposure (days/week) Wh : Anticipated weekly human exposure (days/week) RRDR : Regional Deposited Dose Ratio HEC : Human - Equivalent Concentration inter : Interspecies extrapolation UF intra : Intraspecies variation UF UF: Other UF(s) ET: Extra - thoracic region 

### Route **- to**  **- Route Extrapolation**  More information and details in: Memo, “Route - to - Route Extrapolations” J. Whalen and H. Pettigrew, 10/10/98. HED’s route - to - route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral - equivalent doses. The equation uses a single conversion factor to account for default body weights and respiratory volumes. An activity factor is u sed to account for increased exposure resulting from increased respiration. Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: HED (mg/kg/day) = Dose (s ys temic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kgSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Where: A = absorption ; ratio of deposition and absorption in respiratory tract compared to absorption by

the oral route. CF = conversion f actor ; a L/hr/kg factor which accounts for respiratory volume and body weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98). D = duration; duration of daily animal or human exposure (hours). AF = activity f

actor ; animal default is 1. For humans, the value varies with ventilation rates determined b y occupational/restidential scientists; 0.6 (8.3L /min), 1.2 (16.7 L/min) and 2.1 (29 L/min) Therefore, the occupational HED for sulfentrazone is calculated as follows: **Occupational HED, Ventilation Rate, 8.3 L/min:**  (0.0407 mg/L) x 1 x 0.6 x 11.8 L/hr/kg x 8 hr = 2.317 mg/kg/day **Occupational HED, Ventilation Rate, 16.7 L/min:** 0.0407 mg/L) x 1 x 1.2 x 11.8L/hr/kg x 8 hr = 4.661 mg/kg/day **Occupational HED, Ventilation Rate, 29 L/min:**  (0.0407 mg/L) x 1 x 2.1 x 11.8 L/hr/kg x 8 hr = 8.094 mg/kg/day Based on the current s ulfentrazone label, HED believes exposures can be short - (1 - 30 days) or intermediate - (1 to 6 months) term in duration. Long - term exposures are not anticipated for sulfentrazone based on proposed labeled uses. For the short - and intermediate - term scenarios, inhalation data from the 26 - day inhalation rodent study

was most appropriate for determining HECs. In the RfC methodology , different HECs may be calculated for the same experimental NOAEL due to the following: 1. Different algorithms are used to derive HECs for systemic versus portal - of - entry effects. Ty pically , HECs are calculated separatel y for s ys temic versus portal - of - entry effect. For sulfentrazone, portal - of

- entry irritation was observed and, therefore, only portal - of - entry HECs were derived. 2. Time adjustments are traditionally needed for non - occupational (b ys tander) versus occupational exposure scenarios. Traditionally , HECs for non - occupational e xposure are based on the number of hours an individual may be at home. Therefore, the most conservative estimate of hours spent at home would be 24 hours/day and 7 days/week. In comparison, the average workweek for an occupational worker is 8 hours/day and 5 days/week. The HEC array table reflects the time adjustment in the calculations.Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Appendix **C . Physical/Chemical Properties**  **Table B.1. Physicochem ical Properties of Technical Grade Sulfentrazone.**  Parameter Value Reference Melting range 120 - 122 oC DP# 288712, 3/6/03, G. Kramer, G. Reddy, and L. Liu pH 4.78 at 23 oC Density 0.53 g/cm3 Water solubility 4.0 x 10 2 μg/g Solvent solubility 18.6% w /w in acetonitrile Vapor pressure 8 x 10 - 10 mm Hg Dissociation constant, pKa 6.56 Octanol/water partition coefficient, Log(KOW) 1.49 at pH 5 UV/visible absorption spectrum Not availableSulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Appendix **D .**  **International Residue Limits**  **Sulfentrazone** ( 129081 ; 4/15/2014) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 40 CFR §180.498 (a)(1) General: Compliance with the tolerance levels specified below

is to be determined by measuring only the sum of sulfentrazone ( N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1 H

- 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide) and its metabolite HMS (

