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]phe

nyl]-methanesulfonamide) and its metabolites 

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

methyl-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-y

l]phenyl]methanesulfonamide)] in or on the raw agricultural commodity [Citrus Fruit Crop 

Group 10-10; Berry and Small Fruit Crop Group 13-07; Tree Nut Crop Group 14 and 

Pistachio at 0.15 parts per million (ppm); Crop Group 18 Non-grass animal feed (forage, 

fodder, straw and hay) : alfalfa, forage at 5 ppm; alfalfa, hay at 20 ppm; alfalfa, seed at 3 

ppm; clover, forage at 5 ppm; clover, hay at 20 ppm; clover, seed at 3 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. 

 

 

 

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

 

EPA Registration Division contact: Bethany Benbow (703) 347-8072 

 

 

 

FMC Corporation, 1735 Market Street, Philadelphia, PA 19103 

 

[1F7838] 

 

EPA has received a pesticide petition (1F7838) from FMC Corporation, 1735 Market 

Street, Philadelphia, PA 19103 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 

 

 

 

 
 

 

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 pre-emergence 

and the 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. 

 

 

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 

alfalfa, clover, citrus, tree nuts, berries and small fruit 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. Genotoxicity. 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. 

 

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. 

 

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 

two-generation 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 

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 

treatment-related 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] 

 

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 ingestion 

of both raw and processed agricultural commodities from alfalfa, clover, citrus, tree 

nuts, berries and small fruit. 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-to-mouth 

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-to-mouth 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 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. 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 post-natal 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.