Document ID: EPA-HQ-OPP-2013-0151-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-12-22T05:00Z

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 establishing 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 before EPA rules on the petition.
A. Residue Chemistry
	1. Plant metabolism.
The nature of the residues in plants is understood for the purpose of the proposed tolerance. The metabolism of [14]C-difenoconazole has been studied using both phenyl and triazole labels in wheat, tomatoes, potatoes, grapes, and spring rape.  The 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 Guideline 860.1300.
	2. Analytical method.I.Food [Syngenta Crop Protection, LLC has submitted a practical analytical method (AG-575B, master record identification (MRID) No. 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 been provided to FDA for insertion into pesticide analytical manual (PAM) II. Method REM 147.08 (MRID 46950222) is also available for enforcement method, for the determination of residues of difenoconazole in crops. Residues are qualified by liquid chromatography (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 analytical 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 tolerances.  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.  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 difenoconazole 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/2010/2010-9759.htm.  A summary 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.]

	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 Group 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, millet, oats, rye, and triticale and post-harvest use on potatoes treated with Thesis(TM) 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 DEEM(TM) (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) using 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 water 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 children'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 level (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 expressed 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 only) 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 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 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.]
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 expressed 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. population 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 EPA 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 Document, 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 surface 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 modeling 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 grape 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 assessment purposes and will be considered protective for any ground water exposure concerns.  
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-FCID(TM) 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 subgroup.  At the 99.9th 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 reasonable 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-FCID(TM) 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 aggregate 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 believes 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 broad 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-Shield(TM) as an additive to paint.  For landscape 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 DIFENO-Shield(TM), 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 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 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".  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 two 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 databases.  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 toxicity data, the acute aggregate exposure analysis for all current, pending and proposed uses of difenoconazole 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.  The 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 arising 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.]