EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER ( 11 /19/ 20 10 )

EPA Registration Division contact: Laura Nollen, (703) 305

- 7390

Interregional Research Project Number 4 ( IR

- 4 )

Petition Number 1E7854

EPA has received a pesticide petition , 1E7854, from IR

- 4

, 500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing, pursuant to section 408(d) of the Federal Food, Dru g, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 .532 by establishing a tolerance for residues of cyprodinil, 4

- cyclopropyl

- 6

- methyl

- N

- phenyl

- 2

- pyrimidinamine , in or on the following raw agricultural commodit ies: o nion

, bulb

, subgr oup 3

- 07A at 0. 6 part s per million (ppm) ; o nion

, green , subgroup 3

- 07B , at 4 .0 ppm; c aneberry subgroup 13

- 07A, at 10.0 ppm; b ushberry subgroup 13

- 07B, at 3.0 ppm; f ruit , small vine climbing , except fuzzy kiwifruit, subgroup 13

- 07F at 2.0 ppm; b erry , low gr owing, subgroup 13

- 07G

, except cranberry, at 5.0 ppm; d ragon fruit, at 2.0 ppm; f ruit, pome, group 11

- 10, at 1.7 ppm; v egetable, fruiting, group 8

- 10, at 1.3 ppm; and l eafy greens subgroup 4A at 4 0 ppm. Additionally, the petition proposes to amend the tole rance for residues of cyprodinil in or on the raw agricultural commodity citrus oil from 340 ppm to 6 0 .0 ppm.

Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 180.532 be amended to remove the established tolerances for the res idues of cyprodinil in

or on the following raw agricultural commodit ies : o nion, bulb , at 0. 6 0 ppm ; o nion, green

, at 4. 0 ppm; c aneberry subgroup 13A, at 10 p pm; b ushberry subgroup 13B, at 3.0 ppm; J uneberry, at 3.0 ppm; l ingonberry, at 3.0 ppm; s alal, at 3. 0 ppm; g rape, at 2.0 ppm;

s trawberry, at 5.0 ppm; f

ruit, pome, at 1.7 ppm; t omatillo, at 0.45 ppm; t omato, at 0.45 ppm; and l eafy greens subgroup 4A, except spinach, at 30 ppm.

EPA has determined that the petition contains data or information regarding t he 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 peti tion.

A. Residue Chemistry

1. Plant metabolism. The metabolism of cyprodinil is adequately understood for the purpose of the proposed tolerances. The metabolism of cyprodinil has been characterized2

in plants and animals. No toxicologically signific ant metabolites have been identified. The metabolism profile supports the use of an analytical enforcement method that accounts for only parent cyprodinil.

2. Analytical method. Syngenta Crop Protection has developed and validated analytical methodology for enforcement purposes. This method (Syngenta Crop Protection Method AG

- 631B) has passed an Agency petition method validation for several commodities and is currently the enforcement method for cyprodinil. An extensive database of method validation data using this method on various crop commodities is available.

3. Magnitude o

f residues. Complete residue data to support the requested tolerances have been submitted. The requested tolerances are adequately supported.

In support of the requested tolerance, IR

- 4 has conducted the necessary trials in accordance with the requirement s of the EPA Residue Chemistry Guidelines 860.1500 to determine the magnitude of residue of cyprodinil in or on requested commodities

. B. Toxicological Profile

An assessment of toxic effects caused by cyprodinil is discussed in Unit III.A. and Unit III.B. of the Federal Register dated June 22, 2001 (66 FR 33478) (FRL

- 6778

- 7).

The te chnical cyprodinil product is classified in toxicity categories III & IV [CAUTION] based on acute oral, dermal, inhalation toxicity and eye/skin irritation studies. The formulated end use products are also classified in toxicity categories III & IV [CAUTIO N] based on similar studies.

1. Acute toxicity. The acute toxicity data of cyprodinil show that this chemical is not acutely toxic by the oral, inhalation and dermal routes of exposure. Technical cyprodinil, however, is a dermal sensitizer.

2. Genotoxicty. Cyprodinil was shown to be negative in studies for point mutation, for chromosome aberration, and for DNA repair. These results indicate th at cyprodinil is unlikely to initiate cancer or cause inheritable genetic defects.

3. Reproductive and developmental toxicity. Reproductive Toxicity: In a two

- generation reproduction study in rats, the NOEL for maternal systemic toxicity is 1000 ppm a nd the NOEL for reproductive toxicity is 1000 ppm. Developmental Toxicity: Cyprodinil is not teratogenic. In the rabbit developmental toxicity study, no developmental toxicity was noted even at the highest dose tested (HDT) of 400 mg/k. In the r at develo pmental toxicity study , the developmental and maternal NOELs were both 200 mg/kg based on reduced ossification and body weight in pups and decreased food consumption/weight gain in dams at 1000 mg/kg (HDT).

