EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER (11/25/2013)

Interregional Research Project Number 4 (IR-4) Petition Number, PP#, 4E8273

EPA has received a pesticide petition, PP# 4E8273, from Interregional Research 

Project Number 4, 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 the

tolerance for residues of cyprodinil, 2-Pyrimidinamine, 4-cyclopropyl-6-methyl-Nphenyl-], in or on the raw agricultural commodities artichoke, globe at 4.0 parts per 

million (ppm); acerola at 1.5 ppm; feijoa at 1.5 ppm; guava at 1.5 ppm; jaboticaba at 1.5

ppm; passionfruit at 1.5 ppm; starfruit at 1.5 ppm; wax jambu at 1.5 ppm; fruit, stone

group 12-12 at 2.0 ppm; and pomegranate at 7.0 ppm. Upon approval of the 

aforementioned tolerances, it is proposed that 40 CFR 180.532 be amended to remove the 

established tolerance for the residues of cyprodinil in or on the raw agricultural 

commodity fruit, stone, group 12 at 2.0 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. 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. 
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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

fludioxonil 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 fludioxonil 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. [Insert text.]

2. Genotoxicty. [Insert text.]

3. Reproductive and developmental toxicity. [Insert text.]

4. Subchronic toxicity. [Insert text.]

5. Chronic toxicity. [Insert text.]

6. Animal metabolism. [Insert text.]

7. Metabolite toxicology. [Insert text.]

8. Endocrine disruption. [Insert text.]

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 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 current and pending uses plus proposed new IR-4 uses on artichoke, guava, 

cucumbers (greenhouse), tomatoes (greenhouse and cherry), a postharvest use on 

pomegranate, and an extension of existing stone fruit tolerances to all of Crop Group 12-

12. 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; 

all other processing factors used the DEEM-FCIDTM Version 7.87 defaults. The percent 
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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 

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 2,085 (4.8% 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 

0.027 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 473 (21.1% of the 

cRfD of 0.027 mg/kg-bw/day). Chronic food exposures to the most sensitive 

subpopulation (children 1 - 2 years old) resulted in a MOE of 196 (51.1% 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 artichoke, guava, green-house cucumbers, green-house tomatoes, and postharvest pomegranate 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. For ground water, the currently 

registered uses on almond and grapes provided a combined EDWC of 0.0861 ppb (acute 

and chronic). For surface water, the registered use on peppers provided a combined 
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acute EDWC of 46.9 ppb and the currently registered use on grapes provided a combined 

chronic EDWC of 27.1 ppb. No Percent Cropped Area adjustments were made to the 

surface water EDWCs. Since the surface water EDWCs exceed the ground water 

EDWC, the 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 EDWC of 46.9 ppb was incorporated 

with food residues as “water, direct and indirect, all sources” directly into the DEEMFCIDTM 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 201,072 (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 and proposed uses of 

cyprodinil.

Chronic Exposure from Drinking Water: The chronic EDWC of 27.1 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 4,758 

(2.1% of the cRfD of 0.027 mg/kg-bw/day). The most sensitive subpopulation was all 

infants (<1 year old), with a MOE of 1,845 (5.4% 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 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 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 
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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 430 (23.2% of the cRfD of 0.027 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 185 (54.1% of the cRfD 

of 0.027 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 2,064 

(4.8% 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 483 (20.7% of the 

cRfD of 0.027 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

In 2005 the Codex Alimentarius Commission established Maximum Residue Limits 

(MRLs) for cyprodinil in or on various agricultural commodities including almond hulls, 
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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.