EPA REGI STRATION DIVISION COMPANY NOTICE OF FILING FOR PESTI CIDE

PETITI ONS PUBLISHED IN THE FEDERAL REGI STER 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 s ulfentrazone ( N - [2,4 - dichloro - 5 - [4 - (difluoromethyl ) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1 H

- 1,2,4 - triazo l - 1 - yl ]phenyl] - methanesulfonamide) and its metabolites 3 - hydrox ym ethyl - sulfentrazone ( N - [2,4 - dichloro - 5 - [4 - (difluoromethyl ) - 4,5 - dihydro - 3 - hydrox ym ethyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl ]phenyl]methanesulfonamide) and 3 - desmethyl sulfentrazone ( N - [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 5 - oxo - 1 H1,2,4 - triazol - 1 - yl ]phenyl]methanesulfonamide) in or on the raw agricultural commodity soy bean, v egetable , 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 pe tition. 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 pending proposed post - emergence use s w ere similar in that the major metabolites were 3 - hydroxy methyl sulfentrazone and 3 - desmethylsulfentrazone. In rotational crops, sulfentrazone is metabolized via four different pathways: (i) Oxidation of the 3 - methyl group to form 3 - hydrox ym ethylsulfentrazone, followed by further oxidation to form sulfentrazone carbox yl ic acid which is decarbox yl ated to 3 - desmethyl sulfentrazone; (ii) hydrolysis of the trifluoromethyl group to form desdifluoromethyl sulfentrazone which is oxidized and decarbox yl ated to for m desdifluoromethyl desmethyl sulfentrazone; (iii) hydroly sis of the sulfonamide group to form desmethylsulfonyl sulfentrazone; and (iv) scission of the phenyl and triazole rings to produce methyl triazole. The corresponding phenylmetabolites are believed to remain bound. EPA determined that tolerances based on the parent and 3 - hydroxy methyl sulfentrazone are therefore appropriate.2 2. Analytical method. There is a practical anal ytical method for detecting and measuring levels of sulfentrazone and its m etabolites 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 anal ytical enforcement method for sulfentrazone was used with minor modification that eliminat ed several clean - up and derivatization steps that was required for GC/MSD but not for L C/MS/MS. The anal ytical method for sulfentrazone involves separate anal ys es for parent and its metabolites. The parent is anal yz ed b y evaporation and reconstitution of the sample prior to anal ys is by L C/MS/MS GC/ECD. The metabolites samples were refluxed in the presence of acid and cleaned up with solid phase extraction prior to anal ys is 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 analy ses of the RACs determined that the residues of sulfentrazone and its metabolites would not exceed the establi shed 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 m g/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 ty

phimurium) yielded negative results, both with and without metabolic activation. A mouse ly mphoma forward gene mutation assay yielded negative results with equivocal results without activation. A mouse micronucleus assay test w as 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 e stablished a maternal NOEL of 25 mg/kg/day

b as ed on decreased body weight gain, increased spleen weight, and microscopic changes in the spleen, and a fetal NOEL of 10 mg/kg/day w as based on fetal death, reduced body w eights, and alterations in skeletal development at higher doses. As upplemental oral developmental toxicity s tudy c onducted 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 previousl y conducted developmental study on sulfentrazone in rats and did not alter the study conclusions.3

In a dermal developmental study in the rat at doses of 0, 5, 25, 50, 100 and 250 mg/kg/day , a maternal (sy stem ic) 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 o ssified lumbar vertebral arches, hy poplastic or wavy

ribs, and incompletely

o ssified 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 (incompletel y ossified or unossified) was not judged to be treatment - related. At 2 50 mg/kg/day , the mean numbers of thoracic vertebral and rib ossification sites were significantl y decreased, a high - dose effect of treatment with sulfentrazone consistent with the significant treatment - related hy poplasia observed in the skeletal evaluatio n of the ribs. Therefore, the developmental (fetal) Lo west Observed Effect Level (LOEL) is 250 mg/kg/day b ased on decreased fetal body w eight; increased incidences of fetal variations: hy poplastic or wavy

ribs, incompletel y ossified lumbar vertebral arches , and incompletely o ssified 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 i n 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 fo r the dosing period (GD 7 - 19) and for the study d uration (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 (sy stemic) LOE L is 250 mg/kg/day , based upon increased abortio ns, clinical signs (hematuria and decreased feces), and reduced body weight gain. The maternal (s ys temic) NOEL is 100 mg/kg/day . S keletal evaluation in fetuses revealed dose - and treatment - related findings at the 375 mg/kg/day dose level. These included si gnificant increases in both the fetal and litter incidences of fused caudal vertebrae (a malformation) and of partially f used nasal bones (a variation). In addition, at 375 mg/kg/day , significant treatment - related reductions in ossification site averages w ere observed for metacarpals and both fore - and hindpaw phalanges. Therefore, the developmental (fetal) LOELi s 250 mg/kg/day , based upon increased resorptions, decreased live fetuses per litter, and decreased fetal weight. The developmental (fetal) NOEL i s 100 mg/kg/day . A two - generation reproduction study in the rat at dietary

