EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4) 

Petition Number (PP#) 2E8020

EPA has received a pesticide petition, PP# 2E8020, from IR-4, Rutgers, The State 

University of New Jersey, 500 College Road East, Suite 201-W, Princeton, NJ 08540

proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act 

(FFDCA), 21 U.S.C. 346a (d), to amend 40 CFR part 180.498 by establishing a tolerance 

for residues 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 3-

hydroxymethyl-sulfentrazone (N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-

hydroxymethyl-5-oxo-1H-1,2,4-triazol-1-yl]phenyl]methanesulfonamide) and 3-

desmethyl sulfentrazone (N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-5-oxo-1H1,2,4-triazol-1-yl]phenyl]methanesulfonamide) in or on the raw agricultural commodity

soybean, vegetable, succulent (Edamame) at 0.15 ppm. EPA has determined that the 

petition contains data or information regarding the elements set forth in section 408 (d) 

(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted 

data at this time or whether the data supports granting of the petition. Additional data 

may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism of sulfentrazone in plants is adequately 

understood for the existing and proposed tolerances. Crop residues found after the preemergence and the pending proposed post-emergence uses were similar in that the major 

metabolites were 3-hydroxymethyl sulfentrazone and 3-desmethyl sulfentrazone. In 

rotational crops, sulfentrazone is metabolized via four different pathways: (i) Oxidation 

of the 3-methyl group to form 3-hydroxymethyl sulfentrazone, followed by further 

oxidation to form sulfentrazone carboxylic acid which is decarboxylated to 3-desmethyl

sulfentrazone; (ii) hydrolysis of the trifluoromethyl group to form desdifluoromethyl 

sulfentrazone which is oxidized and decarboxylated to form desdifluoromethyl desmethyl

sulfentrazone; (iii) hydrolysis of the sulfonamide group to form desmethylsulfonyl 

sulfentrazone; and (iv) scission of the phenyl and triazole rings to produce methyl 

triazole. The corresponding phenyl metabolites are believed to remain bound. EPA 

determined that tolerances based on the parent and 3-hydroxymethyl sulfentrazone are 

therefore appropriate.
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2. Analytical method. There is a practical analytical method for detecting and 

measuring levels of sulfentrazone and its metabolites in or on food with a limit of 

quantitation that allows monitoring of food with residues at or above the levels set or 

proposed in the tolerances. The analytical enforcement method for sulfentrazone was 

used with minor modification that eliminated several clean-up and derivatization steps 

that was required for GC/MSD but not for LC/MS/MS. The analytical method for 

sulfentrazone involves separate analyses for parent and its metabolites. The parent is 

analyzed by evaporation and reconstitution of the sample prior to analysis by LC/MS/MS 

GC/ECD. The metabolites samples were refluxed in the presence of acid and cleaned up 

with solid phase extraction prior to analysis by LC/MS/MS.

3. Magnitude of residues. Sulfentrazone was applied to succulent pea and 

succulent lima bean trials in the appropriate EPA regions. The RACs were harvested at 

the appropriate growth stages. The subsequent analyses of the RACs determined that the 

residues of sulfentrazone and its metabolites would not exceed the established tolerances.

IR-4 is requesting that the extrapolation of this data be used in support of the proposed 

tolerance in vegetable soybean (edamame).

B. Toxicological Profile

1. Acute toxicity. A battery of acute toxicity studies placed technical 

sulfentrazone in Toxicity Categories III and IV. No evidence of sensitization was 

observed following dermal application in guinea pigs. In an acute neurotoxicity study in 

rats at gavage doses of 0, 750, or 2,000 mg/kg, a NOEL of 250 mg/kg and a LOEL of 750 

mg/kg were based upon increased incidences of clinical signs, Functional Observation 

Battery (FOB) findings, and decreased motor activity which were reversed by day 14 

post-dose. There was no evidence of neuropathology.

2. Genotoxicty. A reverse gene mutation assay (salmonella typhimurium) yielded 

negative results, both with and without metabolic activation. A mouse lymphoma 

forward gene mutation assay yielded negative results with equivocal results without 

activation. A mouse micronucleus assay test was negative following intraperitoneal 

injection of 340 mg/kg.

