### UNITED ST A TES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OF F IC E OF CH E MICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM

Dat e : 05 -J UN

- 2014



### SUBJECT: Sulfentrazone- Preliminary Human-Health Risk Asse s sment for Registration Review and the R i sk Assessment for the Section 3 Registration Request for a New Use on Apples

PC C od e: 129081 Deci s ion Nos.: 476747

, 483232 Pe tjtion No.: 3 £ 8 2 0 2 DP Barcode: 0410365 Re gistrat ion N os. : 279-3370

, 279-3189

, & 279-3220 Regulatory Action: Section 3 and Registration Review Risk Asses s m e nts R isk Ass e ssment Type: Single Chemical / Ag g regate Case No.: 72 3 1 TXRN o .: NA CAS No .: 1 22836-35-5 M RID No.: NA 40 CFR: § 180.498



### From: George F

. Kramer

, Ph.D.

, Senior

# Chemist**~~** Kelly M

. Lowe, Environmental Scientist /) 

## /lL //**~** 

## .

Th rou gh :

To: Anwar Y. Dunbar

, Ph.D.

, Pharmacologist**{~ iftv**  

# 7 · /'l**•"-- ~**  

### Risk Assessment Branch 1 (RAB 1) Hea l th E ffects Division (HED; 7509P)

Charles W. Smith III

, Branch Chief RABI / HED (7509P )

Lau r a Nollen/Barbara Madden

, RM 05 Registration Division (RD, 7505P)

and

Christina Scheltema Pes t icide Reevaluation Division (7509P)

As part of Registration Review, th e Pesticide Re

- e v aluation Division (PRD) of OPP ha s 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 that will resu l t from the current l y registered uses of pestic i des

. This memorandum serves a s HED's P reliminary Registration Review risk assessment of the dietary, occupat i onal and residential handler, postapplication exposure , and aggregate risk f rom the reg i stered/proposed uses of sulfentrazone

.

In addition, the Registration Div i sion (RD) requested that HED conduct an exposure and risk

Page I of57Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 2 of 57 

### assessment for the proposed new use of sulfen trazone on apples. This memorandum provides HED’s human-health risk assessmen t conducted in support of this re quest to establish tolerances for residues of sulfentrazone 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-(difluor omethyl)-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 uses are provided in this document. Th e risk assessment, dietar y risk assessment, and residue chemistry review were provided by George Kramer (RAB 1), the occupational/residential exposure and risk assessment was provided by Ke lly Lowe (RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), and the drinking water assessment was provided by Michael Barrett of the Environmenta l Fate and Effects Division (EFED).Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### Table of Contents

1.0 Executive Summary ............................................................................................................. ........................... 5 2.0 Recommendations ............................................................................................................... ............................ 7 2.1 Data Deficienci es/Data Needs .................................................................................................. ........... 8 2.2 Tolerance Cons iderations ...................................................................................................... .............. 8 2.2.1 Enforcement Analy tical Me thod ................................................................................................. ............. 8 2.2.2 Recommended To lerances ........................................................................................................ ............... 8 2.2.3 Revisions to Petitione d-For Tolerances ........................................................................................ ......... 10 2.2.4 International Harmonization ................................................................................................... ............... 11 2.3 Label Recomm endations ......................................................................................................... .......... 11 3.0 Ingredient Profile ............................................................................................................ ............................... 11 3.1 Chemical Identity ............................................................................................................. ................. 11 3.2 Physical/Chemical Properties .................................................................................................. .......... 12 3.3 Use Pattern ................................................................................................................... ..................... 12 3.4 Anticipated Exposure Pathways ................................................................................................. ....... 17 3.5 Consideration of Envi ronmental Justice ........................................................................................ .... 17 4.0 Hazard Characterization and Do se-Response Assessment .......................................................................... .. 17 4.1 Toxicology Studies Ava ilable for An alysis ..................................................................................... .. 18 4.2 Absorption, Distribution, Metabo lism, & Excretion (ADME) .......................................................... 18 4.2.1 Dermal Ab sorption ............................................................................................................. ................... 18 4.3 Toxicological Effects ......................................................................................................... ............... 18 4.4 Safety Factor for Infants and Ch ildren (FQPA Safety Factor) .......................................................... 20 4.4.1 Completeness of the To xicology Database ....................................................................................... ..... 20 4.4.2 Evidence of Ne urotoxic ity ..................................................................................................... ................ 20 4.4.3 Evidence of Sensitivity/Susce ptibility in the Developing or Young Animal ......................................... 20 4.4.4 Residual Uncertainty in th e 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 R ecommendation ............................................................. 23 4.5.4 Summary of Points of Departure and Toxicity Endp oints Used in Human-Health Risk Assessment ... 23 4.6 Endocrine Disruptor Screening Program ......................................................................................... .. 25 5.0 Dietary Exposure an d Risk Assessment .......................................................................................... .............. 26 5.1 Metabolite/Degradate Residue Pr ofile .......................................................................................... ..... 26 5.1.1 Summary of Plant and Anim al Metabolism Studies .............................................................................. 2 6 5.1.2 Summary of Environm ental Degr adation .......................................................................................... .... 26 5.1.3 Comparison of Meta bolic Pathways .............................................................................................. ........ 27 5.1.4 Residues of Concern Su mmary and Ra tionale ..................................................................................... .. 27 5.2 Food Residu e Prof ile .......................................................................................................... ............... 27 5.3 Drinking Water Residue Profile ................................................................................................ ........ 28 5.4 Dietary (Food + Drinking Wa ter) Risk Assessment .......................................................................... 29 6.0 Residential (Non-Occupational) E xposure/Risk Char acteriza tion ................................................................ 29 6.1 Residential Handler Expo sure/Risk Estimates .................................................................................. 30 6.2 Residential Post-application Exposure/Risk Estimates ..................................................................... 32 6.3 Residential Risk Estimates for Use in Aggregat e Assessment .......................................................... 32 6.4 Spray Drift ................................................................................................................... ...................... 33 6.5 Residential Bystander Post-Appli cation Inhalation Exposure ........................................................... 34 7.0 Aggregate Exposure/Ris k Character izatio n ...................................................................................... ............. 34 7.1 Acute Aggreg ate Risk .......................................................................................................... ............. 34 7.2 Short- and Intermediate-T erm Aggregat e Risk ................................................................................. 3 4 7.3 Chronic Aggreg ate Ri sk ........................................................................................................ ............ 35 7.4 Cancer Aggreg ate Ri sk ......................................................................................................... ............. 36 8.0 Cumulative Exposure/Risk Character izati on ..................................................................................... ............ 36 9.0 Occupational Exposure/Ri sk Character izati on ................................................................................... ........... 36 9.1 Handler Risk Assessment ....................................................................................................... ........... 36 9.2 Post-Application Ri sk Assessment .............................................................................................. ...... 41 9.2.1 Inhalation Post-Applica tion Risk A ssessment ................................................................................... .... 41 9.2.2 Dermal Post-Applicatio n Risk Assessment ....................................................................................... .... 41Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 4 of 57 10.0 References .................................................................................................................... ................................. 42 Appendix A. Toxicology Prof ile and Executiv e Summaries ....................................................................... ............... 43 Appendix B. Methodologies for HEC Calc ulations................................................................................ .................... 49 Appendix C. Physica l/Chemical Pr operties ..................................................................................... ........................... 54 Appendix D. Internati onal Residue Limits ..................................................................................... ............................ 55Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### 1.0 Executive Summary

Sulfentrazone is an aryl triazo linone herbicide used to control a variety of broadleaf weeds. Sulfentrazone acts by the same mechanism as the diphenyl ether herbicides in which membrane disruption is initiated by the inhibition of protoporphyrinogen oxidase (PPO) in the chlorophyll biosynthetic pathway and leads to the subsequent build-up of toxic intermediates. Plants emerging from soils treated with sulfentrazone turn ne crotic and die shortly after exposure to light.

This preliminary risk assessment provides inform ation to support the Re gistration Review of sulfentrazone, and addresses the exposures and risk estimates associated with all currently registered and proposed uses. Since the last ri sk assessment, new data have been submitted and policies have changed. This doc ument incorporates changes made to the selected endpoints, toxicological points of departure (PODs), expos ure and risk estimates, recommended tolerances, and the potential for spray-drift e xposure. All data requirements previously addressed during the scoping process have been satisfied (K. Lowe , D369064, 09/09/2009). In addition, this document evaluates the petition submitted by Interregional Research Project No. 4 (IR-4; PP# 3E8202) that proposes new tolerances for residues of su lfentrazone and its metabolites on apples.

Hazard Assessment: Results of mammalian toxicity studie s were consistent with PPO inhibition, given that PPO is an important enzyme in the heme synthetic pathway in mammals. Specifically, toxicity reflective of disruption of heme synthesis (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 mi ce, where the effects were seen at a slightly higher dose. In addition, this hematotoxicity occurred around the same dose level from sh ort- through long-term exposure without increa sing in severity.

Sulfentrazone caused developmental effects via the oral and dermal r outes of exposure. Developmental effects, includi ng decreased fetal body weights a nd reduced/delayed skeletal ossifications, were observed in bot h the oral and dermal developmen tal toxicity studies in the rat in the absence of matern al toxicity. In the two-generati on reproduction study in rats, offspring effects, such as decreased body weights and decreased litter survival were observed at doses that were maternally toxic (decr eased body weight during gest ation 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 effects in the nasal passage and systemic effect s, 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.

Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The sulfentrazone risk assessment team concludes that the 10X FQPA SF should be reduced to 1X since the toxicology database is adequate for assessment of the regist ered 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, an d the conservative nature of the dietary and residential exposure analyses are unlikely to underestimate exposure [tol erance-level residues, 100% crop treated (%CT); use of 2012 Residential Standard Operating Procedures (SOPs)].Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### Dose Response Assessment: The two-generation reproductive toxi city 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 in cidental oral exposure scenarios. The acute neurotoxicity (ACN) study (NOAEL = 250 mg/kg/da y) was selected for assessment of acute dietary (all populations excluding females 13-49 year s 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 exposure (all durations). For all expo sure scenarios except inhalation, a 100X uncertainty factor was applie d [10X interspecies ex trapolation; 10X for intraspecies variation; 1X FQPA SF (when applicable)]. For i nhalation exposure scenarios, a 30X uncertainty factor was applied [3X interspecies ex trapolation; 10X for intr aspecies variation; 1X FQPA SF (when applicable)].

Dietary Risk Estimates (Food + Drinking Water ): Acute and chronic ag gregate 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 Stat es Department of Agriculture (USDA) National Health and Nutrition Examination Survey, Wh at We Eat in America, (NHANES/WWEIA; 2003- 2008). The acute and chronic an alyses assumed tolerance-leve l residues, 100% %CT, DEEM (ver. 7.81) default processing factors, and modele d 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), respectively.

Residential (Non-Occupational) Exposure and Risk Assessment: The proposed use on apples will not result in residential e xposure; however, there are currently registered turf uses (e.g., residential turf, golf courses) that were assessed as part of Regi stration Review. All dermal and inhalation exposure risk estimates for residentia l handlers are not of c oncern [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 postapplication dermal risk estimates ar e 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 dr ift for sulfentrazone.

Aggregate-Risk Estimates: In accordance with FQPA, HE D must consider and aggregate pesticide exposures and risks from three majo r sources: food, drinking wa ter, and residential exposures. Acute, chronic, shor t-, and intermediate-term aggregat e 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 ch ronic aggregate risks are made up only of dietary sources; therefore, the expos ure estimates provided in the dietary exposure analyses represent acute and chronic aggregate ex posure, respectively. Sh ort- and intermediateterm aggregate risks are made up of dietary and non-dietary sources of exposure. Since sulfentrazone is used on turf, re sidential handler and post-appli cation exposures are expected. Short-term exposures exist for adults and children from the registered turf application use. In addition, intermediate-term exposures exist for ch ildren from incidental soil ingestion. All aggregate sulfentrazone risk estimate s are not of concern to HED.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### Occupational Exposure and Risk Assessment: A quantitative assessment of occupational exposure has been conducted for all of the registered and pro posed uses. The occupational handler exposure and risk estimates indicate that the short- and intermediate-term dermal and inhalation MOEs are not of con cern 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 postapplication dermal exposure and risk estimates we re assessed, and are greater than the level of concern (LOC) of 100 on the day of applic ation (MOEs = 430 to 8,200). Since the postapplication assessment is not a concern on Day 0 (12 hours following applica tion), the restrictedentry interval (REI) is based on the acute toxi city of sulfentrazone technical material. Sulfentrazone is classified as acute Toxicity Ca tegory III for acute oral, acute dermal, and acute inhalation toxicity. It is clas sified 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 ch emical require a 12-hour REI under 40 CFR 156.208(c)(2)(iii).

Based on the Agency's current practices, a quant itative non-cancer occupational post-application inhalation exposure assessment was not performed for sulfentrazone at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposur e assessment for sulfentrazone.

Environmental Justice Considerations: Potential areas of environm ental 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 Ad dress Environmental Justice in Minority Populations and Low-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 Handlers E xposure 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 pursuan t to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirement s. For certain studies, the ethics review may have included review by the Human Studies Review Bo ard. Descriptions of da ta sources, as well as guidance on their use, can be found at the following Agency websites: http://www.epa.gov/pesticides/science/handler-exposure-data .html and http://www.epa.gov/pe sticides/science/post-appexposure-data.html.



### 2.0 Recommendations

HED has examined the toxicology and residue ch emistry databases for sulfentrazone. Pending resolution of the deficiencies outlined below, there are no other residue chemistry, residential, occupational, or toxicology data deficiencies th at would preclude the continuation of permanent tolerances for residues of sulfentrazone and its metabolites as outlined in Table 2.2.2.1.

For the proposed use on apples, HED concludes th at the residue chemistry database supports the establishment of the permanent to lerance listed in Table 2.2.2.1.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### 2.1 Data Deficiencies/Data Needs

860.1650 Submittal of Analytical Reference Standards

Analytical standards for sulf entrazone (expiration date 7/ 1/15) and its metabolites DMS (expiration date 8/1/17) and HMS (expiration date 8/31/18) ar e currently available at the EPA National Pesticide Standards Repository (persona l communication with Theresa Cole, 4/21/14). However, as the existing stocks are depleted, th e Repository has requested that the registrant provide additional amounts of sulfentrazone (5 g) and HMS (3 g). They should be sent to the Analytical Chemistry Lab, 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/Analytical 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 an alytical method for the purposes of tolerance enforcement. 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 soybeans (PP# 4F04407). A petition method validation (PMV) wa s successfully completed by the Agency’s Analytical Chemistry Laboratory (ACL). The li mit of quantitation (LOQ) 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 Analytical 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 concern were not successfully recovered by the FDA MRMs.

Samples of raw agricultural and pr ocessed commodities from the a pple studies were analyzed for residues of sulfentrazone and its metabolites DMS and HMS using a liquid chromatograph equipped with tandem mass spectrometers (LC/MS/MS) me thod. The validated LOQ was 0.025-0.05 ppm for each analyte. These methods are adequate for da ta collection based on acc eptable 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, includi ng its metabolites and degradates in/on various raw agricultural commodities ra nging from 0.05 ppm to 0.60 ppm.

Table 2.2.2.1 is a summary of the proposed and HED-recommended tolerances for residues ofSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### sulfentrazone per se

.

Table 2.2.2.1. To lerance Summary for Sulfentrazone (40 CFR §180.498).

Commodity Proposed / Established Tolerance

(ppm) HEDRecommended 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 commoditie s in the table below. 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]methanesul fonamide) and its metabolite HMS ( N

-(2,4-dichloro5-(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 sulfen trazone in or on the following commodities. Soybean, seed 0.05 (2) Tolerances are established for the co mbined residues of the fr ee 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 determined by measuring only the sum of sulfentrazone ( N

-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro3-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 (PP# 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- 12 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 Assessm ent D410365

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

Commodity Proposed / Established Tolerance

(ppm) HEDRecommended 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 ar e 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 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. Bean, lima, succulent 0.15 Cowpea, 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 specified belo w 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 commodi ties 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 sign ificant 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 Assessm ent D410365

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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 definitions are harmonized with Canada. For those commodities which the US and Canada have in common, the tolerance valu es are harmonized (asparagus, flaxseeds, horseradish roots, dry peas a nd beans, peppermint tops, spearmint tops, sunflower seeds, and cereal grain group 15). For a summ ary of U.S. tolerances and international MRLs, 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 shoul d ensure the appropriate type of glove is listed as required on the label.

3.0 Ingredient Profile

3.1 Chemical Identity

The chemical structure and nomenclature of sulf entrazone and its metabolites are presented in Table 3.1.1.

Table 3.1.1. Nomenclature for Sulfentrazone and its Metabolites.
Chemical structure

Common name Sulfentrazone Company experimental name F6285; FMC 97285 IUPAC name 2',4'-dichloro-5'-(4-difluoromethy l-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 SO 2 CH 3 N N N O

CH 3 CHF 2

Cl Cl

N H SO 2 CH 3 N N N O CHF 2Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 12 of 57 Table 3.1.1. Nomenclature for Sulfentrazone and its Metabolites. Chemical name N-(2,4-dichloro-5-(4-(difluorom ethyl)-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 m obile. It has a 545-day aerobic soil half-life 1 

### and an average Koc coefficient of 45 mL/g. Additiona lly, it has a strong potential to leach into groundwater, as indicated in four completed sm all-scale prospective ground-water monitoring studies, and to move offsite to surface wa ter. It has a low vapor pressure of 8x10 -10 

### mm Hg. A detailed description of the physicochemical prope rties 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, pipe line, and utility rightsof-way and industrial areas), resi dential/commercial turf, and sod fa rms. Most of the uses are soil-directed, and are applied vi a either aerial, chemigation, gr oundboom or handheld equipment. Several labels also allow for a pplication 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 ft 2 

### 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 applicat ion can be made per year, and up to two banded applications directed to the ba se of tree trunk can be made 60 da ys apart. The REI for all the proposed uses is 12 hours. Based on the proposed and registered use patterns, it has been determined that the potential expos ure scenarios that will need to be assessed include short- and intermediate-term occupational and residentia l exposures (handler and post-application).

A summary of the registered 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.

1 90 th percentile upper confidence interval of the mean half-life. Cl Cl

N H SO 2 CH 3 N N N O CHF 2

OHSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 13 of 57 Table 3.3.1. Summary of Registered and Proposed Uses for Sulfentrazone.

