                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                 	OFFICE OF CHEMICAL SAFETY AND
                             	POLLUTION PREVENTION
	



MEMORANDUM

Date:		05-JUN-2014

SUBJECT:	Sulfentrazone  -  Preliminary Human-Health Risk Assessment for Registration Review and the Risk Assessment for the Section 3 Registration Request for a New Use on Apples 

PC Code:  129081
DP Barcode:  D410365
Decision Nos.:  476747, 483232
Registration Nos.:  279-3370, 279-3189, & 279-3220
Petition No.:  3E8202
Regulatory Action:  Section 3 and Registration Review Risk Assessments
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  7231
TXR No.:  NA
CAS No.:  122836-35-5
MRID No.:  NA
40 CFR:  §180.498

From:		George F. Kramer, Ph.D., Senior Chemist
      Kelly M. Lowe, Environmental Scientist
      Anwar Y. Dunbar, Ph.D., Pharmacologist
      Risk Assessment Branch 1 (RAB1)
            Health Effects Division (HED; 7509P)

Through:	Charles W. Smith III, Branch Chief
	RAB1/HED (7509P)

         To:		Laura Nollen/Barbara Madden, RM 05
		Registration Division (RD, 7505P)
		
		and

		Christina Scheltema
		Pesticide Reevaluation Division (7509P)


As part of Registration Review, the Pesticide Re-evaluation Division (PRD) of OPP has requested that HED evaluate the hazard and exposure data and conduct occupational and residential exposure assessments, as needed, to estimate the risk to human health that will result from the currently registered uses of pesticides.  This memorandum serves as HED's Preliminary Registration Review risk assessment of the dietary, occupational and residential handler, post-application exposure, and aggregate risk from the registered/proposed uses of sulfentrazone.  

In addition, the Registration Division (RD) requested that HED conduct an exposure and risk assessment for the proposed new use of sulfentrazone on apples.  This memorandum provides HED's human-health risk assessment conducted in support of this request 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-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide) and DMS (N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-5-oxo-1H-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.  The risk assessment, dietary risk assessment, and residue chemistry review were provided by George Kramer (RAB1), the occupational/residential exposure and risk assessment was provided by Kelly Lowe (RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), and the drinking water assessment was provided by 
Michael Barrett of the Environmental Fate and Effects Division (EFED).
                               Table of Contents

1.0	Executive Summary	5
2.0	Recommendations	7
2.1	Data Deficiencies/Data Needs	8
2.2	Tolerance Considerations	8
2.2.1	Enforcement Analytical Method	8
2.2.2	Recommended Tolerances	8
2.2.3	Revisions to Petitioned-For Tolerances	10
2.2.4	International Harmonization	11
2.3	Label Recommendations	11
3.0	Ingredient Profile	11
3.1	Chemical Identity	11
3.2	Physical/Chemical Properties	12
3.3	Use Pattern	12
3.4	Anticipated Exposure Pathways	17
3.5	Consideration of Environmental Justice	17
4.0	Hazard Characterization and Dose-Response Assessment	17
4.1	Toxicology Studies Available for Analysis	18
4.2	Absorption, Distribution, Metabolism, & Excretion (ADME)	18
4.2.1	Dermal Absorption	18
4.3	Toxicological Effects	18
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	20
4.4.1	Completeness of the Toxicology Database	20
4.4.2	Evidence of Neurotoxicity	20
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	20
4.4.4	Residual Uncertainty in the Exposure Database	20
4.5	Toxicity Endpoints and Point of Departure Selections	21
4.5.1	Dose-Response Assessment	21
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	23
4.5.3	Cancer Classification and Risk Assessment Recommendation	23
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human-Health Risk Assessment	23
4.6	Endocrine Disruptor Screening Program	25
5.0	Dietary Exposure and Risk Assessment	26
5.1	Metabolite/Degradate Residue Profile	26
5.1.1	Summary of Plant and Animal Metabolism Studies	26
5.1.2	Summary of Environmental Degradation	26
5.1.3	Comparison of Metabolic Pathways	27
5.1.4	Residues of Concern Summary and Rationale	27
5.2	Food Residue Profile	27
5.3	Drinking Water Residue Profile	28
5.4	Dietary (Food + Drinking Water) Risk Assessment	29
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	29
6.1	Residential Handler Exposure/Risk Estimates	30
6.2	Residential Post-application Exposure/Risk Estimates	32
6.3	Residential Risk Estimates for Use in Aggregate Assessment	32
6.4	Spray Drift	33
6.5	Residential Bystander Post-Application Inhalation Exposure	34
7.0	Aggregate Exposure/Risk Characterization	34
7.1	Acute Aggregate Risk	34
7.2	Short- and Intermediate-Term Aggregate Risk	34
7.3	Chronic Aggregate Risk	35
7.4	Cancer Aggregate Risk	36
8.0	Cumulative Exposure/Risk Characterization	36
9.0	Occupational Exposure/Risk Characterization	36
9.1	Handler Risk Assessment	36
9.2	Post-Application Risk Assessment	41
9.2.1	Inhalation Post-Application Risk Assessment	41
9.2.2	Dermal Post-Application Risk Assessment	41
10.0	References	42
Appendix A.  Toxicology Profile and Executive Summaries	43
Appendix B.  Methodologies for HEC Calculations.	49
Appendix C.  Physical/Chemical Properties	54
Appendix D.  International Residue Limits	55


1.0	Executive Summary

Sulfentrazone is an aryl triazolinone 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 necrotic and die shortly after exposure to light.

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

Hazard Assessment:  Results of mammalian toxicity studies 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 mice, where the effects were seen at a slightly higher dose.  In addition, this hematotoxicity occurred around the same dose level from short- through long-term exposure without increasing in severity.  

Sulfentrazone caused developmental effects via the oral and dermal routes of exposure.  Developmental effects, including decreased fetal body weights and reduced/delayed skeletal ossifications, were observed in both the oral and dermal developmental toxicity studies in the rat in the absence of maternal toxicity.  In the two-generation reproduction study in rats, offspring effects, such as decreased body weights and decreased litter survival were observed at doses that were maternally toxic (decreased body weight during gestation in both generations).

In a route-specific 28-day dermal toxicity study in adult rabbits, there were no effects up the highest dose tested.  In the route-specific 26-day inhalation study, there were portal-of-entry effects in the nasal passage and systemic effects, including decreased body weights and changes in numerous hematological parameters.

Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumor formation due to treatment with sulfentrazone and genotoxicity studies were all negative.

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 registered and proposed uses, selected endpoints are protective of the effects seen in the neurotoxicity studies as well as the increased susceptibility to offspring observed in developmental studies, and the conservative nature of the dietary and residential exposure analyses are unlikely to underestimate exposure [tolerance-level residues, 100% crop treated (%CT); use of 2012 Residential Standard Operating Procedures (SOPs)].

Dose Response Assessment:  The two-generation reproductive toxicity study in rats [no-observed adverse-effect level (NOAEL) = 14 mg/kg/day] was selected for assessment of acute dietary (females 13-49 years old), chronic dietary, and incidental oral exposure scenarios.  The acute neurotoxicity (ACN) study (NOAEL = 250 mg/kg/day) was selected for assessment of acute dietary (all populations excluding females 13-49 years old) exposure.  The dermal developmental toxicity study in rats (NOAEL = 100 mg/kg/day) was selected for assessment of dermal exposure (all durations).  The route-specific 26-day inhalation study in rats (NOAEL is 0.256 mg/L) was selected for assessment of inhalation exposure (all durations).  For all exposure scenarios except inhalation, a 100X uncertainty factor was applied [10X interspecies extrapolation; 10X for intraspecies variation; 1X FQPA SF (when applicable)].  For inhalation exposure scenarios, a 30X uncertainty factor was applied [3X interspecies extrapolation; 10X for intraspecies variation; 1X FQPA SF (when applicable)].

Dietary Risk Estimates (Food + Drinking Water):  Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID, ver. 3.16) which incorporates consumption data from United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003-2008).  The acute and chronic analyses assumed tolerance-level residues, 100% %CT, DEEM (ver. 7.81) default processing factors, and modeled drinking water estimates.  The resulting acute and chronic dietary risk estimates are not of concern to HED, and the subgroups with the greatest risk estimates utilized <=7% of the acute population-adjusted dose (aPAD; females 13-49 years old) and <=7% of the chronic population-adjusted dose (cPAD; children 1-2 years old), respectively.  

Residential (Non-Occupational) Exposure and Risk Assessment:  The proposed use on apples will not result in residential exposure; however, there are currently registered turf uses (e.g., residential turf, golf courses) that were assessed as part of Registration Review.  All dermal and inhalation exposure risk estimates for residential handlers are not of concern [i.e., margins of exposure (MOEs) were >= 100 for dermal and >= 30 for inhalation risk] at baseline for all scenarios; MOEs were >= 560 for dermal and >= 1200 for inhalation risk.  All residential post-application dermal risk estimates are also not of concern (i.e., MOEs >= 100); all MOEs were >= 610 for adults and >= 360 for children.

A quantitative spray drift assessment for sulfentrazone is not required.  The turf post-application MOEs are protective for any potential exposures related to spray drift for sulfentrazone.

Aggregate-Risk Estimates:  In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  Acute, chronic, short-, and intermediate-term aggregate assessments were included in this risk assessment.  An aggregate cancer risk assessment was not performed because sulfentrazone is not considered to be a carcinogen.  Acute and chronic aggregate risks are made up only of dietary sources; therefore, the exposure estimates provided in the dietary exposure analyses represent acute and chronic aggregate exposure, respectively.  Short- and intermediate-term aggregate risks are made up of dietary and non-dietary sources of exposure.  Since sulfentrazone is used on turf, residential handler and post-application exposures are expected.  Short-term exposures exist for adults and children from the registered turf application use.  In addition, intermediate-term exposures exist for children from incidental soil ingestion.  All aggregate sulfentrazone risk estimates are not of concern to HED.  
Occupational Exposure and Risk Assessment:  A quantitative assessment of occupational exposure has been conducted for all of the registered and proposed uses.  The occupational handler exposure and risk estimates indicate that the short- and intermediate-term dermal and inhalation MOEs are not of concern to HED (i.e., MOEs were >= 100 for dermal and >= 30 for inhalation risk), as long as gloves are worn for the highest application rate for mixing/loading liquids and dry flowables for aerial application to high-acreage crops.  Occupational post-application dermal exposure and risk estimates were assessed, and are greater than the level of concern (LOC) of 100 on the day of application (MOEs = 430 to 8,200).  Since the post-application assessment is not a concern on Day 0 (12 hours following application), the restricted-entry interval (REI) is based on the acute toxicity of sulfentrazone technical material.  Sulfentrazone is classified as acute Toxicity Category III for acute oral, acute dermal, and acute inhalation toxicity.  It is classified as Toxicity Category III for eye irritation potential and Toxicity Category IV for skin irritation potential.  It is not a dermal sensitizer.  Therefore, the acute toxicity categories for this chemical require a 12-hour REI under 40 CFR 156.208(c)(2)(iii).  

Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for sulfentrazone at this time.  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.

Environmental Justice Considerations:  Potential areas of environmental justice concerns, to the extent possible, were considered in this human-health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and 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 Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data 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/pesticides/science/post-app-exposure-data.html.  

2.0	Recommendations

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

For the proposed use on apples, HED concludes that the residue chemistry database supports the establishment of the permanent tolerance listed in Table 2.2.2.1.  

2.1	Data Deficiencies/Data Needs

860.1650 Submittal of Analytical Reference Standards

Analytical standards for sulfentrazone (expiration date 7/1/15) and its metabolites DMS (expiration date 8/1/17) and HMS (expiration date 8/31/18) are currently available at the EPA National Pesticide Standards Repository (personal communication with Theresa Cole, 4/21/14).  However, as the existing stocks are depleted, the Repository has requested that the registrant provide additional amounts of sulfentrazone (5 g) and HMS (3 g).  They should be sent to the 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 analytical 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) was successfully completed by the Agency's Analytical Chemistry Laboratory (ACL).  The limit 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 processed commodities from the apple 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) method.  The validated LOQ was 0.025-0.05 ppm for each analyte.  These methods are adequate for data collection based on acceptable method validation and concurrent recovery data.

2.2.2	Recommended Tolerances

Permanent tolerances have been established in 40 CFR §180.498 for the combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates in/on various raw agricultural commodities ranging from 0.05 ppm to 0.60 ppm.

Table 2.2.2.1 is a summary of the proposed and HED-recommended tolerances for residues of sulfentrazone per se.  

Table 2.2.2.1.  Tolerance Summary for Sulfentrazone (40 CFR §180.498).
                                   Commodity
                    Proposed / Established Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                                   Comments
(a)(1) General. Tolerances are established for the combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum 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) and its metabolite HMS (N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-3-hydroxymethyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone in or on the following commodities.
Soybean, seed
                                     0.05
                                       

(2) Tolerances are established for the combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates, in or on the commodities in the table below. 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-1H-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-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide) and DMS (N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-5-oxo-1H-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
                                     0.15
                                       

Vegetable, soybean, succulent
                                     0.15
                                       

Vegetable, tuberous and corm, subgroup 1C
                                     0.15
                                       

(c) Tolerances with regional registrations. Tolerances with regional registration are established for the combined residues of the free and conjugated forms of sulfentrazone, including its metabolites and degradates, in or on the commodities in the table below. 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-1H-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-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide) and DMS (N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-5-oxo-1H-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 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-1H-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-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide) and DMS (N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone in or on the following commodities when present therein as a result of the application of sulfentrazone to growing crops.
Grain, cereal (excluding sweet corn), Hulls
                                     0.30
                                       

Grain, cereal, forage, fodder and straw, group 16, except sweet corn; forage
                                      0.2
                                     0.20
Correct number of significant figures to be consistent with HED policy
Grain, cereal, forage, fodder and straw, group 16, except sweet corn; hay
                                      0.2
                                     0.20

Grain, cereal, forage, fodder and straw, group 16, except sweet corn; stover
                                      0.1
                                     0.10

Grain, cereal, forage, fodder and straw, group 16, except sweet corn; straw
                                      0.6
                                     0.60

Grain, cereal, group 15, except sweet corn
                                      0.1
                                     0.10

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


2.2.3	Revisions to Petitioned-For Tolerances

Based on the proposed uses and the submitted data, no revisions to petitioned-for tolerances are required.   
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 values are harmonized (asparagus, flaxseeds, horseradish roots, dry peas and beans, peppermint tops, spearmint tops, sunflower seeds, and cereal grain group 15).  For a summary of U.S. tolerances and international 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 should 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 sulfentrazone 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-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)methanesulfonanilide
CAS name
N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide
CAS registry number
122836-35-5
End-use product (EP)
4 lb/gal FlC formulation (Spartan[(R)] 4F Herbicide; EPA Reg. No. 279-3220) and 75% DF formulation (Spartan[(R)] Herbicide; EPA Reg. No. 279-3189)
Chemical structure of DMS metabolite

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

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

3.2	Physical/Chemical Properties

In general, sulfentrazone is persistent and mobile.  It has a 545-day aerobic soil half-life and an average Koc coefficient of 45 mL/g.  Additionally, it has a strong potential to leach into groundwater, as indicated in four completed small-scale prospective ground-water monitoring studies, and to move offsite to surface water.  It has a low vapor pressure of 8x10[-10] mm Hg.  A detailed description of the physicochemical properties of sulfentrazone is provided in Appendix B.   

3.3	Use Pattern

There are numerous end-use product labels registered with sulfentrazone as the active ingredient.  These include liquid, dry-flowable, and granular formulations.  The labeled use sites include various agricultural crops, Christmas tree farms, golf courses, seedling nurseries, landscape ornamentals, non-crop use sites (such as railroad, highway, roadside, pipeline, and utility rights-of-way and industrial areas), residential/commercial turf, and sod farms.  Most of the uses are soil-directed, and are applied via either aerial, chemigation, groundboom or handheld equipment.  Several labels also allow for application 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 application can be made per year, and up to two banded applications directed to the base of tree trunk can be made 60 days apart.  The REI for all the proposed uses is 12 hours.  Based on the proposed and registered use patterns, it has been determined that the potential exposure scenarios that will need to be assessed include short- and intermediate-term occupational and residential exposures (handler and post-application).

A summary of the 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. 

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/tractor-drawn 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 hr
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 or groundboom/tractor-drawn 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/tractor-drawn 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/tractor-drawn 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)
Potato
Soil directed; aerial, groundboom; chemigation; dry bulk fertilizer
Liquid and DF
0.25 lb ai/A
PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only)
Railroad, Highway, Roadside, Pipeline and Utility Rights of-Way, Industrial Areas,
Fence Rows, and Other listed Non-crop Sites
Aerial, handheld or groundboom/tractor-drawn spreader
DF
0.375 lb ai/A, 0.008 lb ai/1000 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 or groundboom/tractor-drawn 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 fertilizer
Liquid and DF
0.25 lb ai/A
PPE = SL w/CR gloves; REI = 12 hr; PHI = NA (preemergence only)
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
                                    Anytime
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 scenarios, dietary exposure is an anticipated exposure pathway as residues of sulfentrazone may be found in/on crops, livestock commodities, and drinking water.  There are residential uses of sulfentrazone and potential for spray drift, so there is exposure in residential and non-occupational settings.  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 justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf).  As a part of every pesticide risk assessment, the Office of Pesticide Programs (OPP) considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are 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 areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.


4.0	Hazard Characterization and Dose-Response Assessment

Sulfentrazone belongs to a class of herbicides that inhibit PPO in target photosynthetic organisms, ultimately resulting in disruption of chlorophyll biosynthesis.  In mammals, PPO is also an important enzyme in heme biosynthesis 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 are consistent with a PPO inhibition.

4.1	Toxicology Studies Available for Analysis

The toxicological database for sulfentrazone is complete for risk assessment purposes.  A 28-day rat immunotoxicity study has been submitted to the Agency and reviewed.  In addition, HED's Hazard Science and Policy Council (HASPOC) met on February 16, 2012 (TXR# 0050684) to evaluate the need for a repeated exposure inhalation toxicity study with sulfentrazone and concluded, based on a weight-of-evidence (WOE) approach, that a subchronic rat inhalation study was required.  Since then, the subchronic 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, Metabolism, & Excretion (ADME)

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

4.3	Toxicological Effects

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

Sulfentrazone caused developmental effects when administered via the oral (rats and rabbits) and dermal (rat) routes of exposure.  Developmental effects in rats and rabbits consisted of reductions in the number of implantations (rats only), increases in early resorptions (rats and rabbits), and reduction in live fetuses per litter (rats and rabbits).  Surviving rat fetuses exhibited reduced/delayed skeletal ossifications, and decreased fetal body weights.  Developmental effects in rats were seen in the absence of maternal toxicity.  In contrast with the rat studies, developmental effects in rabbits were observed at a maternally toxic dose, where clinical signs of toxicity included hematuria (red blood cells in urine), abortions, and decreased body-weight gains.  In the two-generation reproductive toxicity study in rats, developmental effects included an increased duration of gestation, reduced prenatal viability (fetal and litter), reduced litter size, and an increased number of stillborn pups.  Pup body-weight deficits, along with reduced pup and litter postnatal survival, were also observed.  All of the offspring effects were reported in the presence of mild maternal toxicity (decreased body weight and body-weight gain, particularly in F1 females).

A published, non-guideline developmental toxicity study in the rat [DeCastro VL, Destefani CR, Diniz C, Poli P., 2007.  Evaluation of neurodevelopmental effects on rats exposed prenatally to sulfentrazone.  Neurotoxicology 28(6):1249-59] did not conclusively demonstrate developmental neurotoxicity and contains several shortcomings that limit its use for regulatory purposes including the lack of a NOAEL.  The reported effects involving measures of 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 Memo, C. Rodriguez, 19-DEC-2011, 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/day), fetal effects were observed at this dose, and consisted of decreased body weights, 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 vertebral and rib ossification sites.

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

In an ACN study in rats, effects consisted of an increased incidence of clinical signs of toxicity (staggered gait, splayed hind limbs, and abdominal gripping), changes in functional-observation battery (FOB) parameters, and decreased motor activity at a high dose level (750 mg/kg bw).  Complete recovery was observed by day 14, and there was no evidence of neuropathology.  In a rat subchronic neurotoxicity (SCN) study, clinical signs of toxicity, increased motor activity, and/or decreased body weights, body-weight gain, and food consumption were also observed with no evidence of neuropathology.  

In the 28-day rat immunotoxicity study, there were no effects on the immune system and systemic effects consisted of reduced body weight, and increased absolute and relative spleen weights at the highest dose tested.

Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumor formation due to treatment with sulfentrazone, and the Cancer Assessment Review Committee (CARC) previously classified sulfentrazone as "not likely to be carcinogenic to humans" in accordance with EPA proposed Guidelines for Carcinogenic Risk Assessment (April 10, 1996).  The available mutagenicity studies indicate that sulfentrazone is 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.
Based on the results of acute toxicity studies in the rat, sulfentrazone was classified as Toxicity Category III (Toxicity Category IV being the lowest category) for acute toxicity via the oral, dermal, and inhalation routes of exposure.  It was a mild eye irritant (Toxicity Category III), but not a dermal irritant or sensitizer.  

