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 <IP_ADDRESS>.

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

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 <IP_ADDRESS> is a summary of the proposed and HED-recommended tolerances for residues of sulfentrazone per se.

Table <IP_ADDRESS>.  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 <IP_ADDRESS>.  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 <IP_ADDRESS>.  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