N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)me thanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl] -phenyl]methanesulfonamide, including the metabolite N - [2,4 - dichloro - 5 - [4 - (difluoromethyl ) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex Soy bean, seed 0.05 0.05 dry soybeans (2)Compliance with the tolerance levels specified below is to be determined by measuring only the sum of sulfentrazone (

N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo 1 H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide) and its metabolites HMS (N

- (2,4 - dichloro - 5 - (4 - (difluoro methyl) - 4,5 - dihydro - 3 - hydroxymethyl 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide) and DMS ( N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulf entrazone N - [2,4 - dichloro - 5 - [4 -

(difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl] -phenyl]methanesulfonamide, including the metabolites N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide and N - [2,4 - dichloro - 5 - 4 - (difluoromethyl) - 4,5 - dihydro - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex Asparagus 0.15 0.15 Berry and small fruit, group 13 - 07 0.15 Brassica, head and stem, subgroup 5A 0.20 0.2 cabbages Brassica, leafy greens, subgroup 5B 0.40 Corn, field, forage 0.20 Corn, field, grain 0.15 Corn, field, stover 0.30 Flax 0.15 0.15 flaxseeds Fruit, citrus, group 10 - 10 0.15 Horseradish 0.20 0.2 horseradish roots Melon, subgroup 9A 0.15 Nut, tree, group 14 0.15Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex Pea and bean, dried shelled, except soy bean, subgroup 6C 0.15 0.15 Dry (adzuki beans, beans, black- eyed peas, broad beans, catjang seeds, chickpeas, cowpea seed, field peas, grain lupin, guar seeds, kidney beans, lablab beans, lentils, lima beans, moth beans, mung beans, navy beans, pigeon peas, pink beans, pinto beans, rice beans, southern peas, tepary beans, urd beans) Pe a, succulent 0.15 Peanut 0.20 Peanut, meal 0.40 Peppermint, tops 0.30 0.3 Pistachio 0.15 Rhubarb 0.15 Spearmint, tops 0.30 0.3 Sugarcane, cane 0.15 Sugarcane, molasses 0.20 Sunflower subgroup 20B 0.20 0.2 sunflower seeds Turnip, roots 0.15 Turnip, tops 0.60 Vegetable, fruiting, group 8 - 10 0.15 Vegetable, soybean, succulent 0.15 Vegetable, tuberous and corm, subgroup 1C 0.15 

### US Canada Mexico 1 

### Codex (c) Compliance with the tolerance levels specified below

is to be determined by measuring only the sum of sulfentrazone (N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - me thyl - 5 - oxo 1 H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide) and its metabolites HMS (N

- (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide) and DMS ( N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazo ne in or on the following commodities None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex Bean, lima, succulent 0.15 Cow pea, succulent 0.15 Wheat, forage 0.50 Wheat, grain 0.15 0.15 grain, cereal, group 15, except sweet corn; bran Wheat, hay 0.30 Wheat, straw 1.5Sulfentrazone Preliminary Human - Health Risk Assessment D 410365

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### Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex US Canada Mexico 1 

### Codex (d) Indirect or inadvertent residues. Com pliance with the tolerance levels specified below is to be determined by measuring only the sum of sulfentrazone (

N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo 1 H - 1,2,4 - triazol - 1 - yl]phenyl]methanesulfonamide) and its metabolites HMS (

N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide) and DMS ( N - (2,4 - dichloro - 5 - (4 - (difluoromethyl) - 4,5 - dihydro 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex Grain, cereal (excluding sweet corn), Hulls 0.30 Grain, cereal, forage, fodder and straw , group 16, except sweet corn; forage 0.2 Grain, cereal, forage, fodder and straw , group 16, except sweet corn; hay 0.2 Grain, cereal, forage, fodder and straw , group 16, except sweet corn; stover 0.1 Grain, cereal, forage, fodder and straw , group 16, except sweet corn; straw 0.6 Grain, cereal, group 15, except sweet corn 0.1 Grain, cereal, group 15, except sweet corn; bran 0.15 Com pleted: M. Negussie; 04/16/14 1 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.