EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(3/30/2015)

EPA Registration Division contact: [Hope Johnson (PM-21) 703-305-5410]

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

5F8358

EPA has received a pesticide petition (5F8358) 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.

1. by establishing the tolerances for residues of

cyprodinil: 4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine in or on the 

raw agricultural commodity

Vegetable, tuberous and corm, subgroup 1C; at 0.01 parts per million (ppm)

Potato, wet peel; at 0.03 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 

been identified. The metabolism profile supports the use of an analytical 

enforcement method that accounts for only parent cyprodinil.
2

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, Syngenta 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

EPA has evaluated the available toxicity data and considered its validity, completeness, 

and reliability as well as the relationship of the results of the studies to human risk. EPA 

has also considered available information concerning the variability of the sensitivities of 

major identifiable subgroups of consumers, including infants and children. Specific 

information on the studies received and the nature of the toxic effects caused by

cyprodinil as well as the no-observed-adverse-effect-level (NOAEL) from the toxicity

studies can be found at the following website: http://edocket.access.gpo.gov/2012/2012-

20235.htm. A summary of the toxicological endpoints for cyprodinil used for human risk 

assessment is discussed in Unit III.A and B. of the final rule published in the Federal 

Register of August 17, 2012 (77 FR pages 49732-49738) (FRL-9359-7).

1. Acute toxicity. 

2. Genotoxicty.

3. Reproductive and developmental toxicity.

4. Subchronic toxicity.

5. Chronic toxicity.

6. Animal metabolism.

7. Metabolite toxicology. 

8. Endocrine disruption. 

 

C. Aggregate Exposure
3

1. Dietary exposure. Tier II acute and chronic dietary exposure evaluations were 

performed for cyprodinil using the Dietary Exposure Evaluation Model (DEEMFCIDTM Version 3.16) from Exponent and consumption data from the USDA

NHANES “What We Eat in America” survey, 2003-2008. These cyprodinil 

exposure assessments included all registered uses and pending uses, as well as a 

proposed new foliar use for potatoes. 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 were used in these 

assessments when available; all other processing factors used the DEEM-FCIDTM

Version 7.87 defaults. 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. Drinking water estimates were incorporated directly into the acute 

and chronic dietary exposure assessments using the highest estimated drinking 

water concentrations (EDWCs) for surface and ground water. 

i. Food. Acute exposure. The acute dietary (food only) risk assessments for 

cyprodinil were performed for all population subgroups using an acute reference 

dose of 2.0 mg/kg-bw/day based upon an acute neurotoxicity study in rats with a no 

observed adverse effect level (NOAEL) of 200 mg/kg-bw/day and an uncertainty 

factor of 100X to account for intra- and inter-species variations. No additional 

FQPA safety factor was applied. For the purpose of the acute aggregate risk 

assessments, 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 acute 

reference dose (%aRfD). At the 99.9th percentile, acute (food only) exposure to the 

U.S. population resulted in a MOE of 3,154 (3.2% of the aRfD of 2.0 mg/kg-bw/day). 

The most exposed sub-population was all infants <1 year old with a MOE of 1,536 

(6.5% of the aRfD of 2.0 mg/kg-bw/day). Since the Benchmark MOE for this 

assessment was 100 and since the EPA generally has no concern for exposures above 

the Benchmark MOE or below 100% of the aRfD, Syngenta believes that there is a 

reasonable certainty that no harm will result from dietary (food only) exposure to 

residues arising from all current, pending, and proposed uses of cyprodinil.

 

Chronic exposure. The chronic dietary (food only) risk assessments were performed 

for all population subgroups using a chronic reference dose of 0.027 mg/kg-bw/day 

based upon a two year chronic toxicity/carcinogenicity study in rats with a no 

observed adverse effect level (NOAEL) of 2.7 mg/kg-bw/day and an uncertainty 

factor of 100X to account for intra- and inter-species variations. No additional 

FQPA safety factor was applied. For the purpose of 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 only) exposure to the U.S. population resulted in a MOE of 

796 (12.6% of the cRfD of 0.027 mg/kg-bw/day). The most exposed sub-population 
4

was children 1-2 years old with a MOE of 274 (36.6% of the cRfD of 0.027 mg/kgbw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA 

generally has no concern for exposures above the Benchmark MOE or below 100% 

of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will 

result from dietary (food only) exposure to residues arising from all current, 

pending, and proposed uses of cyprodinil.

Cancer. Cyprodinil is classified as “not likely” to be carcinogenic to humans. 

