Document ID: EPA-HQ-OPP-2014-0149-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-02-11T05:00Z

I

 EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITICIN:S PUBLISHED IN THE FEDERAL REGISTER

 EPA Registration Division contact: [Tony Kish,703-308-9443]

 INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In Cil:!ic s where the outline element does not apply,please insert   11NA-Remove" and maintiliin the outline.Please do not change the margins,font,or format in your pesticide petition.Simply replace the instructions that  appear in green,i.e., 11[insert compan::::r name]," with the information specific to your action.

 TEMPLATE:

  [Syngenta Crop Protection LLC] [Syngenta Crop Protection LLC. PP#]
       EP :: has received a pes+icide petition PP#	fron [Syngenta Crop Protectio r
 LLC.,P.O. Box 18300,Greensboro, NC 27419-8300] proposing. pursuant to section
 408{d) ofthe Federal..ood, Drug,anJ Cosmetic Act (FFDCA), 21U.S.C. 346a(d), to amend 40 CFR part 180.475.

       1.   by hrreasing t'le establisred tolerance for residueof [Difenoconazole ::. {2-
          [2-chloro-4-(4-chlorophenoxy)]phenyl-4-methyl-1,3-dioxolan-2-ylmethyl] -l.H-
          1,2,4,-triazole) ]  n or on toe raw agriculturalco 	m 11Hy [Fruit,pome,gr oup

          11-10] tron [1] lPPm) to [3] ppm an   [apple,wet pomace] 'rom [4.5] (p, 	')
          to [7.5] ppm.

 EPA has determined that the petition contains data or inform tion regarding the elements set forth in section 408 (d)(2) of  FDDCA; however,EPA has not fully evalu  ted the sufficiency of the submitted data at this time or whether the data supports gran mg 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  propc sed tolerance.  The metabolism  of  14C-difenoconazole has been studied  using both  p 'tenyl and  triazole   labels  in  wheat,  tomatoes,  potatoes, grapes,   and  spring  rape.    The
 metabolic pathway was the same in these four  separate and distinct  crops.  Therebre, the  metabolism of  difenoconazole is considered  to  be  adequately  understood f:1·· all crops,per EPA Test Guideline 860.1300.

       2 Anal·,tical '71ethod. i. Food [Syngenta Crop Protection,Inc. has submitted ;;
 practical analytical method  (AG-5758,master  record identification (MRID) No.
 428065-04) for detecting and measuring levels of difenoconazole in or on food with  t 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 ha'd:! 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 liquic' chromatography (LC)/mass spectrometry (MS)/(MS) The method is available to any:t ne who is interested,and may be obtained  from the Field Operations Division, Office ol Pesticide Programs.

 ii. Livestock. Syngenta Crop Protection,Inc. has submitted a practicalanalytical met hod (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 toleranu::s. 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 ' r om the Field Operations Division,Office of Pesticide Programs.  Tolerances in meat,milk. poultry or eggs were established for enforcement purposes.]

 3 MC!gn::tude of 'esidues  [Syngenta conducted  adequate magnitude  of residut trials on Fruit, pome,group 11-10 under OPPTS 860.1500 to support  the requested  Jse of difenoconazole. These residue trials satisfy the requested tolerance on Fruit,por·11!,. group 11-10.]

 B. Toxicological Profile

 EPA has evaluated  the available toxicity data and considered its validity,complete ':::!SS, 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  sensiti::  ties of major  identifiable subgroups of consumers, including infants  and children.    Sp r.ific

 information on the studies received and the nature  of the toxic effects cause  by difenoconazole  as  well  as  the   no-observed-adverse-effect-level  (NOAEL} from   the toxicity         stu ...1:          --...         '"'c                          at        the        following       we   .ite: http://edocket.access.gpo.gov/2010/2010-9759.htm.  A summary of the toxicolc ,ical endpoints for l.:  .................... -     e ..:;eu iO::   m....a..  ,-,sk assessment is discussed in Unit III.A
 and B. of the final rule published in the Federal Register of April 28, 2009 (75 FR  r: ges
 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 Ill 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 t e 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 pendin · (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 GC). These assessments utilized  residue data from field trials where difenoconazole was applie:  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 processing factors  _sed the DEEM-FCID(TM) Version 7.87 defaults.  Secondary residues in beef liver and kidne:: 1 were estimated  based on "maximum reasonably balanced diets" and transfer information from feeding studies. Percent crop treated  (%CT) values were estimate:! based upon economic,pest, and competitive pressures. Drinking water estimates v::.::re selected using the higher of the estimated  drinking water concentrations (EDWCs) fn· surface and ground  water.

 i. Food  [Acute exposure.  Acute (food only) risk assessments for difenoconazole we·e 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 lOOX safety factor includes intra- and inter-species variations;no additioP =11
 FQPA safety factor was applied.  For the purpose of the aggregate risk assessment,·:t,e 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 ofthe acute reference dose (%aRfD). At the 99.9th percentile,acute (food only) exposure to the U.S. population resulted in cl MOE of 702 (14.2% 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 344 (29.0% of the aRfD of 0.2.3 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100 and since t' e 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 curnnt, 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
 0.01mg/kg-bw/day, based on a combined chronic toxicity/carcinogenicity study in r  ts with a no observed adverse effect level (NOAH)  of 0.96 mg/kg-bw/day and an uncertainly factor of lOOX.  The lOOX 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 col
 exposure (MOE), which was calculated by dividing the NOAEL by the exposure for en;  h

