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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: [** **Tony Kish (703) 308**  **- 9443**  **] Syngenta Crop Protection LLC. PP#**  **EPA has received a pesticide petition**  **PP# from**  **Syngenta Crop Protection LLC., P.O. Box 18300, Greensboro, NC 27419**  **- 8300**  **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 180.475 1.**  **by establish ing a tolerance for residues of**  **[ Difenoconazole :**  **1 [2**  **- [2**  **- chloro**  **** **4 -**  **(4 -**  **chlorophenoxy) ]**  **phenyl -** **4 -**  **methyl -**  **1,3 -**  **dioxolan -**  **2 -** **ylmethyl ]**  **- 1H**  **- 1,2,4,**  **- triazole) ]**  **in or on the raw agricultural commodity [**  **rapeseed subgroup 20A**  **] at**  **[ 0.1**  **] 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 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 befo re EPA rules on**  **the petition. A. Residue Chemistry**  **1. Plant metabolism.**  **The nature**  **of the**  **residues in**  **plants is**  **understood for**  **the purp**  **ose of**  **the proposed**  **tolerance. The**  **metabolism of**  **14 C**  **- difenoconazole**  **has been**  **studied using**  **both phenyl**  **and triazole**  **labe ls**  **in wheat,**  **tomatoes, potatoes,**  **grapes, and**  **spring rape.**  **T he**  **metabolic pathway was the same in these four separate and distinct crops. Therefore, the**  **metabolism of**  **difenocoanzole is**  **considered to**  **be adequately**  **understood for**  **all crops, per EPA Test Guid**  **eline 860.1300. 2.**  **Analytical method. I.Food**  **[ Syngenta Crop Protection,**  **LLC has submitted a**  **practical analytical method (AG -**  **575B, master record identification (MRID) No.**2

**428065 -** **04) for detecting and measuring levels of difenoconazole in or on food with a limit of quantitation (LOQ) that allows monitoring of food with residues at or above**  **the levels set in the proposed tolerances. EPA has validated this method and copies have bee**  **n provided to FDA for insertion into pesticide analytical manual (PAM) II. Method REM 147.08 (MRID**  **46950222) i s also available for enforcement method, for**  **the determination of residues of difenoconazole in crops. Residues are qualified by liquid chromatogr**  **aphy (LC)/mass spectrometry (MS)/(MS) The method is available to**  **anyone who is interested, and may be obtained from the Field Operations Division, Office of Pesticide Programs.**  **ii. Livestock. Syngenta Crop Protection, Inc. has submitted a practical analy** **tical method (AG**  **- 544A, MRID**  **- 43292401) for detecting and measuring levels of**  **difenoconazole in or on cattle tissues and milk and poultry tissues and eggs, with a LOQ that allows monitoring of food with residues at or above the levels set in the**  **proposed tol erances. EPA has validated this method and copies have been provided**  **to FDA for insertion into PAM II. The method is available to anyone who is interested, and may be obtained from the Field Operations Division, Office of Pesticide Programs.**  **Tolerances in meat, milk, poultry or eggs were established for enforcement purposes.**  **] 3.**  **Magnitude of residues. [**  **Syngenta conducted magnitude of residue trials on**  **canola in Canada to support the**  **requested use of difenoconazole in/on rapeseed**  **subgroup 20A .**  **The maximum residue of difenoconazole on canola was 0.063 ppm. These**  **residue trials satisfy the requested tolerance on**  **rapeseed subgroup 20A**  **. ]**  **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. E**  **PA has**  **also considered**  **available information**  **concerning the**  **variability of the sensitivities of major identifiable subgroups of consumers, including in**  **fants and children.**  **S pecific**  **information on**  **the studies**  **received and**  **the nature**  **of the**  **toxic effects**  **caused by**  **difenoconazole as**  **well as**  **the no**  **- observed**  **- adverse**  **- effect**  **- level**  **(NOAEL) from**  **the toxicity**  **studies can**  **be found**  **at the**  **following website**  **: http://e**  **docket.access.gpo.gov/2010/2010 -**  **9759 .htm.**  **A s**  **ummary of**  **the toxicological**  **endpoints for**  **difenoconazole used**  **for human**  **risk assessment**  **is discussed**  **in Unit**  **III. A**  **and B.**  **of the**  **final rule published**  **in the**  **Federal Register of**  **April 28, 2009 (75**  **FR pages**  **22256 -**  **22263) (FRL -**  **8817 -**  **3 ).**  **1. Acute toxicity.**  **[Insert text.]**3 **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 III/IV acute, short**  **- term, and chronic aggregate**  **exposure evaluations were performed for difenoconazole ([(2S,4R)/(2R/4S)]/[(2R/4R)/(2S,4S) 1**  **- (2**  **- [4**  **- (4**  **- chlorophenoxy)**  **- 2**  **- chlorophenyl]**  **- 4**  **- methyl**  **- 1,3**  **- dioxolan**  **- 2**  **- yl**  **- methyl)**  **- 1H**  **- 1,2,4**  **- triazole) using the Dietary Exposure**  **Evaluation Model (DEEM -**  **FCID TM**  **), version 2.16 from Exponent. These exposure**  **assessments included all current**  **and pending uses**  **. Difenoconazole is currently registered for seed treatment uses on barley, canola, sweet corn, wheat, and**  **imported rye, and for foliar uses on bananas (imported), Brassica vegetables (Crop Group 5), bulb vegetables (Crop Group**  **3), canola, citrus (Crop Group 10 -**  **10), cotton, cucurbit vegetables (Crop Group 9), fruiting vegetables (Crop Group 8**  **- 10), grapes,**  **mango (imported), papaya (imported), pome fruit (Crop Group 11 -**  **10), sugar beets, tree nuts (Crop Group 14), tuberous and corm**  **vegetables (Crop Grou p 1C), and wax**  **apple (imported), carrots, chick peas, soybeans, stone fruit (Crop Group 12),**  **strawberries, seed treatment use on all small grains such as wheat, barley, buckwheat,**4

