Pesticide Petition to Establish Tolerances for Cyantraniliprole

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

PP No. (4F8258)

EPA has received a pesticide petition (PP No. 4F8258) 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 180.672 to establish 

tolerances for residues of cyantraniliprole, 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-

[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide, including its metabolites and degradates,

in or on the following commodities: artichokes, globe (import tolerance) at 0.1ppm; berries, low growing, 

except strawberries (crop subgroup 13-07H, import tolerance) at 0.08 ppm; coffee, bean, green (import 

tolerance) at 0.05 ppm; grapes (import tolerance) at 1.5 ppm; olives (import tolerance) at 1.5 ppm; 

peanuts at 0.01 ppm; peanut hay at 3 ppm; pomegranates (import tolerance) at 0.01 ppm; rice, grain 

(import tolerance) at 0.03 ppm; soybeans, seed at 0.4 ppm; strawberries at 1.0 ppm; vegetables, foliage of 

legume (crop group 7) at 50 ppm; vegetables, leaves of root and tuber (crop group 2) at 40 ppm; 

vegetables, legume, dried shelled, except soybean (crop subgroup 6C) at 0.9 ppm; vegetables, legume, 

edible podded (crop subgroup 6A) at 2 ppm; vegetables, legume, succulent shelled (crop subgroup 6B) at 

0.2 ppm; vegetables, root, except sugar beet (crop subgroup 1B) at 0.4 ppm; tea, dried (import tolerance) 

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 cyantraniliprole is adequately understood to support the proposed 

tolerances. Studies in lettuce, rice, tomato, and cotton when treated at proposed label rates showed no 

significant metabolites. The metabolism of cyantraniliprole in plants was similar regardless of the crop or 

the treatment regime. Cyantraniliprole was the principal residue in most crop fractions at various 

sampling points up to crop maturity. The overall metabolism of cyantraniliprole in rotated crops (wheat, 

red beets, lettuce, and soybeans) was consistent 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. Lactating goat and laying hen metabolism studies were 

conducted. The metabolism of cyantraniliprole in the rat was consistent with that of the lactating goat 

(ruminant) and laying hen.

3. Analytical method. Adequate analytical methodology, high-pressure liquid chromatography with ESIMS/MS detection, is available for enforcement purposes. 

4. Magnitude of residues. Field trials were conducted on artichokes, low growing berries (13-07H0, 

coffee, grapes, olives, peanuts, pomegranates, rice, soybeans, legume and root vegetables, and tea 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 cyantraniliprole-containing 

products in the major crop growing regions.

The results of the field trials substantiate cyantraniliprole as the major residue in harvested raw 

agricultural commodities. 
Pesticide Petition to Establish Tolerances for Cyantraniliprole

B. Toxicological Profile

1. Acute toxicity. Based on EPA criteria, technical cyantraniliprole 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 

cyantraniliprole is not a dermal sensitizer. 

No evidence of neurotoxicity was observed in studies 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 studies 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, clinical pathology and liver histopathology in dogs.

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 potential neurotoxicity were observed in short-term and 

long-term exposure studies in rats, mice, or dogs.

5. Chronic toxicity. Based on the results of chronic feeding studies 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 14C-cyantraniliprole in rats was rapid 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 14C 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 with that observed for the single dose study.
Pesticide Petition to Establish Tolerances for Cyantraniliprole

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 impact 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) of 0.01 mg/kg bw/day is based on a NOAEL of 1 mg/kg bw/day from 

the 1-year oral study in dogs and an uncertainty factor of 100.

1. Dietary exposure

i. Food. Chronic dietary exposure resulting from the currently approved uses and proposed uses of 

cyantraniliprole is within acceptable limits for all sectors of the population. The chronic module of the 

Dietary Exposure Evaluation Model with Food Commodity Intake Database (DEEM-FCIDTM, version 

3.16) was used to conduct the assessment. This model incorporates nationwide food consumption data as

reported by respondents in the 2-day food consumption survey (2003-2008) of the National Health and 

Nutrition Examination Survey (NHANES). The chronic exposure analysis used overall mean field trial 

values, processing factors, and a conservative assumption of 100% crop treated. Secondary residues in 

milk and meat were also included in the analysis. The resultant exposure was within required limits (< 

100% cRfD).

ii. Drinking water. The impact of cyantraniliprole in drinking water on chronic dietary exposure was 

assessed. The highest modeled cyantraniliprole residue value from FIRST Tier 1 surface water and SCI 

GROW Tier 1 groundwater models under worst-case conditions for chronic exposure was determined to 

be in surface water; when this conservative value for drinking water was included with the food residues 

in the chronic exposure assessment the resultant exposure was within required limits (< 100% cRfD).

2. Non-dietary exposure. Residential exposure (non-occupational, non-dietary exposure to consumers) 

was conservatively assessed for dermal post-application exposure (children and adults), 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 incidental 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, therefore, not performed for this analysis.

E. Safety Determination
Pesticide Petition to Establish Tolerances for Cyantraniliprole

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 result to the infants and children from the aggregate 

exposure to cyantraniliprole. No additional safety factors are warranted.

F. INTERNATIONAL TOLERANCES

A number of international tolerances (or Maximum Residue Levels, MRL's) have been 

established for cyantraniliprole.