Crop/Use Site Application Timing and Type of Application Registered Formulations Maximum Application Rate Personal-protective Equipment (PPE), Restricted-entry 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 layer (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/tractordrawn spreader; handheld Liquid 0.0375 lb ai/gal, 0.0086 lb ai/1000 ft 2 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 Applied 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 hrSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 14 of 57 Table 3.3.1. Summary of Registered and Proposed Uses for Sulfentrazone.

Crop/Use Site Application Timing and Type of Application Registered Formulations Maximum Application Rate Personal-protective Equipment (PPE), Restricted-entry Interval (REI), and Preharvest Interval (PHI)

Flax 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)

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 orgroundboom/tractordrawn spreader DF 0.375 lb ai/A, 0.008 lb ai/1000 ft 2 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 ft 2 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/tractordrawn spreader; handheld Liquid 0.0086 lb ai/1000 ft 2 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 ft 2 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 Animal 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 Assessm ent D410365

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Page 15 of 57 Table 3.3.1. Summary of Registered and Proposed Uses for Sulfentrazone.

Crop/Use Site Application Timing and Type of Application Registered Formulations Maximum Application Rate Personal-protective Equipment (PPE), Restricted-entry 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 orgroundboom/tractordrawn spreader DF 0.375 lb ai/A, 0.008 lb ai/1000 ft 2 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 ft 2 or 0.375 lb ai/A Liquid

Residential/Commercial Turf Handheld orgroundboom/tractordrawn spreader DF 0.375 lb ai/A, 0.008 lb ai/1000 ft 2 or 0.019 lb ai/gal REI = 12 hr; PPE = SL w/ waterproof gloves

DF in WSP 0.0066 lb ai/1000 ft 2 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 ft 2 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 ft 2 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 ft 2 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 ft 2 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 ft 2 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 Assessm ent D410365

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Page 16 of 57 Table 3.3.1. Summary of Registered and Proposed Uses for Sulfentrazone.

Crop/Use Site Application Timing and Type of Application Registered Formulations Maximum Application Rate Personal-protective Equipment (PPE), Restricted-entry 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 fertilizer 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 Soybean Anytime Sugar Beets 36 Sugarcane Anytime Sunflowers Anytime Sweet Potatoes 12 Triticale 4 Tobacco Anytime Turf AnytimeSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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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-month rotation for rates above 8.0 oz/A.



### 3.4 Anticipated Exposure Pathways

Based on the registered and proposed sulfentrazone application scen arios, dietary exposure is an anticipated exposure pathway as residues of su lfentrazone 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 exposur e in residential and non-occupationa l settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also potential for post-application exposure for workers re-entering treated sites. This risk assessment considers all of the aforementioned exposure pathways based on the existing and proposed uses of sulfentrazone.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations," (http://epa.gov/complian ce/ej/resources/policy/ex ec_order_12898.pdf). As a part of every pesticide risk assessment, the Office of Pestic ide Programs (OPP) considers a large variety of consumer subgroups according to well-establishe d procedures. In line with OPP policy, HED estimates risks to population subgroups from pes ticide exposures that ar e based on patterns of that subgroup’s food and water consumption, a nd activities in and around the home that involve pesticide use in a residential se tting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s Nati onal 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 da ta are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate , non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas post-application are evaluate d. Further considerations are currently in development as OPP has committed re sources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietar y patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Sulfentrazone belongs to a cla ss of herbicides that inhibit PPO in ta rget photosynthetic organisms, ultimately resulting in disruption of chlorophyll biosynthesis. In mammals, PPO is also an important enzyme in heme biosynthesi s and its inhibition can lead to toxic effects associated with disruption of heme utilization (e .g., red blood cells). Some of the toxicities reported for sulfentrazone in mammals ar e consistent with a PPO inhibition.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### 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 th e 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 repeat ed exposure inhalati on toxicity study with sulfentrazone and concluded, based on a weight-of-evidence (WOE) approach, that a subchronic rat inhalation study was required. Since then, the subchroni c inhalation study has been submitted and reviewed by the Agency. The results from both studies are included in this hazard assessment.

4.2 Absorption, Distribution, Met abolism, & Excretion (ADME)

In radiolabel-based studies in the rat, sulfen trazone was well absorbed via the oral route of administration as indicated by th e excretion of nearly all radi oactivity (~84-104%) in the urine by 72 hours post-dosing. There was no indication of accumulation; only the carcass, liver, and bone showed detectable levels of radioactivit y (<0.5% of the administered) at 72 hours postdosing. The pooled urinary radioactivity consisted almost entirely of HMS; the parent chemical was not detected in urine and found only at very low 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 and a dermal route-specific rat prenatal developmen tal toxicity study that can be used to assess risk vi a the dermal route of exposure.

4.3 Toxicological Effects

Subchronic and chronic toxicity studies in rats, mice, and dogs identified the hematopoietic system as the target of sulfentrazone. Sulfentraz one inhibits the enzyme PPO in target plants and the results of subchronic and chronic toxicity st udies in mammalian systems are consistent with PPO inhibition. Disruption of he me biosynthesis was indicated by signs of anemia [decreases in hematocrit (Hct), hemoglobin (HGB), and mean co rpuscular volume (MCV)] in mice, rats, and dogs at comparable dose levels from short- th rough long-term exposure without a significant increase in severity.

Sulfentrazone caused developmental effects when ad ministered via the oral (rats and rabbits) and dermal (rat) routes of exposure. Developmen tal 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 (r ats and rabbits). Surviving rat fetuses exhibited reduced/delayed skeletal ossifica tions, and decreased fetal body we ights. Developmental effects in rats were seen in the absence of maternal toxicity. In contrast with the rat studies, developmental effects in rabbits we re observed at a maternally toxi c dose, where clinical signs of toxicity included hematuria (red blood cells in urine), abortions, and decreased body-weight gains. In the two-generation re productive 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. P up body-weight deficits, along with reduced pup and litter postnatal survival, were also observed. All of the offspri ng effects were reported in the presence of mild maternal toxi city (decreased body weight and body- weight gain, particularly inSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 19 of 57 

### F 1 

### females).

A published, non-guideline developmental toxicity study in the rat [DeCastro VL, Destefani CR, Diniz C, Poli P., 2007. Evaluation of neurodevelo pmental effects on rats exposed prenatally to sulfentrazone. Neurotoxicology 28(6):1249-59] did not conclusive ly demonstrate developmental neurotoxicity and contains several shortcomi ngs that limit its use for regulatory purposes including the lack of a NOAEL. The reported e ffects involving measures of physical and reflex development are likely secondary effects reflective of the poor general state of the offspring as reported in the rat two-generation reproductive toxicity study at similar dose levels but with a well-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 Me mo, C. Rodriguez, 19-DEC2011, D389975].

No systemic toxicity was seen via the dermal route up to the limit 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/da y), fetal effects were observed at this dose, and consisted of decreased body wei ghts, increased incidences of fetal variations; hypoplastic or wavy ribs, incompletely ossified lumbar vertebral arches, incompletely ossified ischia or pubis, and a reduced number of thoracic ve rtebral and rib o ssification sites.

In the 26-day inhalation toxicity study, effects that were considered treatment related and adverse occurred only at the highest c oncentration tested (1.71 mg/L). Systemic effects at this concentration consisted of si gnificant reductions in red blood cell (RBC) parameters including RBC count, HGB concentrations, Hct, MCV, mean corpuscular HGB (MCH), and/or reticulocytes in both sexes. Portal-of-entry e ffects consisted of an increased incidence of minimal nasal respiratory epith elial hyperplasia in both sexes as well as minimal laryngeal epithelial attenuation in all te st material exposure groups. The effects on hematological parameters were reversible after 28 days of r ecovery, while the nasal injury persisted.

In an ACN study in rats, effects consisted of an in creased incidence of clin ical signs of toxicity (staggered gait, splayed hind limbs, and abdominal gripping), changes in functional-observation battery (FOB) parameters, and decreased motor activity at a high dose level (750 mg/kg bw). Complete recovery was observed by day 14, and th ere 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, ther e were no effects on the immune system and systemic effects consisted of reduced body weight, and increased absolute and relative spleen weights at the highe st 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 Ca rcinogenic Risk Assessment (April 10, 1996). The available mutagenicity studies indicate that sulfentrazone is weakly clastogenic in the in vitro mouse lymphoma 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 Assessm ent D410365

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Page 20 of 57 

### Based on the results of acute toxici ty studies in the rat, sulfentrazone was classified as Toxicity Category III (Toxicity Category IV being the lowest category) fo r acute toxicity via the oral, dermal, and inhalation routes of exposure. It was a mild eye irritant (Tox icity 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 th at the FQPA SF be reduced to 1X for all exposure scenarios. The toxic ity database is complete and dietary and residential exposure analyses are unlikely 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 cl early 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 sulfen trazone is adequate for FQPA evaluation. Developmental toxicity studies in rats and rabbits, a two-genera tion reproduction study in rats, and neurotoxicity studies in rats ar e available for FQPA consideration.

4.4.2 Evidence of Neurotoxicity

In the 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 relatively high doses; 2) effects occurr ed in the absence of neuropathology; 3) there is no evid ence of neurotoxicity in other av ailable studies in the toxicity database; 4) effects are well-c haracterized with clearly esta blished NOAEL/LOAEL values; and 5) the selected PODs are protective of these effects.

