Document ID: EPA-HQ-OPP-2014-0470-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-09-05T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  
Interregional Research project number 4 (IR-4), PP# 4E8274
	EPA has received a pesticide petition, PP#  4E8274, from Interregional Research Project Number 4 (IR-4), [500 College Road East, Suite 201W,  Princeton, NJ 08540 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 by  establishing tolerances 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 commodities ginseng at 0.50 parts per million (ppm); artichoke, globe at 1.5 ppm; fruit, stone, group 12-12 at 2.5 ppm; and nut, tree, group 14-12 at 0.03 ppm. The pesticide petition additionally is proposing to amend 40 CFR part 180.475 by removing the established tolerances for residue of difenoconazole in or on the raw agricultural commodities  fruit, stone, group 12 at 2.5 ppm; nut, tree, group 14 at 0.03 ppm; and pistachio 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 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 difenoconazole is considered to be adequately understood for all crops, per EPA Test Guideline 860.1300.
	2. Analytical method. Syngenta Crop Protection, Inc. 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. [IR-4 conducted adequate magnitude of residue trials on ginseng and artichoke under OPPTS 860.1500 to support the requested use of difenoconazole. These residue trials satisfy the requested tolerance on ginseng and artichoke.]

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 acute, short-term and chronic dietary exposure evaluations were performed for difenoconazole, 1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole, 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 difenoconazole exposure assessments included all current and pending (rapeseed, Crop Group 20) uses plus proposed new post-harvest uses on pome fruit (Crop Group 11-10) and foliar application on dried legumes (Crop Group 6C), artichoke, ginseng, greenhouse cucumbers, and blueberries (Crop Groups 13-07B).  These assessments utilized residue data from field trials where difenoconazole 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 used the DEEM-FCID[TM] Version 7.87 defaults.  Secondary residues in beef liver and kidney were estimated based on "maximum reasonably balanced diets" and transfer information from feeding studies. 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. 
	i. Food. Acute exposure.  Acute (food only) risk assessments for difenoconazole were performed for all population subgroups using an acute reference dose (aRfD) of 0.25 mg/kg-bw/day, based upon a neurotoxicity study in rats with a no observed adverse effect level (NOAEL) of 25 mg/kg-bw/day and an uncertainty factor (UF) of 100X. The 100X safety factor includes intra- and inter-species variations; no additional FQPA 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).  At the 99.9[th] percentile, acute (food only) exposure to the U.S. population resulted in a MOE of 715 (14.0% 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 347 (28.8% of the aRfD of 0.25 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 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, and proposed uses for difenoconazole.
Chronic exposure.  Chronic (food only) risk assessment for difenoconazole were performed for all population subgroups using a chronic reference dose (cRfD) of 0.01 mg/kg-bw/day, based on 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 uncertainly factor of 100X.  The 100X safety factor includes intra- and inter-species variations; no additional FQPA safety factor was 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 expressed as a percent of the chronic reference dose (%cRfD).  Chronic (food only) exposures to the U.S. population resulted in a MOE of 1,305 (7.4% of the cRfD of 0.01 mg/kg-bw/day).  The most exposed sub-population was children (1-2 years old) with a MOE of 393 (24.5% of the cRfD of 0.01 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 reference dose, Syngenta believes that there is a reasonable certainty that no harm will result from chronic dietary (food) exposure to residues arising from all current, pending, and proposed uses for difenoconazole.
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 (CGA169374) determined as total toxic residues of difenoconazole and its degradate (CGA205375) were determined using Tier l models SCI-GROW (Screening Concentration in Ground Water) to estimate pesticide concentrations in ground water and Tier II model PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analysis Modeling System) to estimate pesticide concentration in surface water.  All registered and proposed uses on artichoke, ginseng, green-house cucumbers and blueberries were assessed.  Based on the SCI-GROW modeling, the currently registered golf course turf use provided a ground water acute and chronic EDWC of 0.0136 ppb.  Based on the PRZM/EXAMS modeling, the currently registered grape use provided a surface water acute EDWC of 20.0 parts per billion (ppb) and a surface water chronic EDWC of 13.5 ppb.  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 acute surface water EDWC of 20.0 ppb was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources" to model the acute drinking water exposures.  Exposure contributions at the 99th percentile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food (alone) exposures for each population subgroup.  Acute drinking water exposure U.S. population resulted in a MOE of 30,084 (0.3% 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 19,592 (0.5% of the aRfD of 0.25 mg/kg/day).  Since the benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures 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 registered and proposed uses for difenoconazole.

