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 1E7890

EPA has received a pesticide petition 1E7890 from Interregional Research Project 

Number 4 (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-1H-1,2,4-triazol-1-yl]phenyl]methanesulfonamide)

in or on the raw agricultural commodities rhubarb at 0.2 ppm; turnip, roots at 0.2 ppm;

turnip, tops at 0.7 ppm; and sunflower subgroup 20B at 0.2 ppm; tolerances with regional 

registrations in or on wheat, forage at 0.45 ppm (Pacific Northwest only); wheat, hay at 

0.20 ppm (Pacific Northwest only); wheat, grain at 0.20 ppm (Pacific Northwest only); 

wheat, straw at 1.4 ppm (Pacific Northwest only); cowpea, succulent at 0.15 ppm 

(Tennessee only); and amending current tolerances in or on the raw agricultural 

commodity bean, lima, succulent at 0.15 ppm from a national tolerance to a regional 

tolerance (Tennessee only). Upon approval of the aforementioned tolerances, the petition

additionally proposes to remove the established tolerances in or on the raw agricultural 

commodities sunflower, seed at 0.2 ppm; and the national tolerance on bean, lima, 

succulent 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 
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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.

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 at the maximum label rates 

for rhubarb, turnips, sunflower and spring wheat to trials in the appropriate EPA regions. 

The RACs were harvested at the appropriate growth stages. The subsequent analyses of 

the RACs and processed parts determined that the residues of sulfentrazone and its 

metabolites would not exceed the established and proposed tolerances.

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 
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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.

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 
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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.

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.
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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 

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 for someone who would be exposed to sulfentrazone 

residues from both dietary and non-dietary routes over a short-term period (i.e. 1-7 days). 

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 will be from 
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ingestion of both raw and processed agricultural commodities from rhubarb, turnips, 

spring wheat and sunflower. A DRES chronic exposure assessment was previously

conducted for asparagus, succulent lima bean, cabbage, field corn forage, field corn 

stover, field corn grain, horseradish roots, dried shelled pea and bean (except soybean) 

subgroup 6C, peanut, peanut meal, peppermint tops, potato, spearmint tops, sugarcane, 

sugarcane molasses and sunflower seed, raw and processed commodities and presented in 

the Sulfentrazone; Establishment of Tolerances, Final Rule (FR / Vol. 68, No. 185: 

55269-55280, September 24, 2003). A Tier 3 short-term exposure analysis has been 

performed to estimate the exposure for all adults, adult females, and toddlers (3 to 4 years 

of age) in the U.S. population for these raw and processed commodities. This analysis 

utilized Dietary Exposure Evaluation Model (DEEM) software; field trial data for 

registered and pending crop uses; percent crop treated information; and consumption data 

from the USDA Continuing Surveys of Food Intake by Individuals (CSFIIs). Short-term 

dietary exposure estimates at the 99.9th percentile for all adults, adult females and 

toddlers were < 2% of the PAD. The short-term dietary exposure to sulfentrazone has 

been demonstrated to be minimal.

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. 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. Cumulative exposure to substances with common mechanism of 

toxicity. Section 408(b)(2)(D)(v) requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information'' concerning 

the cumulative effects of a particular pesticide's residues and “other substances that have 

a common mechanism of toxicity.'' While the Agency has some information in its files 

that may turn out to be helpful in eventually determining whether a pesticide shares a 

common mechanism of toxicity with any other substances, EPA does not at this time 

have the capability to resolve the scientific issues concerning common mechanism of 

toxicity in a meaningful way. EPA is commencing a pilot process to study this issue 
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further through the examination of particular classes of pesticides. The Agency hopes that 

the results of this pilot process will enable the Agency to apply common mechanism 

issues to its pesticide risk assessments. At present, however, the Agency does not know 

how to apply the information in its files concerning common mechanism issues to risk 

assessments, and therefore believes that in most cases there is no “available information'' 

concerning common mechanism that can be scientifically applied to tolerance decisions. 

