Document ID: EPA-HQ-OPP-2016-0049-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-05-19T04:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR 
PESTICIDE PETITIONS 

Docket ID Number: EPA-HQ-OPP-2016-0049

EPA Registration Division contact:  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-methyl-3-(trifluoromethyl)-1H-pyrazol-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; chrysanthemum, 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, bitter; 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, abyssinian; cabbage, seakale; Chinese cabbage, bok choy; collards; cress, garden; cress, upland; hanover salad; 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; Brussels 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 stalk; fern, edible; kale, sea; kohlrabi; palm hearts; prickly 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 leafy greens subgroup 4A at 15 ppm and brassica, 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 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. 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 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 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 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 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 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 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 concentrations occurred at 0.25-9.5 hours.  Plasma [14]C residue concentrations showed steady-state kinetics in male and female rats after multiple low dose administrations (10 mg/kg bw for 14 days).
Maximum tissue concentrations at Tmax occurred in the liver.  Clearance 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.  Faecal excretion was the primary route of elimination (90%).  Recovery in urine was much lower (2.5%).  Essentially 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 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 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. Investigational studies did not reveal any adverse effects on androgens by 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, EPA previously determined that toxicological endpoints and points of departure (POD) were not required for oxathiapiprolin. 

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 analysis.

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. Thus, 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. 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.