EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(5/5/2011)

EPA Registration Division contact: [Shaja Joyner (PM-20) 703-308-3194]

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert “NA-Remove” and 

maintain the outline. Please do not change the margins, font, or format in your 

pesticide petition. Simply replace the instructions that appear in green and brackets, 

i.e., “[insert company name],” with the information specific to your action.

TEMPLATE:

[Syngenta Crop Protection]

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from [Syngenta 

Crop Protection], [P.O. Box 18300, Greensboro, NC 27409] 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.

(Options (pick one)

1. by establishing a tolerance for residues of

[cyprodinil: 2-pyrimidinamine, 4-cyclopropyl-6-methyl-N-phenyl-] in or on 

the raw agricultural commodity [] at [] 

Leafy petioles subgroup 04B, at 30 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 cyprodinil is adequately understood for 

the purpose of the proposed tolerances. The metabolism of cyprodinil has been 

characterized in plants and animals. No toxicologically significant metabolites have 
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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, eight crop-field trials were conducted with 

various commercially available celery cultivars, and the soil types and 

meteorological conditions at the eight trial sites adequately represented the diversity 

of conditions under which celery may be commercially grown. These trial sites 

satisfied the requirements of OPPTS 860.1500 for number and regional distribution. 

The study design consisted of 2 plots at each trial site: a non-treated control (UTC) 

plot and a treated (TRT) plot. The TRT plot received four broadcast foliar 

applications of 14 oz product/acre/application (or 56 oz product/acre/ season), which 

equates to 0.328 lb cyprodinil/acre + 0.219 lb fludioxonil/acre (or a seasonal rate of 

1.3 lb cyprodinil/acre + 0.9 lb fludioxonil/acre). The treatments were applied with a 

tank-mix volume of 15 - 40 gallons/acre (GPA) at the minimum 7-day retreatment 

interval (RTI), and the raw agricultural commodity (RAC) was harvested on the 

day of the last application to support a 0-day pre-harvest interval (PHI). This use 

pattern would be the ‘worst-case’ application as per the proposed-use label.

 

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.
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3. Reproductive and developmental toxicity. Reproductive Toxicity: In a twogeneration 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 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 (DEEMFCIDTM, version 2.16) from Exponent. These cyprodinil exposure assessments 

included all current and pending uses and a proposed use on celery at a 0-day preharvest interval (PHI). The proposed celery and pending spinach uses combined 

with the existing use on leafy vegetables (Group 4A) completes the representative 

crops for all leafy vegetables (Crop Group 4). 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 
4

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/kg-bw/day, based upon a rabbit study with a no observed adverse effect 

level (NOAEL) of 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 2,434 (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/kgbw/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 867 (10.4% 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 313 (28.7% 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 for the currently registered uses as 

well as proposed uses on celery, spinach, and peppers using Tier l SCI-GROW 
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(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. 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-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 42,206 (0.2% of the aRfD of 1.5 mg/kgbw/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, 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. A new 

product label for Palladium®, containing cyprodinil and fludioxonil, allows 

professional applications to ornamental plants in residential settings. No postapplication residential exposure assessment is required because post-application 

exposure to adults and children from ornamental applications is negligible.

D. Cumulative Effects
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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. The chronic aggregate exposure analysis showed that exposure from all 

current and proposed cyprodinil uses resulted in a MOE of 752 (12.0% 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 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 289 (31.1% 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 

2,301 (4.3% 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 882 (10.2% 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 
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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.