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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITION

EPA Registration Division contact: Sidney Jackson (703) 305-7610

Interregional Research Project Number 4 

PP# 1E7852

EPA has received a pesticide petition (PP) 1E7852 from Interregional Research 

Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of 

New Jersey, 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 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, including its metabolites and degradates, in or on the raw 

agricultural commodities; Vegetable, fruiting, group 8-10 at 0.6 parts per million (ppm), 

Fruit, citrus, group 10-10 at 0.6 (ppm), Fruit, pome, group 11-10 at 1.0 (ppm) and Low 

growing berry subgroup 13-07G, except cranberry at 2.5 ppm, and by amending the 

established tolerance in or on the raw agricultural commodity Vegetable, tuberous and 

corm, subgroup 1C at 4.0 ppm. In addition, the petition proposes to remove established 

tolerance in or on the raw agricultural commodities; potato, processed waste at 0.04

ppm, vegetables, fruiting, group 8 at 0.6 ppm, Fruit, citrus, group 10 at 0.6 ppm, Fruit, 

pome, group 11 at 1.0 ppm and strawberry at 2.5 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 support 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 14C-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.
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2. Analytical method. i. Food. 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 magnitude of residue trials on potatoes 

under OPPTS 860.1500 to support the requested use of difenoconzole. These residue 

trials satisfy the requested tolerance on potato. 

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. 

2. Genotoxicity.
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3. Reproductive and developmental toxicity.

4. Subchronic toxicity.

5. Chronic toxicity.

6. Animal metabolism.

7. Metabolite toxicology. 

8. Endocrine disruption. 

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-FCIDTM), version 2.16 

from Exponent. These exposure assessments included all current and pending uses as 

well as IR4 residue data to accommodate the proposed new post-harvest use on potatoes 

treated with ThesisTM brand fungicide product containing difenoconazole. 

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). Pending uses include carrots, chick peas, soybeans, stone fruit 

(Crop Group 12), strawberries, and a seed treatment use on all small grains such as 

wheat, barley, buckwheat, millet, oats, rye, and triticale. For the proposed potato postharvest 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) 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 
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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 99.9th 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/kgbw/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 
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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-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 

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-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 

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 subpopulation was all infants <1 year old, with a MOE of 1,336 (7.2% of the cRfD of 0.01 
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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-ShieldTM 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-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 

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 shortterm 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 
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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, shortterm, 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.