**millet, oats, rye, and triticale and**  **post -**  **harvest use on potatoes treated with ThesisTM**  **brand fungicide product containing difenoconazole**  **. For the post -**  **harvest use, difenoconazole IR** **- 4 residue data was used. Residue values used in these assessments**  **were obtained from residue field trials conducted at the maximum labeled treatment**  **rate and harvested at the minimum pre -**  **harvest interval (PHI). Experimental processing factors were used for apple juice (0.03x), citrus oil (47x), citrus pulp (4.1x),**  **cottonseed oil (6.3x), grape juice (0.6x), grape raisins (3.5x ), orange juice (0.1x), potato**  **dry flakes (0.01x), soybean hulls (11.3x), soybean meal (2.2x), soybean oil (0.7x), sugar beet molasses (0.58x), sugar beet sugar (0.33x), tomato paste (1.61x), and tomato**  **puree (0.55x); all other processing factors utilized either the DEEMTM (version 7.87)**  **default processing factors or theoretical concentration factors listed in OPPTS860.1520. Anticipated residues in meat, milk, and eggs were calculated by**  **constructing a theoretical “maximum reasonably balanced diet” (MRBD) u sing the**  **OPPTS 860.1000 Table 1 feedstuffs (June 2008 revision). Percent crop treated (%CT)**  **values were estimated based upon economic, pest, and competitive pressures. Drinking water estimates were selected using the higher of the estimated drinking**  **wate r concentrations (EDWCs) for surface and ground water. All consumption data**  **for these assessments were taken from the USDA’s Continuing Survey of Food Intake by individuals (CSFII) with the 1994** **- 1996 consumption database and the Supplemental**  **CSFII childre n’s survey (1998) consumption database.**  **] i.**  **Food. [** **The difenoconazole acute food risk assessment was performed using an acute reference dose (aRfD) of 0.25 mg/kg** **- bw/day based upon an acute**  **neurotoxicity study in rats with a no observed adverse effect leve l (NOAEL) of 25**  **mg/kg -**  **bw/day and an uncertainty factor of 100X. The 100X safety factor includes intra**  **- and inter** **- species variations; no additional FQPA safety factor was applied. For**  **the purpose of aggregate risk assessment, the exposure values were expr essed in**  **terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each subpopulation. In addition, exposure was expressed as a**  **percent of the acute reference dose (%aRfD). At the 99.9 th**  **percentile, acute (food onl**  **y) exposure to the U.S. population resulted in a MOE of 864 (11.6% of the aRfD of 0.25 mg/kg** **- bw/day). The most exposed sub**  **- population was children (1**  **- 2 years old)**  **with a MOE of 481 (20.8% of the aRfD of 0.25 mg/kg -**  **bw/day). Because the Benchmark MOE for t**  **his assessment is 100 and the EPA generally has no concern for exposures above the Benchmark 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 fr**  **om all current and pending uses plus the proposed post**   ** harvest use on potatoes.** **]**5