4.4	Safety Factor for Infants and Children (FQPA Safety Factor)

The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios.  The toxicity 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 clearly established NOAEL/lowest-observed adverse-effect level (LOAEL) values and selected endpoints are protective for the observed effects.

4.4.1	Completeness of the Toxicology Database

The existing toxicology database for sulfentrazone is adequate for FQPA evaluation.  Developmental toxicity studies in rats and rabbits, a two-generation reproduction study in rats, and neurotoxicity studies in rats are available for FQPA consideration.

4.4.2	Evidence of Neurotoxicity

In 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 occurred in the absence of neuropathology; 3) there is no evidence of neurotoxicity in other available studies in the toxicity database; 4) effects are well-characterized with clearly established NOAEL/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 toxicity studies in rats.  Although developmental toxicity was observed at lower doses than maternal toxicity in both studies in the rat, the concern is low based on the following considerations:  1) the toxicology database for assessing pre- and postnatal susceptibility is complete; 2) there are clear NOAELs and LOAELs for the developmental effects observed via both the oral and dermal routes; 3) the PODs used for assessing dietary and dermal exposure risks are based on developmental and/or offspring toxicity; 4) the portal-of-entry effects seen in the 26-day inhalation study are protective of the developmental toxicity; and 5) there are no residual uncertainties for pre-and/or postnatal toxicity.  

4.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.  The dietary and residential exposure analyses are conservative in nature.  The dietary exposure assessment used tolerance-level residues and assumed 100% CT.  The residential exposure assessment uses the 2012 Residential SOPs and is considered health-protective.  The residential assessment includes an FQPA SF of 10X for inhalation exposures to account for the uncertainty associated with the lack of an appropriate inhalation toxicity study.  
4.5	Toxicity Endpoints and Point of Departure Selections

4.5.1	Dose-Response Assessment

Table 4.5.4 summarizes the toxicological doses and endpoints selected for residential dietary/non-dietary and occupational risk assessment.  The rationale for any changes is provided below and the updated endpoints are included in Table 4.5.4.  The updated endpoints are protective of sulfentrazone's developmental toxicity, which was the critical effect in the database and observed via both the oral and dermal routes of exposure.

Acute Dietary Endpoint (Females 13 - 49 years old):  This acute dietary endpoint is based on increased gestation duration, reduced pre-/postnatal litter and pup survival, reduced litter size, increased number of stillborn pups, reduced postnatal survival (pups and litter), and pup body-weight deficits throughout lactation in both generations of offspring observed in the two-generation reproductive toxicity study in rats.  The developmental effects were reported in the presence of mild maternal toxicity (decreased body weight and body-weight gain, particularly in F1 females).  It has been HED's practice to consider various forms of developmental toxicity, such as the such as reduced prenatal viability, reduced litter size, and increased number of stillborn pups as single-dose effects and, therefore, relevant for the acute dietary (females aged 13-49) exposure scenario in order to protect against potential exposure of pregnant females.  It should be noted that the fetal body-weight deficits and retardation in skeletal development (including decreased numbers of caudal vertebral and metacarpal ossification sites) reported in the oral rat prenatal developmental toxicity study were also evaluated for this acute dietary endpoint.  However, it was concluded that such effects are unlikely due to a single-dose effect and are more appropriate for a repeated-exposure scenario.  Furthermore, EPA has not traditionally considered delays in ossification (and related fetal body-weight deficits) to be single-dose effects.  The conventional 100-fold uncertainty factor (10X inter-, and 10X intraspecies) was applied to the NOAEL (14 mg/kg bw/day).  The FQPA SF was reduced to 1X (see Section 4.4).  Thus, the acute reference dose (aRfD) and aPAD are equivalent at 0.14 mg/kg bw/day. 

Acute Dietary Endpoint (General population, including infants and children):  This acute endpoint is based upon increased incidence of clinical signs, FOB findings, and decreased motor activity at the LOAEL of 750 mg/kg bw seen following a single oral administration in the ACN study.  The aRfD and aPAD are equivalent at 2.5 mg/kg bw/day based on the NOAEL of 250 mg/kg/day from the ACN study and a 100-fold uncertainty factor (10X interspecies, 10X intraspecies, 1X FQPA). 

Chronic Dietary Endpoint (All populations):  The chronic dietary endpoint is based on increased gestation duration, reduced pre-/postnatal litter and pup survival, and pup body-weight deficits throughout lactation in both generations of offspring observed at the LOAEL of 33 and 40 mg/kg/day in males and females, respectively in the rat two-generation reproductive toxicity study.  This LOAEL is based on developmental toxicity, the most sensitive endpoint, and is protective of developmental and chronic effects seen in other studies.  The chronic reference dose (cRfD) and cPAD are equivalent at 0.14 mg/kg bw/day based on the NOAEL of 14 mg/kg/day in the two-generation reproductive toxicity study and a 100-fold uncertainty factor (10X interspecies, 10X intraspecies, 1X FQPA). 

Incidental Oral Endpoint (Short- and intermediate-term):  This endpoint is based on offspring toxicity observed in the rat two-generation reproductive toxicity study in the form of reduced pre-/postnatal litter and pup survival, and pup body-weight deficits throughout lactation in both generations of offspring observed at the LOAEL of 33 and 40 mg/kg/day in males and females, respectively (lowest NOAEL = 14 mg/kg/day for males).  The effects seen in the offspring are appropriate for the population (infants and children) and durations (short- and intermediate-term) of concern.  The LOC for incidental oral risk estimates is for MOEs less than 100, which includes the 10X inter- and 10X-intraspecies 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 appropriate since the developmental effects were seen after repeated exposure via the dermal route.  The LOC for occupational and non-occupational dermal risk estimates is for MOEs less than 100, which includes the 10X inter- and 10X intraspecies factors.  The FQPA SF was reduced to 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 following 26 days of inhalation exposure to the test material.  Portal-of-entry effects at this dose were also observed and manifested as an increased incidence of minimal nasal respiratory epithelial hyperplasia in both sexes as well as minimal laryngeal epithelial attenuation in all test material exposure groups.  As described below, human-equivalent concentrations and doses (HECs and HEDs) were calculated based this subchronic inhalation study.  This inhalation study is protective for the systemic effects (including developmental effects seen in the oral studies) for the following reasons:  1) the dose spread in the inhalation study between the NOAEL and LOAEL is large (40 to 600 mg/kg/day) and the effects in the nasal passage likely start a lower dose than the LOAEL; 2) the reference concentration (RfC) methodology calculations include a 15-fold lower regional deposited dose ratio for portal-of-entry effects (0.213) compared to systemic effects (3.129); and 3) the estimated inhalation HEDs are lower or equivalent (depending on the exposure scenario being assessed) than the oral NOAEL from 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 handler.  Portal-of-entry effects were used to generate HECs and are protective for any systemic effects (portal-of-entry HEC = 0.04 mg/L vs. systemic RBC HEC = 0.60 mg/L for occupational, and portal-of-entry HEC = 0.05 mg/L vs. systemic RBC HEC = 0.801 mg/L).  HEDs were subsequently calculated for occupational handler exposure scenarios based upon ventilation rates of 8.3, 16.7, and 29 L/min (2.317, 4.661, and 8.094 mg/kg/day) and residential-handler exposure scenarios based upon a ventilation rate of 16.7 L/min (1.55 mg/kg/day).  For details regarding the calculation of the HECs and HEDs, see Appendix B.  These HEDs are protective of the systemic effects observed through the inhalation route.  This study is thus appropriate for the route and duration of exposure, and as described above in Section 4.3, use of this inhalation study is protective of any potential developmental effects seen in the oral rat developmental study.

The LOC is 30 which includes interspecies (3X) and intraspecies (10X) uncertainty factors.  The interspecies factor was reduced from 10X to 3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies differences.

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

The Agency must consider risks from individual routes of exposure (oral, dermal, and inhalation) and perform combined exposure and risk assessments if a common toxicity endpoint is established across different routes of exposure.  Since developmental effects (fetal body-weight deficits and skeletal effects) were observed in the studies used to select the PODs for the dermal and oral exposure routes, these routes should be combined.  

4.5.3	Cancer Classification and Risk Assessment Recommendation

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

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

Table 4.5.4.1.  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
UFA = 10X
UFH = 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
UFA = 10X
UFH = 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 
UFA = 10X
UFH = 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) and Intermediate-Term (1-6 months) Incidental Oral 
Offspring
NOAEL = 14 mg/kg/day
UFA = 10X
UFH = 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 weights 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
UFA = 10X
UFH = 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-of-entry NOAEL = 0.256 mg/L, HEC = 0.054 mg/L, HED = 1.55 mg/kg/day
UFA =  3X
UFH = 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.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = extrapolation for use of a LOAEL in the absence of a NOAEL.  FQPA SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.

Table 4.5.4.2.  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- (1-6 months), and Long-Term (>6 months) Dermal
NOAEL =
100 mg/kg/day
UFA = 10X
UFH = 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- (1-6 months), and Long-Term (>6 months) Inhalation
Portal-of-entry NOAEL = 0.256 mg/L

HEC = 0.041 mg/L

HED (8.3 L/min) = 2.317 mg/kg/day

HED (16.7 L/min) = 4.661 mg/kg/day

HED (29 L/min) = 8.094 mg/kg/day
UFA = 3X
UFH = 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. 
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.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = extrapolation for use of a LOAEL in the absence of a NOAEL.  FQPA SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.

4.6	Endocrine Disruptor Screening Program

As required by Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals.  Collectively, these studies include acute, subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity.  These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring.  For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups.  As part of its Registration Review decision for sulfentrazone, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database.  However, as required by FFDCA section 408(p), sulfentrazone is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  The EDSP employs a two-tiered approach to making the statutorily required determinations.  Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data.  Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.  Under FFDCA section 408(p), the Agency must screen all pesticide chemicals.  Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  A second list of chemicals identified for EDSP screening was published on June 14, 2013 and includes some pesticides scheduled for registration review and chemicals found in water.  Neither of these lists should be construed as a list of known or likely endocrine disruptors.  For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website.


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

5.1	Metabolite/Degradate Residue Profile

5.1.1	Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants is adequately understood.  Data concerning the metabolism of sulfentrazone following preemergent applications in soybeans and confined rotational crops were submitted in conjunction with the soybean petition (PP#4F04407).  The HED Metabolism Committee determined that 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 support preemergent uses on all types of crops (G. Kramer, 13-MAR-1996; D220548).  Data concerning the metabolism of sulfentrazone following postemergent applications in corn, soybean, and radish were submitted in conjunction with recent petitions (D389972, 5/9/12, G. Kramer).  The metabolism of sulfentrazone following postemergent application was similar to that seen in rotational crops and following preemergent application to soybean; 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 except 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 sulfentrazone carboxylic acid, which is decarboxylated to DMS.  Sulfentrazone per se and its metabolites HMS and DMS were identified as the residues of concern in meat, milk, poultry, and eggs. 