3. Reproductive and developmental toxicity. A prenatal oral developmental 

toxicity study in the rat with dose levels at 25.0 or 50.0 mg/kg/day established a maternal 

NOEL of 25 mg/kg/day based on decreased body weight gain, increased spleen weight, 

and microscopic changes in the spleen, and a fetal NOEL of 10 mg/kg/day was based on 

fetal death, reduced body weights, and alterations in skeletal development at higher 

doses. A supplemental oral developmental toxicity study conducted in rats at oral dose 

levels of 25.0 and 50.0 mg/kg/day to test for cardiac effects at the request of the EPA, did 

not reveal any significant effects on fetal cardiac development. The results of this study

confirmed the maternal and fetal findings of the previously conducted developmental 

study on sulfentrazone in rats and did not alter the study conclusions.
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In a dermal developmental study in the rat at doses of 0, 5, 25, 50, 100 and 250 

mg/kg/day, a maternal (systemic) No Observed Adverse Effect Level (NOAEL) was 

established at 250 mg/kg/day. Significant treatment-related increases in the fetal and litter 

incidences of incompletely ossified lumbar vertebral arches, hypoplastic or wavy ribs, 

and incompletely ossified or nonossified ischia or pubes occurred at the high-dose (250 

mg/kg/day). An additional significant increase in the high-dose fetal incidence of 

variations in the sternebrae (incompletely ossified or unossified) was not judged to be 

treatment-related. At 250 mg/kg/day, the mean numbers of thoracic vertebral and rib 

ossification sites were significantly decreased, a high-dose effect of treatment with 

sulfentrazone consistent with the significant treatment-related hypoplasia observed in the 

skeletal evaluation of the ribs. Therefore, the developmental (fetal) Lowest Observed 

Effect Level (LOEL) is 250 mg/kg/day based on decreased fetal body weight; increased 

incidences of fetal 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. The developmental (fetal) NOEL is 100 

mg/kg/day.

A developmental toxicity study in rabbits was conducted at gavage dose levels of 0, 100, 

250, or 375 mg/kg/day. Treatment-related incidences of decreased feces and hematuria 

were noted at 250 mg/kg/day or greater. In addition, at the 375 mg/kg/day dose level, five 

rabbits aborted. Significant reductions in mean body weight change were observed for the 

dosing period (GD 7- 19) and for the study duration (GD 0-29, both before and after 

adjustment for gravid uterine weight) at the 250 and 375 mg/kg/day dose levels. 

Therefore, the maternal (systemic) LOEL is 250 mg/kg/day, based upon increased 

abortions, clinical signs (hematuria and decreased feces), and reduced body weight gain. 

The maternal (systemic) NOEL is 100 mg/kg/day. Skeletal evaluation in fetuses revealed 

dose- and treatment-related findings at the 375 mg/kg/day dose level. These included 

significant increases in both the fetal and litter incidences of fused caudal vertebrae (a 

malformation) and of partially fused nasal bones (a variation). In addition, at 375 

mg/kg/day, significant treatment-related reductions in ossification site averages were 

observed for metacarpals and both fore- and hindpaw phalanges. Therefore, the 

developmental (fetal) LOEL is 250 mg/kg/day, based upon increased resorptions, 

decreased live fetuses per litter, and decreased fetal weight. The developmental (fetal) 

NOEL is 100 mg/kg/day.

A two-generation reproduction study in the rat at dietary levels of 14, 33, or 46 

mg/kg/day in males and 16, 40, or 56 mg/kg/day in females established a NOEL for 

systemic and reproductive/developmental parameters of 14 mg/kg/day for males and 16 

mg/kg/day for females. The LOEL for systemic and reproductive/development 

parameters was 33 mg/kg/day for males and 40 mg/kg/day for females. Systemic effects 

were comprised of decreased body weight gains, while reproductive/developmental effect 

at the LOEL included degeneration and/or atrophy in the testes, with epididymal sperm 

deficits, in the second (F1) generation males. Male fertility in the F1 generation was 

reduced at higher doses; litter size, pup survival, and pup body weight for both 

generations were also effected at higher doses.
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A supplemental two-generation rat reproduction study was conducted at dietary intake 

levels of 50, 100, 200, or 500 ppm with a NOEL for reproductive parameters of 200 ppm. 