 population subgroup. In addition,exposure was expressed as a percent of the chror ic reference dose (%cRfD). Chronic (food only) exposures to the U.S. population resui1"E!cl in a MOE of 1,201(8.0% of the cRfD of 0.01mg/kg-bw/day). The most exposed sub· population was children (1-2 years old) with a MOE of 366 {26.2% 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 10C% 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 classifi( d 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 difenoconazo,le (CGA169374) determined as total toxic residues of difenoconazole 21 1d its degradate (CGA205375) were determined using Tier I models SCI-GROW (Screen 1g Concentration in Ground Water) to estimate pesticide concentrations in ground wa':f't and Tier II model PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analysis Mode ing System) to estimate  pesticide concentration in surface water.  All registered  and proposed uses on pome fruit  and legumes were assessed. Based on the PRZM/EXM/IS 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. Based o · the SCI-GROW modeling, the currently registered golf course turf  use provided a ground water acute and chronic EDWC of 0.0136 ppb.  Since the surface water EDWCs excetd the ground water EDWC,the surface water values were used for risk assessment purposes and will be considered protective for any ground water exposure concern:.

 Acute Exposure from Drinking Water:   The acute surface water EDWC of 20.0 ppb \II'.as input  directly into the DEEM-FCIDT"' software as "water, direct and indirect,all sources" to model the acute drinking water exposures.  Exposure contributions at the 99.9th percentile of exposures were determined by taking the difference between the aggregate (food +drinking water) exposures and the food (alone) exposures for eacb population subgroup.  Acute drinking water exposure U.S.population resulted in a lvlOE of 28,902 {0.3% ofthe aRfD of 0.25 mg/kg-bw/day). The most exposed sub-populat:on was children (1- 2 years old) with a MOE of 18,811(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 above the Benchmark MOE or below 100% o.; the aRfD, Syngenta believes that there is a reasonable certainty that no harm will re!itJIt from acute drinking water exposure to residues arising from the registered,pending 11nd proposed uses for difenoconazole.

 Chronic Exposure from Drinking Water.  The chronic surface water EDWC ·)f
 13.5 ppb was input directly into the DEEM-FCID software as "water, direct ant 1 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 b% 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 thiH assessment was 100 and since EPA generally has no concern for exposures above the Benchmark MOE or below 100% of the cRfD, Syngenta believes tl' 1t
 there is a reasonable certainty that no harm will result from chronic drinking W<tter
 exposure to residues arising from all registered, pending and proposed uses ror
 difenoconazole.]

 2. Non Dieta-y Exposure The use of difenoconazole on ornamentals and flov.''l' gardens (Inspire(R), Ready-to-Use spray) and golf courses (Quadris ToprM, Heritage Top··", Briskway(TM)) may result in residential handler or post-application exposures to selecte:1 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) fron· a
 2-generation reproductive study in rats with an uncertainty factor of lOOX, 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), whi·:' 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 gardenr:.1 s 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 i, 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,modift, 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 (USTIF) are designed to provide the Agency with more
 complete  toxicological and residue information for 1,2,4 triazole and two conjugate:::. 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 database·:; For the purposes of this tolerance action,the EPA has not assumed that difenocona;::,)le has a common mechanism  of toxicity with other substances.]

 E. Safety Determination

 1 US   roo"1a i  n. [The acute dietary exposure analysis (food plus water) showed that exposure from all current,pending and proposed  uses of difenoconazo' :! would result in a MOE of 685 (14.6% of the aRfD of 0.25 mg/kg-bw/day) for the gen1:-ral U.S.population, which exceeds the Benchmark MOE of 100.  For the short-term aggregate exposure analysis the corresponding food, water and residential MOEs w1:.re aggregated using the inverse MOE approach.  The short-term aggregate (food,drinl:ing water,and residential) MOE was 205 for the general U.S.population,which exceed.: ·the Benchmark MOE of 100. The chronic dietary exposure analysis (food plus water) showed that exposure from all current, pending,and proposed uses of difenoconazo  e resulted in a MOE of 887 (10.8% of the cRfD of 0.01mg/kg-bw/day) for the general J .S. population,which also exceeds the Benchmark MOE of 100.  Based on the complet1:11ess and reliability of the toxicity  data supporting these petitions,Syngenta believes tha·: 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 'nfonts and children  [The acute dietary exposure analysis (food plus water: showed that exposure from all current, pending and proposed uses of difenoconazol:? would result in a MOE of 338 (29.5% of the aRfD of 0.25 mg/kg-bw/day) for the mo:1 sensitive population subgroup,children 1-2 years old,which exceeds the Benchmark MOE of 100. For the short-term aggregate exposure analysis the corresponding fooc , water and residential MOEs were aggregated using the inverse MOE approach. ThE! short-term aggregate (food, drinking water,and residential) MOE was 413 for child "( n

 (1-2 years),which exceeds the Benchmark MOE of 100.  The chronic dietary exposu analysis (food plus water) showed that exposure from all current,pending, and proposed uses of difenoconazole resulted in a MOE of 317 (30.3% 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 reliabili :y 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 ot · r types of non-occupational exposures.]

 F. International Tolerances

 [Codex Alimentarius Commission established Maximum Residue Limits (MRI.-) for difenoconazole in various agriculturalcommodities including asparagus,banana, beans,except broad bean and soya bean, broccoli,Brussels sprouts, cabbages,heac . carrot,cauliflower,  celeriac,celery,cherries,edible offal {mammalian),eggs, garlic, ginseng, grapes,leek,lettuce,head, lettuce, leaf, mango, meat, milks,nectarine, olilt:::!s, papaya,passion fruit,peach,peas (pods and succulent/immature seeds),plums (including prunes),pome fruits,potato, poultry meat,poultry,edible offal of,rape !;.- ed, soya bean (dry), sugar beet,sunflower seed,tomato,tree nuts,wheat, and wheat sl aw and fodder (dry).]