EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Kable Davis , ( 703) 306

- 0415

ISK Biosciences Corporation

EPA has received a pesticide petition PP 4 F82 5 3 from ISK Biosciences Corporation , 7470 Auburn Road, Suite A, Concord, Ohio, 44077, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a n exemption from the requirement of a tolerance for indirect or inadvertent residues of the insecticide cyclan iliprole , 3

- bromo

- N

- [2

- bromo

- 4

- chloro

- 6

- [[(1

- cyclopropylethyl)amino] carbonyl]phenyl]

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazole

- 5

- carboxamide , including its metabolite NK

- 1375, in or on all f ood commodities not otherwise covered by a tolerance for this insecticide

. In the Federal Register of May 6, 2015, (80 FR 18327 ) (FRL

– 9924

– 00] ), EPA issued a document pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide petition ( PP 4F8253) by ISK Biosciences Corporation requesting that that 40 CFR part 180 be amended by establishing tolerances on various agricultural commodities for residues of the insecticide, Cyclaniliprole. That petition (PP 4F8253) has since been amended to also request an exemption from the requirement of a tolerance for indirect or inadvertent residues of all food commodities which the EPA does not established tolerances. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA ; however, EPA has not fully evaluated the sufficiency of the submitted d a ta 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 me tabolism of cyclaniliprole as well as the nature of the residues in plants is adequately understood for the purposes of th is exemption from tolerance request . Metabolism studies were conducted with three diverse crops, apples, lettuce and potatoes

. All t hree crops showed a similar patter n of metabolism with unchanged cyclaniliprole representing the major residue . The metabolism of cyclaniliprole in plants was limited to one major metabolite, NK

- 1375, and a number of minor metabolites . Hence, parent cycl aniliprole and the metabolite NK

- 13 75 define the residue of

concern.

2. Analytical method. A practical analytical method for Cyclaniliprole and NK

1375 using Liquid Chromatography

- MS/MS is available for analysis of all plant matrices

. This method has been confirmed through independent laboratory validation and is available for enforcement purposes.2

3. Magnitude of residues. Residue trials have been conducted and reported for all labeled crops. The magnitude of residues is adequately understood for the purpo ses of this exemption from tolerance request.

B. Toxicological Profile

1. Acute toxicity. Results from a battery of acute toxicity studies place t echnical cyclaniliprole in Toxicity Category III for oral LD 50 and dermal LD 50 , and Category IV for inhala tion LC 50 , dermal irritation , and eye irritation. Technical cyclaniliprole was not a dermal sensitizer

.
In an acute neurotoxicity study, cyclaniliprole was administered orally to groups of rats at oral doses up to 2000 mg/kg , with no evidence of
neuroto xicity or neurohistopathological change . Consequently, 2000 mg/kg was considered to be the NOEL

. 2. Genotoxic i ty

. The genotoxic potential of cyclaniliprole has been assessed as negative by several in vitro and in vivo mutagenicity studies. Cyclaniliprole did not elicit a genotoxic response in any of the studies conducted.

3. Reproductive and developmental toxicity. Results from a two

- generation study indicate that cyclaniliprole is not a reproductive toxicant. The NOEL for systemic toxicity and reprod uctive performance was 20000 ppm , the highest dose tested (equivalent to 1406 and 1589 mg/kg/day, respectively for P males and females and 1683 and 1835 mg/k g/day for F1 males and females).

Results from developmental studies in rats and rabbits provided no indication of teratogenic effects for fetuses of either species and no evidence of development al effects in the absence of maternal toxicity. For the rat teratology study, d oses up to 1000 mg/kg bwt /day were administered bet ween Da ys 6 and 19 of gestation

. The NOEL for maternal toxicity and developmental toxicity was 1000 mg/kg bwt/day, the highest dose tested. Cyclaniliprole technical was not teratogenic to rats. For the rabbit teratology study, d oses up to 1000 mg/kg bwt /day were administered bet ween Days 6 and 27 of gestation

. The NOEL for maternal toxicity and developmental toxicity was 10 00 mg/kg bwt/day, the highest dose tested. Cyclaniliprole technical was not teratogenic to rabbits.

4. Subchronic toxicity. Short

- term (28

- day) t oxicity studies were conducted in rats and dogs

. Doses evaluated in the rat study were 0, 300, 1250, 5000 and 20000 ppm. S tatistically significant increases in absolute and/or relative liver weight were seen at the highest dose level. There were no asso ciated biochemi cal or histopathological changes and the increased liver weight was therefore considered to be an adaptive hepatic response to the high dose of test substance and not indicative of noteworthy toxicity. Males in all treated groups and female s receiving 20000 or 5000 ppm showed reduced total bilirubin, but in the absence of any associated changes this finding was3

considered to have no toxicological significance. The NOAEL in this 28

- day study was therefore considered to be 20000 ppm, correspo nding to approximately 1800 mg/kg bw/day in both sexes. Doses evaluated in the 28