This study confirmed the reproductive/developmental effects observed in the first twogeneration reproductive toxicity study. It was the conclusion of the RfD/Peer Review 

Committee that, under the conditions of the studies reviewed, sulfentrazone caused 

developmental and reproductive toxicity. The results of these studies elicited a high level 

of concern by the Committee, since the developmental toxicity studies demonstrated 

embryo/fetal toxicity at treatment levels that were not maternally toxic, and significant 

toxic effects were observed primarily in the second generation animals of the 

reproduction study. Because these animals had been exposed to sulfentrazone in utero, 

the possibility that the observed reproductive toxicity resulted from a developmental 

and/or genotoxic mechanism was suggested.

4. Subchronic toxicity. A 90-day subchronic toxicity study was conducted in rats, 

with dietary intake levels of 0, 3.3, 6.7, 19.9, 65.8, 199.3, or 534.9 mg/kg/day for males 

and 0, 4, 7.7, 23.1, 78.1, 230.5, or 404.3 milligrams/kilograms/day (mg/kg/day) for 

females respectively. No Observed Effect Levels (NOELs) of 19.9 mg/kg/day in males 

and 23.1 mg/kg/day in females were based on clinical anemia. 

A 90-day subchronic feeding study was conducted in mice by dietary admix at doses of 0, 

10.3, 17.8, 60.0, 108.4, or 194.4 mg/kg/day for males and 0, 13.9, 29.0, 79.8, 143.6, or 

257.0 mg/kg/day for females, respectively. NOELs of 60 mg/kg/day (males) and 79.8 

mg/kg/day (females) were based on decreases in body weights and/or gains; decreased 

erythrocytes, hemoglobin and hematocrit values; and splenic microscopic pathology.

In a 90-day subchronic feeding study in dogs administered by dietary admix at doses of 0, 

10, 28, or 57 mg/kg/day for males and 0, 10, 28, or 73 mg/kg/day for females, a NOEL of 

28 mg/kg/day was determined for both males and females based on decreases in 

hemoglobin and hematocrit, elevated alkaline phosphatase levels, increased liver weights 

and microscopic liver as well as splenic changes.

A 90-day subchronic neurotoxicity study in the rat was conducted at dietary levels of 30, 

150, or 265 mg/kg/day in males, and 37, 180, or 292 mg/kg/day in females, with a NOEL 

of 30 mg/kg/day in males and 37 mg/kg/day in females. The LOEL was 150 mg/kg/day

for males and 180 mg/kg/day for females based on increased incidences of clinical signs, 

decreased body weights, body weight gains, and food consumption in females and 

increased motor activity in females at week 13. There were no neurohistopathological 

effects on the peripheral or central nervous system.

5. Chronic toxicity. A 12-month feeding study in dogs was dosed at levels of 0.0, 

24.9, or 61.2 mg/kg/day for male dogs and 0.0, 10.4, 29.6, or 61.9 mg/kg/day for female 

dogs in the control through high-dose groups, respectively, with a NOEL of 24.9 

mg/kg/day for males and 29.6 mg/kg/day for females based on hematology effects and 

microscopic liver changes.

An 18-month feeding/carcinogenicity study in mice was conducted with dietary intake of 
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0, 46.6, 93.9, 160.5, or 337.6 mg/kg/day for males and 0, 58.0, 116.9, 198.0, or 407.1 

mg/kg/day for females. A NOEL of 93.9 mg/kg/day in males and 116.9 mg/kg/day in 

females was based on decreases in hemoglobin and hematocrit. There were no treatmentrelated increases in tumors of any kind observed at any dose level.

