Pesticide Petition to Establish Tolerances for Oxathiapiprolin

**I .**  **E.I. du Pont de Nemours and Company** EPA Registration Division Contact : Erin Malone, (703) 347 - 0253 PP No. 3F8220 EPA has received a pesticide petition ( 3F8220 ) from E.I. du Pont de Nemours & Company (“DuPont”) , 1007 Market Street, Wilmington, DE 19898 , proposing pursuant to section 408 (d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a (d), to amend 40 CFR part 180 to establish tolerances for residues of oxathiapiprolin, 1 - (4 - {4 - [(5RS) - 5 - (2,6 - difluorophenyl) -4,5 - dihydro - 1,2 - oxazol - 3 -yl] - 1,3 - thiazol -2 -yl} - 1 -piperidyl) -2 - [5 -methyl - 3 - (trifluoromethyl) - 1H -pyrazol - 1 -yl ] ethanone , in or on the following commodities: grapes (import tolerance) at 0.9 ppm; vegetable, root and tuber vegetables, tuberous and corm vegetables (crop subgroup 1C) at 0.01 ppm; bulb vegetables, onion, bulb (crop subgroup 3 - 07A) at 0.04 ppm; bulb vegetables, onion, green (crop subgroup 3 - 07B) at 2 ppm; fruiting vegetables (crop group 8 - 10) at 0.2 ppm, dried fruiting vegetables at 0.9 ppm; cucurbit vegetables (crop group 9) at 0.2 ppm; Brassica (cole) leafy vegetables, head and stem Brassica (crop subgroup 5A) at 1.5 ppm ; leafy vegetables (except Brassica vegetables), leafy greens (crop subgroup 4A) at 15 ppm; peas, edible podded at 1 ppm; peas, succulent, shelled at 0.05 ppm; ginseng root at 0. 4 ppm; and to establish a Guideline Reference Level for residues of oxathiapiprolin, in or on tobacco, dried leaves at 30 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in se ction 408 (d) (2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism . The metabolism of oxathiapiprolin is adequately understood to support the proposed tolerances. Studies in grape, lettuce and potato when treated at proposed label rates showed no significant metabolites. The metabolism of oxathiapiprolin in plants was similar regardless of the crop or the treatment regime. Oxathiapiprolin was the principal residue in most crop fractions at various sampling points up to crop maturity. The overall metabolism of oxathiapiprolin in rotated crops ( cereals, root vegetables, leafy vegetables ) was consistent with metabolism seen in the primary crops. 2. Livestock Metabolism . The metabolism of oxathiapiprolin in ruminants and poultry is adequately understood to support the proposed tolerances. Lactating goat and monogastric hen metabolism studies were conducted. The metabolism of oxathiapiprolin in the rat was , in general, consistent with that of the lactating goat (ruminant) and monogastric hen. 3. Analytical method. Adequate analytical methodology, high-pressure liquid chromatography with MS/MS detection, is available for enforcement purposes. 4. Magnitude of residues . Field trials to meet country (Canada, the United States) and regional (the EU) requirements were carried out in vineyards (grape), field or protected vegetable s (brassica vegetables, bulb vegetables, cucurbit vegetables, fruiting vegetables, leafy vegetables, peas, and potatoes), ginseng and tobacco. The trials covered a wide range of locations , climates and soil types globally and the data obtained reflect the commercial use of the oxathiapiprolin- containing products in the major crop growing regions.Pesticide Petition to Establish Tolerances for Oxathiapiprolin

The results of these field trials substantiate oxathiapiprolin as the maj or residue at harvest in all crop commodities except potato tubers (which were below the limit of quantification). O xathiapiprolin is likewise the relevant residue in process ed commodities . For commodities of animal origin, there was minimal transfer of oxathiapiprolin resid ues from animal feeding - stuffs containing oxathiapiprolin residues to edible tissues, milk, or eggs. Livestock feeding studies were not conducted. B. Toxicological Profile 1. Acute toxicity. Based on EPA criteria, technical oxathiapiprolin is classified as acute toxicology category IV based on overall results from several studies. This compound is considered acute toxicology category IV for acute oral, dermal and inhalation toxicity and eye and skin irritation. Technical oxathiapiprolin is not a dermal sensitizer. No evidence of neurotoxicity was observed in acute study conducted with oxathiapiprolin in rats. The no observed- effect level (NOEL) and no - observed- adverse - effect- level (NOAEL) in an acute neurotoxicity study were 2000 mg oxathiapiprolin/kg bw , which was the highest dose administered in the study. 2. Genotoxicty. Oxathiapiprolin was evaluated in a battery of in vitro and in vivo genetic toxicology studies. Negative results were obtained in all studies indicating that oxathiapiprolin does no t cause genetic damage and, therefore, does not pose a mutagenic hazard. 3. Reproductive and developmental toxicity . No effects on fertility were observed in one - and two generation reproduction studies in rats . No effects on development were observed in developmental toxicity studies in rats and rabbits . Slight delays in maturation were observed in male rats in the reproduction studies , with a NOAEL of 104 mg/kg bw/day. At much higher doses, decreases in offspring body weight were also observed. 4. Subchronic toxicity. Short -term oral feeding studies with oxathiapiprolin were conducted in rats, mice and dogs with durations of up to 90 days. In addition, two other studies were performed in rats: a 14 - day oral gavage study (conducted as a part of early discovery) and a 28 - day dermal study. No adverse effects were observed in any of these studies. In all cases, the NOAELs were greater than or equal to 1000 mg/kg bw/day. Non- adverse findings observed in these studies were limited to changes in organ weight s, clinical chemistry parameters and liver cytochrome P450 isozymes. Oxathiapiprolin showed no evidence of immunotoxicity in a 28 -day feeding study in mice. Additionally, no indications of a potential for oxathiapiprolin to affect the immune system were noted in the repeated dose toxicity studies with rats, mice or dogs. Based on this, oxathiapiprolin does not appear to pose an immunotoxic hazard. Neurotoxicity endpoints were included in the subchronic (90 - day feeding) study that tested up to intake levels of >1000 mg/kg bw/day in male and female rats. No evidence of neurotoxicity was observed. No treatment related clinical signs indicative of potential neurotoxicity were observed in repeated dose studies in mice or dogs. 5. Chronic toxicity . Based on the results of chronic feeding studies in rats and mice, oxathiapiprolin was not carcinogenic in either species. No indications of chronic toxicity were observed in either study. A one -year toxicity study was also conducted in dogs , with no toxicological ly relevant findings. P ossible test substance -related changes in organ weights and clinical chemistry parameters were observed .Pesticide Petition to Establish Tolerances for Oxathiapiprolin

