Syngenta Crop Protection, LLC

PP# 5F8441

EPA has received a pesticide petition PP# 5F8441 from Syngenta Crop Protection , LLC

, P.O. Box 18300, 410 Swing Road, Greensboro, NC 27419 request ing, pursuant to section 408(d) of the Federal Food, Drug, and Cosme tic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 .685 by establishing a tolerance for residues of o xathiapiprolin in or on the following raw agricultural commodities:

Citrus fruit Crop Group 10

- 10 at 0.06 parts per million (ppm) C itrus oil at 2 .0 parts per million (ppm) C itrus pulp at 0.09 parts per million (ppm) Tuberous and Corm Vegetables, Subgroup 1C at 0.04 parts per million (ppm) P otato, wet peel at 0.07 parts per million (ppm)

EPA has determined that the petition contains data or informa tion 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 oxathiapiprolin is adequately understood to support the proposed tolerances

. Studies in grape, lettuce and potato when treated at the label rates showed no significant meta bolites. The metabolism of oxathiapiprolin in plants was similar regardless of the crop or the treatment regime. Oxathiapiprolin was the principle residue in most crop fractions at various sampling points up to crop maturity. The overall metabolism of oxat hiapiprolin in r otated crops (cereals, root vegetables, leafy vegetables) was consistent with metabolism seen in th e primary crops.

2. Analytical method. Adequate analytical methodology, high

- pressure liquid chromatography with MS/MS detection, is availab le for enforcement purposes

.
3. Magnitude of residues. Field trials to meet the United States requirements were carried out in orchards (citrus ), field ( potato ) . The trials covered a wide range of locations, climates and soil types and the data obtained r eflect the commercial use of the oxathiapiprolin

- containing products in the major US crop growing regions.

The results of these field trials substantiate oxathiapiprolin as the major residue at harvest in the crop commodities. Oxathiapiprolin is likewise the relevant residue in processed commodities.

B. Toxicological Profile

1

. Acute toxicit y. Based on EPA criteria, technical oxathiapiprolin is classified with an overall Toxicity Category IV (Tox Cat IV). This compound is considered a Tox Cat IV2

based on no observed for acute oral, dermal or inhalation toxicity up to the OPPTS testing guidelines limit dose levels tested. Oxathiapiprolin is not an eye or skin irritant and it is not a dermal sensitizer.

No evidence of neurotoxicity was observed in an acut e neurotoxicity study conducted with oxathiapiprolin in rats. The no

- observed

- effect level (NOEL) and no

- observed

adverse

- effect

- level (NOAEL) in an acute neurotoxicity study where 2000 mg oxathiapiprolin/kg bw, which was the highest dose administered in t he 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 po se a mutagenic hazard.

3. Reproductive and developmental toxicity. No effects on fertility were observed in one

and two

- generat ion reproduction studies in rat s. No effects on development were observed in developmental toxicity studies in rats and rabbit s. Slight delays in sexual maturation we r e observed in male rat s in the multi

- generation reproduction studies, with a NOAEL of 104 mg/kg bw/day. D ecreases in offspring body weight were also observed in the multi

- generation reproduction studies at higher do se levels

.
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, a 14 day oral gavage study (conducted as part of early discovery) and a 28

- day derm al study were performed . 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 c hemistry 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 s ubchronic/carcinogen i city 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 1096/1300 mg/kg bw/da y in male / female rats. No evidence of neurotoxicity was observed in the 90

- day dietary toxicity study in rats

. There was also a lack of any treatment related clinical signs indicative of potential neurotoxicity observed in the 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 c onducted in dogs, with no toxicologically relevant findings. Possible test substance

- related changes in organ weights and clinical chemistry parameters were observed.

6. Animal metabolism. [ 14 C]Oxathiapiprolin was investigated in rats after single low and3

high dose administration, and after multiple treatments at low doses. At the low does (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 does administrations (10 gm/kg bw f or 14 days)

Maximum tissue concentrations at T max 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 tiss ues indicate very low potential for accumulation.

Plasma terminal elimination half

- lives r an ged from 40

- 51 hours following single or multiple low

- dose administration. Excretion in urine and feces was >95% complete by 48 hours after single dosing. The pat tern of excretion was similar after multiple dosing. Fecal excretion was the primary route of elimination (≥90%). Recovery in urine was much lower (≤2.5%). Essentially no excretion occurred by exhalation.

