EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Maggie Rudick, (703) 347-0257

TEMPLATE:

ISK Biosciences Corporation

Petition # 4F8253

EPA has received a pesticide petition (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 a tolerance for 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 the raw agricultural 

commodities Pome Fruit (Crop Group 11-10) at 0.3 parts per million (ppm), Tree Nuts 

(Crop Group 14-12) at 0.02 ppm, Stone Fruit (Crop Group 12-12) at 0.7 ppm

Fruiting Vegetables, (Crop Group 8-10) at 0.2 ppm, Cucurbit Vegetables, (Crop 

Group 9) at 0.2 ppm, Small Fruit Vine Climbing Subgroup except Fuzzy Kiwifruit 

(Crop Group 13-07F), at 0.9 ppm. Additionally tolerances are proposed for the 

crops in the proposed Crop Subgroup 4–14A, Leafy greens subgroup at 7.0 ppm 

including amaranth, Chinese; amaranth, leafy; aster, Indian; blackjack; cat’s 

whiskers; chervil, fresh leaves; cham-chwi; cham-namul; chipilin; chrysanthemum, 

garland; cilantro, fresh leaves; corn salad; cosmos; dandelion; dang-gwi; dillweed; 

dock; dol-nam-mul; ebolo; endive; escarole; fameflower; feather cockscomb; good 

king henry; huauzontle; jute, leaves; lettuce, bitter; lettuce, head; lettuce, leaf; 

orach; parsley, fresh leaves; plantain, buckhorn; primrose, English; purslane, 

garden; purslane, winter; radicchio; spinach; spinach, malabar; spinach, New 

Zealand; spinach, tanier; swiss chard; and violet, Chinese; crops in the proposed 

Crop Subgroup 4–14B, Brassica leafy greens subgroup at 15 ppm including 

Arugula; broccoli raab; broccoli, Chinese; cabbage, abyssinian; cabbage, seakale; 

Chinese cabbage, bok choy; collards; cress, garden; cress, upland; hanover salad; 

kale; maca; mizuna; mustard greens; radish, leaves; rape greens; rocket, wild; 

shepherd’s purse; turnip greens; and watercress; crops in the proposed Crop 

Subgroup 22B, Leaf petiole vegetable subgroup at 7.0 ppm including Cardoon; 

celery; celery, Chinese; fuki; rhubarb; udo; zuiki and the crops in the proposed 

Crop Group 5–14: Brassica Head and Stem Vegetable at 1.5 ppm including 

broccoli; Brussels sprouts; cabbage; cabbage, Chinese, napa; and cauliflower. 

Tolerances are also proposed for the animal feed commodities Almond, hulls at 8.0

parts per million (ppm), Apple, wet pomace at 0.96 parts per million (ppm), in animal 

tissues and meat by products: cattle, fat at 0.08 ppm; cattle, kidney at 0.08 ppm; 

cattle, liver at 0.1 ppm; cattle, meat at 0.02 ppm; cattle, meat byproducts at 0.02 
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ppm; goat, fat at 0.08 ppm; goat, kidney at 0.08 ppm; goat, liver at 0.1 ppm; goat, 

meat at 0.02 ppm; goat, meat byproducts at 0.02 ppm; horse, fat at 0.08 ppm; horse, 

kidney at 0.08 ppm; horse, liver at 0.1 ppm; horse, meat at 0.02 ppm; horse, meat 

byproducts at 0.02 ppm; milk at 0.01 ppm; sheep, fat at 0.08 ppm; sheep, kidney at 

0.08 ppm; sheep, liver at 0.1 ppm; sheep, meat at 0.02 ppm; and sheep, meat 

byproducts at 0.02 ppm and for the import commodity Tea (dried and instant) at 40

parts per million (ppm). 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

tolerance. 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.

3. Magnitude of residues. For the pome fruit crop group, trials were conducted 

at 27 sites in the USA and Canada on apple (17) and pear (10). Three

applications at the target rate of 0.089 lb a.i./A (100 g ai/ha) at 14 day 

intervals were made to the treated plots with an average seven-day preharvest interval. The highest residues found were 0.166 ppm on apple and 

0.17 ppm on pear. The average residues found were 0.065 ppm on apple and

0.111 ppm on pear. In a processing study, residues were found to 

concentrate in the apple pomace (3.2x) and were reduced in the juice (0.13x).

For the tree nut crop group, trials were conducted at 10 sites in the USA on 

almonds (5) and pecans (5). Three applications at the target rate of 0.089 lb 

a.i./A (100 g ai/ha) at 14 day intervals were made to the treated plots with a 

thirty-day pre-harvest interval. The highest residues found were 0.02 ppm 

on almond nutmeats, 0.02 ppm on pecan nutmeats and 3.58 ppm on almond 

hulls. The average residues found were <0.01 ppm on almond nutmeats, 

<0.01 ppm on pecan nutmeats and 2.26 ppm on almond hulls.

