EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(11/19/2010) 

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] 

[lnscrt petition number] 

I"PA has r~ccived a pesticide petition (!insert petition number]) from [Syngenta 

Crop Protection], (P. 0. Box 18300, Greensboro, NC 274091 proposing, pursuanr to 

sec tion 408(J) ofthc Federal Food. Drug. and Cosmetic Act (ffDCA), 21 U.S.C. 

~46a(d ). to umend 40 CFR part 180.532. 

(Options (pick one) 

1. by establishing the tolerances Cor residues or 

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

raw agricult ura l L:ommodity (] at 11 

Nut, Tree, Group 14-12; at 0.04 ppm with the exceptions of almond and 

pistachio which will retain their currently established tolerances of 0.02 ppm and 

0.10 ppm, respectively 

EPA ha!:> tktcrmincd that the petition contains data or information regarding the elements 

set rorth in section 408 (d)(2) of FDDCA: htmcver. EPA has not tully evaluated the 

suflicicncy or the suhmitted data at this time or "' hcther the data supports granting of the 

petition. AdJitional data may be needed bd'or~ EPA rules on the petition. 

A. Residue ( 'hemislry 

I . Plant meluhuhsm. The metabolism of cyprodinil is adequately understood for 

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

- • • SSI 
2 

characterized in plants and animals. No toxicologicaUy significant metabolites have 

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

enforcement method that accounts for only parent cyprodinil. 

2. AnaZvtical method. Syngenta Crop Protection has developed and validated 

analytical methodology for enforcement purposes. This method (Syngenta Crop 

Protection Method AG-631B) bas passed an Agency petition method validation for 

several commodities and is currently the enforcement method fot· cyprodinil. An 

extensive database of method validation data using this method on va rious crop 

commodities is available. 

3. Magnitude (J.fresidues. 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. 

13. Toxicological Profile 

EPA has evaluated the available tox.icity data and considered its validity. completeness. 

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

has also considered avai lable information concerning the variabi lity 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 eJTects caused by 

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

studies can be found at the following website: http://edocket.access.gpo.gov/20 12/2012-

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

assessment is disc ussed in lJnit fli .A and B. of the final rule published in the Federal 

Register oC August 17.20 12 (77 FR pages 49732-49738) (FRL-9359-7). 

1. A cute toxici~~·. [In~ert text.] 

2. Genotoxicty. [Insert text.] 

3. Reproductive and developmeutal toxici~v. [Insert text.] 

4. Suhcllronic toxici~r. [Insert text.] 

5. Chro1tic toxicity. [Insert text.] 

6. Anima/metabolism. [Insert text.] 

7. Metabolite toxicology. [Insert text.] 

8. Endocrine disruption. [Insert text. I 
3 

1. Dierury exposutl!. Tier II acute and chronic dietary exposure evaluations were 

performed for cyprodinil using the Dietar-y Exposure Evaluation Model (DEEMFCIDn• 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 (including almond and pistachio), 

all pending uses, and proposed new uses on Tree Nuts Crop Group 14-12 {pecan and 

filbert). These assessments utilized residue data fr om 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-FCID'~'"1 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. A cure ex1w.wre. The acute dieta ry (food only) risk assessments for 

cyprodinil were performed for all population subgroups using an acute reference 

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

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

factor of 1 OOX 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 ma rgin 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 (%aRID). At the 99.91

h percentile, acute (food only) exposure to the 

U.S. population resulted in a MOE of 3,154 (4.2% 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 1,537 

(8.7% of the aRID 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 aRID, 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. 

( 'hronic t>xposure. The chronic reference dose (Rf'D) for cyprodinil is 

0.027 mg/kg-bw/day, based on a chronic rat study with a NOAEL of 2.7 mg/kgbw/day and an uncertainly factor of lOOX for intra- and inter-species variations. No 

additional FQJ> A safety factor was applied. For the purpose of the aggregate risk 

assessment, the exposure values were expressed in terms of ma rgin 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 
4 

chronic reference dose (%cRfO). Chronic (food only) exposure to the U.S. 

population resulted in a MOE of 797 (12.5% of the cRID of 0.027 mglkg-bw/day). 

The most exposed sub-population was children 1-2 years old with a MOE of 274 

(36.5% of the cRfO of 0.027 mg!kg-bw/day). Since the Benchmark MOE fo.r this 

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

the Benchma rk 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 44 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 dcgradate 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 I 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 ().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 EOWCs. Since the surface water 

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

assessment purposes and considered protective for any ground water exposure 

concerns. 

Acute Erposurefi·om Drinking /-Vater: The acute surface water EDWC of 48.2 ppb 

was input directly into the DEEM-FCJDTM software as "water, direct and indirect, 

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

· exposure contributions at the 99.91

h 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 144,404 (0.1% ofthe aRID of 

2.0 mglkg-bw/day). The most sensitive subpopulation was children 6-12 years old, 

with a MOE of 143,266 (0.1 (Yo of the aRID of 2.0 mglkg-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 aRID, 

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

acute drinking water exposure to residues arising from alJ current, pending, and 

proposed uses of cyprodinil. 

Chronic E'-Cposurefrom Drinking J·Vater: The chronic surface water EDWC of 25.5 

ppb was input directly into the DEEM.-FCIDTM software as Hwater, direct and 

indirect, all sources" to model the chronic drinl<ing water exposures. Chronic 
5 

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

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

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

Since the Benchmarli. 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 cypr·odinil. 

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. Incidental exposure to 

consumers from spray drift from non-residential uses were not included in the 

aggregate consumer risk; this approach agrees with the EPA's current policy and 

practice. 

D. Cwmr/ative ljfi:cts 

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 Sc{/etv Dc:tamino/ ion . 

1. (_!.S. population. The acute dietary exposure analysis (food plus water) showed that 

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

a MOE of 3,086 (4.3% of the aRID 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 (14.5% of the cRfD of 

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

Benchma rk 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. lnjhnts aiUl 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 1,523 (8.8% of the aRID of 2.0 mg/l<g-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 (39.4(% of the cRfD of 0.027 mg/l<g-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, Syngcnta 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. 

3. Females J 3-49 y ears ofage. The acute aggregate exposure analysis showed that 

exposure to all cun·ent and proposed cyprodinil uses would result in a MOE of 

3,185 (4.2% of the aRID of2.0 mglkg-bw/day) for females 13-49 years old, which 

exceeds the Benchma rk MOE of l 00. The chronic aggrega te exposure analysis 

showed that exposure to all current and proposed cyprodinil uses would result in a 

MOE of 769 (13.0% 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 h uman carcin ogenic 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. lnfernafiollal Toleronces 

Codex Alimentarius Commission established Maximum Residue Limits (MRLs) for 

cyprodinil in or on various agricultural commodities including almond bulls, 

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

grapes (currants, raisins, and sultan.as), 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.