5.1.2	Summary of Environmental Degradation

Sulfentrazone is expected to be persistent under most environmental conditions.  Sulfentrazone half-lives in aerobic soil metabolism, anaerobic aquatic metabolism, and terrestrial field dissipation studies are one year or longer (1.5 years, 9 years, and 1 to 2 years, respectively).  Sulfentrazone is stable towards abiotic hydrolysis.  Direct photolysis in water appears to be the only transformation pathway with observed half-lives of 12 hours at pH 5 and 1 hour at pHs 7 and 9.  Many of the photolytic products are formed by cleavage of the C to N bond between the phenyl and triazolo rings.  Although methyl triazole was the major degradate detected in the aqueous photolysis study, the fate of this degradate in the natural environment is unknown because the field dissipation and the groundwater monitoring studies did not monitor this degradate.  However, photolytic breakdown would be more significant in shallow waters of low turbidity than in deep waters of high turbidity.  The major transformation product observed in soils is the carboxylic acid of sulfentrazone (3-carboxylic acid sulfentrazone).  This degradate, together with parent sulfentrazone, has been detected in groundwater so far in prospective ground-water monitoring studies.  In a variety of soils ranging in texture from sand to silty clay loam, sulfentrazone is very mobile (Kd, 0.2 to 0.8; average Koc 43).  The pKa of sulfentrazone is 6.5 and, therefore, sulfentrazone would be more mobile in neutral to alkaline soils than in acidic soils.  The pKa of the carboxylic acid of sulfentrazone is not known, but it may be comparable to that of parent sulfentrazone and exhibit a similar behavior as the parent in neutral-alkaline soils.  The HED Metabolism Assessment Review Committee (MARC) concluded that parent and 3-carboxylic acid sulfentrazone are the residues of concern for the drinking-water assessment (Memo, G. Kramer et al., 10-APR-2003; D288713).  HED continues to consider the given 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 different 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 desdifluoromethyl sulfentrazone which is oxidized and decarboxylated to form desdifluoromethyl desmethyl sulfentrazone.  (3) Hydrolysis of the sulfonamide group to form desmethylsulfonyl sulfentrazone.  (4) Scission of the phenyl and triazole rings to produce methyl triazole.  The corresponding phenyl metabolites are believed to remain bound.  The metabolism of sulfentrazone in animals (livestock and rats) differs from that in plants as metabolism proceeds only by oxidation of the 3-methyl group to form HMS, followed by further oxidation to form sulfentrazone carboxylic acid which is decarboxylated to DMS.  Sulfentrazone carboxylic acid was also the major transformation product observed in soils.

5.1.4	Residues of Concern Summary and Rationale

The residues of concern in primary crops, rotational crops, livestock, and drinking water, as identified by the MARC, are shown in Table 5.1.4 below.

Table 5.1.4.  Residues of Concern in Crops, Livestock, and Drinking Water.
Matrix
Tolerance Expression
Residues for Risk Assessment
Primary Crops, except soybean seed
sulfentrazone, HMS, DMS
(free and conjugated)
sulfentrazone, HMS, DMS 
(free and conjugated)
Soybean, seed
sulfentrazone, HMS
sulfentrazone, HMS
Rotational Crops
sulfentrazone, HMS, DMS
(free and conjugated)
sulfentrazone, HMS, DMS
(free and conjugated)
Livestock
sulfentrazone, HMS, DMS
sulfentrazone, HMS, DMS
Water
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 of sulfentrazone and its metabolites HMS and DMS in/on several food commodities; these established tolerances range from 0.15 ppm (various plant commodities) to 0.60 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 connection with regional registrations; these include tolerances for residues in/on succulent lima bean, succulent cowpea, and wheat grain at 0.15 ppm.  Finally, tolerances are established under 40 CFR §180.498(d) for inadvertent and indirect combined residues of sulfentrazone and its metabolites HMS and DMS in/on cereal grain (excluding sweet corn) bran, forage, grain, hay, hulls, stover, and straw at 0.1-0.6 ppm as a result of the application of sulfentrazone to growing crops.  Pending uses are for the nongrass animal feeds crop group 18 (PP#1F7838) and apples (PP#3E8202).  Additional residue data and a ruminant feeding study are required for proposed use on nongrass animal feeds (Memo, G. Kramer, D389972, 09-MAY-2012).

The submitted field trial residue data for all registered crops are adequate.  The recently submitted field trial residue data apple are also adequate.  The field trial data reflect the proposed use patterns; an adequate number of trials were conducted in the appropriate geographic regions; and samples were analyzed for the residue of concern using validated data-collection methods.  The storage intervals were also validated.  However, an additional six clover trials are required to support the proposed use on nongrass animal feeds (Memo, G. Kramer, D389972, 09-MAY-2012).

HED previously determined that, based on the established 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-MAY-2012).   

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

5.3	Drinking Water Residue Profile

Drinking water residues provided by EFED (Memo, M. Barrett, 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 estimated drinking water concentrations (EDWCs) were Tier 1 estimates for ground water using the Pesticide Root Zone Model-Ground Water (PRZM-GW) model version 1.07 (Screening Concentration In Ground Water) and surface water using the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) model.  The proposed use on apples carries the maximum single and annual application rates for all currently registered uses (0.375 lb ai/ A).  Previous estimates of sulfentrazone residues in drinking water were done separately for parent 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 drinking water sources.  This revised assessment has now taken a total toxic residues (TTR) approach to assessing exposure, instead of providing values for each compound individually.

For surface water, the highest acute (peak) sulfentrazone 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 value 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 Concentrations of Sulfentrazone and 3-Carboxylic Acid Sulfentrazone in Drinking Water Due to the Use of Sulfentrazone.
                                       
                                   Scenario
                             Surface Water (ug/L)
                              Groundwater (ug/L)

                                     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 dietary (food and drinking water) exposure and risk assessments were conducted using DEEM-FCID, ver. 3.16 which incorporates consumption data from the USDA NHANES/WWEIA; 2003-2008.  The acute and chronic 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 sulfentrazone.  Females 13-49 years old have a lower aPAD than the general population.  As a result, even though the exposure estimate for females 13-49 years old was lower than the estimate for infants <1 year old, females 13-49 years old is the population subgroup with the highest risk estimate (<=7% aPAD).  The highest chronic exposure estimate was for the population subgroup children 1-2 years old, which utilized 7.1% of the cPAD for sulfentrazone.  

--------------------------------------------------------------------------------
Table 5.4.1.  Summary of Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk for Sulfentrazone.[1]
Population Subgroup
                               95[th] Percentile
                               cPAD (mg/kg/day)
                             Exposure (mg/kg/day)
                                     %cPAD

                               aPAD (mg/kg/day)
                             Exposure (mg/kg/day)
                                     %aPAD
                                       
                                       
                                       
General U.S. Population
                                      2.5
                                   0.011114
                                    <1.0
                                     0.14
                                   0.003973
                                      2.8
All Infants (<1 year old)
                                       
                                   0.026754
                                      1.1
                                       
                                   0.008577
                                      6.1
Children 1-2 years old
                                       
                                   0.022692
                                    <1.0
                                       
                                   0.009881
                                      7.1
Children 3-5 years old
                                       
                                   0.017984
                                    <1.0
                                       
                                   0.007889
                                      5.6
Children 6-12 years old
                                       
                                   0.011833
                                    <1.0
                                       
                                   0.004817
                                      3.4
Youth 13-19 years old
                                       
                                   0.008607
                                    <1.0
                                       
                                   0.003225
                                      2.3
Adults 20-49 years old
                                       
                                   0.009187
                                    <1.0
                                       
                                   0.003498
                                      2.5
Adults 50-99 years old
                                       
                                   0.008301
                                    <1.0
                                       
                                   0.003314
                                      2.4
Females 13-49 years old
                                     0.14
                                   0.009363
                                      6.7
                                       
                                   0.003450
                                      2.5
[1]  The populations with the greatest risk and exposure estimates are bolded.


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

The proposed use on apples is not expected to result in residential exposure.  The previous exposure assessment for sulfentrazone assessed the registered residential uses on turfgrass using the 2012 Residential SOPs (Memo, K. Lowe, D389974, 17-MAY-2012) and covers most of the scenarios necessary for Registration Review.  Residential handler and post-application scenarios were assessed at a maximum application rate of 0.375 lb ai/A for liquid, granular, and dry flowable formulations (identified in the 2009 scoping document for sulfentrazone; Memo, K. Lowe et al., D369064, 09-SEP-2009).  There were no residential risk estimates of concern identified.

Updated risk estimate tables have been included in this memo for residential handlers since the inhalation POD and LOC for sulfentrazone has been changed since the previous assessment.  In addition, updated risk estimates have been included for the post-application episodic granular ingestion scenario based on a revised maximum percent active ingredient for granular formulations identified during the label review of registered sulfentrazone labels.     

6.1	Residential Handler Exposure/Risk Estimates

Table 6.1.1 provides a summary of the residential handler exposures and risk estimates for sulfentrazone.  All dermal and inhalation exposure risk estimates for residential handlers are not of concern (i.e., MOEs >= 100 for dermal and MOEs >= 30 for inhalation) at baseline for all scenarios.  


Table 6.1.1.  Residential Handler 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 ai/A
                                     0.5 A
                                     0.036
                                     2,700
                                   0.000052
                                    30,000
                                   Backpack
                                       
                                      69
                                      1.1
                              0.019 lb ai/gallon
                                   5 gallons
                                     0.095
                                     1,100
                                    0.0013
                                     1,200
                                 Sprinkler can
                                       
                                     13.4
                                     0.022
                             0.000008 lb ai/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/residential-exposure-sop.html).
[3]  Dermal Dose = Dermal Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x 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) x Application Rate (lb ai/acre or gal) x 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).


6.2	Residential Post-application Exposure/Risk Estimates

Table 6.2.1 provides a summary of the residential post-application exposures and risk estimates for sulfentrazone.  All risk estimates for post-application exposure are not of concern (i.e., MOEs >= 100); all MOEs were >= 610 for adults and >= 360 for children.  