- day dog study were 0, 100, 1000, 10000 and 30000 ppm. The male dog at 30000 ppm showed a small decrease in bodyweight gain when compared with the control male. At 10000 pp m, male and female dogs both showed relatively higher absolute and relative weights of the liver; centrilobular hepatocellular hypertrophy was observed in the male dog, and higher ALP levels were detected in the female dog. No clear treatment

- related (tox ic) changes were observed in the dog of either sex at 1000 or 100 ppm.
S ubchronic (90

- day) feeding studies were conducted in rats, mice, and dogs. Doses evaluated in the r at study were 0, 6 00, 60 00 and 200 00 ppm. The NO A EL was 20 000 ppm in males ( equiv alent to 1 331 mg/kg bwt/day ) and 6000 ppm for female s ( equivalent to 467 mg/kg bwt/day ). T he treatment

related changes observed in females treated at 20000 ppm included prolongation of APTT, and increases in liver, heart, and ovary weight. Doses evalua t ed in the mouse study were 0, 2 00, 1 2 00 and 8 000 ppm. Dietary administration to mice for 13 weeks was well tolerated, causing no adverse changes. The no

- observed

- adverse

- effect level (NOAEL) in this study was 8000 ppm (equivalent to 1023 mg/kg bw/day in males and 1350 mg/kg bw/day in females). Doses eval uated in the dog study were 0, 1 00, 1 000 and 10000 ppm . The NO AEL was 1000 ppm for males (26.8 mg/kg bw/day) and 10000 ppm for females (270 mg/kg bw/day). Males receiving 10000 ppm showed significantly increase d absolute and relative weight of the liver (138% and 136% of control respectively), with one showing cen t rilobular hepatocellular hypertrophy.

5. Chronic toxicity. An 18

- month oncoge nicity study was conducted in mice with dietary concentration s of 0, 2 00, 1250 and 8000 ppm

. The no

- observed

adverse

- effect level (NOAEL) in this study was 8000 ppm (equivalent to 884 mg/kg bw/day in males and 1316 mg/kg bw/day in females). There was no evidence of carcinogenicity.

A 1

- year chronic toxicity study was conducted in rats with dietary concentrations of 0, 200, 2000, 6000 and 20 000 ppm technical cyclaniliprole. The systemic NO A EL was considered to be 20000 ppm (males, 955 mg/kg bw/day; females, 1213 mg/kg bw/day) , the highest dose tested.

A 2

- year ch ronic toxicity/carcinogenicity study was conducted in rats wit h dietary concentrations of 0, 200, 2 000 , 6000 and 20 000 ppm technical cyclaniliprole

. Th e no - observed

- adverse

- effect level (NOAEL) for toxicity was determined to be 6000 ppm for males (249 mg/ kg/day) and 20000 ppm for females (1041 mg/kg bw/day)

. The only non

- neoplastic histopathological change attributed to cyclaniliprole was a small increase in the incidence of hypertrophic follicular cells in the thyroid of males receiving 20000 ppm. The N OAEL for carcinogenicity was 20000 ppm in both males and females4

(834 and 1041 mg/kg bw/day respectively). There was no evidence of carcinogenicity.

A 52

- week chronic toxicity study was conducted in dogs with dietary concentrations of 0, 50, 150, 1 000 and 10 ,000 ppm. The NO A EL was 1000 ppm (males, 27.2 mg/kg bw/day; females, 27.6 mg/kg bw/day) . The LOEL

was 10 ,000 ppm (males, 259 mg/kg bw/day; females, 288 mg/kg bw/day) based on increased absolute and relative liver weights

.

6. Animal metabolism. The metabolism of cyclaniliprole in rats and goats is adequately understood. Cyclaniliprole is r apidly excreted mainly via the fec es
. The majority of excreted material was unchanged cyclaniliprole, with several minor metabolites present in feces, bile, urine a nd tissues. There are no significant qualitative differences between rat and ruminant metabolic pathways.

7. Metabolite toxicology

. No toxicologically significant metabolites were detected in plant or animal metabolism studies. The residue of concern fo r tolerance setting purposes is the parent compound and the major plant metabolite, NK

- 1375 . Consequently, there is no additional concern for toxicity of metabolites.

8. Endocrine disruption

. The submitted studies include evaluation of the potent ial eff ects on reproduction and development and an evaluation of the pathology of the e ndocrine organs following short or long

- term exposure. The data demonstrate no treatment

- related effects on the endocrine system.

9. Immunotoxicity

. Four

- week immuno toxicity studies were conducted in female mice

. There was no effect on the immune system at any dose tested. The NOEL was greater than 20,000 ppm ( ≥1690 mg/kg bwt/day). The NOEL for functional immunotoxicity by cyclaniliprole was greater than 8000 ppm (i.e. >1352 mg/kg bw/day) , the highest dose tested

.