**Chronic Exposure . The difenoconazole chronic food risk assessment was performed**  **for all population subgroups using a chronic reference dose of 0.01 mg/kg -**  **bw/day based upon a combined chronic toxicity/carcinogenicity study in rats with a no**  **observed adverse effect level ( NOAEL) of 0.96 mg/kg** **- bw/day and an uncertainty**  **factor of 100X. The 100X safety factor includes intra -**  **and inter -**  **species variations; no additional FQPA safety factor was applied. For the purpose of aggregate risk**  **assessment, the exposure values were expre ssed in terms of margin of exposure**  **(MOE), which was calculated by dividing the NOAEL by the exposure for each subpopulation. In addition, exposure was expressed as a percent of the chronic**  **reference dose (%cRfD). Chronic food exposure to the U.S. popula tion resulted in a**  **MOE of 603 (15.9% of the cRfD of 0.01 mg/kg -**  **bw/day). The most exposed subpopulation was children (1**  **- 2 years old) with a MOE of 241 (39.9% of the cRfD of**  **0.01 mg/kg -**  **bw/day). Because the Benchmark MOE for this assessment is 100 and the E**  **PA generally has no concern for exposures above the Benchmark 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 and pending uses**  **plus the proposed post -**  **harvest use on potatoes. Cancer**  **. A cancer dietary assessment was not conducted. Difenoconazole is classified**  **as a Group C, “possible human carcinogen,” with a non -**  **linear (MOE) approach for human risk characterization (CPRC Documen**  **t, 7/27/94, Memo, P. V. Shah, March 3, 2007, HED Doc. No. 0054532).**  **ii. Drinking**  **water**

**. [** **The Estimated Drinking Water Concentrations (EDWCs) of difenoconazole were determined using Tier 1 screening model SCI**  **- GROW (version 2.3)**  **which estimates pesticide concentration in ground water and Tier II PRZM/EXAMS (PE version 5.0) which estimates surfac**  **e water exposures. EDWCs for**  **difenoconazole from currently registered and pending uses were determined.**  **For the proposed post**   ** harvest use on potatoes, there will be no environmental exposure to ground water** **and/or surface water. Based on the SCI**  **- GROW mo**  **deling results, the highest**  **groundwater EDWC for difenoconazole was 0.0123 ppb (acute and chronic)**  **based on the currently registered citrus use**  **. Based on**  **Tier II PRZM/EXAMS modeling for**  **surface water conducted by EPA (D367382), the currently registered g**  **rape use provided the highest**  **EDWCs of 15.8 ppb and 10.4 ppb for acute and chronic, respectively**  **(adjusted for 0.87 Percent Cropped Area, PCA). Since the surface water**  **EDWCs exceed the ground water EDWC, the surface water values were used for risk assessm**  **ent purposes and will be considered protective for any ground water exposure concerns.** 6

**Acute Exposure from Drinking Water :**  **The peak (acute) EDWC of 15.8 ppb (0.0158 ppm) for surface water was input directly into the DEEM**  **- FCIDTM software as “water,**  **direct and indirect, all sources” to obtain the acute dietary exposure from water.**  **Drinking water exposures were determined by taking the difference between the aggregate exposures (food + drinking water) and food exposures (food only) for each**  **population subgr oup.**  **At the 99.9 th**  **percentile, acute drinking water exposure to the U.S. population resulted in a MOE of 58,685 (0.2% of the aRfD of 0.25 mg/kg** **- bw/day).**  **The most exposed subpopulation was children 1**  **- 2 years old**  **, with a MOE of 15,664 (0.6% of the aRfD of 0.25 mg/kg** **- bw/day).**  **Because the Benchmark MOE for this assessment is 100 and the EPA generally has no concern for exposures above the**  **Benchmark or below 100% of the aRfD, Syngenta believes that there is a reason able**  **certainty that no harm will result from acute exposure to drinking water residues arising from all current and pending uses plus the proposed post** **- harvest use on**  **potatoes. Chronic Exposure from Drinking Water** **. The annual average (chronic) EDWC of**  **10. 4**  **ppb (0.0104 ppm) for surface water was input into the DEEM**  **- FCIDTM software as**  **“water, direct and indirect, all sources” to obtain the chronic dietary exposure from water. Drinking water exposures were determined by taking the difference between**  **the aggre gate exposures (food + drinking water) and food exposures (food only) for**  **each population subgroup. Chronic**  **drinking water exposure to the U.S. population**  **resulted in a MOE of 4,379 (2.2% of the cRfD of 0.01 mg/kg -**  **bw/day). The most**  **exposed sub -**  **population was all infants <1 year old,**  **with a MOE of 1,336 (7.2% of the cRfD of 0.01 mg/kg** **- bw/day).**  **Because the Benchmark MOE for this assessment is 100 and the EPA generally has no concern for exposures above the Benchmark or below**  **100% of the cRfD, Syngenta beli eves that there is a reasonable certainty that no harm**  **will result from chronic exposure to drinking water residues arising from all current and pending uses plus the proposed post** **- harvest use on potatoes.**  **] 2.**  **Non -**  **dietary exposure .**  **[ Difenoconazole is a br** **oad spectrum fungicide used in residential applications for landscape ornamentals and materials protection.**  **Difenoconazole is formulated in Difenoconazole 2EC for protection of landscape ornamentals and in DIFENO**  **- ShieldTM as an additive to paint. For land**  **scape ornamentals, these residential exposure assessments were run in support of**  **registered uses of Difenoconazole 2EC at a maximum single application rate of 8.0 oz product/A (0.13 lb ai/A) for prevention of diseases in roses. For paints containing**  **DIFEN O**  **- ShieldTM, these exposure assessments assumed a maximum application rate of**  **0.01% ai w/w. The toxicological endpoints established by the EPA in the August 2007 HED difenoconazole risk assessment were used (NOAEL = 1.25 mg/kg** **- bw/day). The** 7

