**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**  **- 2**  **1 ) 703**  **- 30**  **5 -**  **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 pe tition. 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 **( 5F**  **8358 )**  from **Synge nta 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 tolerance s for residues of

**c yprodinil:**  **4 -**  **cyclopropyl -**  **6 -**  **methyl -**  **N -**  **phenyl -**  **2 -**  **pyrimidinamine** in or on the raw agricultural commodity **Vegetable, tuberous and corm, subgroup 1C ;**  **at 0.**  **0 1**  **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 full y evaluated the sufficiency

of the submitted data at this time or whether the data supports granting of the petition. Additional data may be need ed 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 validat ed**  **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 o**  **f the requested tolerance,**  **Syngenta has conducted the necessary trials in acco**  **rdance 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

a s well as the relationship of the results of the s tudies to human risk. E PA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children. S pecific information on the studies received and the nature of the toxic effects caused by cy prodinil 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 cy prodinil 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 d** 

**evelopmental toxicity. 4.**  **Subchronic toxicity. 5.**  **Chronic toxicity. 6.**  **Animal metabolism. 7.**  **Metabolite toxicology .**  **8. Endocrine disruption**  **.** C. Aggregate Exposure3

1. Dietary exposure. **Tier II acute and chronic dietary exposure evaluations were performed for cyprodinil using the Dietary Exposure Evaluation Model (DEEM**  **** **FCID TM**  **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 cy** **prodinil 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 processi ng factors used the**  **DEEM -**  **FCID TM**  **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 info**  **rmation 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 ex

posure . **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 (NO**  **AEL) of 200 mg/kg -**  **bw/day and an uncertainty factor of 100X to account for intra**  **- and inter** **- species variations. No additional**  **FQ PA safety factor was applied. For the purpose of the acute aggregate risk**  **assessments, the exposure values were expressed in te rms 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 99.9**  **th percentile, acute (food only) ex**  **posure 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**  **asse ssment 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 rat s 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**  **FQ PA safety factor was applied. For the purpose of aggregate risk assessment, the**  **ex posure 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 (f**

**ood 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/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 dietary (food only) exposure to res**  **idues 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 Estima ted 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 prop osed 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 chr onic 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 gro und water exposure**  **concerns.** Acute Exposure from Drinking W ater : **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 99.9**  **th 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 ex** **posure 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 as**  **sessment 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 aris**  **ing from all current, pending, and proposed uses of cyprodinil.**  Chronic Exposure from Drinking W ater : **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 chr onic 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 cRf D 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 w ill 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/l**  **oader/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 po**  **st -**  **application exposure to adults and children from ornamental applications is**  **negligible. Residential exposure**  **assessments were performed for cyprodinil to evaluate exposures resulting from off****** **site drift of agricultural products into residential areas; t he 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 i ncluded**  **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 w hether 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 us es 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 carcinogeni c 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 cur rent, 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 u ses 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 e vidence 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 M**  **aximum R**  **esidue Limits (MRLs)**  **for cyprodinil in or on**  **various agricultural commodit ies 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, raspberr ies (red and black),**  **summer squash, stone fruits, straw and fodder of cereal grains, strawberry, tomato, wheat, and various meat, milk, and egg commodities.**