4. Subchronic toxicity. Subchronic Oral Toxici ty: In subchronic studies, the lowest NOEL is 50 ppm based on a rat study. Subchronic Dermal Toxicity: For female rats3

receiving dermal applications of cyprodinil; NOEL was 5 mg/kg/.day; the NOEL for the male rats in this study is 125 mg/kg/day.

5. Ch ronic toxicity. Chronic Oral Toxicity: Two chronic studies found NOELs of 75 ppm in a 24

- month rat study and 2500 ppm in a one

- year Beagle study. Neither study found evidence of carcinogenicity for cyprodinil.

6. Animal metabolism. The metabolism of cy prodinil in rats is adequately understood.

7. Metabolite toxicology

. The residue of concern for tolerance setting purposes is the parent compound. The EPA has reviewed the hazard profile of the pryimidine

m etabolites (CGA

- 249287, NOA

- 422054) of cyprodinil. EPA has concluded that the toxicity of the CGA

- 249287 and NOA

- 422054 metabolites is no greater than that of the parent.

8. Endocrine disruption

. Cyprodinil does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system. Developmental toxicity studies in rats and rabbits and a reproduction study in rats gave no indication that cyprodinil might have any effects on endocrine function related to development and

r eproduction. The chronic studies also showed no evidence of a long

- term effect related to the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. Tier II acute and chronic dietary exposure evaluations wer e performed for cyprodinil using the Dietary Exposure Evaluation Model (DEEM

- FCID TM

, version 2.16) from Exponent. These cyprodinil exposure assessments included all current and pending uses and proposed uses on spinach and peppers (bell and non

- bell). Th e proposed bell (Group 8

- 10B) and non

- bell (Group 8

- 10C) pepper uses combined with the existing use on tomatoes completes the representative crops for all fruiting vegetables (Crop Group 8

- 10). These assessments utilized residue data from field trials whe re cyprodinil was applied at the maximum intended use rate and samples were harvested at the minimum PHI to obtain maximum residues. Empirically derived processing factors for apple juice (0.39X), apple pomace (5.22X), grape juice (0.29X), dried prune (2. 05X), tomato puree (0.52X), and tomato paste (2.3X) were used in these assessments. All other processing factors used the DEEM

- FCID TM Version 7.87 defaults. All consumption data for these assessments was taken from the USDA’s Continuing Survey of Food In take by individuals (CSFII) with the 1994

- 96 consumption database and the Supplemental CSFII children’s survey (1998) consumption database. The percent of crop treated value was assumed to be 100% for all commodities. Secondary residues in beef liver and kidney were estimated based on “maximum reasonably balanced diets” and transfer information from feeding studies.

i. Food. Acute exposure

. The acute dietary (food only) risk assessment for females 13

- 49 years old (the only population subgroup for whi ch an acute toxicological endpoint has been established) was performed using an acute reference dose (aRfD) of 1.5 mg/kg

bw/day, based upon a rabbit study with a no observed adverse effect level (NOAEL) of4

150 mg/kg

- bw/day and an uncertainty factor (UF) of 100X for intra

- and inter

- species variations; no additional FQPA safety factor was applied. For the purpose of the aggregate risk assessment, the exposure value was expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAE L by the exposure for each population subgroup. In addition, exposure was expressed as a percent of the acute reference dose (%aRfD). Acute food exposure to the females 13

- 49 years subpopulation resulted in a MOE of 2,465 (4.1% of the aRfD of 1.5 mg/kg

- b w/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from acute dietary (food ) exposure to residues arising from all current, pending, and proposed uses for cyprodinil.

Chronic exposure. The chronic reference dose (RfD) for cyprodinil is 0.03 mg/kg

- bw/day, based on a chronic rat study with a NOAEL of 2.7 mg/kg

- bw/day and an uncertainly factor of 100X for intra

- and inte r

- species variations; no additional FQPA safety factor was applied. For the purpose of the aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for e ach population subgroup. In addition, exposure was expressed as a percent of the chronic reference dose (%cRfD). Chronic food exposures to the U.S. population resulted in a MOE of 1,049 (8.6% of the cRfD of 0.03 mg/kg

- bw/day). Chronic food exposures to the most sensitive subpopulation (children 1

- 2 years old) resulted in a MOE of 347 (26.0% of the cRfD of 0.03 mg/kg

- bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the r eference dose, Syngenta believes that there is a reasonable certainty that no harm will result from chronic dietary (food) exposure to residues arising from all current, pending, and proposed uses for cyprodinil.

ii. Drinking water. The Estimated Drinki ng Water Concentrations (EDWCs) of cyprodinil and its degradate CGA249287, reported as combined total residues (cyprodinil plus CGA249287) were determined using Tier l SCI

- GROW (version 2.3) which estimates pesticide concentrations in ground water and Tier II PRZM/EXAMS (PE version 5.0) which estimates pesticide concentrations in surface water. This drinking water assessment was conducted to assess all currently registered uses, the pending use on tree nuts as well as the proposed uses on spinach, and pepp ers. For ground water, the currently registered uses on almond and grapes and the pending use on tree nuts provided the highest combined EDWC of 0.1076 ppb (acute and chronic). For surface water, the proposed use on peppers provided the highest combined acute EDWC of 46.314 ppb and the currently registered use on grapes provided the highest combined chronic EDWC of 22.691 ppb. The surface water EDWCs have been corrected for a 0.87 PCA factor. Since the surface water EDWCs exceed the ground water EDWC, the surface water values will be used for risk assessment purposes and considered protective for any ground water exposure concerns.