Table 6.2.1.  Short-Term Residential Post-application Exposure and Risk Estimates for Sulfentrazone.
                                   Lifestage
                      Post-application Exposure Scenario
                              Dose (mg/kg/day)[1]
                                    MOEs[2]
                                 Combined MOEs
                              Liquid formulation
                                     Adult
                                     Turf
                                       
                              Liquid formulation
                                       
                                       
                                 0.375 lb ai/A
                                    Dermal
                          Physical Activities on Turf
                                     0.16
                                      610
                                      N/A
                                       
                                       
                                       
                                    Mowing
                                    0.0033
                                    30,000
                                       
                                       
                                       
                                       
                                    Golfing
                                     0.013
                                     7,800
                                       
                         Child 11 to < 16 years old
                                       
                                    Dermal
                                    Mowing
                                    0.0033
                                    30,000
                                       
                                       
                                       
                                       
                                    Golfing
                                     0.013
                                     7,800
                                       
                         Child 6 to < 11 years old
                                       
                                    Dermal
                                    Golfing
                                     0.015
                                     6,600
                                       
                           Child 1 to< 2 year old
                                       
                                    Dermal
                          Physical Activities on Turf
                                     0.28
                                      360
                                      310
                                       
                                       
                                 Hand to Mouth
                                    0.0057
                                     2,500
                                       
                                       
                                       
                                Object to Mouth
                                    0.00017
                                    81,000
                                      N/A
                                       
                                       
            Short- and Intermediate-term Incidental Soil Ingestion
                                 1.3 x 10[-5]
                                   1,100,000
                                       
                             Granular formulation
                                     Adult
                                     Turf
                                       
                             Granular formulation
                                       
                                       
                                 0.375 lb ai/A
                                    Dermal
                          Physical Activities on Turf
                                     0.036
                                     2,800
                                      N/A
                                       
                                       
                                       
                                    Mowing
                                    0.00066
                                    150,000
                                       
                                       
                                       
                                       
                                    Golfing
                                    0.0026
                                    39,000
                                       
                         Child 11 to < 16 years old
                                       
                                    Dermal
                                    Mowing
                                    0.00066
                                    150,000
                                       
                                       
                                       
                                       
                                    Golfing
                                    0.0026
                                    39,000
                                       
                         Child 6 to < 11 years old
                                       
                                    Dermal
                                    Golfing
                                    0.0030
                                    33,000
                                       
                          Child 1 to < 2 year old
                                       
                                    Dermal
                          Physical Activities on Turf
                                     0.061
                                     1,600
                                     1,500
                                       
                                       
                                 Hand to Mouth
                                    0.00057
                                    25,000
                                       
                                       
                                       
                                Object to Mouth
                                   0.000035
                                    400,000
                                      N/A
                                       
                                       
            Short- and Intermediate-term Incidental Soil Ingestion
                                 1.3 x 10[-5]
                                   1,100,000
                                       
                                       
                                    0.4% ai
                          Episodic Granular Ingestion
                                     0.11
                                      130
                                       
[1]  Dose (mg/kg/day) equations provided in Appendix B.
[2]  MOE = POD (dermal = 100 mg/kg/day and incidental oral = 14 mg/kg/day) / Dose (mg/kg/day).  LOC = 100.

6.3	Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate assessment for sulfentrazone.
   * The recommended residential exposure for use in the adult short-term aggregate assessment reflects dermal exposure from applications to turf via backpack sprayer.
   * The recommended residential exposure for use in the children 1 < 2 years old short-term aggregate assessment reflects dermal and hand-to-mouth exposures from post-application exposure to turf applications.

Table 6.3.1.  Recommendations for the Residential Exposures for the Sulfentrazone Aggregate Assessment.
                                   Lifestage
                               Exposure Scenario
                              Dose (mg/kg/day)[1]
                                    MOE[2]
                                       
                                       
                                    Dermal
                                 Inhalation[3]
                                     Oral
                                     Total
                                    Dermal
                                 Inhalation[3]
                                     Oral
                                     Total
                                  Short-term
                                     Adult
                                     Male
                     Handler  -  MLA liquids via backpack
                                     0.18
                                      N/A
                                      N/A
                                     0.18
                                      560
                                      N/A
                                      N/A
                                      560
                          Child 11 < 16 years old
         Post-application exposure from golfing (liquid formulation) 
                                     0.013
                                      N/A
                                      N/A
                                     0.013
                                     7,800
                                      N/A
                                      N/A
                                     7,800
                           Child 6 < 11 years old
         Post-application exposure from golfing (liquid formulation) 
                                     0.015
                                      N/A
                                      N/A
                                     0.015
                                     6,600
                                      N/A
                                      N/A
                                     6,600
                            Child 1 < 2 year old
    Post-application exposure from activities on turf (liquid formulation) 
                                     0.28
                                      N/A
                                    0.0057
                                     0.28
                                      360
                                      N/A
                                     2,500
                                      310
[1]  Dose = the highest dose for each applicable lifestage of all residential scenarios assessed.  Total = dermal + incidental oral (where applicable).
[2]  MOE = the MOEs associated with the highest residential doses.  
[3]  Inhalation risk estimates were not combined with dermal or oral risk estimates in this assessment since the toxicological effects in the inhalation toxicological study were portal-of-entry and different from those seen in the dermal and oral toxicological studies.

6.4	Spray Drift

Off-target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors.  Sprays that are released and do not deposit in the application area end up off-target and can lead to exposures to those it may directly contact.  They can also deposit on surfaces where contact with residues can eventually lead to exposures (e.g., children playing on lawns where residues have deposited next to treated fields).  The potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating 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 labels for use on turf, thus it was considered whether the risk assessment for turf may be considered protective of any type of exposure resulting from spray drift.  If the maximum application rate on crops adjusted by the amount of drift expected is less than or equal to existing turf application rates, the existing turf assessment is considered protective of spray drift exposure.  The proposed maximum single application rate of sulfentrazone for several registered agricultural crops is 0.375 lb ai/A.  The highest fraction of spray drift noted for any application method immediately adjacent to a treated field results in a deposition fraction of 0.26 of the application rate.  A quantitative spray drift assessment for sulfentrazone is not required because the maximum application rate for a crop/target site multiplied by the adjustment factor for drift of 0.26 is less than the maximum direct spray residential turf application rate (0.375 lb ai/A) for any sulfentrazone products.  The turf post-application MOEs are protective for any potential exposures related to spray drift for sulfentrazone and have previously been discussed in Section 5.2.  

6.5	Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for sulfentrazone at this time primarily because of the low acute inhalation toxicity (Toxicity Category III) and the low vapor pressure (8 x 10[-10] mm Hg).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for sulfentrazone.

7.0	Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  

7.1	Acute Aggregate Risk

Acute aggregate risk results from exposure to residues in food and drinking water alone.  The acute dietary exposure analysis included both food and drinking water.  Therefore, acute aggregate risk is equivalent to the acute dietary risk, as discussed in 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 takes into account short- and intermediate-term residential exposure plus chronic exposure to food and water (considered to be a background exposure level).  Sulfentrazone is currently registered for uses that could result in short- and intermediate-term residential exposure, and RAB1 has determined that it is appropriate to aggregate chronic exposure through food and water with short- and intermediate- term residential exposures to sulfentrazone.  For short- and intermediate-term exposures, incidental oral and dermal exposure risk assessments are appropriate to aggregate due to similarities in the toxicity endpoints observed between the oral and dermal routes.  The short- and intermediate-term incidental oral and dermal exposures are combined with chronic dietary (food and water) exposure for determination of aggregate short- and intermediate-term exposures.  HED uses chronic dietary exposure when conducting short- and intermediate-term aggregate assessments as they have determined that these will more accurately reflect exposure from food over the HED defined short- and intermediate-term interval than will acute exposure. 

Adults may potentially be exposed to sulfentrazone through dermal, inhalation, 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 exposure scenario with the greatest risk estimate; therefore, the exposure estimates for 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 and dietary (food and drinking water) exposures; therefore, it was appropriate to aggregate these exposures for the short- and intermediate-term duration.  Children 1-2 years old represent the population subgroup for children with the greatest exposure; therefore, the exposure estimates for children 1-2 years old are protective of other children population subgroups.  The LOC is 100; therefore MOEs <100 are risk estimates of concern.  

Tables 7.2.1 and 7.2.2 summarize the short- and intermediate-term aggregate exposures and risk estimates for 1-2 year olds and adults.  The aggregate short- and intermediate-term MOEs are >100 for adults and children; therefore, aggregate exposures to sulfentrazone are not of concern to HED.

Table 7.2.1.  Short- and Intermediate-term Aggregate Risk Calculations for Children 1-2 Years Old.
                                  Population
                                      LOC
                Background Dietary + Incidental Oral Exposures
                             Residential Exposures
                Aggregate MOE (food, water, and residential)[4]
                                       
                                       
                  Chronic Food and Water Exposure (mg/kg/day)
                    Incidental Oral Exposure (mg/kg/day)[1]
                                  Oral MOE[2]
                          Dermal Exposure (mg/kg/day)
                                 Dermal MOE[3]
                                       
                            Children 1-2 years old
                                      100
                                   0.009881
                                    0.0057
                                      900
                                     0.28
                                      360
                                      260
[1]  Short-term 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 Aggregate Risk Calculations for Adults.
                                  Population
                              Dietary Exposure[1]
                        Dermal Residential Exposure[2]
                Aggregate MOE (food, water, and residential)[3]
                                       
                  Chronic Food and Water Exposure (mg/kg/day)
                                      MOE
                          Dermal Exposure (mg/kg/day)
                                      MOE

                            General U.S. Population
                                   0.003973
                                     3500
                                     0.18
                                      560
                                      480
[1]  MOE dietary = [(short- or intermediate-term oral NOAEL = 14 mg/kg/day)/(chronic dietary exposure)].  
[2]  MOE dermal = [(short- or intermediate-term dermal NOAEL = 100 mg/kg/day)/(high-end dermal residential exposure)].  
[3]  Aggregate MOE = 1/[(1/dietary MOE) + (1/dermal MOE) + (1/inhalation MOE)].

7.3	Chronic Aggregate Risk

The chronic aggregate risk assessment results from long-term exposure to residues in food and drinking water, as there are no residential scenarios that result in long-term exposure.  The chronic dietary exposure analysis included both food and drinking water and, therefore, the chronic aggregate risk assessment is equivalent to the chronic dietary risk assessment discussed in Section 5.4, above.  All risk estimates are not of concern.   

7.4	Cancer Aggregate Risk

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

8.0	Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to sulfentrazone and any other substances 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 the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.


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

9.1	Handler Risk Assessment

The occupational handler exposure and risk estimates indicate that the short- and intermediate-term dermal and inhalation MOEs are not of concern to HED (i.e., MOEs >100 for dermal and MOEs >30 for inhalation), as long as gloves are worn for the highest application rate for mixing/loading liquids and dry flowables for aerial application to high-acreage crops.