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 t oxicity studies in ra ts. 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 toxicolo gy database for assessing pre- and postnatal susceptibility is complete; 2) there are clear NOAELs and LO AELs for the developmental effects observed via both the oral and dermal rout es; 3) the PODs used fo r assessing dietary and dermal exposure risks are based on developmental and/or offspring toxic ity; 4) the portal-ofentry effects seen in the 26-day inhalation study are protective of the developmental toxicity; and 5) there are no residual uncertainties fo r pre-and/or postnat al toxicity.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainti es in the exposure database. The dietary and residential exposure analyses are conservative in nature. The dietary expos ure assessment used tolerancelevel residues and assumed 100% CT. The re sidential exposure asse ssment uses the 2012 Residential SOPs and is consider ed health-protective. The resi dential assessment includes an FQPA SF of 10X for inhalation expo sures to account for the uncertain ty associated with the lack of an appropriate inhala tion toxicity study.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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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 dose s and endpoints selected for residential dietary/non-dietary and occupationa l risk assessment. The rationa le for any changes is provided below and the updated endpoints are include d 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 a nd dermal routes of exposure.

Acute Dietary Endpoint (F emales 13 - 49 years old): This acute dietary endpoint is based on increased gestation duration, reduc ed pre-/postnatal litter and pup survival, reduced litter size, increased number of stillborn pups, reduced pos tnatal survival (pups and litter), and pup bodyweight deficits throughout lact ation in both generations of offspring observed in the twogeneration reproductive toxicity st udy in rats. The developmenta l effects were reported in the presence of mild maternal toxi city (decreased body weight and body- weight gain, particularly in F 1 

### females). It has been HED’s practice to consider various fo rms of developmental toxicity, such as the such as reduced prenatal viabi lity, reduced litter size, and increased number of stillborn pups as single-dose eff ects and, therefore, relevant for the acute dietary (females aged 13-49) exposure scenario in orde r to protect against pot ential exposure of pregnant females. It should be noted that the fetal body-weight defici ts and retardation in skeletal development (including decreased numbers of caudal vertebral and metacarpal ossification sites) reported in the oral rat prenatal developmen tal toxicity study were also ev aluated for this acute dietary endpoint. However, it was concluded that such effects are unlikely due to a single-dose effect and are more appropriate for a repeated-expos ure 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 popul ation, including infants and children): This acute endpoint is based upon increased in cidence of clinical signs, FO B findings, and decreased motor activity at the LOAEL of 750 mg/ kg bw seen following a single or al 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 un certainty 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, respectively in the rat two-generation reproductive toxicity study. This LOAEL is based on developmental t oxicity, the most sens itive 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 to xicity study and a 100-fold uncertainty factor (10X interspecies, 10X in traspecies, 1X FQPA).

Incidental Oral Endpoint (Shor t- and intermediate-term): This endpoint is based on offspringSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### toxicity observed in the rat tw o-generation reproductive toxicity study in the form of reduced pre-/postnatal litter and pup survival, and pup body- weight deficits throu ghout lactation in both generations of offspring observe d at the LOAEL of 33 and 40 mg/ kg/day in males and females, respectively (lowest NOAEL = 14 mg/kg/day for male s). The effects seen in the offspring are appropriate for the population (infan ts and children) and durations (short- and intermediate-term) of concern. The LOC for incide ntal oral risk estimates is for MOEs less than 100, which includes the 10X inter- a nd 10X-intraspecies factors. 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 appropria te since the developmental effects were seen after repeated exposure via the dermal route. The LOC for occupational and nonoccupational dermal risk estimates is for MOEs less than 100, which includes the 10X inter- and 10X intraspecies factors. The FQPA SF was reduced to 1X (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 for both sexes based on significant reductions in RBC parameters, including RBC count, HGB, Hct, MCV, MCH, and/or reticulocytes in male and female rats followi ng 26 days of inhalation exposure to the test material. Portal-of-entry effects at this dose we re also observed and mani fested as an increased incidence of minimal nasal resp iratory epithelial hyperplasia in both sexes as well as minimal laryngeal epithelial attenu ation in all test material exposure groups. As described below, humanequivalent concentrations and doses (HECs a nd HEDs) were calculated based this subchronic inhalation study. This inhalation study is prot ective 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 LOA EL is large (40 to 600 mg/kg/day) and the effects in the nasal passage likely start a lo wer dose than the LOAEL; 2) the reference concentration (RfC) methodology ca lculations include a 15-fold lower regi onal deposited dose ratio for portal-of-entry effects (0.213) compar ed to systemic effects (3.129); and 3) the estimated inhalation HEDs are lower or equivale nt (depending on the exposure scenario being assessed) than the oral NOAEL from the developmental study.

HECs derived from this study were based upon the increased incidence of minimal nasal respiratory epithelial hyperplasia in male and female rats. The resulting HECs are 0.04 and 0.05 mg/L for occupational handler and residential ha ndler. Portal-of-entry effects were used to generate HECs and are protective for any systemic effects (portal-of-ent ry HEC = 0.04 mg/L vs. systemic RBC HEC = 0.60 mg/L for occupationa l, 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 vent ilation rates of 8.3, 16.7, and 29 L/min (2.317, 4.661, and 8.094 mg/kg/day) and residentia l-handler exposure scenarios ba sed upon a ventilation rate of 16.7 L/min (1.55 mg/kg/day). For details regardi ng 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 appr opriate for the route and duration of exposure, and as described above in Section 4.3, use of this inhalation st udy is protective of any potential developmental effects seen in the oral rat developmental study.

The LOC is 30 which includes interspecies (3X) a nd intraspecies (10X) uncertainty factors. TheSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### interspecies factor was reduced from 10X to 3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynami c) interspecies differences.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

The Agency must consider risks fr om individual routes of exposur e (oral, dermal, and inhalation) and perform combined exposure and risk asse ssments if a common toxicity endpoint is established across different routes of exposure. Since developmental eff ects (fetal body-weight deficits and skeletal eff ects) 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 Ri sk Assessment Recommendation

The CARC has classified sulfentrazone as “not likely to be carcinogenic” to humans (TXR #: 011910) in accordance with EPA proposed Guidelin es for Carcinogenic Risk Assessment (April 10, 1996).

4.5.4 Summary of Points of Departure and T oxicity Endpoints Used in Human-Health Risk Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Sulfentrazone for Use in Residential and Dietary Human-Health Risk Assessment.
Exposure Scenario POD Uncertainty/ FQPA SFs RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects

Acute 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-generation 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. Acute 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 motor 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-generation 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 days) andIntermediateTerm (1-6 Offspring NOAEL = 14 mg/kg/day UF A = 10X UF H = 10X 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 Assessm ent D410365

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Page 24 of 57 Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Sulfentrazone for Use in Residential and Dietary Human-Health Risk Assessment.
Exposure Scenario POD Uncertainty/ FQPA SFs RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects

months) Incidental Oral and reduced postnatal survival in both generations. Short- (1-30 days), Intermediate- (1- 6 months), and Long-Term (>6 months) 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 days), Intermediate- (1- 6 months), and Long-Term (>6 months) Inhalation Portal-ofentry 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. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among member s of the human population (intraspecies). UF L = extrapolation for use of a LOAEL in the absence of a NOAEL. FQ PA SF = FQPA Safety Factor. P AD = population-adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Sulfentrazone for Use in Occupational Human-Health Risk Assessment.

Exposure Scenario POD Uncertainty/ FQPA SFs RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects

Short- (1-30 days), Intermediate- (1-6months), and LongTerm (>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 days), Intermediate- (1-6months), and LongTerm (>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 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 Assessm ent D410365

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Page 25 of 57 Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Sulfentrazone for Use in Occupational Human-Health Risk Assessment.

Exposure Scenario POD Uncertainty/ FQPA SFs RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects

L/min) = 4.661 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 member s of the human population (intraspecies). UF L = extrapolation for use of a LOAEL in the absence of a NOAEL. FQ PA SF = FQPA Safety Factor. P AD = 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 by Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews nu merous studies to a ssess potential adverse outcomes from exposure to chemicals. Collectivel y, these studies include acute, subchronic, and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of its Registration Re view decision for sulfentrazone, EPA reviewed these data and selected the most sensitive endpoint s for relevant risk assessment scenarios from the existing hazard database. However, as requi red by FFDCA section 408(p), sulfentrazone is subject to the endocrine screen ing part of the Endocrine Disr uptor Screening Program (EDSP).

EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relations hip between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pe sticide 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 in gredients 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 Assessm ent D410365

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### scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or lik ely endocrine disruptors. For fu rther information on the status of the EDSP, the policies and proced ures, the lists of chemicals, fu ture lists, the test guidelines and the Tier 1 screening batte ry, please visit our website. 3



### 5.0 Dietary Exposure and Risk Assessment D415626, G. Kramer, 05-JUN-2014 (residue chem istry 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 adequately understood. Data concerning the metabolism of sulfentrazone following preemerge nt applications in soybeans and confined rotational crops were submitte d in conjunction with the so ybean petition (PP#4F04407). The HED Metabolism Committee determined th at the parent compound, sulfentrazone, and the metabolite HMS are the residues of concern in soybeans, 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 translated to suppor t preemergent uses on all types of crops (G. Kramer, 13-MAR-1996; D220548). Data concer ning the metabolism of sulfentrazone following postemergent applications in corn, soybean, and radish were submitted in conjunction with recent pe titions (D389972, 5/9/12, G. Kramer). The metabolism of sulfentrazone following postemergent application wa s similar to that seen in rotational crops and following preemergent application to s oybean; no additional major metabolites were identified. HED concludes metabolism 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 excep t soybean seed, where the residues of concern are sulfentrazone 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 only by oxidation of the 3-methyl group to HMS, followed by further oxidation to form su lfentrazone carboxylic acid, which is decarboxylated to DMS. Sulfentrazone per se and its metabolites HMS and DMS were identified as the residues of concer n in meat, milk, poultry, and eggs.

