Pesticide Petition to Establish Tolerances for Cyantraniliprole

I. E.I. du Pont de Nemours and Company

PP No. (1F7894)

EPA has received a pesticide petition (PP No. 1F7894) 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 cyantraniliprole, 3-bromo-1-(3-chloro-2-pyridinyl)- N -[4-cyano-2-methyl-6- [(methylamino)carbonyl]phenyl]-1 H -pyrazole-5-carboxamide, including its metabolites and degradates, in or on the following commodities: almond hulls at 30 ppm; berries and small fruits, bushberries (crop subgroup 13-07B) at 4 ppm; Brassica (cole) leafy vegetables, head and stem Brassica (crop subgroup 5A) at 2 ppm; Brassica (cole) leafy vegetables, leafy Brassica greens (crop subgroup 5B) at 30 ppm; bulb vegetables, onion, bulb (crop subgr oup 3-07A) at 0.04 ppm; bulb vegeta bles, onion, green (crop subgroup 3-07B) at 8 ppm; cattle, fat at 0.01 ppm; cattle, liver at 0.04 ppm; cattle, meat at 0.01 ppm; cattle, meat byproducts, except liver at 0.01 ppm; cherries at 6 ppm; citrus fruits (crop group 10-10) at 0.7 ppm; cotton gin byproduct at 10 ppm; cucurbit vegetables (c rop group 9) at 0.3 ppm; fruiting vegetables (crop group 8-10) at 2 ppm; goat, fat at 0.01 ppm; goat, liver at 0.04 ppm; goat, meat at 0.01 ppm; goat, meat byproducts, except liver at 0.01 ppm; hog, fat at 0.01 ppm; hog, liver at 0.04 ppm; hog, meat at 0.01 ppm; hog, meat byproducts, except liver at 0.01 ppm; horse, fat at 0.01 ppm; horse, liver at 0.04 ppm; horse, meat at 0.01 ppm; horse, meat byproducts, except liver at 0.01 ppm; leafy vegetables (except Brassica vegetables) (crop group 4) at 15 ppm; milk at 0.01 ppm; milk, fat at 0.04 ppm; oilseeds, except cotton gin byproduct (crop group 20) at 1 ppm; pome fruits (c rop group 11-10) at 0.8 ppm; root and tuber vegetables, tuberous and corm ve getables (crop subgroup 1C) at 0.15 ppm; sheep, fat at 0.01 ppm; sheep, liver at 0.04 ppm; sheep, meat at 0.01 ppm; sheep, meat byproducts, except liver at 0.01 ppm; stone fruits, except cherries (crop group 12) at 1.5 ppm; tree nuts, except almond hulls (crop group 14) at 0.06 ppm; citrus, oil at 6 ppm; citrus, raw peel at 2 ppm; and potato, wet peel at 0.3 ppm.

In addition, DuPont is proposing pursuant to secti on 408 (d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a (d), to amend 40 CFR part 180 to establish indirect or inadvertent tolerances for residues of cyantraniliprole, 3-bromo-1-(3-chloro-2-pyridinyl)- N -[4-cyano-2-methyl-6- [(methylamino)carbonyl]phenyl]-1 H -pyrazole-5-carboxamide, including its metabolites and degradates, in or on the following commodities: foliage of legum e vegetables (crop group 7), forage at 0.15 ppm, hay at 0.6 ppm; forage, fodder and straw of cereal grains (crop group 16), forage at 0.06 ppm, hay and straw at 0.15 ppm; grass forage, fodder, and hay (crop gr oup 17), forage at 0.06 ppm, hay at 0.15 ppm; leaves of root and tuber vegetables (human food or animal feed) (crop group 2) at 0.04 ppm; nongrass animal feeds (forage, fodder, straw, and hay) (crop group 18), forage at 0.06 ppm, hay at 0.15 ppm; peanut hay at 0.03 ppm; and root and tuber vegetables, root vegetables (crop subgroup 1A) at 0.03 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 gran ting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism

. The metabolism of cyantraniliprole is ad equately understood to support the proposed tolerances. Studies in lettuce, rice, tomato, and cott on when treated at proposed label rates showed no significant metabolites. The metabolism of cyantranilipro le in plants was similar regardless of the crop or the treatment regime. Cyantraniliprole was the principal residue in most crop fractions at variousPesticide Petition to Establish Tolerances for Cyantraniliprole

sampling points up to crop maturity. The overall metabolism of cyantraniliprole in rotated crops (wheat, red beets, lettuce, and soybeans) was consiste nt with metabolism seen in the primary crops.

2. Livestock Metabolism

. The metabolism of cyantraniliprole in ruminants and poultry is adequately understood to support the proposed tolerances. Lact ating goat and laying hen metabolism studies were conducted. The metabolism of cyantraniliprole in the ra t was consistent with that of the lactating goat (ruminant) and laying hen.

3. Analytical method

. Adequate analytical methodology, high-pr essure liquid chromatography with ESIMS/MS detection, is available for enforcement purposes.

4. Magnitude of residues . Field trials were conducted on corm vegetables (potatoes), bulb vegetables, leafy vegetables, brassica vegetables, legume vegetables, cucurbits vegetables, fruiting vegetables, citrus fruit, pome fruit, stone fruit, bushberries, tree nuts, and oilseeds with formulations containing cyantraniliprole. The trials covered a wide range of locations, climates, and soil types globally and the data obtained reflect the commercial use of the cy antraniliprole-containing products in the major crop growing regions.

The results of the field trials substantiate cyan traniliprole as the major residue in harvested raw agricultural commodities. For instances of residue in processing factions, the relevant residue was found to be cyantraniliprole parent plus the metabolite IN-J9Z38. Residues in commodities of animal origin were relevant only for cattle.

