EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(11/19/2010)

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, Drug, 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 commodities: onion,

bulb, subgroup 3-07A at 0.6 parts per million (ppm); onion, green, subgroup 3-07B, at 

4.0 ppm; caneberry subgroup 13-07A, at 10.0 ppm; bushberry subgroup 13-07B, at 3.0 

ppm; fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13-07F at 2.0 ppm; 

berry, low growing, subgroup 13-07G, except cranberry, at 5.0 ppm; dragon fruit, at 2.0

ppm; fruit, pome, group 11-10, at 1.7 ppm; vegetable, fruiting, group 8-10, at 1.3 ppm; 

and leafy greens subgroup 4A at 40 ppm. Additionally, the petition proposes to amend 

the tolerance for residues of cyprodinil in or on the raw agricultural commodity citrus oil 

from 340 ppm to 60.0 ppm.

Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 

180.532 be amended to remove the established tolerances for the residues of cyprodinil in 

or on the following raw agricultural commodities: onion, bulb, at 0.60 ppm; onion, green, 

at 4.0 ppm; caneberry subgroup 13A, at 10 ppm; bushberry subgroup 13B, at 3.0 ppm; 

Juneberry, at 3.0 ppm; lingonberry, at 3.0 ppm; salal, at 3.0 ppm; grape, at 2.0 ppm; 

strawberry, at 5.0 ppm; fruit, pome, at 1.7 ppm; tomatillo, at 0.45 ppm; tomato, at 0.45 

ppm; and leafy greens subgroup 4A, except spinach, at 30 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 cyprodinil is adequately understood for the 

purpose of the proposed tolerances. The metabolism of cyprodinil has been characterized 
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in plants and animals. No toxicologically significant 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 of 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 requirements 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 technical 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 

[CAUTION] 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 that 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 and 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 rat developmental 

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 Toxicity: In subchronic studies, the lowest 

NOEL is 50 ppm based on a rat study. Subchronic Dermal Toxicity: For female rats 
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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. Chronic 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 cyprodinil 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 

metabolites (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 

reproduction. 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 were 

performed for cyprodinil using the Dietary Exposure Evaluation Model (DEEM-FCIDTM, 

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). 

The 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 

where 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-FCIDTM Version 7.87 defaults. 

All consumption data for these assessments was taken from the USDA’s Continuing 

Survey of Food Intake 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 which an acute toxicological endpoint has 

been established) was performed using an acute reference dose (aRfD) of 1.5 mg/kgbw/day, based upon a rabbit study with a no observed adverse effect level (NOAEL) of 
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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 NOAEL 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-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 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 inter-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 each 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 reference 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 Drinking 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 peppers. 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 and indirect, all sources” directly into the DEEM-
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FCIDTM software to model the aggregate (food and water) exposures. The acute drinking 

water exposure contributions at the 99.9th 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 99.9th 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 result 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 

infants (<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 residential 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 

assessment 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 EPA 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 has 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. 
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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/kgbw/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 that 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) for 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 supporting 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 analysis 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 that 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 current, 

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 

grapes (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, strawberries, 

tomatoes, wheat, and wheat bran.