Chronic Exposure from Drinking Water.  The chronic surface water EDWC of 13.5 ppb was input directly into the DEEM-FCID software as "water, direct and indirect, all sources" to model the chronic drinking water exposures.  Chronic drinking water exposure to the U.S. population resulted in a MOE of 3,396 (2.8% of the cRfD of 0.01 mg/kg-bw/day).  Chronic drinking water exposure to the most exposed sub-population (all infants, <1 year old) resulted in a MOE of 1,317 (7.3% of the cRfD of 0.01 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since EPA generally has no concern for exposures 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 registered and proposed uses for difenoconazole.

      2. Non Dietary Exposure: The use of difenoconazole on ornamentals and flower gardens (Inspire(R), Ready-to-Use spray) and golf courses (Quadris Top(TM), Heritage Top(TM), Briskway(TM)) may result in residential handler or post-application exposures to selected subgroups.  A short-term toxicological dermal and inhalation endpoint of 1.25 mg/kg-bw/day was selected based upon the no observed adverse effect level (NOAEL) from a 2-generation reproductive study in rats with an uncertainty factor of 100X, which includes intra- and inter-species variations; no additional FQPA safety factor was applied.  Exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each subgroup.  Adult gardeners 19+ years old had a short-term residential MOE of 249 and youth gardeners had a short-term residential MOE of 363; there were no other exposed subgroups.  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the Benchmark MOE, Syngenta believes that there is a reasonable certainty that no harm will result from short-term residential exposure to residues arising from all current, pending, and proposed uses for difenoconazole. 
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. The acute dietary exposure analysis (food plus water) showed that exposure from all current, pending and proposed uses of difenoconazole would result in a MOE of 699 (14.3% of the aRfD of 0.25 mg/kg-bw/day) for the general U.S. population, which exceeds the Benchmark MOE of 100.  For the short-term aggregate exposure analysis the corresponding food, water and residential MOEs were aggregated using the inverse MOE approach.  The short-term aggregate (food, drinking water, and residential) MOE was 207 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 difenoconazole resulted in a MOE of 943 (10.2% of the cRfD of 0.01 mg/kg-bw/day) for the general U.S. population, which also exceeds the Benchmark MOE of 100.  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 to residues arising from all current, pending, and proposed uses of difenoconazole, including anticipated dietary exposure from food, water, and all other types of non-occupational exposures.
	2. Infants and children. The acute dietary exposure analysis (food plus water) showed that exposure from all current, pending and proposed uses of difenoconazole would result in a MOE of 341 (29.3% of the aRfD of 0.25 mg/kg-bw/day) for the most sensitive population subgroup, children 1-2 years old, which exceeds the Benchmark MOE of 100.  For the short-term aggregate exposure analysis the corresponding food, water and residential MOEs were aggregated using the inverse MOE approach.  The short-term aggregate (food, drinking water, and residential) MOE was 438 for children (1-2 years), 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 difenoconazole resulted in a MOE of 337 (28.6% of the cRfD of 0.01 mg/kg-bw/day) for the most sensitive population subgroup, children 1-2 years old, which exceeds the Benchmark MOE of 100.  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 difenoconazole, including anticipated dietary exposure from food, water, and all other types of non-occupational exposures.
F. International Tolerances
	Codex Alimentarius Commission established Maximum Residue Limits (MRLs) for difenoconazole in various agricultural commodities including asparagus, banana, beans, except broad bean and soya bean,  broccoli, Brussels sprouts, cabbages, head, carrot, cauliflower,  celeriac, celery, cherries, edible offal (mammalian), eggs, garlic,  ginseng, grapes, leek, lettuce, head, lettuce, leaf, mango, meat, milks, nectarine, olives, papaya, passion fruit, peach, peas (pods and succulent/immature seeds), plums (including prunes), pome fruits, potato, poultry meat, poultry, edible offal of, rape seed, soya bean (dry), sugar beet, sunflower seed, tomato, tree nuts, wheat, and wheat straw and fodder, dry.