6. Rat metabolism . [ 14 C]Oxathiapiprolin was investigated in rats after single low and high dose administration, and after multiple treatments at low doses. At the low dose (10 mg/kg bw) absorption was 31 -49%, and declined to 5.4 - 7.7% at the high dose (200 mg/kg bw). P eak plasma concentrations occurred at 0.25 - 9.5 hours. P lasma 14 C residue concentrations showed steady- state kinetics in male and female rats after multiple low dose administration s (10 mg/kg bw for 14 days). Maximum tissue concentrations at T max occurred in the liver. C learance was rapid for liver and other tissues by 168 hours after dosing. All tissues at 168 hours, including the carcass, collectively retained <0.05% of the dose. The pattern of distribution was similar between sexes and single and multiple dose administration. The low percentage and concentration values in tissues indicate very low potential for accumulation. Plasma terminal elimination half - lives ranged from 40 - 51 hours following single or multiple low - dose administration. Excretion in urine and faeces was >95% complete by 48 hours after single dosing. The pattern of excretion was similar after multiple dosing. F aecal excretion was the primary route of elimination (  90%). Recovery in urine was much lower (  2. 5 %). E ssentially no excretion occurred by exhalation. Oxathiapiprolin metabolism pathways mainly involved hydroxylation at various ring carbons and ring opening. Pyrazole -piperidine bridge cleavage followed by further oxidation resulted in pyrazole metabolites. 7. Metabolite toxicology . Oxathiapiprolin is considered to be the only molecule of toxicological relevance. Toxicology studi es conducted with metabolites support this conclusion. 8. Endocrine disruption . No relevant effects were observed on any endocrine tissue in short- and long-term studies in rats, mice and dogs to suggest an adverse impact on estrogen or androgen pathways or on steroid biosynthesis . The reproduction studies in rats provided sufficient information to fully interpret the effects of oxathiapiprolin on reproduction. No observations in that study suggested an adverse effect on estrogen. Additionally, investigational studies were conducted that suggest no adverse effects on estrogen. The slight delay in maturation observed in male rats in the reproduction studies may be exacerbated by weight effects; however, the data suggest that other factors are involved. Inve stigational studies did not reveal any adverse effects on androgens by oxathiapiprolin in rats. C. Aggregate Exposure The residue of concern is parent oxathiapiprolin only. No acute dietary risk assessment was needed since there is no acute toxicity endpoint. The chronic studies in dogs, rats, and mice were considered, but not used, as a basis for the chronic reference dose (cRfD), since no adverse findings occurred in these studies. The lowest NOAEL was observed in the multigeneration reproduction study in rats. Therefore, the cRfD 1.04 mg/kg/day is based on the NOAEL of 104 mg/kg bw/day from the multigeneration reproduction study in rats and a 100 - fold safety factor. 1 . Dietary exposurePesticide Petition to Establish Tolerances for Oxathiapiprolin

i. Food. There is no population in the chronic risk assessment for oxathiapiprolin with an exposure greater than 1 % of the chronic reference dose. ii. Drinking water . No acute dietary endpoint was identified. Therefore, an acute drinking water risk assessment wa s not necessary . Chronic drinking water exposure values were calculated for oxathiapiprolin using EPA screening concentration models for ground water and surface water. The groundwater concentrations for oxathiapiprolin were less than those in surface water, so surface water values were used in the dietary risk assessment. When the surface water concentration was included for drinking water in the chronic aggregate assessment to evaluate chronic exposure and risk from food and drinking water, all populations including the general U.S. population and all subpopulations had an exposure less than 1 % of the chronic reference dose (cRfD), indicating a significant margin of safety and reasonable certainty that oxathiapiprolin residues in drinking water will not contribute significantly to the aggregate chronic human health risk. 2. Non - dietary exposure . The Margin of Exposure (MOE) estimated for inhalation while smoking treated tobacco leaves indicates that there are no inhalation intake concerns. Since there are no residential or home uses non - dietary exposure has not been assessed. D. Cumulative Effects A determination has not been made that oxathiapiprolin has a common mechanism of toxicity with other substances. Oxathiapiprolin does not appear to produce a common toxic metabolite with other substances. A cumulative risk assessment was, therefore, not performed for this analysis. E. Safety Determination 1. U.S. population . Based on risk assessments performed using worst - case exposure assumptions there is a reasonable certainty that no harm will result to the general population from the aggregate exposure to oxathiapiprolin. No additional safety factors are warranted. 2. Infants and children . Based on the risk assessments performed using worst - case exposure assumptions there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure to oxathiapiprolin. No additional safety factors are warranted. F. INTERNATIONAL TOLERANCES No tolerances have been established to date for oxathiapiprolin .