C. Aggregate Exposure

1. Dietary exposure

. Exposure assessments were conducted to evaluate the
po tential risk due to dietary exposure of the U.S. population to residues of cyclaniliprole

.

For acute dietary exposure, an Acute Reference Dose (a RfD ) is not identified for Cyclaniliprole since there was no evidence of initial acute effects in the
acute or al or short

- term toxicity studies, or the developmental toxicity studies in rats and rabbits. There were no effects seen in t he acute neurotoxicity study at the limit dose level of 2000 mg/kg/day. No initial acute effects were seen in the 90

- day neurotox icity study.
For chronic dietary exposure, the chronic reference dose ( c RfD) is 0. 2725

mg/kg bwt /day , based on the NOAEL from the dog 1

- year toxicity study ( 27.2 mg/kg bwt /day ) and dividing by an uncertainty factor of 100. The chronic population adjusted d ose (cPAD) is also 0. 272 mg/kg bwt /day since the FQPA safety factor is anticipated to be 1 for cyclaniliprole

.

i. Food. Tier 1 chronic dietary exposure analyses were conducted for cyclaniliprole in/on all labeled crops including pome fruit, tree nuts, st one fruit, non

- brassica and brassica (cole) leafy vegetables, fruiting vegetables, cucurbit vegetables and berry and small fruit vine climbing crop groups to determine the exposure contribution of th is commodity to the diet and to ascertain the chronic ris k potential. In addition, the contribution from tea (dried and instant) based on imported tea was calculated as well as contributions from meat and milk residues based on the animal feed items of almond, hulls and apple, wet pomace. The exposure estimate s were based on the proposed tolerance leve l residues , average processing factors and a market share of 100% crop treated as a conservative assumption

. The

c onsumption data were from the USDA’s National Health and Nutrition Examination Survey/What We Eat i n America NHANES/WWEIA dietary survey conducted in 2003

- 2008 (2 day food consumption data) using the Dietary Exposure Evaluation Module (DEEM

- FCID) software, version 3 .16.

U sing all of the worst case exposure scenarios listed above, the Tier 1 chronic die tary e xposure estimates resulted in an estimated exposure for the general U.S. population of 0.00 3649 mg/kg bwt /day. This exp osure corresponds to 1.3 % of the cPAD . The highest exposure estimate calculated was for the subgroup children, 1

- 2 years . This e xposure was determined to be 0.00 6608 mg/kg bwt /day ( 2.4 % of the cPAD)

. The chronic dietary exposure analysis is summarized in the table below.

Population Exposure Estimate % of cPAD Subgroup (mg/kg body wt/day) U.S. Population 0.003649 1.3

All In fants (< 1 year old) 0.003487 1.3 Children (1

- 2 years old) 0.006608 2.4 Children (3

- 5 years old) 0.005366 2.0 Children (6

- 12 years old) 0.003323 1.2 Youth (13

- 19 years old) 0.002571 0.9 Females (13

- 49 years old) 0.003633 1.3 Adults (20

- 49 years old) 0.003465 1.3

Adults (50+ years old) 0.003867 1.46

It can be concluded that long

- term dietary exposure to cyclaniliprole through residues on all commodities should not be of cause for concern.

ii. Drinking water

. Using FIRST and SCIGR O W models , estimates of cyclaniliprole residues in surface and ground water were calculated . The highest EEC value of 1.860 ug/L was used as input into the DEEM/FCID model for drinking water (direct and indirect sources)

.

2. Non

- dietary exposure

. Based on t he proposed use s for cyclaniliprole on the crops noted above , non - occupational exposure of cyclaniliprole would not be expected to the general population . The only anticipated exposure route for the US population is via the diet (food and water only). Therefore, residenti al risk assessments for the incidental oral, dermal, and inhalation exposure routes are not required.

O ccupational post

- application exposure is possible. For dermal short

- t erm exposure, no toxicity was found at 1000 mg/kg in a 28

- day rat dermal toxicity study. Therefore, in the absence of any hazard identified for dermal
exposure , a dermal post

- application risk assessment was not conducted. Potential inhalation exposure was not considered since it is negligible when assessing re

- entry risks.

Occupat ional exp osure for mixing/loading and applying cyclaniliprole was considered. Potential exposure was considered negligible since MOE s were greater than 10,000 for all calculations.

D. Cumulative Effects

EPA has not made a common mechanism of toxicity finding as to cyclaniliprole and
any other substances, and cyclaniliprole 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 cyclaniliprole has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. Based on the completeness and reliability of the toxicity data and the conservative exposure assessments, there is a reasonable certainty that no harm will result from the aggregate exposure of residues of cyclaniliprole

.

2. Infants and children

. Based on the completeness and reliability of the toxicity data and the conservative exposure assessments, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure of residues of cyclaniliprole

.

F. International Tolerances7

Presently, t here are no Codex maximum residue levels (MRLs) established for residues of cyclaniliprole on any crop.