5.1.2 Summary of Environmental Degradation

Sulfentrazone is expected to be persistent und er most environmental co nditions. Sulfentrazone half-lives in aerobic soil metabolism, anaerobic a quatic metabolism, and terr estrial field dissipation studies are one year or longer (1.5 ye ars, 9 years, and 1 to 2 years, respectively). Sulfentrazone is stable towards abiotic hydrolysis. Direct photoly sis 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 photolytic products are formed by cleavage of th e C to N bond between the phenyl and triazolo

3 See http://www.epa.gov/endo/

.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### rings. Although methyl triazole was the major de gradate 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 mon itor this degradate. However, photolytic breakdown would be more significant in shallow waters of low turbidit y than in deep waters of high turbidity. The major transformation product obs erved in soils is th e carboxylic acid of sulfentrazone (3-carboxylic ac id sulfentrazone). This degradate, together with parent sulfentrazone, has been detected in groundwater so far in prospective ground-w ater monitoring studies. In a variety of soils ranging in textur e from sand to silty clay loam, sulfentrazone is very mobile (K d, 

### 0.2 to 0.8; average K oc 

### 43). The pK a 

### of sulfentrazone is 6.5 and, ther efore, sulfentrazone would be more mobile in neutral to alkaline soils than in acidic soils. The pK a 

### of the carboxylic acid of sulfentrazone is not known, but it may be comparable to that of parent su lfentrazone and exhibit a similar behavior as the parent in neutral-alkaline soils. The HED Metabolism Assessment Review Committee (MARC) concluded that parent and 3-carboxylic acid sulfen trazone are the residues of concern for the drinking-water assessment (Memo, G. Kramer et al. , 10-APR-2003; D288713). HED continues to consider the give n metabolites 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 di fferent pathways: (1) Oxidation of the 3-methyl group to form 3-hydroxymethyl sulfentrazone or HMS, followed by further oxidation to form sulfentrazone carboxylic acid which is decarboxylated to 3-desmethyl sulfentrazone or DMS. (2) Hydrolysis of the trifluoromethyl group to form de sdifluoromethyl sulfentraz one which is oxidized and decarboxylated to form desdifluoromethyl de smethyl sulfentrazone. (3) Hydrolysis of the sulfonamide group to form desmethylsulfonyl su lfentrazone. (4) Scission of the phenyl and triazole rings to produce methyl triazole. Th e corresponding phenyl metabolites are believed to remain bound. The metabolism of sulfentrazone in anim als (livestock and rats) differs from that in plants as metabolism proceeds only by oxidation of the 3-methyl group to form HMS, followed by further oxidation to form sulfen trazone carboxylic acid which is decarboxylated to DMS. Sulfentrazone carboxylic acid was also the majo r transformation product observed in soils.

5.1.4 Residues of Concern Summary and Rationale

The residues of concern in primary crops, rota tional 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 Cr ops, Livestock, an d Drinking Water. Matrix Tolerance Expression Re sidues 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 not 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 soybean seed at 0.05 ppm. In addition, permanent tolerances are established under 40 CFR §180.498(a)(2) for the combined residues ofSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### sulfentrazone and its metabolites HMS and DMS in/on several food commodities; these established tolerances range from 0.15 ppm (vari ous plant commodities) to 0.60 ppm (turnip tops). Tolerances for the combined residues of sulfentrazone and its metabolites HMS and DMS have been established under 40 CFR §180.498(c) in co nnection 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 establishe d under 40 CFR §180.498(d) for inadvertent and indirect combined residues of sulfentrazone a nd its metabolites HMS and DMS in/on cereal grain (excluding sweet corn) bran, fora ge, 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 (P P#3E8202). Additional residue data and a ruminant feeding study are required for pr oposed use on nongrass animal feeds (Memo, G. Kramer, D389972, 09-MAY-2012).

The submitted field trial residue data for all registered crops are adequate. The recently submitted field trial residue data apple ar e also adequate. The field tria l data reflect the proposed use patterns; an adequate number of trials were conducted in the appropriate geographic regions; and samples were analyzed for the residue of concer n 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, D389972, 09-MAY-2012).

HED previously determined that, based on the es tablished sulfentrazone tolerances for soybean 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 (Memo, G. Kramer, D389972, 09-MAY2012).

Rotational crop studies for corn, rice, sorghum, a nd wheat were submitted in conjunction with the soybean petition (PP#4F04407). Permanent toleran ces have been established for indirect or inadvertent residues of sulfentrazone and its metabolites, HMS and DMS, in cereal grains (excluding sweet corn), bran, fora ge, grain, hay, hulls, stover, and straw. The labeled rotational crop restrictions (Table 3.3.2) are ade quate for use rates up to 0.375 lb ai/A.

5.3 Drinking Water Residue Profile

Drinking water residues provi ded by EFED (Memo, M. Barre tt, 21-MAY-2014; D415627) were incorporated directly into the acute and chronic dietary analyses as “water, direct, all sources” and “water, indirect, all sources.” The estima ted drinking water concen trations (EDWCs) were Tier 1 estimates for ground water using the Pesticide Root Zone Model-Ground Water (PRZMGW) model version 1.07 (Screening Concentrat ion In Ground Water) and surface water using the Pesticide Root Zone Model/Exposure Analys is Modeling System (PRZM/EXAMS) model. The proposed use on apples carries the maximu m single and annual appl ication rates for all currently registered uses (0.375 lb ai/ A). Prev ious estimates of sulf entrazone residues in drinking water were done separately for pare nt and the 3-carboxylic acid sulfentrazone degradate. Sulfentrazone and 3-carboxylic acid sulfentrazone have a potential to reach both surface and ground waters that may be used as dr inking water sources. This revised assessment has now taken a total toxic residues (TTR) appro ach to assessing exposure, instead of providing values for each compound individually.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### For surface water, the highest acute (peak) su lfentrazone value is 37.3 ppb and the 10-year average value is 5.3 ppb. For ground water, the highest daily value (peak) sulfentrazone value is 134 ppb and the post-breakthrough-average va lue is 98 ppb. EDWCs of 0.134 ppm and 0.098 ppm were used in the acute and chronic analyses, respectively.

Table 5.3. Estimated Tier 1 Concen trations of Sulfentrazone and 3-Carboxylic Acid Sulfentrazone in Drinking Water Due to the Use of Sulfentrazone.

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



### 5.4 Dietary (Food + Drinking Water) Risk Assessment

Acute and chronic aggregate di etary (food and drinking water) exposure and risk assessments were conducted using DEEM-FCID, ver. 3.16 whic h incorporates consumption data from the USDA NHANES/WWEIA; 2003-2008. The acute and chronic analyses assumed tolerance-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 year old, which utilized 1.1% of the aPAD for su lfentrazone. 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 estima te for infants <1 year old, females 13-49 years old is the population subgroup w ith the highest risk estimate ( ≤ 7% aPAD). The highest chronic exposure estimate was for the population subgroup children 1-2 years old, wh ich utilized 7.1% of the cPAD for sulfentrazone.

Table 5.4.1. Summary of Acute and Chronic Dietary (Food and Drin king 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 ri sk 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 sulfentrazon e assessed the registered resi dential 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. Re sidential handler and po st-application scenariosSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### were assessed at a maximum application rate of 0.375 lb ai/A for liqui d, 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 resi dential 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 incl uded for the post-applic ation episodic granular ingestion scenario based on a revised maximum percent activ e ingredient for granular formulations identified during the label review of registered sulfentrazone labels.

6.1 Residential Handler Ex posure/Risk Estimates

Table 6.1.1 provides a summary of the residential handler exposur es and risk estimates for sulfentrazone. All dermal and inhalation exposur e 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 Assessm ent D410365

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Page 31 of 57 Table 6.1.1. Residential Handl er Non-cancer Exposure and Risk Estimates 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/ft 2 1200 ft 2 0.054 1,900 0.000005 310,000 Spoon 6.2 0.087

100 ft 2 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 Mixer/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/ft 2 1000 ft 2 0.0017 60,000 0.0000024 660,000
Mixer/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 a i/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/ft 2 1000 ft 2 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/reside ntial-exposure-sop.html).

3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Ra te (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 = Inhalation Unit Exposure (mg/lb ai) × Applica tion Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ Body Weight (80 kg).

6 Inhalation MOE = Inhalation NOAEL (1.55 mg /kg/day) ÷ Inhalation Dose (mg/kg/day).Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### 6.2 Residential Post-applicatio n Exposure/Risk Estimates

Table 6.2.1 provides a summar y of the residential post-applica tion exposures and risk estimates for sulfentrazone. All risk estimates for post-app lication 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 Residentia l Post-application Exposure and Risk Estimates for Sulfentrazone.
Lifestage Post-application Expos ure 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) equati ons provided in Appendix B.

2 MOE = POD (dermal = 100 mg/kg/day and incidental oral = 14 mg/kg/day) ÷ Dose (mg/kg/day). LOC = 100.



### 6.3 Residential Risk Estimates fo r Use in Aggregate Assessment

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate assessment for sulfentrazone.

