**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 sec tion 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 - triazol - 1 - yl ]phenyl] - methanesulfonamide) and its metabolites 3 - hydroxy methyl - sulfentrazone (N

- [2,4 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxy methyl - 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 H - 1,2,4 - triazol - 1 - yl ]phenyl]methanesulfonamide) in or on the raw agricultural commodit ies r hubarb 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 regi onal 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) ; c owpea, succulent at 0.15 ppm (Tennessee onl y) **;** and amending current tolerances in or on the raw agricultural commodity

b ean, l ima , 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 r

ules 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 pre emergence and the pending proposed post - em ergence use s were similar in that the major metabolites were 3 - hydroxy methyl sulfentrazone and 3 - desmeth ylsulfentrazone. In rotational crops, sulfentrazone is metabolized via four different pathway s: (i) Oxidation of the 3 - methyl group to form 3 - hydrox ym e thyl sulfentrazone, followed by further2

oxidation to form sulfentrazone carbox yl ic acid which is decarbox yl ated to 3 - desmeth yl sulfentrazone; (ii) h ydrolysis of the trifluoromethyl group to form desdifluoromethyl sulfentrazone which is oxidized and decarbo xylated to form desdifluoromethyl desmeth yl 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 phenylmetabolite s are believed to remain bound. EPA determined that tolerances based on the parent and 3 - hydroxy methyl sulfentrazone are therefore appropriate. 2. Analytical method. There is a practical anal yt ical 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 anal yt ical 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 L C/MS/MS. The anal yt ical method for sulfentrazone involves separate anal ys es for parent and its metabolites. The parent is anal yz ed b y evaporation and rec onstitution 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 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 anal ys es of the RACs and processed parts determined that the re sidues 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 cl inical 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 n egative 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 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 e stablished a maternal NOEL of 25 mg/kg/day

b ased on decreased body weight gain, increased spl een weight, and microscopic changes in the spleen, and a fetal NOEL of 10 mg/kg/day w as based on3

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 an y 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. In a dermal developmental study i n the rat at doses of 0, 5, 25, 50, 100 and 250 mg/kg/day , a maternal (sy stemic) No Observed Adverse Effect Level (NOAEL) wa s 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 250 mg/kg/day , the mean numbers of thoracic vert ebral 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 evaluation of the ribs. Therefore, the developmental (fe tal) 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; an d 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 incidence s 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 d ose levels. Therefore, the maternal (sy stemic) LOE L is 250 mg/kg/day , based upon increased abortions, clinical signs (hematuria and decreased fec es), 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 d ose level. These included significant increases in both the fetal and litte r 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 were 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 is 100 mg/kg/day . A two - generation reproduction study i n 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 males and 16 mg/kg/day

f or females. The LOEL for sy stemic and reproductive/development4

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 i n the F1 generation was reduced at higher doses; litter size, pup survival, and pup body w eight 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 l evel 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 primaril 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 suggested. 4. Subchronic toxicity. A 90 - day s ubchronic toxicity

s tudy w as conducted in rats, with dietary

i ntake 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 Eff ect Levels (NOELs) of 19.9 mg/kg/day i n 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 female s 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, 15 0, 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, de creased 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 ys tem.5 5. Chronic toxicity. A 12 - month feedi ng study i n 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 24.9 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 i n mice was conducted with dietary i ntake of 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 i n 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 dose level. In a 24 - month chronic feeding/oncoge nicity 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 urin ary 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 administered dose). The proposed metabolic pathway

ap peared 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 the 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 ti me 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 day s). 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 toddl ers were less than 100% of the PAD. i. Food. The primary

source for human exposure to sulfentrazone will be from6

ingestion of both raw and processed agricultural commodities from rhubarb, turnips, spring wheat and sunflower . A DRES chronic exposure as sessment 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 soy bean) 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 expo sure anal ys is 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 commodi ties. This analy sis utilized Dietary

Exposure Evaluation Model (DEEM) sof tware; field trial data for registered and pending crop uses; percent crop treated information; and consumption data from the USDA Continuing Survey s of Food Intake by Individuals (CSFIIs). Short - term dietary exposure estimates at the 99.9 th 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 met abolite 3 - carbox yl ic 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 - ap plication 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 (SO Ps) for R esidential 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 toddl ers 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'' concern ing 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 eventuall y determining whether a pestici de shares a common mechanism of toxicity with an y 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 issue7

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 do es 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 t olerance 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 aff ect tolerance decision. The Agency

expects that most tolerance decisions will fall into the area in between, where EPA cannot reasonabl y determine whether a pesticide does or does not share a common mechanism of toxicity with other chemicals (and, if so, h ow 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 Ag ency will also revisit such decisions when the Agency determines how to appl y common mechanism information to pesticide risk assessments. In the case of sulfentrazone, EPA has determined that it does not now have the capability 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 sulfentrazon e, 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 NOELof 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 us ed to estimate the absorbed (s ys temic) 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 aggre gate MOEs for all US population is 5,646 , f or adults 20 - 49 years is 10,095 , for females 13 - 49 years is 10,641, for youth 13 - 19 years is 7,621 and fo r children 3 - 5 years old is 3,9 0 4 . Further, the calculated short - term drinking water levels of concern (DWL OC) for all US population is 4,900 μg/Lfor 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 clearl y illustrate low risk potential. 2. Infants and children . Risk to infants and children were determined b y use of developmental toxicity

studies in rats and a two - generation reproduction study in rats.8

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 develop ment 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 s ys temic and reproductive/developmental parameters of 14 mg/kg/day for males and 16 mg/kg/day for females. The LOEL for systemic and repro ductive/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, w ith 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 weight for both generations were also affected at higher doses. FFDCA section 408 p rovides 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 no t 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 the re 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 Analy sis 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 reasonabl y 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 mo st 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 L evels (MRL s) for sulfentrazone.