Document ID: EPA-HQ-OPP-2013-0712-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-12-30T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER
EPA Registration Division contact: Lois Rossi, (703) 305-7090
Interregional Research Number 4 (IR-4)
Pesticide petition # 3E8202
EPA has received a pesticide petition, PP# 3E8202 from IR-4, 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, (N42,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-lH-1,2,4-triazol-1-yl]phenyll-methanesulfonamide) and its metabolites 3- hydroxymethyl-sulfentrazone (N-12,4-dichloro-514-(difluoromethyl)-4,5-dihydro-3-hydroxymethyl-5-oxo-1H-1,2,4-triazol-1-yl] phenyllmethanesulfonamide) and 3- desmethyl sulfentrazone (N42,4-dichloro-5-14-(difluoromethyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl[phenyllmethanesulfonamide) in or on the raw agricultural commodity Apple 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.  
I. Plant metabolism. The metabolism of sulfentrazone in plants is adequately understood for the existing and proposed tolerances. Crop residues found after the
A. Residue Chemistry
Pre-emergence and 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 desmethyisuifonyi suifentrazone; 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 soil-applied at the maximum label rate to the side of apple orchard rows 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 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 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 Fl generation was reduced at higher closes; 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 RID/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 clogs 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 - 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 Exposure6
1.	Dietary exposure. A short-term aggregate exposure assessment was conducted to determine the total exposure to sulfentrazone residues from both dietary and non-dietary 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. Pending crops include apples. In June 2012, a sulfentrazone acute and chronic aggregate dietary (food and water) exposure and risk assessment was conducted for the Section 3 registration request for new uses on: rhubarb, turnip roots and tops, sunflower subgroup 20B, succulent cowpea, succulent lima bean, succulent vegetable soybean, wheat (spring), citrus fruit group 10-10, low-growing berry group 13-07, tree nut group 14, pistachios, and crop group 18 nongrass animal feeds (DP Barcodes: D389973, D394757; PC Code: 129081). The Agency concluded that there is a reasonable certainty that no harm will result to the general population and to infants and children from aggregate exposure to sulfentrazone residues. A Tier 1 exposure analysis was 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 proposed 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 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. The EECs for chronic exposures are estimated to be 7.8 ppb for surface water and 26.0 ppb for ground water (Drinking water exposure assessment for the Section 3 new use registration of sulfentrazone on rhubarb, turnip roots and tops, sunflower subgroup 20B, succulent cowpea, succulent lima bean, succulent vegetable soybean, wheat (spring), citrus fruit group 10-10, low-growing berry group 13-07, tree nut group 14, pistachios, and crop group 18 nongrass animal feeds (DP Barcode: D393777 and D397770; PC Code: 129081). The use pattern for apples is within currently-labeled rates, thus Tier I drinking water models continued to be used in this assessment.

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 highly conservative 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
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
I. 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 low er 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 2.2`)/0 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 Children 1-2, which utilizes less than 7"/0 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.