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 4F8253 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 an exemption from the requirement 

of a tolerance for indirect or inadvertent residues of the insecticide cyclaniliprole,3-

bromo-N-[2-bromo-4-chloro-6-[[(1-cyclopropylethyl)amino] carbonyl]phenyl]-1-(3-

chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, including its metabolite NK-1375,

in or on all food 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 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 cyclaniliprole as well as the nature of 

the residues in plants is adequately understood for the purposes of this

exemption from tolerance request. Metabolism studies were conducted with 

three diverse crops, apples, lettuce and potatoes. All three crops showed a 

similar pattern 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 cyclaniliprole and the metabolite NK-1375 define the residue of 

concern.

2. Analytical method. A practical analytical method for Cyclaniliprole and NK1375 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.
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3. Magnitude of residues. Residue trials have been conducted and reported for 

all labeled crops. The magnitude of residues is adequately understood for 

the purposes of this exemption from tolerance request.

B. Toxicological Profile

1. Acute toxicity. Results from a battery of acute toxicity studies place technical 

cyclaniliprole in Toxicity Category III for oral LD50 and dermal LD50, and 

Category IV for inhalation LC50, 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 

neurotoxicity or neurohistopathological change. Consequently, 2000 mg/kg 

was considered to be the NOEL.

2. Genotoxicity. 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 reproductive 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/kg/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 developmental effects in the absence of maternal toxicity. For the rat 

teratology study, doses up to 1000 mg/kg bwt/day were administered between 

Days 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, doses up to 1000 mg/kg bwt/day were administered between 

Days 6 and 27 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 rabbits.

4. Subchronic toxicity. Short-term (28-day) toxicity studies were conducted in 

rats and dogs. Doses evaluated in the rat study were 0, 300, 1250, 5000 and

20000 ppm. Statistically significant increases in absolute and/or relative liver 

weight were seen at the highest dose level. There were no associated 

biochemical 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 females receiving 20000 or 5000 ppm showed reduced total 

bilirubin, but in the absence of any associated changes this finding was 
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considered to have no toxicological significance. The NOAEL in this 28-day 

study was therefore considered to be 20000 ppm, corresponding 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 ppm, 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 (toxic) 

changes were observed in the dog of either sex at 1000 or 100 ppm. 

Subchronic (90-day) feeding studies were conducted in rats, mice, and dogs. 

Doses evaluated in the rat study were 0, 600, 6000 and 20000 ppm. The 

NOAEL was 20000 ppm in males (equivalent to 1331 mg/kg bwt/day) and 

6000 ppm for females (equivalent to 467 mg/kg bwt/day). The treatmentrelated changes observed in females treated at 20000 ppm included

prolongation of APTT, and increases in liver, heart, and ovary weight. 

Doses evaluated in the mouse study were 0, 200, 1200 and 8000 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 evaluated in the dog study were 0, 100, 1000 and 

10000 ppm. The NOAEL 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 increased absolute and relative weight of the liver 

(138% and 136% of control respectively), with one showing centrilobular 

hepatocellular hypertrophy. 

5. Chronic toxicity. An 18-month oncogenicity study was conducted in mice with 

dietary concentrations of 0, 200, 1250 and 8000 ppm. The no-observedadverse-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 20000 ppm technical cyclaniliprole. 

The systemic NOAEL 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 chronic toxicity/carcinogenicity study was conducted in rats with 

dietary concentrations of 0, 200, 2000, 6000 and 20000 ppm technical 

cyclaniliprole. The 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 NOAEL for carcinogenicity was 20000 ppm in both males and females 
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(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, 1000 and 10,000 ppm. The NOAEL 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 rapidly excreted mainly via the

feces. The majority of excreted material was unchanged cyclaniliprole, with 

several minor metabolites present in feces, bile, urine and 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 for 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 

potential effects on reproduction and development and an evaluation of the 

pathology of the endocrine organs following short or long-term exposure.

The data demonstrate no treatment-related effects on the endocrine system.

9. Immunotoxicity. Four-week immunotoxicity 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 

potential risk due to dietary exposure of the U.S. population to residues of 

cyclaniliprole.

For acute dietary exposure, an Acute Reference Dose (aRfD) is not identified 

for Cyclaniliprole since there was no evidence of initial acute effects in the 

acute oral or short-term toxicity studies, or the developmental toxicity 

studies in rats and rabbits. There were no effects seen in the acute 

neurotoxicity study at the limit dose level of 2000 mg/kg/day. No initial acute 

effects were seen in the 90-day neurotoxicity study.

For chronic dietary exposure, the chronic reference dose (cRfD) is 0.272 
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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 dose (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, stone 

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 this commodity to the diet and to 

ascertain the chronic risk 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 estimates were based on 

the proposed tolerance level residues, average processing factors and a 

market share of 100% crop treated as a conservative assumption. The 

consumption data were from the USDA’s National Health and Nutrition 

Examination Survey/What We Eat in 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.

Using all of the worst case exposure scenarios listed above, the Tier 1 chronic 

dietary exposure estimates resulted in an estimated exposure for the general 

U.S. population of 0.003649 mg/kg bwt/day. This exposure corresponds to 

1.3% of the cPAD. The highest exposure estimate calculated was for the 

subgroup children, 1-2 years. This exposure was determined to be 0.006608

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 Infants (< 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 1.4
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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 SCIGROW 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 the proposed uses 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, residential 

risk assessments for the incidental oral, dermal, and inhalation exposure 

routes are not required.

Occupational post-application exposure is possible. For dermal short-term 

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. 

Occupational exposure for mixing/loading and applying cyclaniliprole was 

considered. Potential exposure was considered negligible since MOEs 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 Tolerances
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Presently, there are no Codex maximum residue levels (MRLs) established for 

residues of cyclaniliprole on any crop.