**worse case short**  **- term margin of exposure (MOE) for all uses assessed was for adults**  **applying paint with an airless sprayer, with a combined (inhalation and dermal) MOE of 387. Because the residential MOE exceeds the EPA’s Benchmark MOE of 100,**  **Syngenta believes that there is a reasonable certainty that no harm will result from**  **short -** **term exposures arising from all current and pending uses plus the proposed**  **post -**  **harvest use on potatoes. ]**  **D. Cumulative Effects [**  **Cumulative Exposure to Substances with a Common Mech anism 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 s**  **ubstances that have a common mechanism of toxicity”. An ongoing series of studies being conducted by**  **the U.S. Triazole Task Force (USTTF) are designed to provide the Agency with more complete toxicological and residue information for 1,2,4 triazole and tw**  **o conjugates, triazolylalanine and triazolyl acetic acid, metabolites common to most of the triazole**  **fungicides. Upon completion of review of those data, EPA will prepare a more sophisticated assessment based on the revised toxicological and exposure data**  **bases. For the purposes of this tolerance action, the EPA has not assumed that**  **difenoconazole has a common mechanism of toxicity with other substances. ]**  **E. Safety Determination 1.**  **U.S. population. [**  **Using the conservative assumptions described above, and**  **based on the completeness and reliability of the toxicity data, the acute aggregate**  **exposure analysis for all current, pending and proposed uses of difenoconazole resulted in a MOE of 852 for the U.S. population. The short** **- term aggregate exposure**  **analysis for all current, pending and proposed uses of difenoconazole resulted in a MOE of 248 for the U.S. population. The chronic aggregate exposure analysis for all**  **current, pending and proposed uses of difenoconazole resulted in a MOE of 530 for the U**  **.S. population. Because the worst case aggregate MOE of 205 for short -** **term aggregate exposures exceeds the Benchmark MOE of 100, Syngenta believes that**  **there is a reasonable certainty that no harm will occur to the U.S. Population from acute, short** **- term,**  **and chronic aggregate exposures arising from all current and pending uses plus the proposed post** **- harvest use on potatoes.**  **] 2.**  **Infants and children .**  **[ Using the conservative assumptions described above,**  **and based on the completeness and reliability of the t oxicity data,**  **the acute aggregate exposure analysis for all current, pending and proposed uses of difenoconazole** 8

**resulted in a MOE of 466 for children 1**  **- 2 years old**  **. The short -** **term aggregate exposure analysis for all current, pending and proposed uses of**  **difenoconazole resulted in a MOE of 333 for**  **children 1 -**  **6 years old . T**  **he chronic aggregate exposure**  **analysis for all current, pending and proposed uses of difenoconazole resulted in a MOE**  **of 223 for children 1 -**  **2 years old. Because the worst case aggregate MOE for**  **chronic exposures of 223 for children 1 -**  **2 years old exceeds the Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to**  **infants and children from acute, short** **- term, and chronic**  **aggregate exposures ar ising**  **from all current and pending uses plus the proposed post** **- harvest use on potatoes.**  **] F. International Tolerances**  **[ Codex Maximum Residue Limits (MRLs) for residues of difenoconazole**  **per se have been established on a number of commodities including banana, grapes, meat**  **milk eggs, milks, peach, plums, pome fruit, potatoes, soybeans, tomatoes, and wheat .**  **]**