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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS 

PUBLISHED IN THE FEDERAL REGISTER 

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

Dragonberry/YW International Produce, PP#

EPA has received a pesticide petition PP# 4E8296 from [Dragonberry/YW 

International Produce, Inc., 386 S. Sequoia Parkway, Canby, Oregon 97013] 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 an import tolerance for residues of [Difenoconazole :1 [2-[2-

chloro-4-(4-chlorophenoxy)]phenyl-4-methyl-1,3-dioxolan-2-ylmethyl]-1H1,2,4,-triazole) ] in or on the imported [dragonfruit] at [1.5] (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 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 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.

2. Analytical method.

i. Plant. Syngenta Crop Protection, Inc. has previously 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) 
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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. Dragonberry/YW International Produce., an importer

of dragon fruit submitted a proposal to EPA’s Chemistry Science Advisory Council 

(ChemSAC) requesting approval of the difenoconazole use on dragonfruit based on 

residue data on wax jambu. ChemSAC concluded that it is acceptable to set a 

temporary import tolerance on dragonfruit based upon wax jambu residue data. 

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 can be found at http://www.regulations.gov in document 

“Difenoconazole. Human Health Risk Assessment for Postharvest Use on Tuberous and 

Corm Vegetables Subgroup 1C. and Low growing Berry Subgroup 13-07G, Except 

Cranberry,” dated May 30, 2012 at p. 34 in docket ID number EPA-HQ-OPP-2011-0300. 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 July 19, 2012.

1. Acute toxicity. Difenoconazole possesses low acute toxicity by the oral, dermal 

and inhalation routes of exposure. It is not an eye or skin irritant and is not a sensitizer.
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2. Reproductive, developmental toxicity, Subchronic toxicity. Subchronic and 

chronic studies with difenoconazole in mice and rats showed decreased body weights, 

decreased body weight gains and effects on the liver. In an acute neurotoxicity study in rats, 

reduced fore-limb grip strength was observed on day 1 in males and clinical signs of 

neurotoxicity were observed in females at the limit dose of 2,000 milligrams/kilograms 

(mg/kg). In a subchronic neurotoxicity study in rats, decreased hind limb strength was 

observed in males only at the mid- and high-doses. However, the effects observed in acute 

and subchronic neurotoxicity studies are transient, and the dose-response is well 

characterized with identified no-observed-adverse-effects-levels (NOAELs). No systemic 

toxicity was observed at the limit dose in the most recently submitted 28-day rat dermal 

toxicity study.

3. Chronic toxicity. There is no concern for increased qualitative and/or quantitative 

susceptibility after exposure to difenoconazole in developmental toxicity studies in rats and 

rabbits, and a reproduction study in rats as fetal/offspring effects occurred in the presence of 

maternal toxicity. There are no indications in the available studies that organs associated 

with immune function, such as the thymus and spleen, are affected by difenoconazole.

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-FCIDTM 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) and proposed 

use on dragonfruit. 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-FCIDTM 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 
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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 99.9th 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 subpopulation 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 subpopulation 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).
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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-FCIDTM 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/kgbw/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.
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2. Non Dietary Exposure: The use of difenoconazole on ornamentals and flower 

gardens (Inspire®, Ready-to-Use spray) and golf courses (Quadris TopTM, Heritage TopTM,

BriskwayTM) may result in residential handler or post-application exposures to selected 

subgroups. A short-term toxicological dermal and inhalation endpoint of 1.25 mg/kgbw/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 
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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 
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(dry), sugar beet, sunflower seed, tomato, tree nuts, wheat, and wheat straw and 

fodder, dry.