Pesticide Petition to Establish Tolerances for Oxathiapiprolin

**EPA REGISTRATION DIVISION -**  **COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS**  **Docket ID Number: EPA -**  **HQ -**  **OPP -**  **2016 -**  **0049 EPA Registration Division c**  **ontact : Sidney Jackson, (703) 305**  **- 7610**  **lnterregional Research Project No.4 (IR -**  **4) Pesticide Petition**  **Number: 5E8437** EPA has received a pesticide petition (PP 5E8437 ) from lnterregional Research Project No.4 (IR 4), Rutgers, The State University of New Jersey , 500 College Road East, Suite 201W, Princeton, NJ 08540, 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 the residues of the fungicide oxathiapiprolin, 1 - [4 - [4 - [5 - (2,6 - difluorophenyl) - 4,5 - dihydro - 3 - isoxazolyl] - 2 - thiazolyl] - 1 - piperidinyl ] - 2 - [5 - me thyl - 3 - (trifluoromethyl) - 1H - py razol - 1 - yl ] - ethanone in or on Basil, fresh leaves, at 10.0 parts per million (ppm); basil, dried leaves, at 80 ppm; Caneberry subgroup13 - 07A, at 0.5 ppm; additionally, as designated in proposed “Tolerance Crop Grouping Program IV” (79 FR 68153, 11/14/2014), tolerances are proposed for: i) all individual crops in the proposed leafy

greens subgroup, 4 - 14A at 15 ppm including amaranth, Chinese; amaranth, leafy ; aster, Indian; blackjack; cat’s whiskers; chervil, fresh leaves; cham - chwi; cham - na - mul; chipilin; chry santhemum, garland; cilantro, fresh leaves; corn salad; cosmos; dandelion; dang gwi; dillweed; dock; dol - nam - mul; ebolo; endive; escarole; fameflower; feather cockscomb; good king henry ; huauzontle; jute, leaves; lettuce, b itter; lettuce, head; lettuce, leaf; orach; parsley , fresh leaves; plantain, buckhorn; primrose, English; purslane, garden; purslane, winter; radicchio; spinach; spinach, malabar; spinach, New Zealand; spinach, tanier; swiss chard; and violet, Chinese; ii) all individual crops in the proposed brassica leafy greens, subgroup 4 - 14B at 10 ppm including, arugula; broccoli raab; broccoli, Chinese; cabbage, ab ys sinian; cabbage, seakale; Chinese cabbage, bok choy ; collards; cress, garden; cress, upland; hanover sa lad; kale; maca; mizuna; mustard greens; radish, leaves; rape greens; rocket, wild; shepherd’s purse; turnip greens; and watercress; iii) all individual crops in the proposed brassica head and stem vegetable, group 5 - 14 at 1.5 ppm including broccoli; Bruss els sprouts; cabbage; cabbage, Chinese, napa; and cauliflower; and iv) all individual crops in the proposed stalk and stem vegetable, subgroup 22A at 2 ppm including agave; aloe vera; asparagus; bamboo, shoots; celtuce; fennel, florence, fresh leaves and s talk; fern, edible; kale, sea; kohlrabi; palm hearts; prickl y pear, pads; and prickly pear, Texas, pads. Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 180 .685 be amended to remove the established tolerances for the residues of oxathiapiprolin in or on the raw agricultural commodities l eafy greens subgroup 4A at 15 ppm and b rassica, head and stem, subgroup 5A at 1.5 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d) (2) of the FFDCA; however, EPA has not full y 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.Pesticide Petition to Establish Tolerances for Oxathiapiprolin

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 significa

nt 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 metaboli sm 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 adequatel y understood to s upport 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 m ethod. Adequate anal ytical methodology , high - pressure liquid chromatography with MS/MS detection, is available for enforcement purposes. 4. Magnitude of residues . IR - 4 and Canada have submitted field trial data for oxathiapiprolin on basil, asparagus, caneberry , and mustard greens. The number and locations of the field trials are in accordance with OPPTS Guideline 860.1500. Field trials were carried out using the maximum number of applications and minimum pre - harvest interval (PHI) for all the crops. The results of these field trials substantiate oxathiapiprolin as the major residue at harvest in all crop commodities. 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 an 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 w ere 2000 mg oxathiapiprolin/kg bw, which was the highest dose administered in the study. 2. Genotoxicty. Ox athiapiprolin 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 not 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 effec ts on development were observed in developmental toxicity

studies in rats and rabbits. Slight delays in maturation were observed inPesticide Petition to Establish Tolerances for Oxathiapiprolin

male rats in the reproduction studies, with a NOAELof 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 stu dy

(conducted as a part of earl y 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 milligram per kilogram (mg/kg ) body weight (bw) /day . Non - adverse findings observed in these studies were limited to changes in organ weights, clinical chemistry parameters and liver cy

tochrome P450 isozy

mes. 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 sy stem 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. Neurotoxici ty

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 neuro toxicity 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 observ ed in either study. A one - ye ar toxicity study was also conducted in dogs, with no toxicologically

relevant findings. Possible test substance - related changes in organ weights and clinical chemistry

parameters were observed. 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). Peak plasma con centrations occurred at 0.25 - 9.5 hours. P lasma 14 C residue concentrations showed steadystate kinetics in male and female rats after multiple low dose administrations (10 mg/kg bw for 14 day s). Maximum tissue concentrations at T max occurred in the liver. C learance was rapid for liver and other tissues by

1 68 hours after dosing. A ll tissues at 168 hours, including the carcass, collectively

retained <0.05% of the dose. The pattern of distribution was similar between sexes and singl e 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. Ex cretion in urine and faeces was >95% complete by 4 8 hours after single dosing. T he pattern of excretion was similar after multiple dosing. F aecal excretion was the primary

route of elimination (  90%). Recovery i n urine was much lower (  2.5%). Essenti ally

no excretion occurred by exhalation.Pesticide Petition to Establish Tolerances for Oxathiapiprolin

Oxathiapiprolin metabolism pathway s mainly involved hydroxylation at various ring carbons and ring opening. P yr azole - piperidine bridge cleavage followed by f urther oxidation resulted in py razole metabolites. 7. Me tabolite toxicology . Oxathiapiprolin is considered to be the onl y molecule of toxicological relevance. Toxicology

studies 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 biosy nthesis. The reproduction studies in rats provided sufficient information to fully

interpret the effects of oxathiap iprolin 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. Investigational studies did not reveal any adverse effects on androgens b y oxathiapiprolin in rats. C. Aggregate Exposure The residue of concern is parent oxathiapiprolin only . Due to the limited toxicity observed in the oxathiapiprolin toxicological database, E PA previously determined that toxicological endpoints and points of departure (POD) were not required for oxathiapip rolin. 1. Dietary exposure While dietary

exposure to oxathiapiprolin may occur through food and drinking water, no risks of concern are anticipated due to the lack of toxicity at anticipated human exposure levels from the proposed new uses for oxathiapiprolin. 2. Non - dietary exposure . 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 anal ys is. E. Safety Determination 1 . U.S. population . While dietary exposure to oxathiapiprolin may occur through food and drinking water, no risks of concern are anticipated due to the lack of toxicity at anticipated human exposure levels from the proposed new uses for oxathiapiprolin. Thu s, 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.Pesticide Petition to Establish Tolerances for Oxathiapiprolin

2. Infants and children . While dietary exposure to oxathiapiprolin may occur through food and drinking water, no risks of concern are anticipated due to the lack of toxicity at anticipated human exposure levels from the proposed new uses for oxathiapiprolin. Thus, 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 on the proposed new uses.