Where it is clear that a particular pesticide may share a significant common mechanism 

with other chemicals, or where it is clear that a pesticide does not share a common 

mechanism with other chemicals, a Common mechanism issues may affect tolerance 

decision. The Agency expects that most tolerance decisions will fall into the area in 

between, where EPA cannot reasonably determine whether a pesticide does or does not 

share a common mechanism of toxicity with other chemicals (and, if so, how that 

common mechanism should be factored into a risk assessment). In such circumstances, 

the Agency will reach a tolerance decision based on the best, currently-available and 

usable information, without regard to common mechanism issues. However, the Agency

will also revisit such decisions when the Agency determines how to apply common 

mechanism information to pesticide risk assessments. In the case of sulfentrazone, EPA 

has determined that it does not now 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

1. U.S. population. An oral NOEL of 25 mg/kg/day was used to determine dietary

Margin of Exposures (MOEs) for all adults and adult females. This NOEL was derived 

from a prenatal oral developmental toxicity study in rats and was based on fetal death, 

reduced body weight and alterations in skeletal development. A dermal NOEL of 100 

mg/kg/day was used to determine non-dietary (dermal) MOEs. This NOEL was derived 

from a dermal teratology rat study and was also based upon decreased fetal body weight 

and increased skeletal development variations. Additionally, the dermal absorption of 

10% was used to estimate the absorbed (systemic) exposures for the aggregation of the 

oral and dermal route exposures (note: this is only appropriate in cases such as this 

where the relevant endpoints have the same effect). The acute dietary, non-dietary and 

aggregate MOEs for all US population is 5,646, for adults 20-49 years is 10,095, for 

females 13-49 years is 10,641, for youth 13-19 years is 7,621 and for children 3-5 years 

old is 3,904. Further, the calculated short-term drinking water levels of concern 

(DWLOC) for all US population is 4,900 μg/L for adults 20-49 years is 4,900 μg/L, for 

females 13-49 years is 4,200 μg/L, for youth 13-19 years is 4,200 μg/L and for children 

3-5 years old is 1,400 μg/L. These MOEs and DWLOC are considered to be acceptable 

and to clearly illustrate low risk potential.

2. Infants and children. Risk to infants and children were determined by use of 

developmental toxicity studies in rats and a two-generation reproduction study in rats. 
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The oral developmental toxicity studies resulted in 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 based on fetal death, reduced body

weights, and alterations in skeletal development at higher doses. A dermal developmental 

toxicity study in rats resulted in a developmental (fetal) NOEL of 100 mg/kg/day based 

on decreased fetal body weight and increased incidences of fetal alterations, comprised 

primarily of skeletal variations and reductions in mean numbers of ossification sites. A 

two-generation reproduction study in rats resulted in 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, and reproductive/developmental effects at the LOEL 

included degeneration and/or atrophy of 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 

affected at higher doses. FFDCA section 408 provides that EPA shall apply an 

additional safety factor for infants and children in the case of threshold effects to account 

for pre- and post-natal toxicity and the completeness of the data base, unless EPA 

determines that such an additional factor is not necessary to protect the safety of infants 

and children. Based on current data requirements, the data base relative to pre- and postnatal toxicity is complete. EPA has determined that there is evidence of increased 

quantitative susceptibility following in-utero exposure in the developmental toxicity

studies in rats via the oral and dermal routes, and there is evidence for increased 

qualitative susceptibility following prenatal and/or postnatal exposure in the 2-generation 

reproduction study in rats. The EPA performed A Degree of Concern Analysis and 

concluded that concerns are low for the quantitative susceptibility of rats fetuses observed 

following oral and dermal exposures, the qualitative susceptibility of rabbit fetuses seen 

via the oral route, and the qualitative susceptibility seen in the 1- and 2-generation 

reproduction studies. The EPA concluded that there is a complete toxicity data base for 

sulfentrazone and exposure data are complete or are estimated based on data that 

reasonably accounts for potential exposures. The EPA determined that the 10X safety 

factor to protect infants and children should be reduced to 1X. The percent of the RfD 

that will be utilized by the aggregate exposure to sulfentrazone for the most exposed 

subgroup would be < 2% of the PAD for children (1 to 6 years old) Therefore, EPA 

concludes that there is a reasonable certainty that no harm will result to infants and 

children from aggregate exposure to sulfentrazone.

F. International Tolerances. There are no Codex Alimentarius Commission (Codex) 

Maximum Residue Levels (MRLs) for sulfentrazone.