B. Toxicological Profile

1. Acute toxicity. Based on EPA criteria, technical cyantran iliprole is classified as acute toxicology category IV based on overall results from several studi es. This compound is considered acute toxicology category IV for acute oral, dermal and inhalation toxicity and eye and skin irritation. Technical cyantraniliprole is not a dermal sensitizer.

No evidence of neurotoxicity was observed in studi es conducted with cyantraniliprole in rats. The NOAEL in an acute neurotoxicity study was 2000 mg/kg bw and was the highest dose administered in the study.

2. Genotoxicty. Cyantraniliprole was evaluated in a battery of in vitro and in vivo genetic toxicology studies. Negative results were obtained in all st udies indicating that cyantraniliprole does not cause genetic damage and, therefore, does not pose a mutagenic hazard.

3. Reproductive and developmental toxicity . Based on the results of a two-generation reproduction study in rats and a developmental toxicity studies in rats and rabbits, cyantraniliprole does not pose a specific concern for effects on reproduction or development.

4. Subchronic toxicity. The primary toxicological findings in short-term, repeated-dose feeding toxicity studies included non-adverse increases in liver weight in rats, mice, and dogs due to a pharmacological response to liver metabolism, an effect on thyroid hormones and associated thyroid gland histopathology in rats, a non-adverse increase in the degree of lipid in adrenal cortical cells in both rats and mice, and changes in body weight, nutritional parameters, clin ical pathology and liver histopathology in dogs.Pesticide Petition to Establish Tolerances for Cyantraniliprole

Dermal application of cyantraniliprole to rats for 28 days did not result in any treatment related findings up to and including a maximum dose of 1000 mg/kg bw/day.

Cyantraniloprole showed no evidence of immunotoxicity in 28-day feeding studies in rats or mice and no evidence of neurotoxicity in a 90-day feeding study in rats.

No treatment related clinical signs indicative of pot ential neurotoxicity were ob served in short-term and long-term exposure studies in rats, mice, or dogs.

5. Chronic toxicity . Based on the results of chronic feeding studi es in rats and mice, cyantraniliprole is not a carcinogen. The lowest NOAEL following chronic, long-term feeding is 5.7 mg/kg/day is based on liver enzyme changes, liver histopathology and arteritis in the one-dog study.

No treatment related clinical signs indicative of potential neurotoxicity were observed in long-term exposure studies in rats, mice, or dogs.

6. Rat metabolism

. The absorption of 14 C-cyantraniliprole in rats was ra pid with peak concentrations occurring at 1-2.5 hours after low or high (10 or 150 mg/kg bw) dose administration. Tissue distribution

of the absorbed dose was extensive and indicated low potential for accumulation. Excretion was substantially complete by 24-48 hours after dosing.

Following 14 days of dose administration the 14 C residues were readily eliminated from the plasma and tissues and confirmed minimal potential for accumulation. The profile of metabolites in urine and faeces

indicated extensive metabolism consistent w ith that observed for the single dose study.

7. Metabolite toxicology

. Cyantraniliprole 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 im pact on estrogen or androgen pathways or on steroid biosynthesis. Effects on thyroid hormone homeostatis were observed in rats following dietary exposure and demonstrated to be due to increased clearance of thyroid hormone as a result of enzyme induction.

C. Aggregate Exposure

The residue of concern is parent cyantraniliprole only.

No acute dietary risk assessment was needed since there is no acute tox endpoint.

The chronic reference dose (cRfD) 0.057 mg/kg/day is based on the NOEL of 5.7 mg/kg/day from a oneyear dog tox study and a 100X safety factor.

1. Dietary exposure

i. Food

. There is no population in the chronic risk assessment for cyantraniliprole with an exposure greater than 5% of the chronic reference dose.

ii. Drinking water

. No acute dietary endpoint was identified. Therefore, an acute drinking water risk assessment is not considered necessary. One can concl ude with reasonable certainty that residues of cyantraniliprole in drinking water do not contribute signi ficantly to the aggregate acute human health risk.Pesticide Petition to Establish Tolerances for Cyantraniliprole

Chronic drinking water exposure analyses were cal culated for cyantraniliprole using EPA screening concentration models for ground water SCI-GRO W and surface water FIRST. The groundwater concentrations for cyantraniliprole were less than those in surface wa ter, so surface water values were used in the dietary risk assessment.

When the surface water concentration of 1.1 ppb was in cluded for drinking water in the chronic aggregate assessment to evaluate chronic exposure and risk from food and drinking water, no population including the general U.S. population and all subpopulations had an exposure greater 5% of the chronic reference dose (cRfD), indicating a significant margin of safety. These results indicate that a reasonable certainty exists that cyantraniliprole residues in drinking water will not contribute significantly to the aggregate

human risk.

2. Non-dietary exposure . Residential exposure (non-occupational, non-dietary exposure to consumers) was conservatively assessed for dermal post-application exposure (children and a dults), and for children the oral exposures via hand-to-mouth, object-to-mouth, and incidental ingestion of soil were also assessed. The margins of exposure (MOE) greatly exceed the 100-fold MOE required for these routes

and from the combined children’s incide ntal oral ingestion. Therefore, residential non-dietary exposure is

not a concern.

D. Cumulative Effects

A determination has not been made that cyantraniliprole has a common mechanism of toxicity with other substances. Cyantraniliprole does not appear to produce a common toxic metabolite with other substances. A cumulative risk assessment was, th erefore, 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 cyantraniliprole. 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 r esult to the infants and children from the aggregate exposure to cyantraniliprole. No additional safety factors are warranted.

F. INTERNATIONAL TOLERANCES

No tolerances have been establishe d to date for cy antraniliprole.