HED has no data to assess exposures to pilots using open cockpits.  The only data available is for exposure to pilots in enclosed cockpits.  Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, and socks); per the Agency's Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application.  With this level of protection, there are no risk estimates of concern for applicators.

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential.  While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades.  According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of Global Positioning System (GPS) for swath guidance in agricultural aviation has grown steadily from the mid-1990s.  Over the same time period, the use of human flaggers for aerial pesticide applications has decreased 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 and characterize the exposure potential for human flaggers in agricultural aerial applications.

Table 9.1.1.  Occupational Handler Non-Cancer Exposure and Risk Estimates for Sulfentrazone.  
                               Exposure Scenario
                                Crop or Target
                             Dermal Unit Exposure 
                                (μg/lb ai)[1]
                           Inhalation Unit Exposure 
                                (μg/lb ai)[1]
                     Maximum Application Rate (lb ai/A)[2]
                            Area Treated (acres)[3]
                                    Dermal
                                  (LOC = 100)
                                  Inhalation
                                  (LOC = 100)
                                       
                                       
            Mitigation Level = baseline unless indicated otherwise
            Mitigation Level = baseline unless indicated otherwise
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                 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
                                     1,800
                                       
                                      Sod
                                       
                                       
                                       
                                      350
                                     0.432
                                      230
                                    0.0148
                                      310
                                       
                        Field crop, typical acreage[8] 
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                          Field crop, high-acreage[9]
                                       
                                       
                                       
                                     1,200
                                     1.48
                              0.336 (SL w/gloves)
                                      68
                               300 (SL w/gloves)
                                    0.0504
                                      92
                                       
                                       
                                       
                                       
                                     0.25
                                       
                                     0.987
                                      100
                                    0.0336
                                      140
                                       
                                       
                                       
                                       
                                     0.19
                                       
                                     0.751
                                      130
                                    0.0255
                                      180
                                       
                                       
                                       
                                       
                                     0.16
                                       
                                     0.632
                                      160
                                    0.0215
                                      220
                    Chemigation application of dry flowable
                                      Sod
                                     227 
                                     8.96
                                     0.375
                                      350
                                     0.432
                                      230
                                    0.0148
                                      310
                                       
                   Field crop, typical and high-acreage[8,9]
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                      60
                                    0.0741
                                     1,300
                                    0.00253
                                     1,800
                   Groundboom application of a dry flowable
                     Golf course (fairways, tees, greens)
                                     227 
                                     8.96
                                     0.375
                                      40
                                    0.0494
                                     2,000
                                    0.00168
                                     2,800
                                       
                         Field-grown ornamental crops
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                      60
                                    0.0741
                                     1,300
                                    0.00253
                                     1,800
                                       
                                      Sod
                                       
                                       
                                       
                                      80
                                    0.0987
                                     1,000
                                    0.00336
                                     1,400
                                       
                        Field crop, typical acreage[8]
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                          Field crop, high-acreage[9]
                                       
                                       
                                       
                                      200
                                     0.246
                                      410
                                    0.0084
                                      550
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
                                      750
   On-farm Impregnation of Dry Flowable  Formulation on Dry Bulk Fertilizers
                                     227 
                                     8.96
                                     0.375
                                      160
                                     0.246
                                      410
                                    0.0084
                                      550
       Loading/applying granular for tractor-drawn spreader application
                     Golf course (fairways, tees, greens)
                                      8.4
                                      1.7
                                     0.375
                                      40
                                    0.00183
                                    55,000
                                   0.000319
                                    25,000
                                       
                                     Sod 
                                       
                                       
                                       
                                      80
                                    0.00365
                                    27,000
                                   0.000638
                                    13,000
                                       
                             Christmas tree farms
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                      60
                                    0.00274
                                    36,000
                                   0.000479
                                    17,000
                   Aerial application of liquid formulation
           Nursery (ornamentals, vegetables, trees, container stock)
                                     220 
                                       
                              37.6 (SL w/gloves)
                                    0.219 
                                     0.375
                                      60
                                    0.0717
                                     1,400
                                   0.0000616
                                    76,000
                                       
                                      Sod
                                       
                                       
                                       
                                      350
                                     0.419
                                      240
                                   0.000359
                                    13,000
                                       
                        Field crop, typical acreage[8] 
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                         Field crop, high-acreage[9] 
                                       
                                       
                                       
                                     1200
                                     1.43 
                                       
                              0.245 (SL w/gloves)
                                      70 
                                       
                               410 (SL w/gloves)
                                    0.00123
                                     3,800
                                       
                                       
                                       
                                       
                                     0.25
                                       
                                     0.957
                                      100
                                   0.000821
                                     5,700
                                       
                                       
                                       
                                       
                                     0.19
                                       
                                     0.728
                                      140
                                   0.000624
                                     7,500
                Chemigation application of a liquid formulation
                                      Sod
                                      220
                                    0.219 
                                     0.375
                                      350
                                     0.419
                                      240
                                   0.000359
                                    13,000
                                       
                   Field crop, typical and high-acreage[8,9]
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                      60
                                    0.0717
                                     1,400
                                   0.0000616
                                    76,000
                 Groundboom application of liquid formulation
                     Golf course (fairways, tees, greens)
                                      220
                                    0.219 
                                     0.375
                                      40
                                    0.0478
                                     2,100
                                   0.0000411
                                    110,000
                                       
                         Field-grown ornamental crops
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                      60
                                    0.0717
                                     1,400
                                   0.0000616
                                    76,000
                                       
                                      Sod
                                       
                                       
                                       
                                      80
                                    0.0957
                                     1,000
                                   0.0000821
                                    57,000
                                       
                        Field crop, typical acreage[8] 
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                          Field crop, high-acreage[9]
                                       
                                       
                                       
                                      200
                                     0.239
                                      420
                                   0.000205
                                    23,000
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
                                     2,200
      On-farm Impregnation of Liquid Formulation on Dry Bulk Fertilizers
                                     220 
                                    0.219 
                                    0.375 
                                      160
                                     0.191
                                      520
                                   0.000164
                                    28,000
                                  Applicator
                           Aerial spray application
           Nursery (ornamentals, vegetables, trees, container stock)
                                     2.08
                             (engineering control)
                                    0.0049
                             (engineering control)
                                     0.375
                                      60
                                   0.000678
                                    150,000
                                  0.00000138
                                   5,900,000
                                       
                                      Sod
                                       
                                       
                                       
                                      350
                                    0.00396
                                    25,000
                                  0.00000804
                                   1,000,000
                                       
                        Field crop, typical acreage[8]
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                          Field crop, high-acreage[9]
                                       
                                       
                                       
                                     1200
                                    0.0136
                                     7,400
                                   0.0000276
                                    290,000
                         Groundboom spray application
                     Golf course (fairways, tees, greens)
                                     78.6
                                     0.34
                                     0.375
                                      40
                                    0.0171
                                     5,800
                                   0.0000638
                                    36,000
                                       
                         Field-grown ornamental crops
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                      60
                                    0.0257
                                     3,900
                                   0.0000956
                                    24,000
                                       
                                      Sod
                                       
                                       
                                       
                                      80
                                    0.0342
                                     2,900
                                   0.000128
                                    18,000
                                       
                        Field crop, typical acreage[8]
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                          Field crop, high-acreage[9]
                                       
                                       
                                       
                                      200
                                    0.0855
                                     1,200
                                   0.000319
                                     7,300
                       Mechanically-pressurized handgun
              Rights-of-way (e.g., utilities, railroad, roadways)
                                     1,300
                                      3.9
                              0.019 lb ai/gallon
                                 1000 gallons
                                     0.358
                                      280
                                   0.000926
                                     8,700
                 Tractor-drawn Spreader granular application 
                     Golf course (fairways, tees, greens)
                                      9.9
                                      1.2
                                     0.375
                                      40
                                    0.00216
                                    46,000
                                   0.000225
                                    36,000
                                       
                                     Sod 
                                       
                                       
                                       
                                      80
                                    0.0043
                                    23,000
                                    0.00045
                                    18,000
                                       
Christmas tree farms
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                      60
                                    0.00323
                                    31,000
                                   0.000338
                                    24,000
                                    Flagger
                     Flagger for aerial spray application
           Nursery (ornamentals, vegetables, trees, container stock)
                                      11
                                     0.35
                                     0.375
                                      60
                                    0.00359
                                    28,000
                                   0.0000985
                                    82,000
                                       
                                      Sod
                                       
                                       
                                       
                                      350
                                    0.0209
                                     4,800
                                   0.000574
                                    14,000
                                       
                  Field crop, typical and high-acreage[9,10]
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                            Mixer/Loader/Applicator
                          Dry Flowables via Backpack
Railroad, Highway, Roadside, Pipeline and Utility Rights of-Way, Industrial Areas,
Fence Rows, and Other listed Non-crop Sites
                                     8,260
                                     2.58
                              0.019 lb ai/gallon
                                  40 gallons
                                     0.091
                                     1,100
                                   0.0000245
                                    190,000
                                       
            Landscaping, turf (lawns, athletic fields, parks, etc.)
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                Dry Flowables via Manually-Pressurized Handwand
            Landscaping, turf (lawns, athletic fields, parks, etc.)
                                    100,000
                                      30
                              0.019 lb ai/gallon
                                  40 gallons
                                      1.1
                             0.00474 (SL w/gloves)
                                      91
                             21,000 (SL w/gloves)
                                   0.000285
                                    28,000
              Dry Flowables via Mechanically-pressurized Handgun
                     Golf course (fairways, tees, greens)
                                     1,960
                                      42
                                     0.375
                                       5
                                    0.0533
                                     1,900
                                   0.000985
                                     4,700
                                       
            Landscaping, turf (lawns, athletic fields, parks, etc.)
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                             Liquids via Backpack
                              Christmas Tree farm
                                     8,260
                                     2.58
                              0.0375 lb ai/gallon
                                  40 gallons
                                     0.18
                                      560
                                   0.0000484
                                    96,000
                                       
Railroad, Highway, Roadside, Pipeline and Utility Rights of-Way, Industrial Areas,
Fence Rows, and Other listed Non-crop Sites
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
            Landscaping, turf (lawns, athletic fields, parks, etc.)
                                       
                                       
                              0.019 lb ai/gallon
                                       
                                     0.091
                                     1,100
                                   0.0000245
                                    190,000
                   Liquids via Manually-pressurized Handwand
            Landscaping, turf (lawns, athletic fields, parks, etc.)
                                    100,000
                                      30
                              0.019 lb ai/gallon
                                  40 gallons
                                      1.1
                             0.00474 (SL w/gloves)
                                      91
                             21,000 (SL w/gloves)
                                   0.000285
                                    28,000
                 Liquids via Mechanically-pressurized Handgun
                     Golf course (fairways, tees, greens)
                                     1,140
                                      1.9
                                     0.375
                                       5
                                     0.031
                                     3,200
                                   0.0000445
                                    100,000
                                       