7. Metabolite toxicology

. Oxathiapiprolin is consi dered 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, m ice 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 th at 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 weigh t 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

1. Dietary exposure. Subsequent to the filing of a pesticide petition by E.I. du Pont de Nemours and Company, Wilmington, DE (DuPont), EPA established tolerances for residues of the fungicide 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

- methy l

- 3

- (trifluoromethyl)

- 1H

- pyrazol

- 1

- yl] ethanone, in or on: Brassica, head and stem (Subgroup 5A); ginseng; grape; leafy greens (Subgroup 4A); onion, bulb (Subgroup 3

- 07A); onion, green (Subgroup 3

- 07B); pea, edible

- podded; pea, succulent shelled; tomato, d ried; vegetable, cucurbit (Group 9); vegetable, fruiting (Group 8

- 10); and vegetable, tuberous and corm (Subgroup 1C). With this Notice

- of

- Filing, Syngenta is requesting new tolerances for its proposed uses on pota to and citrus (Crop Group 10

- 10 ). There is no expectation of residues of oxathiapiprolin in the meat, milk, or eggs of ruminants and/or poultry resulting from any current or proposed uses and no tolerances have been proposed for4

those commodities at this time

.
The EPA stated in its June 25, 20 15 human health safety technical review of the DuPont petition (DP Barcode D417279) that toxicological studies for oxathiapiprolin did not demonstrate any treatment related effects and did not subsequently establish any oral, dermal, or inhalation (acute, chronic, or short

- term) endpoints for assessment of
consumer exposures , and in keeping with the EPA’s current policy and practice with respect to oxathiapiprolin, Syngenta has not conducted any consumer risk assessments for its proposed uses on citrus frui t (crop g roup 10

- 10) , tuberous and corm vegetables (subgroup 1C)

.

i. Food

Acute exposure

. Due to the lack of toxicological endpoints and Points

- of

- Departure (PODs), a quantitative acute dietary risk assessment was not conducted. While dietary exposure t o 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.

Chronic exposure

. Due to the lack of toxicological endpoints and PODs, a quantitative chron ic dietary risk assessment was not conducted. 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.

Cancer

. A cancer diet ary assessment was not conducted. Oxathiapiprolin is classified as "not likely to be carcinogenic to humans." No treatment

- related increase in tumors was observed in carcinogenicity studies in rats and/or mice.

ii. Drinking water

. Due to the lack of tox icological endpoints and PODs, a quantitative drinking water assessment was not conducted

.

2. Non

- dietary exposure

Residential Exposure

. There is no residential handler exposure scenarios associated with the proposed use on turfgrass (i.e., golf courses and commercial landscapes). Residential exposures are also expected for adults and children conducting post

- application activities on treated golf course (turf). However, since no toxicological endpoints of concern were identified for oxathiapiprolin an d no PODs were selected, a quantitative residential risk assessment was not conducted. Although there is a proposed use on ornamental plants, the proposed use is only for nurseries and commercial greenhouses. HED notes that there are no direct homeowner applications of oxathiapiprolin to ornamentals; however, treated ornamentals could be purchased at a retail location for use in a residential setting. HED considers post

- application exposure resulting from this scenario to be negligible. Furthermore, a q uantitative residential post

- application assessment for the use of oxathiapiprolin on commercial ornamentals was not performed because of the lack of potential exposure and the absence of toxicological endpoints or PODs.5

Occupational Exposure

. Although t here is potential for occupational handler and post

application exposure, risk estimates for OXTP were not quantitatively assessed because no dermal or inhalation toxicological endpoints were identified or PODs selected. The PPE statement on proposed labe ls requires handlers to wear baseline clothing (i.e., long

sleeved shirt, long pants, shoes plus socks), no chemical

- resistant gloves and no respirator. No additional PPE recommendations are needed based on HED’s risk assessment. The PPE determination an d REIs on proposed labels should be based on the acute toxicity of OXTP.

D. Cumulative Effects

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, E PA has not made a common mechanism of toxicity finding as to oxathiapiprolin and any other substances and oxathiapiprolin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that oxathiapiprolin h as a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released b y EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA' s website a t: http://www. epa.gov/pesticides/cumulative

. E. Safety Determination

1. U.S. population. There is the potential for dietary (food and drinking water) and residential exposures associated with all current and proposed uses of oxathiapiprolin. However, due to the lack of toxicity at the human exposure levels anticipated for oxathiapiprolin based on the proposed use patterns, no quantitative dietary, residential, or aggregate exposure assessments are required and no risks of concern are anticipated.

2. Infants and chil dren

. There is the potential for dietary (food and drinking water) and residential exposures associated with all current and proposed uses of oxathiapiprolin. However, due to the lack of toxicity at the human exposure levels anticipated for oxathiapiproli n based on the proposed use patterns, no quantitative dietary, residential, or aggregate exposure assessments are required and no risks of concern are anticipated.

F. International Tolerances

Codex Alimentarious Commission has not yet established Maximu m Residue Limits (CXLs) for oxathiapiprolin

.