Acute Exposure from Drinking Water : The acute EDWC of 46.314 ppb was incorporated with food residues as “water, direct an d indirect, all sources” directly into the DE EM

-5

FCIDTM software to model the aggregate (food and water) exposures. The acute drinking water exposure contributions at the 99.9 th percentile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food (only) exposures for each population subgroup. Acute drinking water exposure at the 99.9 th percentile for females (13

- 49 years), the only population subgroup for which an acute toxicological endpoint has been established, resulted in a MOE of 76 ,570 (0.1% of the aRfD of 1.5 mg/kg

- bw/day). Since the Benchmark MOE for this assessment was 100, and since the EPA generally has no concern for exposures below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will res ult from acute drinking water exposure to residues arising from all current, pending and proposed uses of cyprodinil.

Chronic Exposure from Drinking Water : The chronic EDWC of 22.691 ppb was incorporated with food residues as “water, direct and indirect , all sources” directly into the DEEM

- FCIDTM software to obtain chronic dietary (food and water) exposures. Chronic drinking water exposure to the U.S. population resulted in a MOE of 5,645 (1.6% of the cRfD of 0.03 mg/kg

- bw/day). The most sensitive subpopulation was all infant s (<1 year old), with a MOE of 1,722 (5.2% of the cRfD of 0.03 mg/kg

- bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the RfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from all current, pending and proposed uses of cyprodinil.

2. Non

- dietary exposure

. Cyprodinil is not currently registered for any uses that would result in res idential handler (mixer/loader/applicator) exposure. The product label for Palladium®, containing cyprodinil and fludioxonil, allows professional applications to ornamental plants in residential settings. No post

- application residential exposure

assessme nt is required because post

- application exposure to adults and children from ornamental applications is negligible.

D. Cumulative Effects

Cumulative Exposure to Substances With a Common Mechanism of Toxicity . Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity”. The E PA does not have, at this time, available data to determine whether cyprodinil has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. For the purposes of this tolerance action, the EPA ha s not assumed that cyprodinil has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. An acute toxicological endpoint has not been established for the U.S. population, so an acute exposure assessment was not performed for the U.S. population.6

The chronic aggregate exposure analysis showed that exposure from all current and proposed cyprodinil uses resulted in a MOE of 885 (10.2% of the cRfD of 0.03 mg/kg

bw/day) for the U.S. population, which exceeds the Benchmark MOE of 100. A cancer exposure analysis was not performed, since there is no evidence of human carcinogenic potential for cyprodinil. Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes th at there is a reasonable certainty that no harm will result from aggregate exposure from all current, pending, and proposed uses of cyprodinil.

2. Infants and children

. An acute toxicological endpoint has not been established for infants and children, so an acute exposure assessment was not performed for infants and children. The chronic aggregate exposure analysis showed that exposure from all established and proposed cyprodinil uses resulted in a MOE of 318 (28.4% of the cRfD of 0.03 mg/kg

- bw/day) fo r children 1

- 2 years old, which exceeds the Benchmark MOE of 100. A cancer exposure analysis was not performed, since there is no evidence of human carcinogenic potential for cyprodinil. Based on the completeness and reliability of the toxicity data supp orting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure from all current, pending, and proposed uses of cyprodinil.

3. Females 13

- 49 years of age

. The acute aggregate exposure analys is showed that exposure to all current and proposed cyprodinil uses would result in a MOE of 2,388 (4.2% of the aRfD of 1.5 mg/kg

- bw/day) for females 13

- 49 years old, which exceeds the Benchmark MOE of 100. The chronic aggregate exposure analysis showed t hat exposure to all current and proposed cyprodinil uses would result in a MOE of 1,044 (8.6% of the cRfD of 0.03 mg/kg

- bw/day) for females 13

- 49 years old, which exceeds the Benchmark MOE of 100. A cancer exposure analysis was not performed, since there is no evidence of human carcinogenic potential for cyprodinil. Based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure from all cu rrent, pending, and proposed uses of cyprodinil.

F. International Tolerances

Codex maximum residue levels have been established for residues of cyprodinil in or on almonds, apples, barley, beans (except broad bean and soya bean), cucumbers, dried
gra pes (currants, raisins and sultanas), eggplant, eggs, grapes, lettuce (head & leaf), meat & meat

- by

- products, milk, onions (bulb), pears, peppers (sweet), poultry, prunes, raspberries, squash (summer), stone fruits, straw and fodder of cereal grains, straw berries, tomatoes, wheat, and wheat bran.