            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
                                     4,400
                            Granulars via Backpack
                              Christmas Tree farm
                                      15
                                     23.8
                                     0.375
                                       5
                                   0.000407
                                    250,000
                                   0.000112
                                    42,000
                                       
           Nursery (ornamentals, vegetables, trees, container stock)
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                      Water Soluble Packets via Backpack
                         Residential/ Commercial Turf
                                     8,260
                                     2.58
                              0.0033 lb ai/gallon
                                  40 gallons
                                    0.0158
                                     13000
                                  0.00000426
                                   1,100,000
            Water Soluble Packets via Manually-Pressurized Handwand
                                       
                                    100,000
                                      30
                                       
                                       
                                     0.191
                                    140000
                                   0.0000495
                                    160,000
          Water Soluble Packets via Mechanically-Pressurized Handgun
                                       
                                     1,350
                                      18
                                 0.287 lb ai/A
                                       5
                                    0.0281
                                     11000
                                   0.000323
                                    14,000
[1]  Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2013); Level of mitigation:  Baseline, Eng. Controls.
[2]  Based on registered and proposed labels.
[3]  Exposure Science Advisory Council Policy #9.1 and Registrant information.
[4]  Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x 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 (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated (A/day) / BW (80 kg).
[7]  Inhalation MOE = Inhalation NOAEL (2.317, 4.661, or 8.094 mg/kg/day) / Inhalation Dose (mg/kg/day).
[8]  Field crops, typical acreage category covers the following crops:  apples, asparagus, Brassica head and stem, Brassica leafy greens, cabbage, citrus fruits, tree nuts, grapes and berries, edamame, fallow cropping systems, flax, fruiting vegetables, okra, horseradish, lima beans, melons, rhubarb, strawberry, succulent peas, tobacco, turnips, Christmas tree farms (where applicable).
[9]  Field crops, high-acreage crops category covers the following crops: corn, dry shelled peas and beans, mint, peanuts, peppermint, spearmint, potato, soybeans, sugarcane, sunflower, wheat.  

9.2	Post-Application Risk Assessment

9.2.1	Inhalation Post-Application Risk Assessment

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for sulfentrazone at this time primarily because of the low acute inhalation toxicity (Toxicity Category III) and the low vapor pressure (8 x 10[-10] mm Hg).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for sulfentrazone.

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

9.2.2	Dermal Post-Application Risk Assessment

Most of the registered uses and the proposed use on apples are soil-directed preplant or preemergent uses where no crop foliage is present.  Currently, HED has no transfer coefficients or other data to assess post-application dermal exposures to soil by occupational workers.  In general, such exposures are considered to be negligible.  Therefore, for the soil-directed uses, post-application exposures and risks to occupational workers were not assessed. 

The registered uses on turf (golf courses and sod farms) and ornamentals are not specifically soil directed and, therefore, could result in potential post-application exposures.  The short- and intermediate-term post-application exposure scenarios associated with the registered uses of sulfentrazone are summarized in Table 9.2.2.2.  All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 430 to 8,200) on day 0 (12 hours after application) and, therefore, are not of concern to HED.

Table 9.2.2.2.  Occupational Post-application Non-Cancer 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 x F x (1-D)[t] x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day.  
[2]  Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 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 based on the acute toxicity of sulfentrazone.  Sulfentrazone is classified as acute Toxicity Category III for acute oral, acute dermal, and acute inhalation toxicity.  It is classified as Toxicity Category III for eye irritation potential and category IV for skin irritation potential.  It is not a dermal sensitizer.  Short- and intermediate-term post-application risk estimates were not a concern on day 0 (12 hours following application) for all post-application activities.  Under 40 CFR 156.208 (c) (2) (iii), ais classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to sulfentrazone.  

10.0	References
      
Recent RA 
J. Van Alstine, et al., 14-JUN-2012; D389082

Scoping Document
K. Lowe, et al., 09-SEP-2009; D369064

HASPOC Memo
D. Smegal, 02-MAR-2012; TXR # 0050684; and
Re-Classification of Peer-Reviewed Developmental Neurotoxicity Study in Rats:  C. Rodriguez, 19-DEC-2011; D389975.

ORE Memo
K. Lowe, D417171; 05-JUN-2014

Dietary Memo
G. Kramer, D417172; 05-JUN-2014

cc:  G. Kramer (RAB1)
RDI:  RAB1 (5/14/14)
 G.F. Kramer:S10957:PY-S:(703)305-5079:7509P:RAB1

Appendix A.  Toxicology Profile and Executive Summaries

The requirements (40 CFR 158.340) for food uses for sulfentrazone are in Table A.1.  Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1.  Toxicological Data Requirements for Sulfentrazone.
                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Primary Eye Irritation	
870.2500    Primary Dermal Irritation	
870.2600    Dermal Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)	
870.3150    Oral Subchronic (nonrodent)	
870.3200    28-Day Dermal	
870.3465    28-Day Inhalation	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3700a  Developmental Toxicity (rodent)	
870.3700a  Dermal Developmental Toxicity (rodent)	
870.3700b  Developmental Toxicity (nonrodent)	
870.3800    Reproduction	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Oncogenicity (rat)	
870.4200b  Oncogenicity (mouse)	
870.4300    Chronic/Oncogenicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial	
870.5300    Mutagenicity -- Gene Mutation - mammalian	
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations	
870.5xxx    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)	
870.6100b  90-Day Neurotoxicity (hen)	
870.6200a  ACN Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Develop. Neurotoxicity	
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                      --
                                      --
                                      yes
                                      yes
                                      --
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      no
                                      yes
                                      yes
                                      --
                                      yes

Table A.2.  Acute Toxicity Profile  -  Sulfentrazone.
                                 Guideline No.
                                  Study Type
                                    MRID(s)
                                    Results
                               Toxicity Category
                                   870.1100
                               Acute oral [rat]
                                   41911605
                         LD50 = 2855 (M & F) mg/kg
                                      III
                                   870.1200
                              Acute dermal [mice]
                                   41911606
                         LD50 = 711 (M & F) mg/kg
                                      III
                                   870.1200
                                 Acute dermal
                                   42286400
                            LD50 >2000 mg/kg/day
                                      III
                                   870.1300
                            Acute inhalation [rat]
                                   42471002
                4-hour, whole body exposure; LC50 >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/A

Table A.3.  Toxicity Profile 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, and severity of splenic micropathology (increased incidence and severity of extramedullary hematopoiesis).  Four-week recovery period reversed all the treatment related effects except extramedullary hematopoiesis; however, severity was reduced.
870.3150
90-Day oral toxicity (dog)
42932102 (1992)
Acceptable/Guideline
0, 300, 800 & 2000 ppm
M/F:  0/0, 10/10, 28/28, & 57/73
mg/kg/day
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 and spleen (pigmented sinusoidal microphages in the liver, swollen centrilobular hepatocytes and pigmented reticuloendothelial cells in the spleen).
870.3200
28-Day dermal toxicity (rabbit)
44248301 (1996)
Acceptable/Guideline
0, 10, 30, 100, 300, & 1000 mg/kg/day
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 and 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 Developmental-Toxicity Study in Rats (MRID 42932104).
870.3700
Prenatal dermal developmental (rat)
MRID 42932105 (1992)
Acceptable/Guideline
0, 5, 25, 50, 100, & 250 mg/kg/day
Maternal NOAEL >250 mg/kg/day.
Maternal LOAEL was not established.
Developmental NOAEL = 100 mg/kg/day.
Developmental LOAEL = 250 mg/kg/day, based on decreased fetal body weight; increased incidence of fetal variations: hypoplastic or wavy ribs, incompletely ossified lumbar vertebral arches, and incompletely ossified ischia or pubis; and reduced number of thoracic vertebral and rib 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, decreased 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 & F1) and reduced premating body-weight gain in second-generation (F1) 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 F1 males.
Offspring Toxicity NOAEL = 14 (M) and 16 (F) mg/kg/day.
Offspring Toxicity LOAEL = 33 (M) and 40 (F) mg/kg/day, based on reduced prenatal viability (fetal & litter), reduced litter size, increased no. of stillborn pups, reduced pup and litter postnatal survival and decreased pup body weights throughout lactation.
870.3800
One-Generation reproduction and fertility effects (rat)
43869101(1995)
Acceptable/Nonguideline
0, 50, 100, 200, & 500 ppm
F0 M/F:  0, 3.9/4.1, 7.8/13.4, 16/16, & 40/43 mg/kg/day
F1 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, (F1 females), based on decrease in pre-mating body-weight gain (10%).
Offspring and Reproductive Toxicity NOAEL = 16
mg/kg/day (M/F) mg/kg/day.
Offspring and Reproductive Toxicity LOAEL F1 = 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 presence or in absence of S9 activation.  The positive controls induced the expected mutagenic responses in the appropriate tester strain.  Sulfentrazone was considered not mutagenic under any test condition.
870.5300
In vitro mammalian cell gene mutation assay (mouse lymphoma)
43004604 (1992)
Acceptable/Guideline
Mouse lymphoma (L5178Y TK[+/-] CHO) cells were exposed to sulfentrazone technical (94.2%) in non-activated dose ranges of 424-1308 ug/mL (Trial 1) and 1308-3000 ug/mL (Trial 2); With S9 activation dose ranges of 424-1407 ug/mL (Trial 1) and 915-1800 ug/mL (Trial 2).
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 presence 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 evidence of a cytotoxic effect on the target organ and no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow cells.
870.5450
Dominant lethal
assay - rodent
44248302 (1996)
Acceptable/Guideline
In dominant lethal assay, male rats were dosed at 0, 100, 225, or 450 mg/kg/day for 5 days, and mated to untreated females sequentially for 10 weeks to determine the level of fetal deaths due to dominant lethal mutations.
There were no significant differences from 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.) was administered to Sprague-Dawley rats (five 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-day pretreatment with non-radioactive sulfentrazone (50 mg/kg/day).
Sulfentrazone was readily absorbed and 84 to 104% of the administered dose was excreted in urine and feces within 72 hours.  There were no major sex differences in the pattern of excretion.  Almost all the radioactivity in the urine was HMS (84-104% of the administered dose).  In the feces, HMS accounted for 1.26-2.55% of the administered dose.  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 in dams) during gestation.  The results of this non-guideline study were published in the open literature.  Due to limitations in study conduct and reporting of the statistical analysis, the study is of limited value in risk assessment.  