Therefore, a cancer risk assessment was not performed 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 currently registered uses 

(including almond and pistachio), all pending uses, and proposed uses for 

representative crops of Tree Nut Crop Group 14-12. The Tier l SCI-GROW 

(version 2.3) model was used to estimate ground water concentrations, and the Tier 

II Surface Water Concentration Calculator (v. 1.106) was used to estimate surface 

water concentrations. For ground water, the currently registered uses on almond 

and grapes provided a combined EDWC of 0.086 ppb (acute and chronic). For 

surface water, the registered use on grapes provided a combined acute EDWC of 

48.2 ppb and a combined chronic EDWC of 25.5 ppb. No Percent Cropped Area 

adjustments were made to the surface water EDWCs. Since the surface water 

EDWCs exceed the ground water EDWC, surface water values were used for risk 

assessment purposes and considered protective for any ground water exposure 

concerns.

Acute Exposure from Drinking Water: The acute surface water EDWC of 48.2 ppb

was input directly into the DEEM-FCIDTM software as “water, direct and indirect, 

all sources” to model the acute drinking water exposures. The acute drinking water 

exposure contributions at the 99.9th percentile of exposures was 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 to the U.S. population resulted in a MOE of 126,024 (0.1% of the aRfD of 

2.0 mg/kg-bw/day). The most sensitive subpopulation was children 3-5 years old, 

with a MOE of 91,491 (0.1% of the aRfD of 2.0 mg/kg-bw/day). Since the 

Benchmark MOE for this assessment was 100 and since the EPA generally has no 

concern for exposures above the Benchmark MOE or 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 surface water EDWC of 25.5 

ppb was input directly into the DEEM-FCIDTM software as “water, direct and 

indirect, all sources” to model the chronic drinking water exposures. Chronic 

drinking water exposure to the U.S. population resulted in a MOE of 5,057 (2.0% of 

the cRfD of 0.027 mg/kg-bw/day). The most sensitive subpopulation was all infants 
5

(<1 year old), with a MOE of 1,961 (5.1% of the cRfD of 0.027 mg/kg-bw/day). 

Since the Benchmark MOE for this assessment was 100 and since the EPA generally 

has no concern for exposures above the Benchmark MOE or below 100% of the 

cRfD, 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. Residential exposure 

assessments were performed for cyprodinil to evaluate exposures resulting from offsite drift of agricultural products into residential areas; the most-exposed subgroup 

was children 1-6 years old via hand-to-mouth incidental oral exposures from play 

activities on turf, with a MOE of 1,472 (Benchmark MOE = 100). Incidental 

exposure to consumers from spray drift from non-residential uses were not included 

in the aggregate consumer risk estimates in accordance with EPA’s current policy 

and practice.

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. The acute dietary exposure analysis (food plus water) showed that 

exposure from all current, pending, and proposed uses of cyprodinil would result in 

a MOE of 3,077 (3.3% of the aRfD of 2.0 mg/kg-bw/day) for the general U.S. 

population, which exceeds the Benchmark MOE of 100. The chronic dietary 

exposure analysis (food plus water) showed that exposure from all current, pending, 

and proposed uses of cyprodinil resulted in a MOE of 688 (14.6% of the cRfD of 

0.027 mg/kg-bw/day) for the general U.S. population, which also 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 
6

exposure to residues arising from all current, pending, and proposed uses of 

cyprodinil.

2. Infants and children. The acute dietary exposure analysis (food plus water) showed 

that exposure from all current, pending, and proposed uses of cyprodinil resulted in 

a MOE of 1,522 (6.6% of the aRfD of 2.0 mg/kg-bw/day) for the most sensitive 

population subgroup, all infants <1 year old, which exceeds the Benchmark MOE of 

100. The chronic aggregate dietary (food plus water) exposure analysis showed that 

exposure from all current, pending, and proposed uses of cyprodinil would result in 

a 254 (39.5% of the cRfD of 0.027 mg/kg-bw/day) for the most sensitive population 

subgroup, 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 to infants and children from aggregate 

exposure to residues arising from all current, pending, and proposed uses of 

cyprodinil.

F. International Tolerances

Codex Alimentarius Commission established Maximum Residue Limits (MRLs) for

cyprodinil in or on various agricultural commodities including almond hulls, 

almonds, apple, barley, beans (except broad bean and soy bean), cucumber, dried 

grapes (currants, raisins, and sultanas), edible offal, eggplant, grapes, lettuce (head 

and leaf), bulb onion, pear, sweet peppers, prunes, raspberries (red and black), 

summer squash, stone fruits, straw and fodder of cereal grains, strawberry, tomato, 

wheat, and various meat, milk, and egg commodities.