I

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITICIN:S 

PUBLISHED IN THE FEDERAL REGISTER

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

INSTRUCTIONS: Please utilize this outline in preparingthe 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,orformat in your pesticide 

petition.Simply replace the instructions that appear ingreen,i.e.,

11

[insert compan••r 

name],"withthe 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 hrreasingt'le establisred tolerance for residueof [Difenoconazole ::. {2-

[2-chloro-4-(4-chlorophenoxy)]phenyl-4-methyl-1,3-dioxolan-2-ylmethyl]-l.H1,2,4,-triazole) ] n or on toe raw agriculturalco m 11Hy [Fruit,pome,group

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 regardingthe 

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
2

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 monitoringof 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:tne 

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 detectingand measuring levels of difenoconazole in or 

on cattle tissues and milk and poultry tissues and eggs,with a LOQthat 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·1!,. 

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
3

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 Illacute,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-FCIDTM Version 3.16} from Exponent and
4

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 preharvest interval (PHI) to obtain maximum residues. Empirically derived processing 

factors were used in these assessments when available;all other processing factors _sed 

the DEEM-FCIDTMVersion 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 dividingthe 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 subpopulation 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
5

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 Imodels 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 Exposurefrom 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
6

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®,Ready-to-Use spray) and golf courses (Quadris ToprM,Heritage Top··", 

BriskwayTM) may result in residentialhandler 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 residentialMOE of 249 and youth gardenr:.1 s 

had a short-term residentialMOE 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
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[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" concerningthe 

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 triazolylacetic 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 residentialMOEs 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··

occupationalexposures.]

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 residentialMOEs were aggregated using the inverse MOE approach. ThE! 

short-term aggregate (food, drinking water,and residential) MOE was 413 for child "( n
8

(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).]