l evels of 14, 33, or 46 mg/kg/day

i n males and 16, 40, or 56 mg/kg/day in females established a NOELf or sy stemic and reproductive/developmental parameters of 14 mg/kg/day f or male s and 16 mg/kg/day

f or females. The LOEL for sy stemic and reproductive/development parameters was 33 mg/kg/day f or males and 40 mg/kg/day f or females. Sy stemic effects were comprised of decreased body weight gains, while reproductive/developmental effect at the LOEL included degeneration and/or atrophy in the testes, with epididy mal 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 w eight for both gen erations were also effected at higher doses.4

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 b y 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 pri maril y 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 sugges ted. 4. Subchronic toxicity. A 90 - day s ubchronic toxicity

s tudy w as 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 f or males and 0, 4, 7.7, 23.1, 78.1, 230.5, or 404.3 milligrams/kilograms/day (mg/kg/day) for females respectivel y. 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 f or males and 0, 13.9, 29.0, 79.8, 143.6, or 257.0 mg/kg/day

f or females, respectively . NOEL s of 60 mg/kg/day ( males) and 79.8 mg/kg/day

( females) were based on decreases in body w eights and/or gains; decreased erythrocy tes , hemoglobin and hematocrit values; and splenic microscopic pathology . In a 90 - day

subchronic feeding study in dogs administered b y 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 NOELof 28 mg/kg/day

w as 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 th e 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 base d 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 s y stem. 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

f or 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, respectivel y, with a NOELo f 2 4.9 mg/kg/day

f or males and 29.6 mg/kg/day f or females based on hematology e ffects and microscopic liver changes. An 18 - month feeding/carcinogenicity s tudy in mice was conducted with dietary intake of5

0, 46.6, 93.9, 160.5, or 337.6 mg/kg/day f or males and 0, 58.0, 116.9, 198.0, or 407.1 mg/kg/day

f or females. A NOEL of 93.9 mg/kg/day in males and 116.9 mg/kg/day i n females was based on decreases in hemoglobin and hematocrit. There were no treatment related increases in tumors of any kind observed at any do se 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 orall y administered dose of sulfentrazone was excreted in the urine, and that the pooled urinary

radioactivity

consisted almost entirely of 3 - hydrox ymethyl sulfentrazone. Pooled fecal radioactivity showed that the major metabolite consisted of 3 - hydrox ym ethyl - sulfentrazone (1.26 to 2.55% of the admini stered dose). The proposed metabolic pathway

appeared to be conversion of the parent compound mainly to 3 - hydrox ym ethyl - sulfentrazone (excreted in urine and feces). 7. Metabolite toxicology . NA - Remove. 8. Endocrine disruption . An evaluation of th e potential effects on the endocrine sy stems 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 resid ues 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 b y 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; Pe a, Succulent; Flax; Strawberry ; Tuberous and Corm Vegetable, Subgroup 1C; and Miscellaneous Fruiting Vegetables was conducted b y the EPA Health Effects6

Division (PC Code 129081; DP Barcode D384090). A Tier 1 exposure analy sis has been performed to estimat e 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 pen ding minor crop uses, acceptable bridging residue data, and consumption data from the USDA Continuing Survey s of Food Intake b y Individuals (CSFIIs) were inputs into the Dietary

Exposure Evaluation Model (DEEM) software - ver. 2.14. No significant additio nal 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 - carbox yl ic acid for acute exposures are estimated to be 35.8 ppb fo r 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 - to mouth behavior of toddlers. A worst case short - term non - dietary exposure anal ys is 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 , respectivel y. 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. Cumu lative 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 currentl y have the cap ability to appl y 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 Determination7 1. US Population . An aPAD of 0.14 mg/kg/day was u sed in the acute dietary risk assessment for females (13 - 49 y rs) based on an oral NOAEL of 14 mg/kg/day with a composite UF of 100X (UF A = 10X; UF H = 10X and FQPA SF =1X). This NOAEL was derived from a 2 - generation reproductive toxicity study in rats base d 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 (UF A = 10X; UF H = 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 L OAEL 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 decrease d mean fetal weights, and retardation in skeletal development evidenced b y an increased number of litters with any variation and b y decreased number of caudal vertebral and metacarpal ossification sites observed at the developmental L OAEL of 25 mg/kg/day . Acute dietary

exposure estimates at the 95 th 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 al l 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 U S General Population category

utilized less than 2% of the cPAD. 2. Infants and Children . Acute dietary

exposure estimates at the 95 th percentile for all Infants and Children subgroups are less than 1% aPAD. For chronic exposure, the most highl y 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.8