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 physicochemical 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 (1994), the methodology for RfCs derivation is an estimate of the quantitative dose-response assessment of chronic non-cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species-specific relationships of exposure concentration to deposited/delivered dose.  This adjustment is influenced by the physicochemical properties of the inhaled compound as well as the type of toxicity observed (e.g., systemic vs. portal-of-entry), and takes into consideration the PK differences between animals and humans.  Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation exposures (e.g., acute and short-term exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition that can be applied to shorter duration of exposures provided the assumptions underlying the methodology are still valid.  These assumptions, in turn, vary depending on the type of toxicity observed.  Thus the derivation of a HEC for inhaled gases is described by the following equation:

Where:
PODstudy:  Point of departure identified in the critical toxicology study
Danimal exposure:  Duration of animal exposure (hrs/day; days/wk)
Danticipated exposure:  Anticipated human duration of exposure (hrs/day; days/wk)
RGDR:  Regional Gas Dose Ratio

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR).  Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is then used to determine the RDDR.  The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the rth region or target tissue.

	RDDRr = (RDDr/Normalizing Factor)A
		     (RDDr/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 σg defined from an aerosol inhalation study.  The values for the species-specific parameters used to calculate the RDDR are provided in the EPA document "Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry."


Regional Deposited Dose Ratio (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 fractionanimal/deposited fractionhuman
	= (171.5/15)animal/(13800/200)human * 0.439/0.341
	= 0.213

The magnitude of the UFs applied is dependent on the methodology used to calculate risk.  The RfC methodology takes into consideration the PK differences but not the PD differences.  Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X.  Thus, the UF when using the RfC methodology is customarily 30X.

B.1.  HEC Calculations for Short- and Intermediate-term Residential Exposure:

Assume residents will be exposed for 24 hrs/day and 7 days/week:
   
HEC = NOAELstudy * (daily duration of exposureanimal/daily duration of exposurehuman) * (days/week of exposureanimal/days/week of exposurehuman) * RDDR
            
Residential Handler Outdoor HEC = 0.256 mg/L * 0.213 = 0.054 mg/L
Residential Handler Outdoor HEC = 0.256 mg/L * (5/7) * 0.213 = 0.038 mg/L
Indoor Postapp. Handler Outdoor HEC = 0.256 mg/L * (6/18) * (5/7) * 0.213 = 0.0129 mg/L
Bystander HEC = 0.256 mg/L * (6/24) * (5/7) * 0.213 = 0.00974 mg/L

Table B.1.  HEC Array for Residential Risk Assessment.
                                Relevant Study
                                     LOAEL
                                    (mg/L)
                                     NOAEL
                                    (mg/L)
                                      Da
                                      Dh
                                      Wa
                                      Wh
                                     RDDR
                                  HEC (mg/L)
                                     inter
                                     intra
                                      UF
                    Short-& Intermediate-Term Exposure
                              Inhalation  -  Rat
                            (MRID 49253902) 26-day
                                      ET
                                     1.71
                                     0.256
                       See equations listed above table
                                       
                                     0.213
                     Handler/Outdoor Postapp.- 0.054 mg/L
                                       3
                                      10
                                      NA
                                       
                                       
                                       
                                       
                                       
                                       
                          Indoor Posapp.- 0.038 mg/L
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
              Indoor Postapp. (Adults and Children)- 0.0013 mg/L
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                            Bystander- 0.00974 mg/L
                                       
                                       
                                       
Long-Term Exposure:  Not appropriate for sulfentrazone.

Key for Array Tables
LOAEL: Lowest-observed adverse-effect level
NOAEL: No-observed adverse-effect level
Da: Daily animal exposure (hrs/day)
Dh: Anticipated daily human exposure (hrs/day)
Wa: Weekly animal exposure (days/week)
Wh: Anticipated weekly human exposure (days/week)
RRDR: Regional Deposited Dose Ratio
HEC: Human-Equivalent Concentration
inter: Interspecies extrapolation UF 
intra: Intraspecies variation UF
UF: Other UF(s)	
ET: Extra-thoracic region

Route-to-Route Extrapolation

More information and details in:  Memo, "Route-to-Route Extrapolations" J. Whalen and H. Pettigrew, 10/10/98.

HED's route-to-route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral equivalent doses.  The equation uses a single conversion factor to account for default body weights and respiratory volumes.  An activity factor is used to account for increased exposure resulting from increased respiration.  

Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: 
HED (mg/kg/day) = Dose (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 absorption 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 strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98).
D	=	duration; duration of daily animal or human exposure (hours).
AF	=	activity factor; animal default is 1.  For humans with a ventilation rate of 16.7 			L/min, the value is 1.2.

Therefore, the residential HED for sulfentrazone is calculated as follows:

Residential Handler and Outdoor Postapplication HED:  (0.05427 mg/L) x 1.2 x 11.8 L/hr/kg x 2 hr x 1 = 1.554 mg/kg/day 

B.2.  HEC Calculations for Short- and Intermediate-term Occupational Exposure:
Assume workers will be in the field for 8 hrs/day and 5 days/week:
   
HEC = NOAELstudy * (daily duration of exposureanimal/daily duration of exposurehuman) * (days/week of exposureanimal/days/week of exposurehuman) * RDDR

HEC = 0.256 mg/L * (6/8) * (5/5) * 0.213 = 0.041 mg/L.

Table B.1.  HEC Array for Occupational Risk Assessment.
                                Relevant Study
                                     LOAEL
                                    (mg/L)
                                     NOAEL
                                    (mg/L)
                                      Da
                                      Dh
                                      Wa
                                      Wh
                                     RDDR
                                  HEC (mg/L)
                                     inter
                                     intra
                                      UF
                    Short-& Intermediate-Term Exposure
                              Inhalation  -  Rat
                            (MRID 49253902) 26-day
                                      ET
                                     1.71
                                     0.256
                                       6
                                       8
                                       5
                                       5
                                     0.213
                                     0.041
                                       3
                                      10
                                      NA
Long-Term Exposure:  Not appropriate for sulfentrazone.

Key for Array Tables
LOAEL: Lowest-observed adverse-effect level
NOAEL: No-observed adverse-effect level
Da: Daily animal exposure (hrs/day)
Dh: Anticipated daily human exposure (hrs/day)
Wa: Weekly animal exposure (days/week)
Wh: Anticipated weekly human exposure (days/week)
RRDR: Regional Deposited Dose Ratio
HEC: Human-Equivalent Concentration
inter: Interspecies extrapolation UF 
intra: Intraspecies variation UF
UF: Other UF(s)	
ET: Extra-thoracic region

Route-to-Route Extrapolation

More information and details in:  Memo, "Route-to-Route Extrapolations" J. Whalen and H. Pettigrew, 10/10/98.

HED's route-to-route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral-equivalent doses.  The equation uses a single conversion factor to account for default body weights and respiratory volumes.  An activity factor is used to account for increased exposure resulting from increased respiration.  

Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: 

HED (mg/kg/day) = Dose (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 absorption 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 strain (Table 1 of J. Whalen and H. 				Pettigrew, 10/10/98).
D	=	duration; duration of daily animal or human exposure (hours).
AF	=	activity factor; animal default is 1.  For humans, the value varies with ventilation 			rates determined by occupational/restidential scientists; 0.6 (8.3L/min), 1.2 (16.7 			L/min) and 2.1 (29 L/min)

Therefore, the occupational HED for sulfentrazone is calculated as follows:

Occupational HED, Ventilation Rate, 8.3 L/min:  (0.0407 mg/L) x 1 x 0.6 x 11.8 L/hr/kg x 8 hr = 2.317 mg/kg/day 
Occupational HED, Ventilation Rate, 16.7 L/min:  0.0407 mg/L) x 1 x 1.2 x 11.8L/hr/kg x 8 hr = 4.661 mg/kg/day
Occupational HED, Ventilation Rate, 29 L/min:  (0.0407 mg/L) x 1 x 2.1 x 11.8 L/hr/kg x 8 hr = 8.094 mg/kg/day

Based on the current sulfentrazone label, HED believes exposures can be short- (1-30 days) or intermediate- (1 to 6 months) term in duration.  Long-term exposures are not anticipated for sulfentrazone based on proposed labeled uses.  For the short- and intermediate-term scenarios, inhalation data from the 26-day inhalation rodent study was most appropriate for determining HECs.  In the RfC methodology, different HECs may be calculated for the same experimental NOAEL due to the following:

1. Different algorithms are used to derive HECs for systemic versus portal-of-entry effects.  Typically, HECs are calculated separately for systemic versus portal-of-entry effect.  For sulfentrazone, portal-of-entry irritation was observed and, therefore, only portal-of-entry HECs were derived.  
2. Time adjustments are traditionally needed for non-occupational (bystander) versus occupational exposure scenarios.  Traditionally, 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 would be 24 hours/day and 7 days/week.  In comparison, the average workweek for an occupational worker is 8 hours/day and 5 days/week.  The HEC array table reflects the time adjustment in the calculations.



Appendix C.  Physical/Chemical Properties

Table B.1.  Physicochemical Properties of Technical Grade Sulfentrazone.
Parameter
Value
Reference
Melting range
120-122 ºC
DP# 288712, 3/6/03, G. Kramer, G. Reddy, and L. Liu
pH
4.78 at 23 ºC

Density
0.53 g/cm[3]

Water solubility
4.0 x 10[2] ug/g

Solvent solubility
18.6% w/w in acetonitrile

Vapor pressure
8 x 10[-10] mm Hg

Dissociation constant, pKa
6.56

Octanol/water partition coefficient, Log(KOW)
1.49 at pH 5

UV/visible absorption spectrum
Not available



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

None
Commodity
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US
Canada
Mexico[1]
Codex
Asparagus
0.15
0.15


Berry and small fruit, group 13-07
0.15



Brassica, head and stem, subgroup 5A
0.20
0.2 cabbages


Brassica, leafy greens, subgroup 5B
0.40



Corn, field, forage
0.20



Corn, field, grain
0.15



Corn, field, stover
0.30



Flax
0.15
0.15 flaxseeds


Fruit, citrus, group 10-10
0.15



Horseradish
0.20
0.2 horseradish roots


Melon, subgroup 9A
0.15



Nut, tree, group 14
0.15



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-oxo-1H-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-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide) and DMS (N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-5-oxo-1H-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
1.5








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-oxo-1H-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-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide) and DMS (N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide, calculated as the stoichiometric equivalent of sulfentrazone 
                                       
                                       
                                     None
Commodity
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US
Canada
Mexico[1]
Codex
Grain, cereal (excluding sweet corn), Hulls
0.30



Grain, cereal, forage, fodder and straw, group 16, except sweet corn; forage
0.2



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



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



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



Grain, cereal, group 15, except sweet corn
0.1



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








Completed:  M. Negussie; 04/16/14
1 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.