In a 24-month chronic feeding/oncogenicity study in rats at dietary doses of 0, 24.3, 40.0, 

82.8, or 123.5 mg/kg/day for males and 20.0, 36.4, 67.0, or 124.7 mg/kg/day for females, 

an overall NOEL of mg/kg/day in males and 36.4 mg/kg/day in females was based on 

hematology effects and reduced body weights. There was no evidence of an oncogenic 

response.

6. Animal metabolism. A metabolism study in rats indicated that approximately 84 

to 104% of the orally administered dose of sulfentrazone was excreted in the urine, and 

that the pooled urinary radioactivity consisted almost entirely of 3-hydroxymethyl 

sulfentrazone. Pooled fecal radioactivity showed that the major metabolite consisted of 3-

hydroxymethyl-sulfentrazone (1.26 to 2.55% of the administered dose). The proposed 

metabolic pathway appeared to be conversion of the parent compound mainly to 3-

hydroxymethyl-sulfentrazone (excreted in urine and feces).

7. Metabolite toxicology. NA - Remove.

8. Endocrine disruption. An evaluation of the potential effects on the endocrine 

systems of mammals has not been determined; however, no evidence of such effects was 

reported in the chronic or reproductive toxicology studies described above. There was no 

observed pathology of the endocrine organs in these studies. There is no evidence at this 

time that sulfentrazone causes endocrine effects.

C. Aggregate Exposure

1. Dietary exposure. A short-term aggregate exposure assessment was conducted 

to determine the total exposure to sulfentrazone residues from both dietary and nondietary routes. Aggregate exposure to sulfentrazone was evaluated for two separate 

products (crop herbicide and residential lawn/turf herbicide). Exposure from these two 

uses occurred by multiple routes (dietary, dermal and incidental ingestion). Aggregation 

is conducted for dietary and non-dietary residential exposures and it is to represent 

reasonable conditions of exposure. The aggregate exposure estimates for all adults, adult 

females and toddlers were less than 100% of the PAD.

i. Food. The primary source for human exposure to sulfentrazone would be from 

ingestion of both raw and processed agricultural commodities, including all registered 

and pending crops. In December 2010, the Revised Acute and Chronic Aggregate 

Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 

registration request to add new uses on: Brassica, Head and Stem, Subgroup 5A; 

Brassica, Leafy Greens, Subgroup 5B; Melon Subgroup 9A; Fruiting Vegetable, Group 8 

and Okra; Pea, Succulent; Flax; Strawberry; Tuberous and Corm Vegetable, Subgroup 

1C; and Miscellaneous Fruiting Vegetables was conducted by the EPA Health Effects 
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Division (PC Code 129081; DP Barcode D384090). A Tier 1 exposure analysis has been 

performed to estimate the exposure for the U.S. general population as well as all adults, 

adult females, and children (all ages) sub-populations for raw and processed commodities 

that might be associated with sulfentrazone residue. Field trial data for registered and the 

pending minor crop uses, acceptable bridging residue data, and consumption data from 

the USDA Continuing Surveys of Food Intake by Individuals (CSFIIs) were inputs into 

the Dietary Exposure Evaluation Model (DEEM) software - ver. 2.14. No significant 

additional dietary risk was identified for registered and pending minor crops.

ii. Drinking water. Based on the FIRST and SCI-GROW models the EECs of 

sulfentrazone plus its major metabolite 3-carboxylic acid for acute exposures are 

estimated to be 35.8 ppb for surface water and 26 ppb for groundwater. (Drinking Water 

Exposure Assessment for Section 3 New Use Registration of Sulfentrazone on 

Head/Stem Brassica Subgroup 5A, Leafy Greens Subgroup 5B, Melon Subgroup 9A, 

Fruiting Vegetable Group 8, Okra, Succulent Pea, Strawberry and Tuberous/Corm 

Vegetables Subgroup 1C. PC Code No. 129081; DP Barcode: D349322; 8/28/2008). 

