EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(2/19/2010)

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 180.532.

(Options (pick one)

1. by establishing an import tolerance for residues of

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

the raw agricultural commodity [] at [] 

Fruit, Pome, Group 11, at 1.7 part 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, eighteen residue trials were completed to 

determine the magnitude of the residues of cyprodinil after five broadcast foliar 

applications of Vangard WG. Mature fruit were collected 0 days after the last 

application. These studies were conducted to support a change in the use pattern 

(shorter PHI) for the use of cyprodinil on Fruit, Pome, Group 11. Site Selection and 

number of trials were determined to satisfy the requirements listed in OPPTS 

860.1500, Crop Field Trials – Required Number of Field Trials for Crop Groups 

and – Suggested Distribution of Field Trials by Region for Crops. Apple trials were 

conducted accordingly - 3 trials located in Region 1, 1 trial in Region 2, 2 trials in 

Region 5, 1 trial in Region 9, 1 trial in Region 10 , and 4 trials in Region 11. The 

required number of pear trials were also conducted accordingly – 1 trial in Region 

1, 2 trials in Region 10, and 3 trials in Region 11. At all sites, Vangard WG was 

applied 5 times at 0.25 lb a.i./A with a 7 day retreatment interval and a pre-harvest 

interval of 0 days for a maximum of 1.25 lb a.i./A. Trial parameters included 

concentrate and dilute cover sprays, simulation of aerial application, the use of an 

adjuvant, and residue decline. Apple and pear samples were collected 0 days after 

application. Processing samples were previously reported in ABR-95049 (MRID 

43908445) and there were no detectable residues (<0.01ppm) in the apple juice 

samples at the exaggerated 3X and 5X application rates. The maximum residues 

found in processed apple commodities at the 1X treatment was 0.057 ppm and 0.020 

ppm in wet pomace and composited, unwashed apples, respectively. 

 

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.

 
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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 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 III 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 
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included all current uses and data supporting a reduced 0-day pre-harvest interval 

(PHI) for pome fruit. 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 pre-harvest interval (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. The apple juice processing factor was 

used as a surrogate for pear juice. All other processing factors used the DEEMTM

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. Percent of crop treated values were estimated based upon 

economic, pest and competitive pressures. Secondary residues in animal 

commodities were estimated based on “maximum reasonably balanced diets” 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 observable 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 exposure to the 

females 13-49 years subpopulation resulted in a MOE of 7,315 (1. 4% of the acute 

RfD 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 the current 

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 2,293 (3.9% 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 531 (16.9% 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 
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reasonable certainty that no harm will result from chronic dietary (food) exposure 

to residues arising from the current and proposed uses for cyprodinil.

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of 

cyprodinil and CGA294287 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 the new use rate 

pattern on pome fruit (0.25 lb ai/A x 5 applications at 7 day intervals) which 

supports a reduced pre-harvest interval (PHI) from 72 days to 0 day. EDWCs from 

this new use rate pattern do not exceed the EDWCs from the current crop driver 

(based on grapes). The EDWCs for grapes were updated in this assessment based on 

model inputs from a recent EPA drinking water assessment (DP Barcode D342973, 

2-May-2008) and an updated Vangard® WG label. For ground water, the currently 

registered uses on almond and grapes at a rate of 3 x 0.469 lb a.i./A (1.4 lbs 

a.i./A/year) provided the highest EDWC (acute and chronic) of 0.0401 ppb for 

cyprodinil and 0.0675 ppb for CGA249287. The combined ground water EDWC is 

0.1076 ppb (acute and chronic). For surface water, the NY grapes standard PRZM 

scenario using three aerial applications (as a worst-case assumption for 2 aerial + 1 

ground) at 0.469 lb a.i./A (1.4 lbs a.i./A/year) with a 7-day interval between 

treatments provided acute EDWCs of 36.409 ppb for cyprodinil and 3.008 ppb for 

CGA249287, for a combined total residue of 39.417 ppb. The chronic EDWCs were 

22.159 ppb for cyprodinil and 0.532 ppb for CGA249287 resulting in a combined 

total residue of 22.691 ppb. The surface water EDWCs have been corrected for a 

0.87 PCA factor. These surface water EDWCs exceed the EPA’s surface water 

EDWCs (34.56 ppb for acute and 20.05 ppb for chronic) published in a 2008 Final 

Rule (FR 73, No. 167, 27-Aug-2008) and will therefore be used for this Notice of 

Filing (NOF). Since surface water EDWCs exceed the ground water EDWC, the 

Syngenta surface water values will be used for risk assessment purposes and 

considered protective for any ground water concentration concerns.

Acute Exposure from Drinking Water: The acute EDWC of 39.417 ppb (0.039417 

ppm) 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 286,807 (<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 reference 

dose, Syngenta believes that there is a reasonable certainty that no harm will result 

from acute drinking water exposure to residues arising from all current and 

proposed uses of cyprodinil.

Chronic Exposure from Drinking Water: The chronic EDWC of 22.691 ppb (0.022691 
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ppm) was incorporated with food residues as “water, direct and indirect, all 

sources” directly into the DEEM-FCIDTM software to obtain chronic dietary 

(drinking water) exposures. Chronic drinking water exposure to the U.S. 

population resulted in a MOE of 5,645 (1.6% of the RfD 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 RfD 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 drinking water exposure to residues arising 

from all current 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

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 1,631 (5.5% 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 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 
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all established and proposed cyprodinil uses resulted in a MOE of 466 (19.3% 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 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 

7,133 (1.4% 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 2,139 (4.2% 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 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.