 The recommended residential exposure for us e in the adult short-term aggregate assessment reflects dermal exposure from app lications 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 ha nd-to-mouth exposures fr om post-application exposure to turf applications.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 33 of 57 Table 6.3.1. Recommendations for th e Residential Exposures for the Sul fentrazone 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 560

Child 11 < 16 years old Postapplication
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 Postapplication
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 Postapplication
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 re sidential scenarios assessed. Total = dermal + incidental ora l (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 vi a many types of pathways and it is governed by 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 cont act. They can also deposit on surfaces where contact with residues can eventua lly lead to exposures (e.g., children playing on lawns where residues have deposited next to treated fields). Th e potential risk estimates from these residues can be calculated using drif t modeling coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorp orating spray drift into risk assessment include assessing exposures for children (1 to <2 years 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 labe ls for use on turf, thus it was considered whether the risk assessment for turf may be considered protec tive of any type of exposure resulting from spray drift. If the maximum app lication rate on crops ad justed by the amount of drift expected is less than or equal to existing turf application rates, the existing turf assessment is considered protective of spra y drift exposure. The proposed maximum single application rate of sulfentrazone for several regist ered agricultural crops is 0.375 lb ai/A. The highest fraction of spray drift noted for any applica tion method immediately adjacent to a treated field results in aSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 34 of 57 

### 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 applicat ion rate (0.375 lb ai/A) 5 

### for any sulfentrazone products. The turf postapplication MOEs are protective for any poten tial 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 quant itative post-application inhalation exposure assessment was not performed for sulfentrazone at this time primarily because of the low acute inhalation toxicity (Toxic ity Category III) and the low vapor pressure (8 x 10 -10 

### mm Hg). However, volatilization of pestic ides may be a source of post-application i nhalation exposure to individuals nearby pesticide app lications. 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 received 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 fo r a quantitative post -application inhalati on 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 th e risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED consider s both the route and duration of exposure.

7.1 Acute Aggregate Risk

Acute aggregate risk results from exposure to re sidues in food and drinking water alone. The acute dietary exposure analysis included both food and drinki ng water. Therefore, acute aggregate risk is equivalent to the acute dietary risk, as discusse d in Section 5.4, above. All risk estimates are not of concern.

7.2 Short- and Intermediate-Term Aggregate Risk

Short- and intermediate-term aggregate exposure ta kes into account short- and intermediate-term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). Sulfentrazone is currently registered for uses that could result in short- and intermediate-term reside ntial exposure, and RAB1 has determined that it is appropriate to aggregate chronic exposure through food and water wi th short- and intermed iate- term residential exposures to sulfentrazone. For short- and in termediate-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 Assessm ent D410365

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Page 35 of 57 

### 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 co mbined with chronic dietary (food and water) exposure for determination of aggregate short- and intermediate-term exposures. HED uses chronic dietary exposure when conducting short- a nd intermediate-term aggregate assessments as they have determined that these will more accu rately reflect exposure from food over the HED defined short- and intermediate-term interval than will acute exposure.

Adults may potentially be exposed to sulfentr azone through dermal, inha lation, and dietary (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 expo sure scenario with the greatest risk estimate; therefore, the exposure estimates fo r this scenario are protective of other exposure scenarios. For young children, due primarily to their hand-to-mouth activities, short-term oral (non-dietary) exposures are expected along with dermal a nd dietary (food and dri nking water) exposures; therefore, it was appropriate to aggregate these exposures for th e short- and intermediate-term duration. Children 1-2 years old represent the populati on subgroup for children with the greatest exposure; therefore, the exposur e estimates for children 1-2 year s 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 inte rmediate-term aggregate exposures and risk estimates for 1-2 year olds and adults. The a ggregate short- and inte rmediate-term MOEs are >100 for adults and children; therefore, aggregat e exposures to sulfentrazone are not of concern to HED.

Table 7.2.1. Short- and Intermediate-term Aggregate Risk Calcul ations 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 Incidental Oral Exposure = Hand-to-mouth 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 Aggregat e 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)/(chroni c dietary exposure)].

2 MOE dermal = [(short- or intermediate-term dermal NOAE L = 100 mg/kg/day)/(high-end dermal residential exposure)].

3 Aggregate MOE = 1/[(1/dietary MOE) + (1/dermal MOE) + (1/inhalation MOE)].



### 7.3 Chronic Aggregate Risk

The chronic aggregate risk assessment results fr om long-term exposure to residues in food and drinking water, as there are no re sidential scenarios that result in long-term exposure. The chronic dietary exposure analysis included bot h food and drinking water and, therefore, theSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 36 of 57 

### chronic aggregate risk assessment is equivalent to the chronic dietary risk assessment discussed in Section 5.4, above. All risk es timates are not of concern.

7.4 Cancer Aggregate Risk

An aggregate cancer risk assessment was not perf ormed because sulfentrazone is not considered to be a carcinogen.

8.0 Cumulative Exposure/Ri sk Characterization

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to sulfentrazone and any other s ubstances and sulfentrazone does not appear to produce a toxic metabolite produced by 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 th e cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pestic ides/cumulative/.

9.0 Occupational Exposure/ Risk Characterization D417171, K. Lowe, 05-JUN-2014



### 9.1 Handler Risk Assessment

The occupational handler exposure a nd risk estimates indicate that the short- and intermediateterm dermal and inhalation MOEs are not of c oncern to HED (i.e., MOEs >100 for dermal and MOEs >30 for inhalation), as long as gloves ar e 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. Ther efore, risks to pilots are assessed using the engineering control (enclosed coc kpits) and baseline attire (long- sleeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations fo r engineering controls, pilots are not required to wear protective gloves for the dura tion of the application. With this level of protection, there are no risk es timates of concern for applicators.

The Agency matches quantitative occupatio nal exposure assessment with appropriate characterization of exposure poten tial. 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 A ssociation (NAAA) survey of their membership, the use of Global Positioning Sy stem (GPS) for swath guidance in agricultural aviation has grown steadily from the mid-1990s. Over the same time period, the use of human flaggers for aerial pesticide applications has d ecreased steadily 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 a nd characterize the exposur e potential for human flaggers in agricultural aerial applications.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 37 of 57 Table 9.1.1. Occupational Ha ndler Non-Cancer Exposure and Ri sk Estimates for Sulfentrazone

.

Exposure Scenario Crop or Target Dermal Unit Exposure ( μ g/lb ai) 1 Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum Application

Rate (lb ai/A) 2 Area Treated (acres) 3 Dermal (LOC = 100) I n (L O
Mitigation

Level = b aseline unless indicated otherwise Mitigation Level = baseline unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/da y

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, highacreage 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 8Field crop, highacreage 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 Impregnation 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 0.00031 9

Sod 80 0.00365 27,000 0.00063 8 Christmas tree farms Nursery (ornamentals,

vegetables, trees, container stock) 60 0.00274 36,000 0.00047 9

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 0.000061 6

Sod 350 0.419 240 0.00035 9 Field crop, typical
acreage 8

Field crop, highacreage 9 1200 1.43

0.245 (SL w/gloves) 70

410 (SL w/gloves) 0.00123

0.25 0.957 100 0.00082 1Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 38 of 57 Table 9.1.1. Occupational Ha ndler Non-Cancer Exposure and Ri sk Estimates for Sulfentrazone

.

Exposure Scenario Crop or Target Dermal Unit Exposure ( μ g/lb ai) 1 Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum Application

Rate (lb ai/A) 2 Area Treated (acres) 3 Dermal (LOC = 100) I n (L O
Mitigation

Level = b aseline unless indicated otherwise Mitigation Level = baseline unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/da y

0.19 0.728 140 0.00062 4

Chemigation application of a liquid formulation Sod

220 0.219 0.375 350 0.419 240 0.00035 9 Field crop, typical and high-acreage 8,9 Nursery (ornamentals,

vegetables, trees, container stock) 60 0.0717 1,400 0.000061 6

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

220 0.219 0.375 40 0.0478 2,100 0.000041 Field-grown ornamental crops Nursery (ornamentals,

vegetables, trees, container stock) 60 0.0717 1,400 0.000061 6

Sod 80 0.0957 1,000 0.000082 Field crop, typical
acreage 8Field crop, highacreage 9 200 0.239 420 0.00020 5

Commercial Impregnation 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 0.00016 4
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 0.000001 3

Sod 350 0.00396 25,000 0.000008 0 Field crop, typical
acreage 8Field crop, highacreage 9 1200 0.0136 7,400 0.000027 6

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

78.6 0.34 0.375 40 0.0171 5,800 0.000063 Field-grown ornamental crops Nursery (ornamentals,

vegetables, trees, container stock) 60 0.0257 3,900 0.000095 6

Sod 80 0.0342 2,900 0.00012 8 Field crop, typical
acreage 8Field crop, highacreage 9 200 0.0855 1,200 0.00031 9

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 0.00092 6

Tractor-drawn Spreader

granular application Golf course (fairways, tees, greens)

9.9 1.2 0.375 40 0.00216 46,000 0.00022 5

Sod 80 0.0043 23,000 0.00045 Christmas tree farms Nursery (ornamentals,

vegetables, trees, 60 0.00323 31,000 0.00033 8Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 39 of 57 Table 9.1.1. Occupational Ha ndler Non-Cancer Exposure and Ri sk Estimates for Sulfentrazone

.