 

For the stone fruit crop group, trials were conducted at 36 sites in stone fruit
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growing areas in the USA and Canada on peaches (13), plums (8), sweet 

cherries (8) and tart cherries (7). Three applications at the target rate of 

0.089 lb a.i./A (100 g ai/ha) at 6 to 8 day intervals were made to the treated 

plots with an average seven-day pre-harvest interval. The highest residues 

found were 0.233 ppm on peaches, 0.108 ppm on plums, 0.386 on sweet 

cherries and 0.619 ppm on tart cherries. The average residues found were 

0.079 ppm on peaches, 0.055 ppm on plums, 0.197 ppm on sweet cherries and 

0.326 ppm on tart cherries. In a processing study, residues concentrated in 

dried plums (3.7x).

 

For the leafy (non-brassica) vegetable crop group, trials were conducted at 

31 sites in growing areas in the USA and Canada on head lettuce (11), leaf 

lettuce (11) and spinach (9). Three applications at the target rate of 0.0714 lb 

a.i./A (80 g ai/ha) at 6 to 8 day intervals were made to the treated plots with a 

one-day pre-harvest interval. The highest residues found were 3.21 ppm on 

head lettuce, 3.56 ppm on leaf lettuce and 5.61 ppm on spinach. The average 

residues found were 0.974 ppm on head lettuce, 1.67 ppm on leaf lettuce and 

3.46 ppm on spinach.

 

For the leafy brassica vegetable crop group, trials were conducted at 25 sites 

in growing areas in the USA and Canada on cabbage (10), broccoli (10) and 

mustard greens (5). Three applications at the target rate of 0.0714 lb a.i./A 

(80 g ai/ha) at 6 to 8 day intervals were made to the treated plots with a oneday pre-harvest interval. The highest residues found were 0.57 ppm on 

cabbage, 0.88 ppm on broccoli and 6.83 ppm on mustard greens. The 

average residues found were 0.14 ppm on cabbage, 0.36 ppm on broccoli and 

4.61 ppm on mustard greens.

 

For the fruiting vegetable crop group, trials were conducted at 35 sites in 

growing areas in the USA and Canada on tomatoes (24), bell pepper (9) and 

non-bell pepper (3). Three applications at the target rate of 0.071 lb a.i./A 

(80 g ai/ha) at 6 to 8 day intervals were made to the treated plots with a oneday pre-harvest interval. The highest residues found were 0.111 ppm on 

tomatoes, 0.164 ppm on bell peppers and 0.094 ppm on non-bell peppers. 

The average residues found were 0.036 ppm on tomatoes, 0.070 ppm on bell 

peppers and 0.064 ppm on non-bell peppers. Results from a tomato 

processing study showed that residues did not concentrate in the processed 

fractions (concentration factors of 0.25 and 0.49 for tomato puree and paste, 

respectively).

 

For the cucurbit vegetable crop group, trials were conducted at 28 sites in 

cucurbit growing areas in the USA and Canada on cucumber (9), summer 

squash (9) and cantaloupe (10). Three applications at the target rate of 

0.0714 lb a.i./A (80 g ai/ha) at 6 to 8 day intervals were made to the treated 

plots with a one-day pre-harvest interval. The highest residues found were 

0.028 ppm on cucumber, 0.056 ppm on summer squash and 0.11 ppm on 
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cantaloupe. The average residues found were 0.015 ppm on cucumber, 0.024

ppm on summer squash and 0.049 ppm on cantaloupe.

 

For the small fruit vine climbing crop group, trials were conducted at 15 sites 

in grape growing areas in the USA and Canada on grape vines. Three

applications at the target rate of 0.089 lb a.i./A (100 g ai/ha) at 6 to 8 day 

intervals were made to the treated plots with an average seven-day preharvest interval. The highest residues found were 0.628 ppm on grape. The 

average residues found were 0.211 ppm on grape. In a separate grape 

processing study, residues did not concentrate in raisins or juice (0.45x and 

0.36x concentration factors, respectively).

For the import tolerance on tea, dried and instant, six RAC trials were 

conducted in tea growing regions of Japan. One application at the target 

rate of 0.18 lb a.i./A (200 g ai/ha) was made to the treated plots with a threeday pre-harvest interval. The highest residues found were 29.5 ppm on 

crude tea. The average residues found were 13.92 ppm for cyclaniliprole and 

NK-1375 combined.

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.
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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 

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.
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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 

(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.
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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 

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 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.
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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

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 
9

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

Presently, there are no Codex maximum residue levels (MRLs) established for 

residues of cyclaniliprole on any crop.