The EECs for chronic exposures are estimated to be 7.8 ppb for surface water and 26.0 

ppb for ground water

2. Non-dietary exposure. The primary source for human non-dietary exposure to 

sulfentrazone will be from post-application exposure to treated residential turfgrass. The 

routes of sulfentrazone exposure were dermal post-application exposure for adults and 

toddlers, and post-application incidental ingestion of sulfentrazone due to the hand-tomouth behavior of toddlers. A worst case short-term non-dietary exposure analysis was 

conducted using algorithms and default factors published in US EPA’s Standard 

Operating Procedures (SOPs) for Residential Exposure Assessments. The dermal 

exposure estimates for all adults, adult females and toddlers were 0.013, 0.016 and 0.023 

mg/kg/day, respectively. The exposure estimate for incidental ingestion due to hand-tomouth behavior for toddlers was 0.0026 mg/kg/day. The resulting total (combined oral 

and dermal since the relevant endpoints both have the same effect) non-dietary exposure 

estimates were 0.013, 0.016 and 0.025 mg/kg/day for all adults, adult females and 

toddlers, respectively.

D. Cumulative Effects

The Agency will reach a tolerance decision based on the best currently available 

and useable information, without regard to common mechanism issues. In the case of 

sulfentrazone, EPA has determined that it does not currently have the capability to apply 

the information in its files to a resolution of common mechanism issues in a manner that 

would be useful in a risk assessment. This tolerance determination therefore does not take 

into account common mechanism issues. The Agency will reexamine the tolerances for 

sulfentrazone, if reexamination is appropriate, after the Agency has determined how to 

apply common mechanism issues to its pesticide risk assessments.

E. Safety Determination
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1. US Population. An aPAD of 0.14 mg/kg/day was used in the acute dietary risk 

assessment for females (13-49 yrs) based on an oral NOAEL of 14 mg/kg/day with a 

composite UF of 100X (UFA = 10X; UFH = 10X and FQPA SF =1X). This NOAEL was 

derived from a 2-generation reproductive toxicity study in rats based on offspring toxicity

(i.e., reduced prenatal viability (fetal & litter), reduced litter size, increased number of 

stillborn pups, reduced pup and litter postnatal survival and decreased pup body weights 

throughout lactation) observed at the LOAELs of 33 (males) and 40 mg/kg/day (females). 

An aPAD of 2.5 mg/kg/day was used in the acute dietary risk assessment for general 

population including infants and children based on an oral NOAEL of 14 mg/kg/day with 

a composite UF of 100X (UFA = 10X; UFH = 10X and FQPA SF =1X). This NOAEL 

was derived from an acute neurotoxicity rat study based on increased incidence of 

clinical signs and FOB parameters and decreased motor activity observed at the LOAEL 

of 750 mg/kg/day. 

An cPAD of 0.1 mg/kg/day was used in the chronic dietary risk assessment for all 

populations based on an oral NOAEL of 10 mg/kg/day with a composite UF of 100 X 

(UFA = 10X; UFH = 10X and FQPA SF =1X). This NOAEL was derived from a prenatal 

developmental toxicity study in the rat based upon decreased mean fetal weights, and 

retardation in skeletal development evidenced by an increased number of litters with any

variation and by decreased number of caudal vertebral and metacarpal ossification sites 

observed at the developmental LOAEL of 25 mg/kg/day.

Acute dietary exposure estimates at the 95th percentile for the U.S. general population and 

all population subgroups are less than 1% aPAD. A lower aPAD for females 13-49 years 

old (0.14 mg/kg/day) was considered in the dietary assessment, compared to all other 

population subgroups (2.5 mg/kg/day). The population subgroup with the greatest risk 

was females 13-49 year old, which utilized less than 3% of the aPAD for that sub-group. 

Resulting chronic risk estimates are below HED’s level of concern. The US General 

Population category utilized less than 2% of the cPAD.

2. Infants and Children.

Acute dietary exposure estimates at the 95th percentile for all Infants and Children 

subgroups are less than 1% aPAD. For chronic exposure, the most highly exposed 

population subgroup was Non-nursing Infants, which utilizes less than 5% of the cPAD. 

Resulting acute and chronic risk estimates are below HED’s level of concern.]

F. International Tolerances

There are no Codex Alimentarius Commission (Codex) Maximum Residue 

Levels (MRLs) for sulfentrazone.
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