Exposure Scenario Crop or Target Dermal Unit Exposure ( μ g/lb ai) 1 Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum Application

Rate (lb ai/A) 2 Area Treated (acres) 3 Dermal (LOC = 100) I n (L O
Mitigation

Level = b aseline unless indicated otherwise Mitigation Level = baseline unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/da y

container stock) Flagger

Flagger for aerial spray application Nursery (ornamentals, vegetables, trees, container stock) 11 0.35 0.375 60 0.00359 28,000 0.000098 5

Sod 350 0.0209 4,800 0.00057 4 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 0.000024 5

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) 0.00028 5

Dry Flowables via Mechanically-pressurized Handgun Golf course (fairways, tees, greens) 1,960 42 0.375 5 0.0533 1,900 0.00098 5 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 0.000048 4 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 0.000024 5

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) 0.00028 5

Liquids via Mechanicallypressurized Handgun Golf course (fairways, tees, greens) 1,140 1.9 0.375 5 0.031 3,200 0.000044 5 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 0.00011 2Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 40 of 57 Table 9.1.1. Occupational Ha ndler Non-Cancer Exposure and Ri sk Estimates for Sulfentrazone

.

Exposure Scenario Crop or Target Dermal Unit Exposure ( μ g/lb ai) 1 Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum Application

Rate (lb ai/A) 2 Area Treated (acres) 3 Dermal (LOC = 100) I n (L O
Mitigation

Level = b aseline unless indicated otherwise Mitigation Level = baseline unless indicated otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/da y

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 0.000004 2

Water Soluble Packets via

Manually-Pressurized Handwand 100,000 30 0.191 140000 0.000049 5

Water Soluble Packets via Mechanically-Pressurized Handgun 1,350 18 0.287 lb ai/A 5 0.0281 11000 0.00032 3

1 Based on the “Occupational Pesticide Handl er Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Bas eline, Eng.

Controls.

2 Based on registered and proposed labels.

3 Exposure Science Advisory Council Po licy #9.1 and Registrant information.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷

BW (69 kg).

5 Dermal MOE = Dermal NOAEL (100 mg /kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated

(A/day) ÷ BW (80 kg).

7 Inhalation MOE = Inhalation NOAEL (2.317, 4.661, or 8.094 mg/kg/day) ÷ Inha lation 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 berr ies, edamame, fallow cropping systems, flax, fruiting vegetables, okr a, horseradish, l ima beans, melons, rhubarb, strawberry, succulent p eas, tobacco, turnips, Christmas tree farms (where applicable).

9 Field crops, high-acreage crops category covers the following cr ops: corn, dry shelled peas and beans, mint, peanuts, pepperm int, spearmint,

potato, soybeans, sugarcane, sunflower, wheat.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 41 of 57 

### 9.2 Post-Application Risk Assessment

9.2.1 Inhalation Post-Application Risk Assessment

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for sulfentrazone at this time primarily because of the low acute inhalation toxicity (Toxic ity Category III) and the low vapor pressure (8 x 10 -10 

### mm Hg). However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-applica tion activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dus ts and/or particulates that contain pesticides. The Agency sought expert advice and input on i ssues related to volatilization of pesticides from its FIFRA SAP in Decembe r 2009, and received the SAP’s final report on March 2, 2010 7 

### . The Agency is in the process of eval uating the SAP report as well as available post-application inhalation expos ure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application i nhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post- application inhalation exposure assessment for sulfentrazone.

Although a quantitative occupational post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resultin g from application of pesticides outdoors is likely to result in higher exposure than post -application inhalati on exposure. Therefore, it is expected that these handler inhalation exposure estima tes would be protective of most occupational post-application inhalation exposure scenarios.

9.2.2 Dermal Post-Applicat ion 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-a pplication dermal exposures to so il by occupational workers. In general, such exposures are considered to be ne gligible. Therefore, fo r 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-applicat ion exposures. The short- and intermediate-term post-a pplication exposure scenarios associat ed 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 HED.

7 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 42 of 57 Table 9.2.2.2. Occupational Post-application Non-Ca ncer Exposure and Risk Estimates for Sulfentrazone.

Crop/Site Activities Transfer Coefficient

(cm 2 /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 Pruning, 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/cm 2 ; 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 Interval

The REI specified on the proposed label is base d on the acute toxicity of sulfentrazone. Sulfentrazone is classified as acute Toxicity Ca tegory III for acute oral, acute dermal, and acute inhalation toxicity. It is clas sified as Toxicity Category III for eye irritation potential and category IV for skin irritation potential. It is not a dermal sensitizer. Short- and intermediateterm post-application risk estimates were not a concern on day 0 (12 hours following application) for all post-application activities. Under 40 CFR 156.208 (c) (2) (i ii), ais classified as Acute III or IV for acute dermal, eye irritation and primar y skin irrigation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protecti on Statement interim REI of 12 hours is adequate to protect agricultural worker s from post-application expos ures 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-Reviewe d Developmental Neurotoxicity St udy 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 Assessm ent D410365

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Page 43 of 57 

### Appendix A. Toxicology Prof ile and Executive Summaries

The requirements (40 CFR 158.340) for food uses for sulfentrazone are in Ta ble A.1. Use of the new guideline numbers does not imply that th e 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 In halation Toxicity .............................................. 870.2400 Primar y Eye Irr itation

.................................................... 870.2500 Primar y Dermal Irr itation

.............................................. 870.2600 Derm al Sensiti zation ..................................................... yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Su bchronic (rodent) ............................................... 870.3150 Oral Su bchronic (nonr odent) ......................................... 870.3200 28-Day Dermal .............................................................. 870.3465 28-D ay Inhala tion .......................................................... yes yes yes yes yes yes yes yes 870.3700a Developmental Toxicity (rodent) .................................. 870.3700a Dermal Developm ental Toxicity (rodent) ..................... 870.3700b Developmental Toxicity (nonrodent) ............................ 870.3800 Reproduc tion ................................................................. yes yes yes yes yes yes yes yes 870.4100a Chronic T oxicity (rodent) .............................................. 870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Oncoge nicity (ra t) .......................................................... 870.4200b Oncogenicity (mouse) ................................................... 870.4300 Chroni c/Oncogeni city ................................................... yes yes yes yes yes yes yes yes yes yes 870.5100 Mutagenicity—G ene Mutation - bacterial ..................... 870.5300 Mutagenicity—Gene Mutation - mammalian ............... 870.5xxx Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5xxx Mutagenicity—O ther 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 Screen ing Battery (rat) ......................................... 870.6200b 90-Day Neurotoxicity Screening Battery (rat) .............. 870.6300 Develop. Neurotoxicity ................................................. no

no yes yes

no --

-- yes yes

-- 870.7485 Gene ral Metabo lism ...................................................... 870.7600 Derm al Penetr ation ........................................................ 870.7800 Immunotoxicity ............................................................. yes

no yes yes

-- yes

Table A.2. Acute Toxicity Profile – Sulfentrazone.

Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral [rat] 41911605 LD 50 = 2855 (M & F) mg/kg III 870.1200 Acute dermal [mice] 41911606 LD 50 = 711 (M & F) mg/kg III 870.1200 Acute dermal 42286400 LD 50 >2000 mg/kg/day III 870.1300 Acute inhalation [rat] 42471002 4-hour, whole body exposure; LC 50 >4.13 mg/L III

870.2400 Acute eye irritation [rabbit] 41911608 Corneal opacity, iritis, diffuse irritation within 24, clearing by day 4 III

870.2500 Acute dermal irritation [rabbit] 41911609 Non-irritating IV

870.2600 Skin sensitization [Guinea Pig] 41911610 Not a Dermal Sensitizer N/ASulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 44 of 57 Table A.3. Toxicity Pr ofile for Sulfentrazone Guideline No./

Study Type 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 Systemic Toxicity NOAEL = 19.9 mg/kg/day in males and 23.1 mg/kg/day in females. Systemic 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, 100, 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 Systemic Toxicity NOAEL = 60 mg/kg/day in males and 79.8 mg/kg/day in females. Systemic 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, an d 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 Systemic Toxicity NOAEL = 28 mg/kg/day for males and females. Systemic 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, Hct, MCV, and MCH concentration, and increased absolute liver weights and alkaline phosphatase levels, and microscopic changes in the liver an d 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 Systemic and Dermal Toxicity NOAEL = 1000 mg/kg/day (highest dose tested or HDT). Systemic 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 reduction 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 = 0.256 mg/L. Portal-of-entry LOAEL = 1.71 mg/L based on an increased 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 increased number of litters with any variation and by decreased number of caudal vertebral andSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 45 of 57 Table A.3. Toxicity Pr ofile for Sulfentrazone Guideline No./

Study Type MRID No. (year)/Classification/ Doses Results
metacarpal ossification sites. 870.3700 Prenatal developmental (rat) 43651003 (1992) Acceptable/Non-Guideline 0, 25, & 50 mg/kg/day Study was conducted to evaluate external 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 implantations and percentage of live fetuses, increase in the percentage of early resorptions, and decreased fetal body weights.

