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 

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. Field trials to meet country (Canada, the United States) and regional (the EU) 

requirements were carried out in vineyards (grape), field or protected vegetables (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 major residue at harvest in all crop 

commodities except potato tubers (which were below the limit of quantification). Oxathiapiprolin is 

likewise the relevant residue in processed commodities. For commodities of animal origin, there was 

minimal transfer of oxathiapiprolin residues 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 noobserved-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 twogeneration 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 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. 
Pesticide Petition to Establish Tolerances for Oxathiapiprolin

6. Rat metabolism. [

14C]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 14C 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.

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 exposure
Pesticide 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 was 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.