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 # 4F82 53

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 4 0 CFR part 180 by establishing a tolerance for 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 o r on the raw agricultural commodit ies 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 a maran th, 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; end ive; 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; spin ach; 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; ca bbage, 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 Sub group 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; cab bage; 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, fa t at 0.0 8 ppm; cattle, kidney at 0.08 ppm; cattle, liver at 0.1 ppm; cattle, meat at 0.0 2 ppm; cattle, meat byproducts at 0.0 22

ppm; goat, fat at 0.08 ppm; goat, kidney at 0.0 8 ppm; goat, liver at 0.1 ppm; goat, meat at 0.0 2 ppm; goat, meat byproducts at 0. 0 2 ppm; horse, fat at 0.08 ppm; horse, kidney at 0.08 ppm; horse, live r at 0.1 ppm; horse, meat at 0.0 2 ppm; horse, meat byproducts at 0.0 2 ppm; milk at 0.0 1 ppm; sheep, fat at 0.0 8 ppm; sheep, kidney at 0.0 8 ppm; sheep, liver at 0. 1 ppm; sheep, meat at 0. 0 2 ppm; and sheep, meat byproducts at 0.0 2 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 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

. T he metabolism of cyclaniliprole as well as the nature of the residues in plants is adequately understood for the purposes of th is tolerance. Metabolism studies were conducted with three diverse crops, apples, lettuce and potatoes

. All three 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 cyclaniliprole 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.

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. 0 8 9 lb a.i./A ( 100 g ai/ha) at 14 day intervals were made to the treated plots with a n average seven - day pre

harvest interval. The highest residues found were 0.166 ppm on apple and 0.17 ppm on pear . The a verage residues found were 0.0 65 ppm on app le and 0.111 ppm on pe ar . 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 ( 10 0 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 fruit3

growing areas in the USA and Canada on peaches (13), plums (8), sweet cherries (8) and tart cherries (7)

. Three applicati ons 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 a n 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 spina ch ( 9 )

. Three applications at the target rate of 0.0 714 lb a.i./A (8 0 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 lettu ce 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 2 5 sites in growing areas in the USA and Cana da on cabbage (10), broccoli (10) and mustard greens (5)

. Three applications at the target rate of 0.0 714 lb a.i./A (8 0 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 .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 0.0 71 lb a.i./A (8 0 g ai/ha) at 6 to 8 day intervals were made to the treated plots with a one day pre

- harvest int erval. The highest residues found were 0.111 ppm on tomatoes, 0.164 ppm on bell peppers and 0. 0 94 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

c ucurbit growing areas in the USA and Canada on cucumber (9) , summer squash (9) and cantaloupe (10)

. Three applications at the target rate of 0.0 71 4 lb a.i./A ( 8 0 g ai/ha) at 6 to 8 day intervals were made to the treated plots with a one - day pre

- harvest in terval. The highest residues found were 0.028 ppm on cucumber, 0.056 ppm on summer squ ash and 0.11 ppm on4

cantaloupe. The average residues found were 0.015 ppm on cucumber, 0.0 2 4 ppm on summer squash and 0.049 ppm on cantaloupe.

For the small fruit vi ne 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 0.08 9 lb a.i./A ( 10 0 g ai/ha) at 6 to 8 day intervals were made to the treated plots with an a ve rage seven - day pre

harvest interval. The highest residues found were 0. 628 ppm on grape . The average residues found were 0.2 11 ppm on grape . In a separate grape processing study, residues did not concentrate in raisins or juice (0.45x and 0.36x concentr ation 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 three

day 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 t echnical cyclaniliprole in Toxicity Category III for oral LD 50 and dermal LD 50 , and Category IV for inhalation LC 50 , dermal irritation , and eye irritation. Technical cyclaniliprole was not a dermal sensitizer

.
In an acute neurotoxicity st udy, 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. Genotoxic i ty

. The genotoxic poten tial 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/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 th e absence of maternal toxicity. For the rat teratology study, d oses up to 1000 mg/kg bwt /day were administered bet ween Days 6 and 19 of gestation

. The NOEL for maternal toxicity and developmental toxicity was 1000 mg/kg bwt/day, the highest dose tested.5

Cy claniliprole 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) toxicity studies were conducted in rats and dogs

. Doses evaluated in the rat study were 0, 300, 1250, 5000 and 20000 ppm. S tatisticall y significant increases in absolute and/or relative liver weight were seen at the highest dose level. There were no associated biochemi cal or histopathological changes and the increased liver weight was therefore considered to be an adaptive hepatic respo nse 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 hypertro phy 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.
S ubchronic (90

- day) feeding studies were conducted in rats, m ice, 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 ( equivalent 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 fem ales treated at 20000 ppm included prolongation of APTT, and increases in liver, heart, and ovary weight. Doses evalua ted 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 adver se 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 hepatocellu lar hypertrophy.

5. Chronic toxicity. An 18

- month oncoge nicity study was conducted in mice with dietary concentrations 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.6

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 wa s 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 wit h dietary concentrations of 0, 200, 2 000 , 6000 and 20 000 ppm technical
cy claniliprole

. 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 wa s 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

car cinogenicity.

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 m ajority 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 conce rn for toxicity of metabolites.

8. Endocrine disruption

. The submitted studies include evaluation of the potent ial effects 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

.7

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. 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 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 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 th is commodity to the diet and to ascertain the chronic risk potential. In addition, t he 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 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 in America NHANES/WWEIA dieta ry 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 dietary e xposure estimates resu lted 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 exposure 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.8

Population Exposure Estimate % of cPAD Subgroup (mg/kg body wt/day) U.S. Population 0.003649 1.3 All Infants (< 1 year old) 0.00348 7 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+ ye ars 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 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

cr ops 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.

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 a bsence 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 exp osure for mixing/lo ading 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 of9

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