Supplemental study to the 1992 DevelopmentalToxicity 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 weigh t; 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 ossification 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, d ecreased live fetuses per litter, and decreased fetal weights. 870.3800 Two-Generation reproduction 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 bodyweight 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.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 46 of 57 Table A.3. Toxicity Pr ofile for Sulfentrazone Guideline No./

Study Type MRID No. (year)/Classification/ Doses Results

870.3800 One-Generation reproduction and fertility effects (rat) 43869101(1995) 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 Systemic/Developmental Toxicity NOAEL = 20 (F) mg/kg/day. Systemic/Developmental Toxicity LOAEL = 51 (F) mg/kg/day, (F 1 females), based on decrease in premating 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 patency; 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 Systemic Toxicity NOAEL = 24.9/29.6 mg/kg/day for males/and females. Systemic 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 Systemic Toxicity NOAEL = 93.9 mg/kg/day for males and 116.9 mg/kg/day for females. Systemic 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 Combined chronic toxicity/carcinogenicity rodents (rat) 43345409 (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 Systemic Toxicity NOAEL = 40 mg/kg/day for males and 36.4 mg/kg/day for females. Systemic 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 TA1535, TA1538, TA1537, TA98, and TA100 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 was evident either in presen ce or in absence of S9 activation. The positive controls induced the expected mutagenic responses in the appropriate tester strain. Sulfentr azone 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 In a forward gene-mutation 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 presenceSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 47 of 57 Table A.3. Toxicity Pr ofile for Sulfentrazone Guideline No./

Study Type MRID No. (year)/Classification/ Doses Results
exposed to sulfentrazonetechnical (94.2%) in nonactivated 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). of S9 activation.

870.5395 Mammalian erythrocyte micronucleus test 43004605 (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 eviden ce 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 negative controls in the proportion of early dead: total implants, 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 Systemic Toxicity NOAEL = 250 mg/kg/day. Systemic 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 motor 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.) wasadministered to SpragueDawley rats (five Sulfentrazone was readily absorbed and 84 to 104% of the administered dose was excreted in urine and feces within 72 ho urs. 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, HMSSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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Page 48 of 57 Table A.3. Toxicity Pr ofile for Sulfentrazone Guideline No./

Study Type MRID No. (year)/Classification/ Doses Results
animals/sex/dose) by gavage as a single dose at levels of 50 and 500 mg/kg, or as a single dose of 50 mg/kg following a 14-daypretreatment with nonradioactive sulfentrazone (50 mg/kg/day). accounted for 1.26-2.55% of the administered dose. The proposed metabolic pathway appeared to be conversion of the parent compound mainly to HMS (excreted in the urine). A small amount of HMS was also converted to sulfentrazone 3-carboxylic acid (excreted in the urine and feces).

870.7800 Immunotoxicity (rat) 48748601 (2012) Acceptable/Guideline 0, 500, 1000, or 2000 ppm (0, 42, 87, or 163 mg/kg/day[F]) Systemic NOAEL = 1000 ppm (87 mg/kg/day). Systemic 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 significant 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 indams) during gestation. The results of this nonguideline 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 Assessm ent D410365

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### 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 physicochemi cal properties of the inhaled compound, the type 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 (19 94), the methodology for RfCs derivation is an estimate of the quantitative dose-response asse ssment of chronic non-cancer toxicity for individual inhaled chemicals and includes dosim etric adjustment to account for the speciesspecific relationships of exposure concentration to deposited/deliver ed dose. This adjustment is influenced by the physicochemical properties of the inhaled compound as well as the type of toxicity observed (e.g., systemic vs. portal-of-entry), and take s into consideration the PK differences between animals and humans. Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a li fetime, it can be used for other inhalation exposures (e.g., acute and short-te rm exposures) since the dosimetr ic adjustment incorporates mechanistic determinants of disposition that ca n 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 by the following equation:

Where: POD study 

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

### : Duration of animal expo sure (hrs/day; days/wk) D anticipated exposure 

### : Anticipated human duration of exposure (hrs/day; days/wk) RGDR: Regional Gas Dose Ratio

Calculations used to estimate the inhalation ri sk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional de posited dose ratio (RDDR). Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation ( σ g 

### ), which is then used to determine the R DDR. The RDDR is a multiplicativ e factor used to adjust an observed inhalation particulate exposure concen tration 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 rt h region or target tissue.

RDDR r 

### = (RDD r 

### /Normalizing Factor) A 

### (RDD r 

### /Normalizing Factor) H


### As with calculations for gases, 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 specifically for computing the RDDR from the MMAD and σ g 

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

# HEC = POD * D
D * W
W * RGDR study animal exposure (hrs / day)

human exposure (hrs / day) animal exposure (days / wk)

human exposure (days / wk)Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### Regional Deposited Dose Ra tio (RDDR) for Sulfentrazone

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 fraction human 

### = (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 consid eration the PK differences but not the PD differences

. Consequently, the UF for interspecies extrapolat ion may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variati on is retained at 10X. Thus, the UF when using the RfC methodology is customarily 30X.

B.1. HEC Calculations for Short- and In termediate-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 Out door 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 Assessm ent D410365

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Page 51 of 57 Table B.1. HEC Array for Re sidential 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/LBystander0.00974

mg/L Long-Term Exposure: Not ap propriate 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 extrapolati on converts human and animal valu es from mg/L concentrations to mg/kg oral equivalent doses . The equation uses a single co nversion factor to account for default body weights and respirator y volumes. An activity factor is used to account for increased exposure resulting from increased respiration.

Using the HEC calculated (based upon terminal ai rway inflammation in ma les), a conversion of the inhalation concentration to a dose (mg/ L to mg/kg/day) was conducted as follows: HED (mg/kg/day) = Dose (systemic 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 abso rption in respiratory tract compared to absorption by the oral route. CF = conversion factor; a L/hr/kg factor which accounts for respiratory volume and body weight for a given species and stra in (Table 1 of J. Whalen and H. Pettigrew, 10/10/98). D = duration; duration of daily an imal or human exposure (hours). AF = activity factor; animal default is 1. For humans with a vent ilation rate of 16.7Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### L/min, the value is 1.2.

Therefore, the residential HED for sulf entrazone 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 In termediate-term Occupational Exposure: Assume workers will be in the fi eld 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 ap propriate 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 extrapolati on converts human and animal valu es 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 ai rway inflammation in ma les), a conversion of the inhalation concentration to a dose (mg/ L to mg/kg/day) was conducted as follows:

HED (mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kgSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### Where:

A = absorption; ratio of deposition and abso rption in respiratory tract compared to absorption by the oral route. CF = conversion factor; a L/hr/kg factor which accounts for respiratory volume and body weight for a given species and stra in (Table 1 of J. Whalen and H. Pettigrew, 10/10/98). D = duration; duration of daily an imal or human exposure (hours). AF = activity factor; animal default is 1. Fo r humans, the value vari es with ventilation rates determined by occu pational/restidential scien tists; 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 sulfentrazone label, HED believes exposures can be short- (1-30 days) or intermediate- (1 to 6 months) term in durati on. Long-term exposures are not anticipated for sulfentrazone based on proposed labeled uses. Fo r 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 fo r systemic versus portal-of-entry effects. Typically, HECs are calculated separately for sy stemic versus portal-of-entry effect. For sulfentrazone, portal-of-entry irritation was observed and, th erefore, only portal-of-entry HECs were derived. 2. Time adjustments are traditionally needed for non-occupational (bystander) versus occupational exposure scenarios. Traditiona lly, HECs for non-occupational exposure are based on the number of hours an individual may be at home. Therefore, the most conservative estimate of hours spent at home wo uld 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 th e time adjustment in the calculations.Sulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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### Appendix C. Physical/Chemical Properties

Table B.1. Physicochemical Properti es 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/cm 3 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, pK a 6.56 Octanol/water partition coefficient, Log(K O W ) 1.49 at pH 5

UV/visible absorption spectrum Not availableSulfentrazone Preliminary Human-Health Risk Assessm ent D410365

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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-hydroxymethyl5-oxo-1H-1,2,4-triazol-1- yl)phenyl)methanesulfonamide, 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 Soybean, 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-oxo1 H -1,2,4-triazol-1- yl]phenyl]methanesulfonamide) and its metabolites HMS ( N -(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-3-hydroxymethyl5-oxo-1 H -1,2,4-triazol-1- yl)phenyl)methanesulfonamide) and DMS ( N

-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro5-oxo-1 H -1,2,4-triazol-1- yl)phenyl)methanesulfonamide, 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 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 an d 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 Assessm ent D410365

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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 soybean, 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) Pea, 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-methyl-5-oxo1 H -1,2,4-triazol-1- yl]phenyl]methanesulfonamide) and its metabolites HMS ( N -(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-3-hydroxymethyl5-oxo-1 H -1,2,4-triazol-1- yl)phenyl)methanesulfonamide) and DMS ( N

-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro5-oxo-1 H -1,2,4-triazol-1- yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone 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 Cowpea, 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 Assessm ent D410365

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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. 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-oxo1 H -1,2,4-triazol-1- yl]phenyl]methanesulfonamide) and its metabolites HMS ( N -(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-3-hydroxymethyl5-oxo-1 H -1,2,4-triazol-1- yl)phenyl)methanesulfonamide) and DMS ( N

-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro5-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, ex cept sweet corn; forage 0.2

Grain, cereal, forage, fodder and straw, group 16, ex cept sweet corn; hay 0.2

Grain, cereal, forage, fodder and straw, group 16, ex cept sweet corn; stover 0.1

Grain, cereal, forage, fodder and straw, group 16, ex cept sweet corn; straw 0.6

Grain, cereal, group 15, except
sweet corn 0.1

Grain, cereal, group 15, except sweet corn; bran 0.15

Completed: M. Negussie; 04/16/14

1 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.