**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR**

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (**  **5 /**  **5 /20**  **11 )**  **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**  **pestici de 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 pesti cide 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. **(Opt ions (pick one)**  1. by establishing a tolerance for residues of **[cyprodinil: 2 -**  **pyrimidinamine, 4 -**  **cyclopropyl -**  **6 -**  **methyl -**  **N -**  **phenyl -**  **]** in or on the raw agricultural commodity **[]** at **[] Leafy petioles subgroup 0**  **4 B,**  **at 30**  **parts 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 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 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**2

**been identified. The metabolism profile supports the use of an analytical enforcement method that accounts for only parent cyprodinil.**  2. Analytical method. **Sy ngenta 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 enforceme nt 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,**  **e ight crop**  **- field trials were conducted with**  **various commercially available celery cultivars, and the soil types and meteorological conditions at the eight trial sites adequately represented the diversity**  **of conditions under which celery may be commercially grown. These trial sites**  **satisfied the requirements of OPPTS 860.1500 for number and regional distribution. The study design consisted of 2 plots at each trial site: a non**  **- treated control (UTC)**  **plot and a treated (TRT) plot. The TRT plot received four b roadcast foliar**  **applications of 14 oz product/acre/application (or 56 oz product/acre/ season), which equates to 0.328 lb**  **c yprodinil/acre + 0.219 lb**  **f ludioxonil/acre (or a seasonal rate of**  **1.3 lb c** **yprodinil/acre + 0.9 lb f**  **ludioxonil/acre). The treatments were applied with a**  **tank -**  **mix volume of 15 -**  **40 gallons/acre (GPA) at the minimum 7 -**  **day retreatment interval (RTI), and the raw agricultural commodity (RAC) was harvested on the**  **day of the last application to support a 0 -**  **day pre -**  **harvest interval (PHI). Thi s use**  **pattern would be the ‘worst -**  **case’ application as per the proposed -**  **use label.** 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.**  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 c** **yprodinil, 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

3. Reproductive and developmental toxicity **. Reproductive Toxicity:**  **In a two**   ** generation reproduction study in rats, the NOEL for maternal systemic toxicity is** **1000 ppm and the NOEL for reproductive toxicity is 1000 ppm. D evelopmental**  **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 r at developmental toxicity study**  **, the developmental and materna l**  **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 st udies 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. EP A 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 endocri**  **ne 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 evide**  **nce of a long -**  **term effect related to the endocrine system.**  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**   ** FCID** **TM , version 2.16) from Exponent. These cyprodinil exposure assessments**  **included all current and pending uses and a proposed use on celery at a 0 -**  **day pre**   ** harvest interval (PHI). The proposed celery and pending spinach uses comb** **ined with the existing use on leafy vegetables (Group 4A) completes the representative**  **crops for all leafy vegetables (Crop Group 4). These assessments utilized residue data from field trials where cyprodinil was applied at the maximum intended use**  **rate a nd samples were harvested at the minimum 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** 4

**paste (2.3X) were use d in these assessments. All other processing factors used the**  **DEEM -**  **FCID TM**  **Version 7.87 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 dat abase and the Supplemental CSFII**  **children’s survey (1998) consumption database. 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.**  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 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 FQ**  **PA 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 2,434 (4.1% 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 dietary (food) exposure to residues arising from all current, pending, an**  **d proposed uses for cyprodinil.** Chron ic 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 wa s 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 expre ssed as a percent of the**  **chronic reference dose (%cRfD). Chronic food exposures to the U.S. population resulted in a MOE of 867 (10.4% 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 313 (28.7% 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 reasonabl**  **e 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 degr**  **adate CGA249287, reported as combined total residues**  **(cyprodinil plus CGA249287), were determined for the currently registered uses as well as proposed uses on celery, spinach, and peppers using Tier l SCI**  **- GROW** 5

**(version 2.3), which estimates pesticide conc entrations 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 and**  **the pending use on tree nuts provided the highest combin ed EDWC of 0.1076 ppb**  **(acute and chronic). For surface water, the proposed use on peppers provided the highest combined acute EDWC of 46.314 ppb and the currently registered use on**  **grapes provided the highest combined chronic EDWC of 22.691 ppb. The surf ace**  **water EDWCs have been corrected for a 0.87 PCA factor. Since the surface water EDWCs exceed the ground water EDWC, the surface water values will be used for**  **risk assessment purposes and considered protective for any ground water exposure concerns.**  Ac ute Exposure from Drinking W ater : **The acute EDWC of 46.314 ppb**  **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 99.9**  **th percentile**  **of exposure s 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 99.9**  **th percentile for females (13**  **- 49**  **years), the only popul ation subgroup for which an acute toxicological endpoint has**  **been established, resulted in a MOE of 42,206 (0.2% 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 exposure s 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 W ater : **The chronic EDWC of 22.691 ppb**  **was incorporated with food residues as “water, direct a**  **nd 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 5,645 (1.6% of the cRfD of 0.03 mg/kg**  **- bw/day). The most sens**  **itive subpopulation was all infants, with a MOE of 1,722 (5.2% 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 RfD, Syngenta**  **believes that th ere 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. A new**  **product label for Palladium®, containing cyprodinil and fludioxonil, allows professional applications to ornamental plants in residential settings. No post**  **** **application residen tial exposure assessment is required because post** **- application**  **exposure to adults and children from ornamental applications is negligible.** D. Cumulative Effects6

**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 toleran ce 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 exp**  **osure 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 752 (12.0% of the cRfD of 0.03 mg/kg**  **- bw/day) for the U.S. populatio**  **n, 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 in**  **fants 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 289 (31.1% 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 th**  **e 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 aggre gate exposure analysis showed that**  **exposure to all current and proposed cyprodinil uses would result in a MOE of 2,301 (4.3% 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 exposu re analysis**  **showed that exposure to all current and proposed cyprodinil uses would result in a MOE of 882 (10.2% 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 perf**  **ormed, 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 r**  **esult from aggregate exposure from all current, pending, and proposed uses of**7

**cyprodinil.** F. International Tolerances **Codex maximum residue levels have been established for residues of cyprodinil in or on almond**  **s, apples, barley, beans (except broad bean and soya bean), cucumbers,**  **dried grapes (currant s, 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.**